Osteoprime Ultra [Discontinued] by Integrative Therapeutics

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral betaine hydrochloride for allergic rhinitis, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Asthma. Although there has been interest in using oral betaine hydrochloride for asthma, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Atherosclerosis. Although there has been interest in using oral betaine hydrochloride for atherosclerosis, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Diarrhea. Although there has been interest in using oral betaine hydrochloride for diarrhea, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Dyspepsia. Although there has been interest in using oral betaine hydrochloride for indigestion caused by hypochlorhydria, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Food allergies. Although there has been interest in using oral betaine hydrochloride for food allergies, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Gallbladder disease. Although there has been interest in using oral betaine hydrochloride for gallbladder disease, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Hyperhomocysteinemia. Although there has been interest in using oral betaine hydrochloride for hyperhomocysteinemia, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Hypothyroidism. Although there has been interest in using oral betaine hydrochloride for hypothyroidism, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral betaine hydrochloride for RA, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose. More evidence is needed to rate betaine hydrochloride for these uses.

(Read more about BETAINE HYDROCHLORIDE)

LIKELY EFFECTIVE

• Boron deficiency. Oral boron treats and prevents boron deficiency. Details: Taking boron orally is effective for preventing and treating boron deficiency (7135).

POSSIBLY EFFECTIVE

• Radiation dermatitis. Topical application of sodium pentaborate pentahydrate gel to radiation sites may reduce the risk of dermatitis in patients with breast cancer who are receiving radiotherapy. Details: A small clinical study in patients with breast cancer shows that applying a hydrogel containing sodium pentaborate pentahydrate 3% four times daily during radiotherapy for 5 weeks reduces the risk of moderate to severe dermatitis by 50% when compared with petroleum jelly (Vaseline). However, there is no difference in patient satisfaction (95660). Additionally, a larger clinical trial in patients with breast cancer shows that applying a sodium pentaborate pentahydrate 3% gel to radiation sites 15 minutes before each session for 25 sessions reduces the risk of dermatitis by 90%, erythema by 87%, dry desquamation by 92%, and moist desquamation by 97% when compared with a placebo gel (109557).
• Vaginal candidiasis. Boric acid applied intravaginally seems to reduce vaginal candidiasis. Details: Some limited clinical research shows that applying boric acid powder intravaginally 600 mg once or twice daily for up to 3 weeks can treat candidiasis and other vaginal fungal infections, including resistant and chronic infections (15443,15444,15446,15449,15450,15451,15453); however, this research is limited by low study quality. For Candida glabrata yeast infections, which are less prevalent than Candida albicans infections, some evidence shows that intravaginal boric acid capsules are effective in about 65% to 70% of azole-resistant infections; however, boric acid capsules appear to be less effective than intravaginal flucytosine (Ancobon) (15445,15454). For Candida krusei infections, which are rare and resistant to azole antifungal treatment, boric acid capsules also appear to be effective in some cases (15448).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral boron does not seem to improve athletic performance. Details: A small clinical study in male bodybuilders shows that taking boron 2.5 mg daily for 7 weeks does not increase lean body mass, muscle mass, or testosterone levels when compared with placebo (944). Furthermore, the International Society of Sports Nutrition (ISSN) does not recommend boron supplementation as a nutritional ergogenic aid due to a lack of supportive evidence (101009).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral boron is beneficial for age-related cognitive decline. Details: Two very small clinical studies in healthy older adults show that taking boron 3.25 mg daily for up to 49 days orally might improve cognitive function and fine motor skills when compared with lower amounts of boron (943).
• Diabetic foot ulcers. It is unclear if topical boron is beneficial for use in diabetic foot ulcers. Details: A large clinical study in adults with diabetic foot ulcers shows that applying boron (sodium pentaborate 3%) gel twice daily for 1 month marginally reduces ulcer severity, measured by the Wagner Classification system at 25 days and 2 months, when compared with control; recurrence and infection rate were also modestly reduced at 2 months (112423). However, it is unclear whether the analysis controlled for systemic antibiotic use among the two groups, which effects the validity of these findings.
• Dysmenorrhea. It is unclear if oral boron is beneficial for reducing pain during menstruation. Details: A small clinical study in young females with moderate to severe dysmenorrhea suggests that taking boron tetraborate 10 mg daily, starting two days before and continuing until three days after the start of menstruation for two menstrual cycles, reduces pain levels by 24% and pain duration by 1.5 hours, or 34%. Both pain and pain duration were decreased by only 9% in patients receiving placebo (95428).
• Kidney stones (nephrolithiasis). It is unclear if boron is beneficial for medical expulsive therapy after extracorporeal shockwave lithotripsy. Details: A large clinical study in adults undergoing extracorporeal shockwave lithotripsy for kidney stones conducted in Iran shows that taking boron 10 mg twice daily for 2 weeks does not statistically improve the rate of stone expulsion when compared with tamsulosin; however, boron may have fewer side effects (i.e., orthostatic hypotension, headache, nausea, erectile dysfunction) (112414).
• Kidney transplant. It is unclear if oral boron is beneficial in patients receiving a kidney transplant. Details: Observational research in kidney transplant recipients has found that higher boron intake, as measured by urinary boron levels, is associated with a lower risk of mortality when compared with lower intake. Patients with 24-hour urinary boron levels in the top tertile had a 49% lower risk of all-cause mortality when compared with those in the lowest tertile; however, there was no association with graft failure (109556). It is unclear if these findings can be generalized to boron supplements.
• Obesity. Although there has been interest in using oral boron for obesity, there is insufficient reliable information about the clinical effects of boron for this purpose.
• Osteoarthritis. It is unclear if oral boron is beneficial for osteoarthritis symptoms. Details: Small low quality studies in patients with osteoarthritis suggest that taking boron tetraborate 3-6 mg daily for up to 8 weeks might improve pain and other symptoms when compared with a lower intake of boron (941,36870).
• Osteoporosis. It is unclear if oral boron is beneficial for osteoporosis. Details: Preliminary clinical research in postmenopausal adults shows that taking boron 3 mg daily does not improve bone density when compared with placebo (36872).
• Periodontitis. Small clinical studies suggest that adding topical boric acid to scaling and root planing treatment may be beneficial in periodontitis. Details: A meta-analysis of four small clinical studies in 117 patients with periodontitis shows that using boric acid 0.75% gel or solution in addition to scaling and root planing seems to slightly improve probing pocket depth (PPD) and clinical attachment level (CAL) when compared with placebo or saline control (105690). Another small clinical study in patients with periodontitis shows that using boric acid 0.5% for irrigation in addition to scaling and root planing seems to improve CAL and PPD to a similar degree as using povidone-iodine 0.1% (105691). The available research was conducted in Turkey, Vietnam, and India; it is unknown if these findings are generalizable to other geographic locations.
• Tooth extraction. It is unclear if boron is beneficial for use in periodontal healing after impacted third molar surgery. Details: A moderate-sized clinical study in adults 18 to 40 years old shows that using boron 0.1% to 2.5% and chlorhexidine 0.12% mouthwash for 7 days after impacted third molar surgery marginally improves swelling and self-reported pain on day 7, and the higher boron concentrations also improve pain at day 4 when compared with chlorhexidine alone, but does not improve the number of analgesics used or periodontal scores (112379). However, the validity of these results is limited by a lack of statistical adjustment for multiple comparisons which can lead studies to show differences between treatment groups in error (i.e., false positive findings). Additionally, the study period coincides with the expected recovery time (i.e., 2-7 days), making it unclear if any effects are due to the intervention or control. More evidence is needed to rate boron for these uses.

(Read more about BORON)

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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LIKELY EFFECTIVE

• Copper deficiency. Oral or intravenous copper is beneficial for treatment of copper deficiency. Details: Taking copper orally or intravenously is effective for treating copper deficiency and anemia due to copper deficiency. Copper deficiency is rare. It is seen most commonly in people receiving prolonged parenteral nutrition (7135). Oral cupric sulfate has been used in doses up to 0.1 mg/kg daily (7135). Copper 1-2 mg per day in parenteral nutrition solution has also been used (505).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Oral copper does not seem to be beneficial for Alzheimer disease. Details: Preliminary clinical research shows that taking copper orotate dihydrate, providing 8 mg of elemental copper, daily for 12 months does not improve scores on evaluation scales for Alzheimer disease when compared with placebo (45949). There is also some concern that copper could have detrimental effects. Observational research has found that people with Alzheimer disease have higher levels of copper in their blood than people without the disease (95917); the clinical significance of this finding is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral copper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing copper (NicAzel, Elorac Inc.) 1-4 tablets daily for 8 weeks reduces inflammatory lesions in patients with inflammatory acne when compared with baseline. Other ingredients in this product include nicotinamide, azelaic acid, zinc, pyridoxine, and folic acid; specific quantities are not known (90800). The validity of this finding is limited by the lack of a comparator group.
• Brain tumor. It is unclear if oral copper is beneficial for use in glioblastoma. Details: A moderate-sized open-label clinical study in adults with first recurrence of glioblastoma receiving alkylating chemotherapy shows that taking elemental copper 2.5 mg with disulfiram 400 mg daily for 6 months does not improve survival but does result in significantly more adverse effects (e.g., elevated liver enzymes) when compared with control. The trial was stopped early due to safety concerns (112376).
• Cardiovascular disease (CVD). Although there is interest in using oral copper for CVD prevention, there is insufficient reliable information about the clinical effects of copper for this purpose.
• Chemotherapy-induced acral erythema. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 acral erythema (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced anemia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 anemia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced diarrhea. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 diarrhea (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced leukopenia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 neutropenia or febrile neutropenia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced nausea and vomiting (CINV). Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 vomiting (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chronic venous insufficiency (CVI). It is unclear if compression stockings containing copper are beneficial for lipodermatosclerosis in patients with CVI. Details: Preliminary clinical research shows that using compression stockings impregnated with copper for 8 weeks does not improve overall symptoms of lipodermatosclerosis secondary to chronic venous disease when compared with using a compression stocking without copper. However, the affected surface area may be reduced by approximately 16% by 2 weeks when copper-impregnated compression stockings are used (101809).
• Dental plaque. It is unclear if rinsing the mouth with copper is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing the mouth with a solution of copper 1.1 mmol/L for 4 days decreases plaque accumulation when compared with a placebo solution (46006).
• Diarrhea. Oral copper has only been evaluated in combination with zinc; its effect when used alone is unclear. Details: Preliminary clinical research in children 6 months to 5 years of age presenting to a hospital in India with acute watery or bloody diarrhea shows that taking a solution providing zinc 2 mg/kg and copper 0.2 mg/kg orally daily for 2 weeks does not reduce the duration of diarrhea, the weight of stool, or the need for rehydration when compared with placebo (87166). It also does not seem to reduce the recurrence of diarrhea or improve weight gain over the next 3 months (95540).
• Oral mucositis. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 oral mucositis (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Osteoarthritis. Although there is interest in using topical copper for osteoarthritis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Osteoporosis. Oral copper has only been evaluated in combination with other minerals; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking copper 2.5 mg in combination with zinc 15 mg, manganese 5 mg, and calcium 1000 mg daily for 2 years can slow bone loss when compared with taking either calcium or the trace minerals alone (1994).
• Postoperative infection. It is unclear if copper-impregnated wound dressings are beneficial for the prevention of postoperative infection. Details: Preliminary clinical research shows that using a wound dressing impregnated with copper oxide 3% by weight reduces the incidence of a surgical site infection in the 30-day period following a caesarean section by 39%, but does not reduce length of hospital stay or readmission rate, when compared with a non-copper wound dressing. Eight patients would need to be treated with the copper-impregnated dressing to prevent one infection (105363). This study is limited by the use of a telephone questionnaire to assess the suspicion of infection.
• Systemic lupus erythematosus (SLE). It is unclear if oral copper is beneficial for improving symptoms of SLE. Details: Copper status does not appear to be associated with the risk of SLE (101810). Additionally, one small clinical study shows that taking copper 3 mg daily, alone or in combination with fish oil, for 24 weeks does not affect symptoms of SLE when compared with placebo (12953).
• Tinea pedis. Although there is interest in using topical copper for tinea pedis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Wound healing. It is unclear if topical copper sulfate can improve the healing of umbilical granuloma. Details: A small clinical study in children 1-3 months of age with treatment-naïve umbilical granuloma shows that a single application of copper sulfate to the affected site results in complete resolution in 70% of patients, compared with 90% of patients receiving topical sodium chloride twice daily for 5 days. Some patients who received a second application of copper sulfate experienced full healing; however, it is unclear if this was due to the treatment or natural resolution (109403). More evidence is needed to rate copper for these uses.

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EFFECTIVE

• Folate deficiency. Oral or intravenous folic acid is effective for the prevention or treatment of folate deficiency. Details: Administering folic acid orally or parenterally improves and prevents folate deficiency (505,8739). Clinical research shows that supplementation with folic acid 100 mcg to 5 mg daily during pregnancy decreases the risk of developing megaloblastic anemia by up to 79% (91307).

LIKELY EFFECTIVE

• Kidney failure. Taking folic acid orally reduces homocysteine levels in people with kidney failure who are on hemodialysis. Details: Over 85% of people with kidney failure have hyperhomocysteinemia. Treatment of hyperhomocysteinemia in kidney failure is often more difficult than with normal kidney function (1489,3324,7289,9413,9414,9416). The reasons for this are not fully understood; renal uptake and metabolism of homocysteine may be reduced in severe kidney failure, and hemodialysis may contribute to vitamin deficiencies (6884,9414,9417). Folic acid 0.8-15 mg daily or 3 times weekly is generally used, but the degree of homocysteine reduction varies between 12% to 50%, and normal homocysteine levels (less than 12 µmol/L) cannot always be achieved. Adding vitamin B12 400-1000 mcg daily and vitamin B6 20-50 mg daily produces an additional reduction in homocysteine (1489,6884,7289,7881,9322,9413,9414,9415,9416,9417). Folic acid doses greater than 15 mg daily do not seem to provide additional benefit. Also, doses of 30-60 mg might cause a rebound in homocysteine levels when treatment is stopped (9219). Despite the homocysteine-lowering effect of folic acid in kidney failure, the most robust meta-analysis of 11 clinical trials suggests that folic acid supplementation does not seem to reduce the risk of cardiovascular events (50527). A smaller meta-analysis of 7 clinical trials that used a different primary composite outcome suggests that folic acid might reduce the risk of cardiovascular events by 15% when compared with control (91311). There has also been interest in using a reduced form of folic acid, L-5-methyltetrahydrofolate (L-5-MTHF). One study in patients on hemodialysis suggests that taking L-5-MTHF 17 mg daily for 12 weeks might lower homocysteine levels to a greater extent than an equimolar 15 mg of folic acid (104908). Another clinical trial in patients on hemodialysis suggests that giving intravenous L-5-MTHF 50 mg three times weekly is associated with an increased survival of about 36 months, compared with about 26 months with folic acid 5 mg daily. There was no difference in homocysteine reduction between groups (104909). These results should be interpreted with caution because they have not been replicated, and there was no placebo control. Furthermore, survival may have been affected by the availability of kidney transplants.
• Hyperhomocysteinemia. Oral folic acid, taken alone or in combination with other B vitamins, lowers homocysteine levels in most patients. However, it is unclear if this has cardiovascular benefits. Details: Taking folic acid orally 0.4-5 mg daily lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels at baseline. Folic acid 0.8-1 mg daily seems to provide maximal reduction (9307,9400,9401,9405,9408,11337,11338,50145). Doses above 1 mg daily do not seem to add benefit (9307), except in some people with certain gene mutations that cause homocysteine levels of 20 µmol/L or higher (9408). The higher the initial homocysteine levels, the lower the folic acid dose needed to attain maximum homocysteine reduction (9307). The effects of folic acid supplementation on homocysteine concentrations appear to be greater in females than males (50145). Adding vitamin B6 25-250 mg or vitamin B12 500 mcg seems to further reduce homocysteine levels (1489,9400,9405,9406,9408,107136). Some experts recommend routine use of vitamin B12 in homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Increasing folic acid intake with supplements or folate-fortified cereal products is more effective for reducing homocysteine levels than increasing intake of folate-rich foods (6367). Fortification of cereals and flour with 140 mcg folic acid per 100 grams reduces the mean homocysteine level in the general population by about 7% (7881,9404,9407). Elevated homocysteine levels are considered by some to be an independent risk factor for atherosclerosis progression, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, ischemic stroke, and other vascular complications (3886,3887,6236,7725,9314,9318,50509). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). Although folic acid lowers homocysteine levels, it is not yet known whether this reduces the risk of vascular disease. One meta-analysis shows that taking folic acid can reduce the risk of stroke by about 10% in patients with cardiovascular disease (CVD); the reduction is greatest in patients for whom homocysteine levels are lowered by at least 25% (96157). A meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). However other research does not agree. Meta-analyses of clinical research show that folic acid does not prevent CVD or coronary heart disease, in spite of lowering homocysteine by up to 55%, when individuals with normal or high levels of homocysteine are considered (50539,96147,97619). Furthermore, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or improve secondary prevention of cardiovascular events such as myocardial infarction in people with existing CVD despite a homocysteine-lowering effect (9313,11337,11387,13482,50437,97619). Some research even suggests an increase in CVD risk concurrent with homocysteine lowering (13482). Large randomized controlled trials are needed to confirm or refute these findings. Some researchers hypothesize that different genetic profiles might explain some of these conflicting results. For instance, individuals with a homozygous 677TT MTHFR genotype typically have increased homocysteine levels. However, a meta-analysis suggests that treatment with folic acid does not reduce the risk of ischemic heart disease despite reducing homocysteine levels in individuals with 677TT MTHFR (50456). It has also been theorized that a reduced form of folic acid, 5-methyltetrahydrofolate (5-MTHF) might work better in these individuals. Although [6RS]-5-MTHF has been shown to lower homocysteine levels (104915), studies assessing its cardiovascular benefits are lacking.
• Methotrexate toxicity. Oral folic acid reduces the severity of methotrexate toxicity. Details: Oral folic acid reduces methotrexate toxicity symptoms, such as nausea and vomiting, in the treatment of rheumatoid arthritis (RA) and psoriasis (768,2162,2163,2164,4492,4493,4494,9369,9419). Folic acid also seems to reduce methotrexate-induced hepatic side effects by approximately 36% (50320). Some research shows that a low, 0.8 mg weekly dose of folic acid is equally effective to a higher dose of 5 mg weekly for the prevention of methotrexate toxicity (102388).
• Neural tube birth defects. Oral folic acid helps to prevent neural tube birth defects in newborns. Details: Clinical practice guidelines recommend that anyone capable of becoming pregnant take folic acid 400 mcg daily from fortified foods or supplements to prevent neural tube birth defects in infants. Folic acid 600 mcg daily is advised during pregnancy (94811,96146). This recommendation is based on research showing that a higher intake of folic acid from food and supplements during pregnancy reduces the primary incidence of neural tube birth defects by 41% to 69% (3325,9309,50344,50403,50468,95156). Individuals with a history of children with neural tube birth defects usually take a higher dose of folic acid 4000 mcg daily starting one month before and continuing for up to 3 months after conception (96146). Evidence shows that, when used for secondary prevention, folic acid supplementation reduces the incidence of neural tube defects by 66% to 87% (21235,50263,50344,50403,95156). In the US, foods containing at least 60 mcg of folic acid can be labeled with a health claim stating that healthful diets with adequate folic acid intake may reduce the risk of having a child with a brain or spinal cord defect (102369).

POSSIBLY EFFECTIVE

• Cognitive impairment. Taking folic acid alone, with other B vitamins or with docosahexaenoic acid (DHA), might improve thinking and memory skills in older patients with cognitive impairment. Details: One clinical trial in patients aged 65 years and older with mild cognitive impairment (MCI) shows that taking folic acid 400 mcg daily for 2 years increases IQ scores when compared with placebo (100952). Two small, low-quality clinical studies in patients aged 70-90 years with cognitive impairment and low folate levels or folate deficiency shows that taking folic acid 5 or 15 mg daily for up to 63 days improves cognitive function, including measures such as memory and attention, when compared with placebo or baseline (50301,104911). Folic acid also appears to be beneficial when used in combination with other B vitamins or with DHA. A clinical trial in patients aged 70 years and older with MCI shows that taking folic acid 800 mcg, vitamin B6 20 mg, and vitamin B12 500 mcg daily for 2 years mitigates decline in executive function and, in patients with high baseline homocysteine levels, improves cognition and memory when compared with placebo (50480). Taking folic acid 800 mcg with or without DHA 800 mg daily for 6 months modestly improves cognition, as measured on the full-scale intelligence quotient, when compared with placebo (103978,109196). However, this benefit is no longer present at 6 months after treatment discontinuation (109196).
• Depression. Oral folic acid seems to modestly reduce depression severity when added to conventional antidepressant therapy. It is unclear if folic acid can reduce the prevalence of depression or the risk for suicide. Details: Observational studies suggest that depression is correlated with low folate status, particularly in females (50105,50127,50243). Taking folic acid 0.2-15 mg daily for up to 6 months with conventional antidepressants seems to improve treatment response in patients with major depressive disorder (3657,10884,10887,50566,109190). One meta-analysis shows that taking L-methylfolate or folic acid as an adjunct to treatment with conventional antidepressants modestly reduces depression severity when compared with placebo and conventional antidepressants. The response and remission rates were improved by 36% and 39%, respectively (109190). However, limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy (10886). Also, a small clinical study in adolescents at high familial risk for mood disorders suggests that taking folic acid 2.5 mg daily for up to 36 months does not prevent mood disorders when compared with placebo. However, in the patients that were eventually diagnosed with depression, the time of onset was delayed from 5 months to 15.5 months in the group using folic acid when compared with placebo (91313). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that folic acid is not currently recommended as monotherapy treatment for unipolar depression (110318). Observational research has also evaluated the association between folic acid supplementation and suicidal events in patients with or without depression. One within-person cohort study, in which only 12% of patients were diagnosed with depression, has found that filling a folic acid prescription of 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a reduced risk for suicidal events during the following months when compared with months without a prescription (109201). It is unclear what percentage of these patients, if any, had folate deficiency at baseline.
• Hypertension. Oral folic acid seems to modestly reduce hypertension. Details: A meta-analysis of clinical research shows that taking folic acid 5-10 mg daily for at least 6 weeks reduces systolic blood pressure by 2mmHg and improves flow-mediated dilation by 1.6% in hypertensive individuals (50364). Some research has evaluated folic acid in hypertensive patients when used with antihypertensive drugs. Results show that taking folic acid 400-800 mcg in combination with enalapril 10 mg daily for about 4.5 years does not improve blood pressure when compared with enalapril alone (50302,96158). However, in hypertensive patients with heavy proteinuria, this combination seems to reduce the risk of all-cause mortality by about 41% when compared with enalapril alone (96158).
• Phenytoin-induced gingival hyperplasia. Topical folic acid seems to reduce gingival hyperplasia due to phenytoin. The effect of oral folic acid is unclear. Details: Applying folic acid topically seems to inhibit gingival hyperplasia secondary to phenytoin therapy (2151). However, taking folic acid orally does not seem to improve gingival hyperplasia secondary to phenytoin therapy in adults (2150,2151,2152), although some evidence suggests that taking folic acid 500 mcg daily reduces the risk of phenytoin-induced gingival hyperplasia by 33% in children when compared with placebo (50463).
• Stroke. Although some clinical research has shown that oral folate reduces stroke risk by a small amount, more research is needed to determine who is most likely to benefit. Most individual clinical trials show that folic acid seems to reduce stroke risk only in regions without food-fortification policies. Details: Multiple clinical studies have shown that folic acid supplementation reduces the risk of stroke by 10% to 25% in regions WITHOUT established policies mandating folic acid fortification of grain products (50240,50485,50525,50539,91325,96154,96157,96159,97308). The effect appears to be greatest when folic acid is taken in low doses (usually 0.8 mg daily or lower) (50525,96157,96159), in regions with a low prevalence of statin use (50525,96159), in patients with high cholesterol levels at baseline (96152), in patients who achieve homocysteine reduction of at least 20% (50407,96157), and in patients with the lowest folate levels at baseline (96154,96157). There is also some evidence that the effect of folic acid on stroke risk is greatest in patients with low baseline levels of vitamin B12 (96159). In 2001, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Most research shows that folic acid supplementation does not reduce the risk of stroke in regions WITH established policies mandating folic acid fortification (50240,50485,50525,50539,96157,96159,97308). However, there is some evidence that folic acid may reduce the risk of stroke in patients from regions with folic acid fortification who have recently had a stroke or transient ischemic attack and are not using antiplatelet drugs (90379). Meta-analyses of clinical research have been conducted. However, possible confounding due to the presence or absence of folic acid fortification is unclear. A meta-analysis of the available research in adults with existing CVD shows that folic acid supplementation at a daily dose of less than 2 mg reduces the risk for stroke by about 10% (102386). Also, a meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke by 10% when compared with placebo (97619). In patients with a history of stroke, a meta-analysis shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). It is unclear if folic acid reduces the stroke risk in patients with impaired kidney function. Some research shows that taking folic acid in combination with high doses of vitamin B12 (cyanocobalamin) does not reduce the risk of stroke in these patients (11387,96150). However, there is concern that the lack of benefit may have been due to the decline in kidney function from high doses of cyanocobalamin (96150). Additional research is needed to determine if folic acid supplementation is beneficial in patients with impaired kidney function when used with other forms of vitamin B12 such as methylcobalamin or hydroxycobalamin.
• Vitiligo. Oral folic acid seems to improve vitiligo symptoms. Details: Taking folic acid orally seems to improve symptoms of vitiligo (2153,2154). This finding is supported by a meta-analysis of observational research which shows that patients with vitiligo have higher serum homocysteine levels when compared with patients without vitiligo (100951).

POSSIBLY INEFFECTIVE

• Anemia. Adding oral folic acid to oral iron therapy does not seem to improve hematologic parameters in patients with anemia. Details: In postpartum patients with anemia, clinical research shows that taking iron as ferrous fumarate 600 mg and folic acid 1 mg daily is no more effective than iron alone for improving hemoglobin status (91319). Also, clinical research in non-pregnant menstruating females shows that taking folic acid 0.4 mg daily or 2.8 mg once weekly for 16 weeks with iron 60 mg daily does not reduce anemia or improve iron status when compared with iron alone (109193). During pregnancy, clinical research shows that folic acid supplementation does not decrease the risk of pre-delivery anemia or low hemoglobin levels (91307).
• Age-related cognitive decline. Oral folic acid does not seem to prevent cognitive decline in healthy elderly adults. Details: Most clinical research shows that taking folic acid, alone or in combination with other B vitamins, does not improve cognitive function, including memory, language, or executive function, in elderly adults with age-related cognitive decline (50318,50412,50510). In fact, a large-scale observational study in the US has found that people over 65 years of age who consume large amounts of folic acid (median of 742 mcg daily) have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg daily) (13068). While most research on folic acid for age-related cognitive decline lacks positive findings, many of the studies are small, short-term (<1 year), underpowered to detect significant differences, and not specific to patients with high homocysteine levels. Population research has found that high homocysteine levels are associated with decreased cognition in older adults, suggesting that using folic acid to lower homocysteine levels might mitigate cognitive decline in these patients (50094). Two long-term clinical trials examining the effects of folic acid in elderly adults with high homocysteine levels show mixed results. A large-scale clinical trial of patients aged 50-70 years from the Netherlands who have high homocysteine levels shows that taking folic acid 800 mcg daily for 3 years increases memory, information processing, and other measures of cognitive function when compared with placebo (15271). However, another large-scale clinical trial of patients aged 65 years and older from the Netherlands who have high homocysteine levels shows that taking folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years lowers homocysteine levels, but does not appear to improve overall measures of cognitive function, when compared with placebo (90392). The reasons for the discrepant findings in these two studies are not clear but might relate to differences in the dose of folic acid, duration of treatment, and age of patients included.
• Cataracts. Oral folic acid does not seem to reduce cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or with risk factors for CVD shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of developing cataracts. Furthermore, the risk of cataract extraction was increased by 28% in these patients (96149).
• Diarrhea. Oral folic acid does not seem to reduce the risk of diarrhea, and might even increase the incidence of diarrhea in children. Details: In children aged 6-30 months at risk of malnourishment, clinical research shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of diarrhea when compared with placebo. Enrichment with folic acid, with or without vitamin B12, actually seems to increase the likelihood of having more episodes of both persistent diarrhea and diarrhea lasting over 3 days (90391).
• Fall prevention. Oral folic acid does not seem to reduce the risk of falls. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily, for 2 years, does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Fetal and premature infant mortality. Oral vitamin B12 does not seem prevent mortality in premature infants. Details: Clinical research shows that supplementation with folic acid during pregnancy does not decrease the risk of miscarriage, stillbirth, or neonatal death (91307,96156).
• Leukemia. Oral vitamin B12 does not seem to reduce the risk for pediatric acute lymphoblastic leukemia. Details: A meta-analysis of results from two case-control studies has found that increased folate intake during pregnancy is not associated with a reduced risk of childhood acute lymphoblastic leukemia (50247).
• Male infertility. Oral folic acid does not seem to improve sperm parameters or pregnancy rates in males with infertility. Details: Some small clinical studies show that taking folic acid, alone or with zinc, increases sperm count in males with idiopathic infertility or in males with a grade III varicocele (9334,90194). However, another small study in males with asthenozoospermia shows that taking folic acid 5 mg, selenium 200 mcg, and vitamin E 400 IU daily for 3 months does not improve sperm parameters when compared with placebo (104907). Furthermore, there seems to be no improvement in clinical outcomes. One large, high-quality clinical study in males with idiopathic infertility shows that taking folic acid 5 mg with zinc 30 mg daily for 6 months does not improve sperm morphology, pregnancy rate, or live birth rate when compared with placebo (102085). Folic acid has also been evaluated in combination with other ingredients. A retrospective study in males with or without varicocele-related infertility suggests that taking a specific combination product containing folic acid 0.2 mg, vitamin C, zinc, L-carnitine fumarate, acetyl-L-carnitine, coenzyme Q10, selenium, and vitamin B12 (Proxeed Plus, Sigma-Tau) twice daily for 6 months is associated with improvements in sperm count, sperm concentration, and sperm motility when compared to baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles (111296). The validity of this study is limited by the lack of a comparator group.
• Osteoporosis. Oral folic acid does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly adults or adults with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral folic acid does not seem to improve physical performance in older adults. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years, does not improve hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).
• Pre-eclampsia. Oral folic acid does not seem to prevent pre-eclampsia in pregnant patients. Details: While the effect of low-dose prenatal folic acid is unclear, high-dose folic acid does not seem to reduce the risk of pre-eclampsia. Some population research has found that low-dose folic acid is associated with a 22% reduced odds of pre-eclampsia, while other research has found no association (91308,99370,99372,110447). A large clinical trial evaluating high-dose folic acid in pregnancies at risk for pre-eclampsia shows that taking 4 mg daily, starting at 8-16 weeks of gestation and continuing until delivery, does not reduce the risk of pre-eclampsia when compared with placebo (103929). A secondary analysis of this study in twin pregnancies has also found no benefit with high-dose folic acid supplementation (103977).
• Respiratory tract infections. Oral folic acid does not seem to prevent respiratory tract infections. Details: Clinical research in children aged 6-30 months at risk of malnourishment shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of lower respiratory infections when compared with a supplement not enriched with folic acid and vitamin B12 (90391).

LIKELY INEFFECTIVE

• Colorectal adenoma. Oral folic acid does not prevent colorectal adenomas. Details: Although some population research and one clinical study has found that high folate intake is associated with reduced colorectal adenoma risk (2142,2143,91303), most clinical research does not support this finding. Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for up to 9.2 years, does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389). Other clinical research suggests that taking folic acid does not reduce the occurrence or recurrence of adenomas or incidence of advanced adenomas (34596,50241,50265,50369,50394,50449,50522). Furthermore, treatment with folic acid for more than 3 years seems to be associated with an increased risk of advanced adenomatous lesions (50378).
• Fragile X syndrome. Oral folic acid does not improve symptoms in children with fragile X syndrome. Details: Clinical research shows that taking folic acid orally does not improve symptoms of fragile X syndrome (2155,2156,2157,2158,2159,2160,50575).
• Preterm labor. Oral folic acid does not seem to reduce the risk of preterm birth. Details: Meta-analyses of clinical research show that supplementation with folic acid 200 mcg to 5 mg during pregnancy does not decrease the risk of preterm birth (91307,96155). An observational study in patients with and without epilepsy found that folic acid supplementation during pregnancy was associated with a lower odds of preterm birth in patients receiving antiseizure medications; however, no link between folic acid and preterm labor was reported in patients without epilepsy or in those with epilepsy not receiving antiseizure medications (110447).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal wall defects. It is unclear if oral folic acid helps to prevent abdominal wall defects in newborns. Details: Observational research in a population in northern China has found that taking folic acid supplements until the end of the first trimester modestly reduces the risk of abdominal wall defects and the risk of omphalocele, specifically, in the newborn when compared with not taking folic acid. However, this association was not found in a population in southern China (109191). These differing outcomes may be related to the lower dietary folate intakes in northern China.
• Acne. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing folic acid, vitamin B6, nicotinamide, azelaic acid, zinc, and copper for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared with baseline (90800).
• Age-related macular degeneration (AMD). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to folic acid, other ingredients, or the combination.
• Age-related testosterone deficiency. Folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Alzheimer disease. It is unclear if oral folic acid reduces the risk of developing this condition. Details: Low levels of folate and high levels of homocysteine have been linked to a greater risk of Alzheimer disease (50094). Also, some observational studies have found that higher intake of folate from the diet and supplements in elderly adults is associated with a reduced risk of developing Alzheimer disease when compared with lower intake (13165,15270). One small clinical trial in patients with Alzheimer disease who are taking cholinesterase inhibitors shows that taking folic acid 1 mg daily for 6 months increases the likelihood of treatment response, classified as global improvement in behavioral and/or functional status with no decline in mental status scores, by 78% to 87% when compared with placebo (50246). Also, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). However, not all research agrees. Clinical research in patients with probable Alzheimer disease using routine medications shows that taking folic acid 5 mg, vitamin B12 1 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo (50319). However, all patients in this study were also consuming a folate-fortified diet.
• Angioplasty. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that folic acid 1 mg, vitamin B12 400 mcg, and pyridoxine 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151).
• Atopic dermatitis (eczema). It is unclear if oral folic acid during pregnancy reduces the risk of eczema in the child. Details: Observational research has found that consuming both iron and folic acid supplements during pregnancy is associated with a four-fold reduced risk for developing atopic dermatitis in the child. However, use of either iron or folic acid supplementation alone is not associated with an effect on the child's risk for atopic dermatitis (102387).
• Autism spectrum disorder. It is unclear if oral folic acid intake during pregnancy reduces the risk of autism spectrum disorder in the child. Details: A meta-analysis of population research has found that consumption of folic acid of at least 400 mcg daily from both diet and supplements during pregnancy is associated with a 45% reduced risk of autism in the child at 2-15 years of age. Also, supplementation with folic acid during the prenatal to early period of pregnancy is associated with an approximate 43% reduced risk of autism in the child. This association did not differ between countries with or without a folate fortification program (109198). An individual population study has also found that prenatal folic acid supplementation initiated the first day of the last menstrual period before conception is associated with a 39% reduced odds of autism in the child at age 3.3-10.2 years when compared to pregnancies without folic acid supplementation (91324).
• Beta-thalassemia. There is limited evidence on the oral use of folic acid for beta-thalassemia minor. Details: Patients with beta-thalassemia minor may experience decreased muscle strength and increased bone or muscle pain. A small clinical study in children with this condition shows that taking folic acid 1 mg, with or without L-carnitine 50 mg/kg, daily for 3 months reduces bone pain by 64% to 84% and increases the number of stairs climbed by 2- to 5-fold when compared with baseline (90631). The validity of this finding is limited by the lack of a control group.
• Bipolar disorder. It is unclear if adding oral folic acid to conventional bipolar therapy further improves symptoms. Details: Some clinical evidence suggests that folic acid does not improve the antidepressant effects of lithium in patients with bipolar disorder (50566). However, other clinical evidence suggests that taking folic acid in combination with valproate during the acute phase of mania improves the effects of valproate (50357).
• Breast cancer. It is unclear if oral folic acid reduces breast cancer risk. Details: Some older population research suggests that increased intake or levels of folic acid alone does not affect the risk of breast cancer or breast cancer-related mortality (50218,50224). However, in a specific group of women who also consume high amounts of dietary methionine, cyanocobalamin (vitamin B12), or pyridoxine (vitamin B6), dietary intake of folate is associated with a reduced risk of breast cancer (9328,50224). Also, more recent population research has found that folic acid plus folate dietary intakes between 153-400 mcg are associated with a reduced risk of breast cancer. This risk is further reduced in those who drink relatively large amounts of alcohol (90794). Folate intakes greater than 400 mcg daily do not appear to be protective against breast cancer (90794).
• Cancer. It is unclear if oral folic acid prevents cancer. Details: A large cohort study of children born to mothers with epilepsy on antiseizure medications suggests that prenatal folic acid exposure of 1 mg daily or more, at an average of 4.3 mg daily, is associated with a 2.7-fold greater risk of pediatric cancer when compared with children born to mothers with epilepsy but without prenatal exposure to high-dose folic acid. Additionally, this risk is not present in children of mothers without epilepsy taking high-dose folate (112103). It is unclear how maternal epilepsy, antiseizure medications, and folate interact to increase the risk of pediatric cancers. However, in the absence of clear guidelines, mothers with epilepsy should take no more than 4 mg of folic acid daily (112101,112102).
• Cardiovascular disease (CVD). Although oral folic acid does not seem to prevent most CVD events, some research suggests that increased dietary folic acid might lower the risk of stroke and CVD-related mortality in patients at high risk for CVD. Details: In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Meta-analyses of available research show that folic acid might lower the risk of stroke in patients with CVD (97619,102386,107136). Some clinical research shows that taking folic acid reduces the risk of CVD by 15% in patients with kidney failure or chronic kidney disease (50444,91311). However, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or reduce the risk of death or CVD events in patients with existing hyperhomocysteinemia, coronary heart disease, CVD, kidney disease, or prior stroke, despite having a homocysteine-lowering effect (9313,9322,11337,11387,13482,50437) (50512,50527,96154,96147,97619,102386). Some population research has evaluated adults at high risk for CVD. This research has found that dietary folate intake of at least 382 mcg daily is associated with a modest reduction in CVD-related mortality and possibly all-cause mortality. Consuming folic acid as a component of fortified food in doses of more than 251 mcg daily is associated with a modest reduction in CVD-related mortality. Conversely, folic acid supplementation is associated with a higher risk of CVD and overall mortality, and there is a J-shaped association between folate intake, serum folate levels, and red blood cell folate levels, with both CVD-related and all-cause mortality (109199).
• Cervical cancer. It is unclear if oral folic acid prevents cervical cancer. Details: Epidemiological evidence has found that increasing folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might decrease the risk of precancerous cervical lesions (11074).
• Child development. It is unclear if oral folic acid supplementation during pregnancy improves child development. Details: Clinical research in Northern Ireland shows that taking folic acid 400 mcg daily starting in the 14th week of gestation and continuing until the end of pregnancy improves word reasoning in the child at 7 years of age when compared with placebo. When compared with a historical cohort from Britain, folic acid supplementation was associated with an increase in full scale IQ, verbal IQ, performance IQ, and general language at 7 years of age (102385). At age 11, benefits in word reasoning were no longer significant. However, there were modest benefits in some measures of processing speed when compared with placebo. Verbal comprehension was modestly improved in females, but not males (109192). Observational research in pregnant individuals and their children in Spain has found that taking less than 400 mcg of folic acid daily during pregnancy is associated with lower mental alertness scores in children at ages 7-9 years when compared with folic acid 400-999 mcg daily, while taking folic acid 1000 mcg or more daily during pregnancy was associated with improvements in some measures of working memory in the children. However, no relationship between folic acid dosing and most other measures of cognitive function was identified (110449).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral or injectable folic acid for CFS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Chronic kidney disease (CKD). While adding oral folic acid to enalapril might slow CKD progression, adding folic acid to high-dose vitamin B12 does not seem to be beneficial. Details: Clinical research in adults with hypertension and CKD shows that taking enalapril with folic acid 800 mcg for a median of 4.4 years reduces the risk of worsening kidney function by 21% and slows the rate of kidney function decline by 44% when compared with enalapril alone (96153). However, clinical research does not support the use of folic acid in patients with CKD when used in combination with high-dose vitamin B12 (cyanocobalamin). Vitamin B12 might increase the risk of negative outcomes (50253,50409,96150). More research is needed to determine the benefits of folic acid when used alone.
• Colorectal cancer. It is unclear if oral folic acid prevents colorectal cancer. Details: Although the majority of population research suggests that taking folic acid orally from dietary and supplemental sources reduces the risk of colorectal cancer (505,2140,2144,2145,2250,6271,9325,9326,50109,50427,50450)(91306,91323,96160,109188,110450), clinical evidence in general is not supportive. Most clinical research and meta-analyses of clinical trials suggest that taking folic acid from dietary or supplemental sources does not reduce the risk of colorectal cancer (2141,34596,50394). The reason for this discrepancy is unclear. Some observational research suggests that an inverse association between folate intake and risk of colorectal cancer was not apparent until at least 12 years after baseline folate intake was determined (109188). A meta-analysis of observational studies suggests that the benefits of folic acid supplementation on colorectal cancer risk might be limited to patients with moderate to high alcohol consumption (110450). Other clinical evidence suggests that the beneficial effect of folic acid may be limited to colon, but not rectal, cancer (21501). Furthermore, the beneficial effect for colon cancer may be limited to only certain subtypes. For instance, females with folate intake of at least 400 mcg daily seem to have a 46% reduction in the risk of p53-overexpressing colon cancer, but not p53-negative tumors, when compared with those who consume less than 200 mcg daily (21300). Also, the source of folic acid may influence its effects. Some observational research suggests that dietary folate, but not folic acid supplementation, reduces the risk of colon cancer (21501).
• Congenital heart disease. It is unclear if oral folic acid prevents congenital heart disease. Details: The exact cause of congenital heart disease is unknown but is thought to be a combination of genetic and environmental factors. Population research has found that supplementation with folic acid or folic acid-containing prenatal vitamins during pregnancy is associated with up to a 40% lower risk of congenital heart defects in newborns (99373).
• Dementia. It is unclear if oral folic acid is beneficial for the prevention or treatment of dementia. Details: While some preliminary research shows that folic acid might aid in the prevention and treatment of Alzheimer disease (13165,15270,50246,90374), two small clinical trials show that taking folic acid 15-20 mg daily for 10-12 weeks does not seem to improve cognitive function or the severity of dementia in patients with various forms of dementia, including vascular dementia, Lewy body dementia, probable Alzheimer disease, or dementia due to other causes (50062,50597).
• Diabetes. Small clinical studies suggest that oral folic acid does not improve glycemic control. Details: Meta-analyses of small clinical trials in patients with type 2 diabetes show that folic acid does not reduce glycated hemoglobin (HbA1C) when compared with placebo (50528,109197). Another small clinical study in patients with diabetes who are stabilized on metformin and/or a sulfonylurea shows that taking folic acid 5 mg daily for 8 weeks does not affect HbA1C when compared with placebo (104917). The validity of this study is limited by its small size and lack of blinding. Conversely, a meta-analysis of clinical research shows that taking folate modestly reduces fasting blood glucose and insulin levels, as well as measures of insulin resistance, when compared with placebo or no intervention (109197). There was no clear relationship between these changes and the dose or duration of folate. However, the studies included in this analysis evaluated multiple patient populations; the effect of folate in patients with diabetes, specifically, is unclear. Beyond glycemic control, some research has assessed the impact of dietary folate intake on cardiovascular risk in patients with diabetes. An observational study in Chinese adults with type 2 diabetes has found that dietary intake of folate in the highest quartile is associated with 68% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with folate intake in the lowest quartile (110452). Folic acid has also been evaluated in gestational diabetes. A meta-analysis of 20 studies shows that serum and red blood cell (RBC) folate levels are higher in patients with gestational diabetes than without gestational diabetes. Subgroup analysis suggests that patients with gestational diabetes have higher serum and RBC folate levels in the second trimester than in those without gestational diabetes, while RBC folate levels in patients with gestational diabetes were higher in the first trimester than those without gestational diabetes. Overall, higher serum folate levels are associated with a slight increase in the odds of gestational diabetes when compared with lower serum folate levels (112107).
• Diabetic neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic neuropathy shows that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate), for 24 weeks does not improve neural dysfunction based on vibration perception, but does seem to improve total neuropathy symptoms, when compared with placebo. These symptoms, which include both sensation and pain, decreased by 25% with the B vitamin combination, compared with only 15% in those taking placebo (90375).
• Epilepsy. It is unclear if oral folic acid reduces seizure frequency. Details: A meta-analysis of preliminary clinical research shows that taking folic acid does not reduce seizure frequency in patients with epilepsy (50124). However, there is some speculation that folate deficiency might be linked to increased seizure frequency. A preliminary clinical study in folate-deficient children with epilepsy shows that taking folic acid 5 mg daily for 3 months reduces seizure frequency when compared to baseline, but not when compared with a control group that is not deficient in folate (99371).
• Erectile dysfunction (ED). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with mild erectile dysfunction, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Esophageal cancer. Higher dietary folate intake is associated with a lower risk of esophageal cancer. Details: One meta-analysis of observational research has found that higher levels of dietary folate are associated with a 34% lower risk of esophageal squamous cell carcinoma and a 50% lower risk of esophageal adenocarcinoma when compared with low levels of dietary folate (50208). Another meta-analysis of observational research has found that consuming high amounts of folate is associated with a 36% decrease in the odds of esophageal cancer when compared with lower dietary folate intake (100950).
• Fenofibrate (Tricor)-induced hyperhomocysteinemia. Folic acid seems to attenuate increases in homocysteine in people taking fenofibrate. Details: A small open-label clinical trial in patients taking fenofibrate shows that adding folic acid 10 mg every other day might reduce elevated plasma homocysteine levels by up to 59% when compared with taking fenofibrate alone (9321).
• Gastric cancer. It is unclear if oral folic acid reduces gastric cancer risk. Details: Observational research has found that taking folic acid reduces the risk of gastric cardia adenocarcinoma by 17% and the risk of noncardia gastric cancer by 33%, but does not reduce the risk of gastric cancer overall (50208). Also, a meta-analysis of 13 small clinical studies in patients with gastric precancerous conditions shows that taking folic acid 20-30 mg daily for 3-6 months improves gastric mucosal atrophy and intestinal metaplasia but does not seem to improve symptoms when compared with a control (110448). Whether these findings are associated with a lower risk of gastric cancer is unclear.
• Gout. It is unclear if oral folic acid reduces the risk for gout. Details: An observational study has found that increased dietary folate intake is associated with a lower incidence of gout (50454).
• Head and neck cancer. It is unclear if oral folic acid is beneficial for head and neck cancer prevention. Details: Population research has found that the highest intake of dietary folate is associated with a 50% reduced risk of head and neck cancer when compared with the lowest intake of folate. Each 100 mcg increase per day seems to reduce the risk by about 4% (96151).
• Hearing loss. It is unclear if oral folic acid prevents hearing loss. Details: Low levels of serum folate seem to be a risk factor for sudden sensorineural hearing loss in adults (21283). Observational research in females has found that serum folate levels in the lowest quintile are associated with a 19% increased risk for hearing loss when compared with levels in the second quintile. Also, folate levels in the highest quintile are associated with a 12% lower risk of hearing loss when compared with the second quintile (109807). A clinical study in older adults from the Netherlands shows that taking folic acid 800 mcg daily for 3 years slows the decline of age-related low-threshold hearing loss when compared with placebo (15163). However, at the time of this study, folate enrichment of foods was not allowed in the Netherlands. As a result, baseline folate levels in this study population were about 50% lower than in the US population. The effect of folic acid supplementation in people with higher baseline folate levels is unclear.
• Infertility. It is unclear if oral 5-methyltetrahydrofolate (5-MTHF) in combination with vitamin B6 and vitamin B12 is more beneficial than folic acid alone for increasing pregnancy rate in females undergoing assisted reproductive technology (ART). Details: Retrospective research from Italy suggests that taking 5-MTHF 400 mcg, vitamin B12 5 mcg, and vitamin B6 3 mg daily results in clinical pregnancy and live birth rates of approximately 60% and 49%, respectively, compared with 45% and 35% of those taking folic acid 400 mcg daily. A sub-analysis suggests that beneficial effects on pregnancy rates are limited to individuals aged less than 40 years (109189). The findings from this study are limited by its retrospective design. Also, it is unclear if these findings are generalizable to countries with folate fortification.
• Kidney failure. It is unclear if oral folic acid is beneficial in patients with kidney failure. Details: Because hemodialysis removes folate from the body, there is concern that folate deficiency may cause complications in patients with kidney failure receiving hemodialysis. Observational research in Taiwanese patients with kidney failure undergoing hemodialysis has found that taking folic acid 5 mg daily for an average of 5.8 years is associated with a 31% lower risk of arteriovenous access thrombosis when compared with folic acid 5 mg weekly. However, daily folic acid supplementation was not linked to a lower risk of cardiovascular events, cancer, or mortality when compared with weekly folic acid (110120). Oral folic acid has also been evaluated in combination with other ingredients. A small, low-quality clinical study in adults with kidney failure undergoing regular hemodialysis shows that taking oral folic acid 30 mg daily with thiamine 90 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if these findings are due to folic acid, thiamine, or the combination.
• Lometrexol toxicity. While oral folic acid might reduce lometrexol toxicity, intravenous folic acid does not seem to help. Details: In a phase I trial, intravenous folic acid 5-25 mg administered 1 hour or 3 hours prior to lometrexol 15-30 mg/m2 every 3 weeks does not seem to reduce cumulative lometrexol toxicity (2161). However, in a phase II study, taking oral folic acid 3 mg/m2 daily in addition to lometrexol 10 mg/m2 weekly seems to attenuate cumulative toxicity and improve its tolerability in cancer patients (104948).
• Low birth weight. It is unclear if oral folic acid supplementation during pregnancy reduces the risk of a low birth weight. Details: Clinical research shows that supplementation with folic acid 200 mcg to 5 mg daily during pregnancy increases mean birth weight when compared with placebo (91307). Furthermore, some population research has found that pre- or peri-conception folic acid supplementation, usually 400 mcg daily, is associated with a reduced risk of a child born small-for-gestational age. However post-conception folic acid supplementation is not associated with reduced risk (91304,103983). An observational study in pregnant Chinese patients found that supplementation with folic acid is associated with a 20% lower odds of low birth weight when compared with no supplementation. This association was observed when folic acid was used both before conception and during pregnancy for at least 24 weeks or during pregnancy only for at least 12 weeks. Increased dietary folate intake was not linked to a lower risk of low-birth-weight infants (110446). However, other observational research has found no association between folic acid supplementation during pregnancy and the risk for small-for-gestational age births (110447).
• Lung cancer. It is unclear if oral folic acid reduces lung cancer risk. Details: There does not appear to be a relationship between deficiency of folate and lung cancer (9454). However, consuming at least 130.4 mcg of folate per 1000 kcal daily seems to reduce the risk of lung cancer by 40% in former smokers when compared to those with lower dietary folate intake (50065).
• Melanoma. It is unclear if oral folic acid reduces melanoma risk. Details: Population research has found that folic acid supplementation of 2-2.5 mg daily in combination with vitamin B6 and vitamin B12 is linked with a 53% reduced risk of melanoma (91312).
• Metabolic syndrome. Although there is interest in using oral folic acid for metabolic syndrome, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Nitrate tolerance. It is unclear if oral folic acid helps to prevent the development of tolerance to treatment with nitroglycerin. Details: Some clinical evidence suggests that taking folic acid 1 mg daily for 1 week does not prevent the development of nitroglycerin-induced endothelial dysfunction or tolerance in healthy individuals (50442). However, other research suggests that taking folic acid 10 mg daily for 1 week prevents nitric oxide synthase dysfunction caused by continuous nitroglycerin (9316).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral folic acid is beneficial for NAFLD. Details: A cross-sectional analysis suggests that adults with NAFLD have lower levels of serum folate and its major component 5-MTHF when compared with healthy controls. Additionally, adults with NAFLD seem to consume less supplementary and dietary folate when compared with healthy controls. Overall, serum folate levels are negatively associated with the risk of NAFLD, and inadequate folate intake is associated with an increased risk of NAFLD (112104).
• Oral clefts. It is unclear if oral folic acid reduces the risk of oral clefts in infants. Details: Observational research has found that maternal folic acid supplementation is associated with an up to 49% reduced risk of cleft lip with or without cleft palate (50220,104921). Furthermore, a large clinical trial in pregnancies at-risk for oral cleft suggests that taking a higher dose of folic acid 4 mg from pre-conception until the end of the first trimester results in a similar oral cleft recurrence rate of 2.5%, compared with a 2.9% recurrence with a lower dose of folic acid (400 mcg). Both doses demonstrate a lower incidence of oral clefts when compared with historical rates of 6.3% (91322). Although there is speculation that genetic markers of folate status impact the effect of folic acid on orofacial cleft incidence, the current data do not show a relationship (104921).
• Overall mortality. It is unclear if oral folic acid reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of folic acid in the highest quintile is associated with a 14% to 23% lower risk of all-cause mortality and a 41% to 47% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary folic acid intake (110451).
• Pancreatic cancer. It is unclear if oral folic acid reduces pancreatic cancer risk. Details: Consuming greater than 280 mcg daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer (9327). A meta-analysis of case-control and cohort studies suggests that consuming higher amounts of dietary folate reduces the risk of pancreatic cancer by 51% compared to low levels of dietary folate (50208). However, another meta-analysis of prospective cohort studies suggests that folate/folic acid intake does not significantly affect the overall risk of pancreatic cancer (50499). The contradictory results may be associated with the form of intake or may be related to the gender of the participants. A meta-analysis of clinical research shows that dietary folate, but not folic acid, significantly reduces the risk of pancreatic cancer (50387). Also, one meta-analysis of observational studies has found that high dietary folate decreases the risk of pancreatic cancer in females, but not males (50387).
• Peripheral neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows taking a combination of folic acid 400 mcg, vitamin B12 3 mcg, and uridine monophosphate 50 mg daily (Keltican) for 60 days reduces pain associated with peripheral neuropathy. Use of this product reduces pain intensity by approximately 44%, with loss of burning pain in approximately 50% of patients, strong tingling or pricking in approximately 57% of patients, strong pain attacks in 92% of patients, and numbness in 90% of patients when compared with baseline. Radiating pain and the use of concomitant medications are also reduced (90384). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to folic acid, other ingredients, or the combination.
• Pharyngeal cancer. It is unclear if oral folic acid reduces pharyngeal cancer risk. Details: Population research has found that intake of folic acid and folate from natural, fortified, and supplemented sources, may protect against oropharyngeal cancer. Intake of at least 258-816 mcg total folate/folic acid reduces the odds by 35% when compared with intakes of less than 344 mcg. Furthermore, folate/folic acid may be more beneficial for oral cancer versus pharyngeal cancer and in heavy alcohol users versus non users or light users (91302).
• Polycystic ovary syndrome (PCOS). It is unclear if oral folic acid is beneficial for PCOS. Details: One clinical study in overweight or obese patients with PCOS shows that taking folate 1 mg or 5 mg daily for 8 weeks modestly reduces levels of homocysteine, as well as insulin resistance, when compared with placebo. However, only the 5 mg dose modestly reduces insulin, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Neither dose appears to affect fasting plasma glucose, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo (109200). Other clinical research in patients with PCOS taking metformin shows that taking folate 400 mcg daily for 6 months does not affect glycemic parameters, plasma lipid levels, or hormone levels when compared with placebo (109194). The reasons for discrepancies between studies are unclear but may relate to patient characteristics. One study included only overweight or obese individuals with at least two of the three PCOS criteria, whereas the other study limited enrollment to patients in any weight category but with all three PCOS criteria (109194,109200).
• Pregnancy-induced hypertension. It is unclear if oral folic acid reduces the risk of hypertension during pregnancy. Details: Population research has found that taking folic acid during pregnancy is not associated with a reduced risk of gestational hypertension (91308,99370,99372).
• Restless legs syndrome (RLS). Although there is interest in using oral folic acid for RLS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Schizophrenia. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of folic acid 2 mg and vitamin B12 400 mcg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral folic acid has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Suicidal ideation. It is unclear if oral folic acid reduces the risk of suicidal ideation or suicide attempts. Details: One observational study has evaluated the association between folic acid supplementation and suicidal events in patients with various underlying conditions, including 12% with depression, 15% with anxiety, and 46% with pain. This within-person cohort study found that filling a prescription for folic acid 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a 44% reduced rate of suicidal events during the months after the prescription when compared with the months without the prescription. For the 48% of patients who received folic acid 1 mg daily, each additional month of taking the prescription was associated with a 5% decrease in suicidal events (109201). Prospective clinical research is needed to confirm any benefits of folic acid and to determine whether baseline folate deficiency plays a role in these outcomes. More evidence is needed to rate folic acid for these uses.

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EFFECTIVE

• Bowel preparation. Various magnesium salts are used for cleansing the bowel prior to procedures such as colonoscopy. Details: Various magnesium salts, including citrate, hydroxide, oxide, and sulfate, are ingredients in bowel preparation products available over-the-counter or by prescription only.
• Constipation. Magnesium salts are effective when used short-term orally to treat constipation and chronic idiopathic constipation (CIC). Details: Magnesium citrate, hydroxide, oxide, and sulfate salts are commonly used as laxatives. Magnesium citrate 11.3-17.45 grams has been used; magnesium hydroxide 2.4-4.8 grams, as 30-60 mL of milk of magnesia, has also been used (113483,113484). Magnesium sulfate, also known as Epsom salt, which seems to have the most potent effect, has been used as 10-30 grams (6430,113485). Magnesium salts should only be used for occasional treatment of constipation, and doses should be taken with a full 8-ounce glass of water. Magnesium oxide seems to be beneficial in adults with CIC when taken short-term. Clinical guidelines published by the American Gastroenterology Association and American College of Gastroenterology in 2023 give a conditional recommendation suggesting the use of magnesium oxide over managing CIC without magnesium oxide based on low-quality studies conducted over 4 weeks. The recommended starting dose is 400-500 mg daily with dose titration per symptom response and side effects (112859). A small clinical study in patients with CIC who are not taking chronic medications shows that taking magnesium oxide 1.5 grams in three divided doses daily for 28 days increases spontaneous bowel movements when compared with placebo (104397). It is unknown if magnesium is beneficial for CIC when used long-term.
• Dyspepsia. Magnesium salts are effective when used orally as antacids. Details: Magnesium carbonate, hydroxide, oxide, or trisilicate salts are used orally as antacids to reduce symptoms of gastric hyperacidity or gastroesophageal reflux. Magnesium hydroxide has the fastest onset of action. The onset for magnesium carbonate is slower due to its crystal structure. Magnesium trisilicate has the slowest onset and longest duration of action due to poor solubility (6844). Doses used include magnesium hydroxide 400-1200 mg (5-15 mL of milk of magnesia) up to four times daily, or magnesium oxide 800 mg daily (15).
• Eclampsia. Magnesium sulfate is considered the drug of choice for control of seizures. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (15,12591,12592,61012,61184). Typical doses include 4-6 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). Meta-analyses of clinical research show that treatment with IV or IM magnesium reduces the risk of seizure recurrence by 33% to 69% when compared with phenytoin, and by 47% to 60% when compared with diazepam (19960,60818,60954,60964,61105). One preliminary clinical study shows that lower doses of IV magnesium sulfate (9 grams loading dose and maintenance of 2.5 grams every 4 hours for 24 hours) are as effective as higher doses (14 grams loading dose and maintenance of 5 grams every 4 hours for 24 hours) for reducing the recurrence of eclamptic seizures (89383). It is generally recommended that treatment be continued for at least 24 hours after the last seizure (15). Oral magnesium has not been evaluated for eclampsia.
• Hypomagnesemia. Hypomagnesemia can be effectively treated with oral or parenteral magnesium. Details: Taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesemia associated with alcoholism, cirrhosis of the liver, congestive heart failure (CHF), severe or prolonged diarrhea or vomiting, kidney dysfunction, inflammatory bowel disease (IBD), pancreatitis, malabsorption syndromes, and other conditions (6280,6281,8088,8089). The dose and salt of magnesium for oral replacement therapy should be chosen carefully to avoid causing diarrhea. The gluconate and chloride salts cause less diarrhea, while the oxide salt is more likely to cause diarrhea and should be avoided. Magnesium chloride should also be avoided due to poor solubility which decreases absorption (6430,8099,10664). Orally, magnesium sulfate 3 grams every 6 hours for four doses has been used for hypomagnesemia (15). Parenteral magnesium doses must be individualized according to serum magnesium levels, but a typical starting dose for mild deficiency is 1 gram of magnesium sulfate intramuscularly (IM) every 6 hours for 4 doses (15). For more severe deficiency, 5 grams of magnesium sulfate may be given as an intravenous (IV) infusion in 1 liter of dextrose 5% or normal saline solution over 3 hours (15).
• Pre-eclampsia. Magnesium sulfate is considered the drug of choice for seizure prophylaxis in patients with pre-eclampsia. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during pre-eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (12591,12592,61012,61184). Some meta-analyses show that IV administration of magnesium sulfate reduces the risk of eclampsia when compared with placebo, phenytoin, or diazepam in patients with pre-eclampsia (19960,60818,60960,60979). A typical initial dose is 4-5 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams of magnesium sulfate per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). The optimal duration of prophylaxis has not been determined. A meta-analysis suggests that using a shorter duration of 12 hours or less is not associated with an increase in risk of eclamptic seizures when compared with regimens of 24 hours or longer (108732). However, studies are likely underpowered due to the low incidence of eclampsia. Oral magnesium has been evaluated for the prevention of pre-eclampsia in healthy adults, but taking magnesium citrate 300 mg daily, starting at 12-20 weeks' gestation and continuing until delivery, does not reduce the incidence of pre-eclampsia when compared with placebo (103724).

LIKELY EFFECTIVE

• Cerebral palsy. Most evidence shows that antenatal magnesium reduces the risk of cerebral palsy in preterm infants, although there are some inconsistent results. Details: Most clinical studies and meta-analyses show that antenatal magnesium sulfate reduces the risk of cerebral palsy by about 32% and the risk of motor dysfunction by about 45% in preterm infants (60915,60927,60931,61001,97485,103734,103754,114675,114681). The lowest effective dose of magnesium sulfate seems to be 4 grams intravenously, with or without a maintenance dose of 1 gram/hour until birth or for 24 hours. In obese females, a higher dose, based on body weight, may be needed (97485,97495,103734,103754). However, some studies have inconsistent results (8093,19998,98293,98295,112784). Giving females at risk of imminent preterm birth (prior to 32 weeks), intravenous magnesium sulfate 4.5 grams over 20 minutes followed by 1 gram per hour until birth or for 24 hours, in addition to a standard treatment protocol, does not reduce the incidence of cerebral palsy (112784). Oral magnesium has not been evaluated for this purpose.
• Seizures. Intravenous magnesium sulfate is used for treating seizures of various etiologies. Details: Intravenous magnesium sulfate may be useful for controlling seizures associated with epilepsy, glomerulonephritis, hypothyroidism, and acute nephritis in children (15). Oral magnesium has not been evaluated for this purpose.
• Torsades de pointes. Intravenous magnesium sulfate is the first-line treatment for torsades de pointes after measures to correct precipitating factors have been unsuccessful. Details: Intravenous magnesium sulfate has been used successfully to treat the life-threatening ventricular tachycardia, torsades de pointes (15,6844). The Advanced Cardiac Life Support (ACLS) guidelines of the American Heart Association recommend a dose of 1 to 2 grams diluted in 50-100 mL Dextrose 5% solution given IV over 5-60 minutes, followed by a continuous IV infusion of 0.5-1 gram/hour.

POSSIBLY EFFECTIVE

• Arrhythmia. Magnesium sulfate is effective for the specific type of ventricular tachycardia known as torsades de pointes, and seems to be helpful for treating other types of arrhythmias. Evidence for the role of oral or intravenous magnesium in preventing postoperative arrhythmias is conflicting. Details: Administering magnesium intravenously or orally may be helpful for treating atrial and ventricular tachycardia and fibrillation, and supraventricular tachycardia (9497,13352,13354,13355,13356,60804,60829,60877,61113,111696). Arrhythmias associated with congestive heart failure have been treated with magnesium sulfate 8 grams infused over 12 hours (9497). For rate control in atrial fibrillation, magnesium sulfate 2.5 grams IV over 20 minutes, followed by 2.5 grams IV over 2 hours has been used (13356). For paroxysmal supraventricular tachycardia, single doses of 1-4 grams of magnesium chloride have been used (13352). For atrial tachycardia, 2 grams of magnesium sulfate in 10 mL of dextrose 5% solution has been given IV over 1-10 minutes, followed by 5-10 grams of magnesium sulfate in 250-500 mL dextrose 5% solution as an IV infusion over 5 hours (13354,13355). Research on the effects of intravenous magnesium for preventing arrhythmias after cardiac surgery is conflicting. Some meta-analyses show that intravenous magnesium reduces the risk of atrial fibrillation, ventricular arrhythmias, or supraventricular arrhythmias following cardiac surgery by 23% to 48% when compared with placebo (60814,60826,60828,60838,61008,61033,61181,97487,97490). Doses of magnesium sulfate used include 30 mg/kg in 500 mL normal saline (97490), or 80-100 mg/kg added to the cardioplegia solution (97487). Also, one small study in adults after CABG surgery suggests that taking magnesium hydroxide 1600 mg orally reduces arrhythmia as effectively as receiving magnesium sulfate 2000 mg intravenously (99315). However, other meta-analyses that only include higher-quality trials show that magnesium supplementation does not reduce the risk of ventricular or supraventricular arrhythmias following cardiac surgery (61010,61024,61031,105081). A meta-analysis of clinical trials of intravenous magnesium for prevention of new-onset atrial fibrillation after non-cardiac surgeries shows that it does not reduce the incidence significantly when compared with placebo (112778). However, there was a high risk of bias in the analysis, and variability in types of surgery, and the salt and dose of magnesium used.
• Asthma. Parenteral magnesium sulfate can help to reverse severe acute asthma attacks and reduce the need for hospital admission. It is unclear if nebulized magnesium is beneficial for acute asthma attacks. However, oral magnesium does not seem to be beneficial. Details: Overall, a single dose of intravenous magnesium seems to improve pulmonary function in acute asthma exacerbation and reduce the risk of hospitalization, particularly in patients with severe asthma, and those who have failed initial treatment with nebulized albuterol and intravenous corticosteroids (60888,90023,96483,104398,107365). The typical dose used for adults is 2 grams of magnesium sulfate infused over 20 minutes (15). For children, 25-75 mg/kg, to a maximum of 2 grams, infused over 20-30 minutes has been used (15,96483,107365). However, a post-hoc analysis of one large clinical trial (104400) designed to assess nebulized magnesium in children with acute asthma has found that adding IV magnesium to nebulized magnesium is associated with greater odds of hospitalization when compared with no IV magnesium (105919). This post-hoc analysis did not differentiate between precautionary and necessary hospitalizations. Although some clinical research and a meta-analysis in patients with acute asthma exacerbation show that nebulized magnesium in combination with standard treatment improves airway function, respiratory rate, and clinical asthma severity when compared with standard treatment alone, it is unclear whether these findings are clinically relevant (90016,113466). Most evidence, including larger clinical trials and meta-analyses, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920,113466,114674). Oral magnesium also does not seem to be beneficial. A meta-analysis of small clinical trials in children and adults with asthma shows that taking magnesium supplements orally does not improve lung function or reduce bronchodilator use when compared with control (104404).
• Colorectal cancer. Increasing dietary magnesium intake seems to lower the risk of colon cancer but not rectal cancer. Details: Epidemiological research shows that increased dietary magnesium intake is associated with a reduced risk of colon cancer, but the risk of rectal cancer is not affected (89387,90017,90027,101355).
• Diabetes. Low dietary magnesium may increase the risk of developing type 2 diabetes, but evidence on the use of supplements for treating type 2 diabetes is conflicting. Details: Higher dietary magnesium intake is associated with lower fasting insulin concentrations and a reduced risk of developing type 2 diabetes in adults and obese children (13369,15548,96473,97486,98294,103736,105918,106920). In people with existing type 2 diabetes, hypomagnesemia is found in 25% to 38% of patients, especially in those with poorly controlled diabetes (1172). Population research in adults with type 2 diabetes also shows that a dietary magnesium intake of less than 250 mg daily is associated with a 56% higher risk of mortality. Preliminary subgroup analyses suggest that the risk of mortality is higher in those with glycated hemoglobin (HbA1C) levels above 7% (110051). A meta-analysis of small, heterogeneous clinical studies in adults with type 2 diabetes suggests that magnesium may modestly reduce HbA1C in patients with hypomagnesemia, but not in patients with normal magnesium levels, when compared with control (105075). Individual clinical studies using magnesium supplements in patients with type 2 diabetes or insulin resistance have shown mixed results. Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity, as well as reduce the risk of developing diabetes in high-risk patients (10664,12582,13376,60854,99313,106920), but other research shows no effect (1171,1172,13379,13380,112780). Discrepancies in these findings might reflect differences in magnesium salts and doses used, or differences in baseline magnesium status in study subjects.
• Hypercholesterolemia. Magnesium may help improve lipid levels by a small amount in people with this condition. Details: There is some evidence that taking magnesium oxide 1 gram orally daily for 6 weeks can produce small decreases in low-density lipoprotein (LDL) and total cholesterol levels, and small increases in high-density lipoprotein (HDL) levels in patients with hypercholesterolemia. However, magnesium does not seem to improve lipoprotein (a) levels (1193). Magnesium may also lower triglycerides in people with hypertriglyceridemia (97494).
• Metabolic syndrome. Low dietary and serum levels of magnesium seem to be associated with the development of metabolic syndrome. Details: Higher magnesium intake from diet and supplements is associated with a 27% lower risk of developing metabolic syndrome in healthy females (13371) and a 31% lower risk in healthy young adults (14304). Additional epidemiological research suggests that people with low serum magnesium levels are 6-7 times more likely to have metabolic syndrome than people with normal magnesium levels (13372). In a population analysis of over 6000 individuals without metabolic syndrome at baseline, the risk of developing this condition over a 6-year follow-up period was reduced by 16% in the highest quintile of dietary magnesium intake (median intake 371 mg daily) when compared with the lowest quintile (median intake 203 mg daily). Some, but not all, research suggests that the hazard ratio for metabolic syndrome in relation to magnesium intake may be U-shaped, with higher risk at intakes below about 150 mg daily and above 600 mg daily (108963). A combination of magnesium 20 mEq daily and potassium 40 mEq daily (magnesium potassium citrate) taken orally for 16 weeks reverses metabolic side effects of chlorthalidone, such as increased fasting plasma glucose and hypokalemia, more effectively than potassium chloride 40 mEq daily alone (112932).
• Osteoporosis. Increased dietary and supplemental magnesium intake seems to increase bone mineral density and decrease bone loss in postmenopausal patients. Details: Preliminary clinical research shows that taking magnesium hydroxide orally, 300-1800 mg daily for 6 months, then 600 mg daily for 18 months, or magnesium citrate orally 1830 mg daily for 30 days, might reduce bone loss and bone turnover in postmenopausal patients with osteoporosis (9104,60928). Some epidemiological research also suggests that magnesium intake is related to increased bone mineral density (12501,12502,12503,12504,90014), although not all studies have found an association (12505,98286).
• Postoperative pain. Injectable magnesium has been used with promising results for reducing pain and the need for other analgesics postoperatively. Details: A meta-analysis of 25 clinical trials shows that intravenous (IV) magnesium sulfate, 5-50 mg/kg bolus followed by a continuous infusion of 6 mg/kg or 500 mg hourly during surgery, seems to reduce the 24-hour postoperative use of IV morphine by 24% when compared with placebo (19968). Adding IV magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Additionally, meta-analyses support that adjunctive IV or intrathecal administration of magnesium reduces post-operative pain scores, improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728,114676,114677,114678). However, some data are conflicting. In a meta-analysis of 7 trials, IV magnesium was not associated with lower pain scores over the first 48 hours postoperatively. The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied. Additionally, IV magnesium appears to be less effective than dexmedetomidine (105082). Two moderate-sized clinical studies in patients undergoing total knee arthroplasty in China show that adding magnesium sulfate 2.5 mg/mL to the periarticular infiltration analgesia (PIA) cocktail or administering IV magnesium sulfate 40 mg/kg before anesthesia induction then as a 15 mg/kg infusion during surgery reduces pain scores, increases comfort levels, limits and delays the use of postoperative opioids, prolongs analgesia, and reduces markers of inflammation when compared with the usual PIA cocktail or control (111181,113677). Administering magnesium intravenously also seems to be helpful for pain control after hysterectomy. A 3-gram IV bolus of magnesium sulfate followed by an infusion of 0.5 grams per hour for 20 hours has been used. Lower doses were not effective (6848). In males undergoing laparoscopic radical resection for gastrointestinal cancer, administering IV magnesium intraoperatively, as a loading dose of 40 mg/kg followed by 15 mg/kg/hour through the end of surgery, reduces postoperative catheter-related bladder discomfort and analgesic requirements, when compared with placebo (112783). However, IV magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium IV infusion does not reduce pain when compared with saline in children after tonsillectomy or after elective strabismus surgery (98282,105077).
• Premenstrual syndrome (PMS). Taking magnesium orally seems to relieve symptoms of PMS. Details: There is some evidence that magnesium supplementation can improve symptoms, including mood changes and fluid retention, in some patients with PMS (1187,1188,6847). Doses used include magnesium oxide 333 mg daily for 2 menstrual cycles, or magnesium pyrrolidone carboxylic acid equivalent to 360 mg elemental magnesium three times daily, from the 15th day of the menstrual cycle until onset of menstrual flow (1187,1188). Taking magnesium orally in a dose of 360 mg (elemental magnesium) three times daily for 2 months seems to prevent premenstrual migraine (1186,6847). A combination of magnesium 200 mg daily plus vitamin B6 50 mg daily seems to reduce anxiety-related premenstrual symptoms, including nervous tension, mood swings, irritability, and anxiety, when compared with placebo (8555).
• Vasospastic angina. Intravenous magnesium seems to prevent coronary spasm in patients with this condition. Details: Clinical research shows that administration of intravenous magnesium sulfate 65 mg/kg infused over 20 minutes dilates coronary arteries and suppresses acetylcholine-induced coronary spasms when compared with infusion of a dextrose solution in patients with vasospastic angina (8091).

POSSIBLY INEFFECTIVE

• Altitude sickness. Taking magnesium citrate orally does not seem to reduce acute altitude sickness risk. Details: Clinical research shows that taking magnesium citrate 1200 mg daily orally in three divided doses, beginning 3 days prior to mountain ascent and continuing until mountain descent, does not reduce the risk of acute altitude sickness when compared with placebo (60801).
• Athletic performance. Taking magnesium orally does not seem to improve energy or endurance during athletic activity. Details: Most evidence suggests that taking magnesium orally doesn't increase energy and endurance during athletic activity. Magnesium oxide, aspartate, and orotate salts do not seem to improve exercise performance when used alone or in combination with potassium, vitamin B6, or zinc (2825,2826,2828,2829,2830,60751,113655).
• Bronchiolitis. Intravenous or nebulized magnesium is not beneficial in infants with this condition. Details: Clinical research shows that administering a single IV dose of magnesium sulfate 100 mg/kg to infants with acute bronchiolitis does not improve, and may actually worsen, symptoms when compared with placebo (97482). A clinical study in infants with moderate to severe bronchiolitis shows that adding nebulized magnesium sulfate 40 mg/kg to nebulized epinephrine does not reduce hospital stay or the need for ventilator or oxygen support when compared with epinephrine alone (99317). Oral magnesium has not been evaluated for this use.
• Chemotherapy-induced peripheral neuropathy. Research on the effects of intravenous infusions of magnesium and calcium for preventing oxaliplatin neurotoxicity are inconsistent, but higher quality studies seem to show no benefit. Details: Pooled analyses of cohort studies and clinical trials show that calcium and magnesium infusions can decrease the incidence of severe oxaliplatin-induced neurotoxicity (90028,90029,90031). However, when only clinical trials are considered, the infusions do not appear to be helpful (90005,90029,90031,96474,96479).
• Complex regional pain syndrome. Intravenous magnesium is not beneficial in complex regional pain syndrome type 1. Details: Clinical research shows that receiving magnesium sulfate 70 mg/kg intravenously at the rate of 25 mL/hour for 4 hours each day for 5 days does not improve pain or level of impairment when compared with placebo in patients with chronic complex regional pain syndrome type 1 (89395).
• Emergence delirium. The majority of small clinical studies in adults and children undergoing various surgeries suggest that intravenous (IV) magnesium doesn't reduce the risk of emergence delirium. However, most clinical studies in adults suggest that IV magnesium reduces emergence agitation. Details: A small clinical study in adults undergoing surgery for endovascular aortic aneurysm repair shows that administering IV magnesium 30 mg/kg as a loading dose, followed by a 10 mg/kg/hour infusion for the duration of surgery, does not improve agitation or delirium scores when compared with administering saline (111182). Similarly, a small clinical study in children ages 2-5 years undergoing elective strabismus surgery shows that administering IV magnesium during anesthesia does not seem to prevent the occurrence of emergence delirium when compared with administering saline (105077). In a meta-analysis of 8 clinical trials in children aged 2-16 years undergoing general anesthesia for oral or ophthalmic surgery, giving IV magnesium as a 30 mg/kg loading dose followed by a 10 mg/kg/hour infusion, or as a single dose of 15-30 mg/kg, does not reduce emergence delirium scores, and may actually prolong emergence times (108729). However, there is some conflicting evidence. In patients undergoing radical mastectomy, giving intraoperative magnesium sulfate 30mg/kg over 1 hour, followed by 10 mg/kg/hour until the end of surgery, reduces emergence agitation (odds ratio 0.26) when compared with placebo (112781).
• Menopausal symptoms. Oral magnesium oxide does not seem to be beneficial for menopausal hot flashes. Details: A small, low quality study in postmenopausal patients with a history of breast cancer shows that taking magnesium oxide 400-800 mg orally daily reduces hot flashes when compared with baseline (102454). However, a larger, higher quality clinical study using magnesium oxide 800-1200 mg daily did not show any benefit when compared with placebo (98290).
• Muscle cramps. Oral magnesium does not seem to improve muscle cramp frequency or intensity. Details: Meta-analyses of small clinical trials show that magnesium supplementation for 3-6 weeks does not decrease the frequency or intensity of skeletal muscle cramps, whether the cramps are idiopathic or due to liver cirrhosis or pregnancy, when compared with placebo (90022,104395).
• Sickle cell disease. Intravenous magnesium does not add any benefit to standard therapy for sickle cell disease in children. Details: Clinical research shows that giving magnesium sulfate 40-100 mg/kg (maximum of 2 grams per dose) intravenously every hour for 6-8 doses as an adjunct to standard therapy does not decrease hospital stay, pain, or opioid use, or improve quality of life, when compared with standard therapy and placebo in children with sickle cell disease (89399,98283,101356). Oral magnesium has not been evaluated for this purpose.
• Stillbirth. Magnesium administered during pregnancy does not reduce stillbirth risk. Details: A meta-analysis of clinical research shows that magnesium supplementation does not significantly decrease the risk of stillbirths when administered during pregnancy (60925,60978).
• Tetanus. Intravenous magnesium sulfate does not seem to improve outcomes in patients with this condition. Details: A meta-analysis of clinical research shows that intravenous magnesium sulfate does not reduce mortality when compared with placebo or diazepam in patients with tetanus (61020). While some research shows that magnesium reduces the duration of hospitalization and the need for ventilation when compared with diazepam (61170), magnesium does not seem to improve these outcomes when compared with placebo (60860).
• Traumatic brain injury (TBI). Magnesium does not improve clinical outcomes in patients with moderate to severe TBI. Its effect in patients with concussions is unclear. Details: A meta-analysis of four clinical trials shows that treatment with magnesium does not significantly improve neurological outcomes or reduce the risk of mortality when compared with placebo in patients with moderate to severe TBI (60905). A small observational cohort study in adolescents with concussions has found that adding oral magnesium 400 mg twice daily for 5 days to standard treatment with acetaminophen and ondansetron is associated with a trend toward reduced symptom severity when compared with standard treatment alone (104401). The validity of this study is limited by its observational nature and small cohort size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Intravenous magnesium does not seem to help reduce symptoms of alcohol withdrawal but may reduce the duration of alcoholic delirium. Details: Preliminary clinical research shows that administration of four intramuscular injections of magnesium sulfate 2 grams at 6-hour intervals does not reduce symptoms of alcohol withdrawal when compared with saline (61063). A small observational study in patients with alcoholic delirium has found that administering magnesium sulfate IV 50 mg/kg every 8 hours, in addition to usual sedation, is associated with a reduction of delirium by approximately 2 days, or 4 days when given every 12 hours in addition to dexmedetomidine, when compared with usual sedation alone (111180). However, half of patients had hypomagnesemia at baseline; it is unclear if effects would be similar for patients with normal magnesium levels. Oral magnesium has not been evaluated for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral magnesium for allergic rhinitis, there is insufficient reliable information about the clinical effects of magnesium for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral magnesium is beneficial in children with ADHD. Details: Children with ADHD seem to have lower magnesium levels in their blood and hair (9969,100262,100263). A small clinical study in children aged 7-12 years with ADHD and magnesium deficiency shows that taking magnesium aspartate and lactate 6 mg/kg daily for 6 months might improve hyperactivity and magnesium levels when compared with control (1189). Another small clinical study in children with ADHD but without magnesium deficiency shows that taking magnesium 6 mg/kg daily along with vitamin D 50,000 IU weekly for 8 weeks may modestly improve emotional problems, but not inattention or hyperactivity, as measured on the strength and difficulties questionnaire (SDQ), when compared with placebo (105914).
• Back pain. It is unclear if oral or intravenous magnesium is beneficial for acute or chronic back pain in adults. Details: One open-label clinical study in adults with acute low-back pain shows that taking magnesium 365 mg once daily in addition to taking etodolac 400 mg twice daily for 10 days does not further reduce pain when compared with taking etodolac alone (105913). Magnesium has also been tried for chronic back pain. A small clinical study in patients with chronic low-back pain shows that receiving magnesium sulfate 1 gram in 250 mL normal saline intravenously every 4 hours for 2 weeks, followed by magnesium gluconate 100 mg and magnesium oxide 400 mg by mouth daily for 4 weeks, reduces pain severity when compared with placebo (90035). It is unclear if oral magnesium used alone is beneficial.
• Bariatric surgery complications. It is unclear if oral magnesium supplementation improves metabolic parameters after bariatric surgery. Details: A retrospective study of over 3000 post-bariatric surgery patients suggests that those who take oral magnesium supplements providing 100-450 mg elemental magnesium daily may have improved metabolic parameters over 4 years of follow-up. When patients taking magnesium supplements were compared with those not taking supplements, 11% and 18% had type 2 diabetes, respectively, 30% and 42% had hypertension, respectively, and 16% and 23% had elevated low-density lipoprotein (LDL) cholesterol levels, respectively. For patients with hypomagnesemia at baseline, supplementation seemed to result in greater benefits (108968).
• Bipolar disorder. Taking magnesium orally might improve manic symptoms in some people with bipolar disorder; however, it is unclear how it compares to current standard of care. Details: One preliminary clinical study shows that magnesium 40 mEq daily (Magnesiocard) for 32 weeks has similar effects to lithium in up to 50% of patients treated for rapid cycling bipolar affective disorder (61022). Another preliminary clinical study shows that magnesium oxide 375 mg orally daily plus verapamil 80 mg taken four times daily reduces manic symptoms more effectively than verapamil alone in patients with mania (60742).
• Cancer-related neuropathic pain. It is unclear if intravenous magnesium is beneficial for this condition. Details: Single 500 mg to 1 gram doses of magnesium sulfate seem to relieve neuropathic pain for up to four hours when compared to baseline (6846). The validity of this finding is limited by the lack of a comparator group.
• Cardiac arrest. Intravenous magnesium does not seem to be helpful in cardiac arrest; however, the risk of sudden cardiac death seems to be inversely correlated to higher plasma magnesium levels or dietary intake. It is unclear if magnesium supplementation is associated with similar risk reduction. Details: Administering magnesium intravenously doesn't seem to improve successful resuscitation in people with cardiac arrest (1190). However, higher plasma magnesium levels and higher dietary magnesium intake might reduce the risk of sudden cardiac death, possibly by protecting against fatal ventricular arrhythmias. In the Nurses' Health Study, the risk of sudden cardiac death was 77% lower in females with the highest quartile of plasma magnesium levels when compared with the lowest quartile. Also, the risk was 37% lower in females with the highest quartile of dietary magnesium intake when compared with the lowest quartile (17132).
• Cardiovascular disease (CVD). Evidence regarding the effect of dietary magnesium on CVD risk is conflicting. Details: Epidemiological research in some populations shows that increased dietary magnesium intake is associated with decreased mortality due to strokes, coronary heart disease, ischemic heart disease, and heart failure, but other epidemiological research does not show any effect on these risks (89391,90003,90009,90030,90036,103735). Reasons for the discrepancies may be related to serum levels of magnesium at baseline, risk of cardiovascular disease at baseline, use of concomitant medications such as diuretics, or the presence of concomitant conditions such as kidney dysfunction. A population analysis conducted in Denmark has found that magnesium intake from drinking water may be associated with cardiovascular mortality. The overall risk of cardiovascular death and death due to stroke was reduced by 4% in the lowest 3 quintiles of intake when compared with the highest quintile. However, the risk of death due to acute myocardial infarction was increased by 22% in the lowest quintile when compared with the highest (108726). The relevance of these results is unclear, given that the main dietary source of magnesium is food rather than drinking water.
• Chronic fatigue syndrome (CFS). Limited evidence suggests that magnesium may help improve CFS symptoms, but this is controversial. Details: In people with low red blood cell magnesium, there is some evidence that intramuscular injections of 1 gram magnesium sulfate given once weekly for 6 weeks might improve CFS symptoms (7556). However, there is additional evidence that most patients with CFS have normal magnesium stores, and measurement of red cell magnesium is a poor indicator of total magnesium stores (7557,8084,8085,8086,8087).
• Chemotherapy-induced leukopenia. It is unclear if oral magnesium is beneficial in pediatric patients at risk for cisplatin-induced febrile neutropenia. Details: A small clinical study in children with solid tumors aged 9 years and older shows that taking magnesium 250 mg daily while receiving cisplatin-based chemotherapy reduces febrile neutropenia by 47% and septic shock by 57% when compared with not receiving magnesium. Results from this study suggest that four pediatric patients need to take oral magnesium to avoid one case of febrile neutropenia (104394).
• Chemotherapy-induced nephrotoxicity. It is unclear if intravenous magnesium is beneficial for chemotherapy-induced nephrotoxicity. Details: A meta-analysis of several lower quality clinical studies in adults in Japan with cancer receiving cisplatin shows that pretreatment with intravenous magnesium sulfate 5 to 20 mEq reduces the odds of chemotherapy-induced nephrotoxicity in a dose-dependent manner when compared to standard hydration therapy (115726). The validity of these findings is limited by heterogenous methods between clinical trials, including types of cancer, definitions of nephrotoxicity, and use of other nephroprotective therapies.
• Chronic obstructive pulmonary disease (COPD). Intravenous, but not nebulized, magnesium may be helpful in acute exacerbations of COPD. Details: Administering magnesium sulfate intravenously, 1.2-2.5 grams over 20 minutes, might be helpful for treating acute exacerbations of COPD (1208,6844,103733). Also, giving magnesium sulfate 2 grams intravenously seems to improve exercise capacity when compared with placebo (89384). A meta-analysis of studies using intravenous magnesium sulfate for COPD exacerbations shows that it reduces hospital admission and mean length of stay and improves dyspnea scores when compared with placebo. Based on the relative risk identified in the included studies, seven patients would need to receive intravenous magnesium to prevent one hospitalization. However, intravenous magnesium sulfate does not change the need for non-invasive ventilation and the available research did not evaluate intensive care unit (ICU) admission (108967). Nebulized magnesium has also been evaluated. In patients experiencing a COPD exacerbation, clinical research shows that administering nebulized magnesium sulfate with albuterol three times at 30-minute intervals does not improve pulmonary function as measured by the forced expiratory volume in 1 second (FEV1) when compared with placebo (89393). Also, a meta-analysis of a small number of low-quality studies shows that nebulized magnesium does not reduce hospital admission or the need for ventilatory support, although it might modestly improve dyspnea scores and reduce ICU admissions, when compared with placebo (108967).
• Cluster headache. It is unclear if a single intravenous dose of magnesium sulfate is beneficial for cluster headaches. Details: Administering magnesium sulfate intravenously, 1 gram over 5 minutes, seems to improve cluster headaches when compared with baseline(1184). The validity of this finding is limited by the lack of a comparator group.
• Cognitive impairment. It is unclear if oral magnesium is beneficial for cognitive impairment. Details: A large observational study in adults with end-stage renal disease on hemodialysis suggests that serum magnesium levels of 20.2-22.3 mg/dL are associated with the lowest odds of mild cognitive impairment, while serum magnesium levels below and above that range of values are associated with increased odds of mild cognitive impairment (111695).
• Coronary heart disease (CHD). It is unclear if magnesium supplementation is beneficial for CHD. Details: Clinical research shows that magnesium oxide 800-1200 mg daily for 3 months reduces platelet-dependent thrombosis by 35% when compared with placebo in patients with CHD (60759). It is unclear if this effect improves clinical outcomes. The effect of magnesium supplementation on coronary artery calcium has also been studied. A meta-analysis of 3 clinical studies in 196 patients with chronic kidney disease (CKD) shows that taking magnesium or increasing the concentration of magnesium in dialysate does not improve coronary artery calcification (CAC) scores when compared with standard therapy. However, magnesium reduced carotid intima-media thickness (111179). Similarly, a large clinical study in patients with CKD shows that taking slow-release magnesium hydroxide (Mablet, Denmark) 360 mg twice daily for 12 months does not slow the progression of CAC scores when compared with placebo (111178). This study may not have been adequately powered to detect a difference between groups.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral magnesium is beneficial for COVID-19. Details: A small clinical study in patients hospitalized with moderate COVID-19 shows that taking magnesium 300 mg daily for the duration of hospitalization reduces the number of patients requiring oxygen therapy but not the duration of hospital stay when compared with placebo (114680).
• Depression. It is unclear if magnesium is beneficial for the treatment or prevention of depression in adults. Details: Some population research shows that dietary intake of elemental magnesium between 76-360 mg daily is associated with a reduced risk of depression, but there was no association with greater amounts of magnesium, and other population research shows no association at any intake level (96480,98289). For treatment of mild to moderate depression, one preliminary clinical study shows that taking magnesium chloride 2 grams orally daily for 6 weeks reduces depression scores by 56% and anxiety scores by about 52% when compared to baseline (96477). The validity of these findings is limited by the lack of a comparator group. However, a small clinical study in adults with recurrent depression shows that taking magnesium aspartate 120 mg daily for 8 weeks, along with fluoxetine, does not improve depression scores when compared with patients taking fluoxetine and placebo (111185). Similarly, a very small crossover clinical study in adults with mild or moderate treatment-resistant depression shows that administering a single dose of IV magnesium sulfate 4 grams does not improve depression scores when compared with an infusion of 5% dextrose (96481). However, scores were evaluated 24 hours post-infusion which may be too soon to detect improvement. Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that elemental magnesium in doses of 100-400 mg is not recommended for adjunctive or monotherapy use in patients with depression (110318).
• Diabetic foot ulcers. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with grade 3 diabetic foot ulcers shows that taking magnesium oxide 250 mg plus vitamin E 400 IU daily for 12 weeks modestly reduces ulcer size when compared with placebo (101436). It is unclear if this effect is due to magnesium, vitamin E, or the combination.
• Exercise-induced muscle soreness. It is unclear if oral magnesium reduces muscle soreness in adults after resistance training. Details: A very small study in healthy adults, ages 19-23, shows that taking magnesium glycinate 350 mg daily for 10 days seems to reduce muscle soreness after bench press exercise when compared with placebo (104399).
• Fetal and premature infant mortality. It is unclear if antenatal intravenous (IV) magnesium sulfate administration reduces the risk of fetal and premature infant mortality. Details: Two meta-analyses of up to 7 clinical studies in patients at risk of preterm birth shows that antenatal IV magnesium sulfate administration does not reduce the risk of fetal or neonatal death when compared with placebo (114675,114681).
• Fibromyalgia. It is unclear if oral magnesium is beneficial for this condition. Details: A small clinical study shows that taking magnesium chloride orally 100 mg once daily for one month reduces mild to moderate, but not severe, stress associated with fibromyalgia when compared with placebo. It also reduces pain levels, but not to a clinically significant extent, and it does not affect sleep, fatigue, or quality of life (108964). Another small clinical study shows that taking magnesium citrate 300 mg daily for 8 weeks improves some symptoms of fibromyalgia, such as number of tender points and depression, when compared to baseline (89385). The validity of this finding is limited by the lack of a comparator group. A small clinical study shows that taking a combination of magnesium hydroxide and malic acid (Super Malic tablets) orally decreases fibromyalgia-related pain and tenderness in some patients when compared with placebo (3262). It is unclear if this effect is due to magnesium, malic acid, or the combination.
• Fractures. Population research suggests that higher intakes of magnesium may reduce fracture risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is associated with a 34% lower odds of fracture when compared with lower magnesium intake (101395).
• Gastric cancer. Population research suggests that higher intakes of magnesium may reduce gastric cancer risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is not associated with a reduced risk for gastric cancer when compared with lower intake (103730).
• Hearing loss. Oral magnesium may prevent and improve hearing loss due to environmental factors or loud noises. Details: Clinical research in healthy military recruits shows that taking magnesium aspartate 167 mg daily for 2 months prevents hearing loss from exposure to loud noises during basic military training when compared with placebo (1205). Also, in patients with acute-onset hearing loss that was not caused by environmental factors, taking magnesium aspartate 167 mg daily for 8 weeks seems to improve hearing loss when compared with placebo (60813).
• Hypertension. Oral magnesium supplementation may modestly reduce blood pressure, although these changes are not likely to be considered clinically significant. Details: Most research shows that taking oral magnesium supplements in daily doses that are at least as high as the Recommended Dietary Allowance (RDA) for adults and up to 1000 mg daily can lower diastolic blood pressure by about 2 mmHg in adults with or without hypertension (1192,1199,9465,15165,18111,96482). Significantly lower doses do not seem to have this effect (1180,1195,1197,8098). The effect of magnesium on systolic blood pressure is conflicting. Two meta-analyses shows that taking magnesium 212-970 mg daily does not lower systolic blood pressure in patients with or without hypertension (15165,115728). However, additional meta-analyses show that taking magnesium 120-970 mg daily can lower systolic blood pressure in a dose-dependent manner by about 2-4 mmHg in patients with or without hypertension (18111,96482). The reasons for these discrepant findings are unclear but may be due to heterogenous methods, including dose and duration among clinical studies. In 2022, the US Food and Drug Administration (FDA) approved a qualified health claim stating that inconsistent and inconclusive evidence suggests that diets with adequate magnesium may reduce the risk of high blood pressure. Products bearing this claim must provide at least 84 mg of magnesium daily, but no more than 350 mg daily (107451).
• Hypokalemia. It is unclear if intravenous or oral magnesium is beneficial for hypokalemia in patients with normal magnesium levels. Details: A preliminary retrospective observational study in patients with hypokalemia and unknown serum magnesium levels has found that administering oral or intravenous magnesium is not associated with improved time to normalization of serum potassium levels when compared with no magnesium treatment (110049). However, hypokalemia with concurrent hypomagnesemia can impede potassium repletion and exacerbate hypokalemia-induced rhythm disturbances. Standard of care in patients with hypokalemia and known hypomagnesemia includes prompt treatment with magnesium (110063).
• Impaired glucose tolerance (prediabetes). It is unclear if oral magnesium is beneficial for prediabetes. Details: Preliminary clinical research in patients with prediabetes shows that taking magnesium oxide 250 mg orally daily for 12 weeks does not improve fasting blood glucose levels, insulin resistance, or glycated hemoglobin (HbA1C) levels when compared with placebo. Taking magnesium also did not affect blood pressure, body weight, triglyceride levels, or low-density lipoprotein cholesterol levels; however, it did modestly improve high-density lipoprotein cholesterol levels (110053).
• Insomnia. Oral magnesium may modestly improve sleep complaints in adults, but evidence is conflicting. Details: A meta-analysis of two small clinical studies in healthy older adults with or without insomnia suggests that taking magnesium reduces the time to fall asleep by an average of 17 minutes when compared with placebo (105917). However, it does not increase the time spent asleep. Also, these findings are limited by imprecision and a high risk of bias. Studies included in the analysis used elemental magnesium 500-729 mg daily (as magnesium oxide) for up to 8 weeks (102458,105917). Another small clinical study in patients with poor sleep quality and low magnesium status shows that taking elemental magnesium 320 mg (as magnesium citrate) in divided doses daily for 7 weeks does not improve sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), when compared with a sodium citrate placebo (102456). Magnesium has also been evaluated in combination with other ingredients. A very small crossover clinical study in patients aged 18-40 years without a sleep disorder shows that taking a combination of magnesium 300 mg, L-tryptophan 1000 mg, glycine 3000 mg, tart cherry 220 mg, and theanine 200 mg for 3 days reduces the time to fall asleep by about 24 minutes, increases total time asleep by about 22 minutes, and improves sleep efficiency, but does not improve the total time in bed or wakefulness after falling asleep when compared with cellulose placebo (111184). Another small crossover clinical study in adults with sleep disturbances shows that taking a combination of magnesium 200 mg and melatonin nightly for 4 weeks improves sleep quality, as measured by the PSQI, reduces the length of time it takes to fall asleep by about 17 minutes, and improves some other measures of sleep, such as sleep efficiency and number of awakenings, when compared with placebo. However, despite these improvements, overall sleep quality was still categorized as poor after the intervention (113670). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous (IV) magnesium sulfate can reduce the risk for intraventricular hemorrhage in neonates. Details: A meta-analysis of clinical research in premature infants shows that if the mother received antenatal intravenous magnesium sulfate, the infant had a non-significant trend toward a reduced risk of intraventricular hemorrhage when compared with infants whose mothers received placebo (103727). This analysis may have been insufficiently powered to detect a difference between groups. Another meta-analysis of up to 6 clinical studies, some of which are included in the previously referenced meta-analysis, in patients at risk of preterm birth shows that maternal antenatal (IV) magnesium sulfate administration does not reduce the risk of intraventricular hemorrhage, but does reduce the risk of severe intraventricular hemorrhage by about 24% when compared with placebo (114681).
• Kidney stones (nephrolithiasis). Taking magnesium orally may prevent the recurrence of kidney stones, although evidence is conflicting. Details: Prophylactic treatment with magnesium hydroxide, 200 mg twice daily for one year, followed by 500 mg daily for another year, might decrease the recurrence rate of calcium stone formation (2007). However, magnesium oxide does not seem to benefit patients considered to be recurrent calcium stone formers when compared with placebo, no treatment, or chlorthalidone (8097,38501,61199). Magnesium oxide 300 mg in combination with vitamin B6 10 mg daily seems to decrease urinary oxalate levels in people with hyperoxaluria who have previously had kidney stones (1201), but it is unclear if this effect translates into a reduced incidence of kidney stones.
• Liver cancer. Increased dietary magnesium intake is linked with a lower risk of liver cancer. Details: Observational research in retired older Americans has found that higher dietary magnesium intake is associated with a 35% lower risk of liver cancer when compared with lower intake. This association was especially strong in persons who were moderate or heavy alcohol users (105080).
• Lung cancer. Supplemental or dietary magnesium intake does not seem to reduce the risk of lung cancer. Details: A large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests there is no association between dietary or supplemental magnesium intake and the risk of lung cancer. However, dietary magnesium seems to play an important yet unclear role in lung cancer prevention when taken as part of the diet with alpha-carotene, vitamin C, vitamin E, lycopene, selenium, lutein, and zeaxanthin (112096).
• Migraine headache. Oral magnesium may help prevent migraine in some adults and children. Also, intravenous magnesium may help treat migraine in adults, but evidence is conflicting. Details: A meta-analysis of 4 low-quality clinical studies, in adults with migraine shows that magnesium 122-600 mg daily for 4-16 weeks modestly reduces migraine frequency and severity when compared with placebo(115730). However, clinical significance is unclear, and the validity of these findings is limited by heterogeneous methods between clinical trials, including type of magnesium formulation and dose, patient population, and duration. In contrast, one small clinical study shows that taking magnesium does not reduce migraine frequency and severity by at least 50% in adults when compared with placebo (10661). Limited evidence suggests that adding oral magnesium to conventional treatment may also be beneficial. A clinical study in adults with migraine living in Iran shows that taking magnesium oxide 250 mg twice daily in addition to sodium valproate 200 mg twice daily for 12 weeks modestly reduces severity and duration of migraine, but not migraine frequency, when compared with taking sodium valproate alone (105915). It is unclear if these improvements would be considered clinically significant. For treatment of migraine, some adults with normal magnesium levels respond to intravenous (IV) magnesium sulfate 1 gram over 5 minutes, but most patients who benefit have low magnesium levels at baseline (1185,6844). Effects of IV magnesium in patients with unknown magnesium levels are conflicting. Some preliminary clinical research shows that magnesium 1-2 grams IV alleviates acute migraine for up to 2 hours, but other research has found no benefit (89388,97493,98285). In children, treatment with magnesium oxide orally 15 mg/kg daily in 3 divided doses for up to 16 weeks reduces the frequency and severity of migraine headaches when compared with placebo (10663). However, adding magnesium sulfate 400 mg orally daily to ibuprofen or acetaminophen does not further reduce migraine severity in children (89396).
• Miscarriage. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing magnesium 450 mg, alpha-lipoic acid, hyaluronic acidvitamin B6, and vitamin D daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to magnesium, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo in the control group.
• Myocardial infarction (MI). Research on the effects of intravenous or oral magnesium after myocardial infarction are conflicting. Details: Administering magnesium intravenously doesn't seem to reduce mortality after an acute MI (8999,13357,13358,13359,13360,19990,60872,61082), although there is some conflicting evidence from a meta-analysis of clinical research that shows that intravenous magnesium sulfate may reduce short-term mortality by 55% when compared with placebo (60795,60895). Clinical research with oral magnesium supplementation has found no benefit (1198,6844).
• Neonatal encephalopathy. Intravenous magnesium may improve short-term outcomes in neonates with encephalopathy. Details: A meta-analysis of clinical research shows that intravenous magnesium may improve short term outcomes of neonatal encephalopathy (hypoxic ischemic encephalopathy, HIE). However, long term outcomes are not affected (90025).
• Nocturnal leg cramps. It is unclear if oral magnesium is helpful for nocturnal leg cramps. Details: Some clinical research in adults with nocturnal leg cramps shows that taking magnesium oxide 865 mg daily at bedtime for 4 weeks does not reduce the frequency of leg cramping episodes when compared with placebo (96478). However, four weeks may be too short a time to see a benefit. In other clinical research, taking oral magnesium oxide monohydrate 226mg daily at bedtime for 60 days reduces the frequency of leg cramps when compared with placebo. This reduction was not seen after 30 days. Magnesium also reduced cramp duration and improved sleep quality, but did not affect pain scores, at 60 days when compared with placebo (106919).
• Nonalcoholic fatty liver disease (NAFLD). Oral magnesium hydroxide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with NAFLD shows that taking magnesium hydroxide 150 mg and L-carnitine 2000 mg daily for 16 weeks does not improve liver stiffness scores when compared with baseline or controls who took placebo for 8 weeks followed by this magnesium and L- carnitine combination for 8 weeks. Taking magnesium and L-carnitine also did not improve levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) when compared to baseline (111177).
• Obesity. Evidence on the use of magnesium for weight loss in obese patients is conflicting; any benefit is likely small at best. Details: A meta-analysis of 7 clinical studies in obese patients shows that taking magnesium reduces body mass index (BMI) by 0.3 when compared with control (103723). Another meta-analysis of 7 studies in obese patients shows that while magnesium supplementation does not reduce weight, it reduces waist circumference by 2 cm when compared with placebo (103729). Interestingly, subgroup analyses did not find that the dose of magnesium or baseline magnesium levels impacted effectiveness. One subgroup analysis found that magnesium supplementation lasting 12 weeks or less seemed to be more beneficial for obesity than supplementation lasting longer than 12 weeks (103723).
• Overall mortality. It is unclear if oral or IV magnesium reduces the risk of overall mortality. Details: A meta-analysis of heterogeneous observational studies has found that increased dietary magnesium intake, but not supplemental magnesium intake, is associated with a modestly reduced risk of overall mortality (105073). A meta-analysis of 3 small, low-quality clinical studies in ICU patients shows that administering IV magnesium 24-30 mmol or as a target-directed dose for 3 days reduces overall mortality when compared with patients who did not receive magnesium (111290). However, some studies included patients with hypomagnesemia; it is unclear if effects would be similar for patients with normal levels of magnesium.
• Osteoarthritis. Population research has not found a link between magnesium intake and osteoarthritis risk. Details: Observational research has found that dietary and supplemental magnesium intake is not associated with the risk of developing osteoarthritis (101395).
• Pain (acute). It is unclear if locally injected or intravenous magnesium is helpful for acute pain. Details: Preliminary clinical research in patients with renal colic shows that intravenous (IV) magnesium sulfate, 50 mg/kg infused over 20 minutes, is as effective as IV morphine sulfate 0.1 mg/kg for controlling acute renal pain at 20 minutes after the dose (107367). Magnesium has also been evaluated in a dental procedure. A single-center clinical study in India in adults with irreversible pulpitis requiring a root canal shows that a local injection of 0.2 mL of 10% magnesium sulfate with lidocaine and epinephrine reduces perioperative pain when compared to lidocaine with epinephrine alone (115729).
• Pain (chronic). Population research suggests that higher intakes of magnesium may modestly reduce the risk for chronic pain. Details: A cross-sectional observational study has found that increased magnesium intake is associated with a 7% to 8% reduced risk for chronic pain. The association was found to be stronger in females than in males (103732).
• Parturition. It is unclear if topical magnesium is beneficial for labor duration. Details: A single-center clinical study in Iranian adults shows that applying 10 mL of a 50% magnesium sulfate solution directly to the cervix during the active phase of labor reduces the time to vaginal delivery by approximately 1.5 hours and improves the childbirth experience, as reported by patients, when compared with placebo. However, clinical significance is unclear (115727).
• Perioperative anxiety. It is unclear if oral magnesium is beneficial for perioperative anxiety. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves anxiety and depression scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Physical performance. Oral magnesium may modestly improve physical performance in otherwise healthy, elderly females. Details: Clinical research in otherwise healthy elderly females shows that taking a magnesium oxide supplement (Easymag, Sanofi-Aventis) 900 mg daily for 12 weeks modestly improves walking speed and chair stand speed in elderly females when compared with no treatment (90026).
• Polycystic ovary syndrome (PCOS). It is unclear if oral magnesium is beneficial for improving metabolic indices in patients with PCOS. Details: Two small clinical studies in patients with PCOS show that taking magnesium oxide orally, 250 mg daily for 8 weeks, does not affect insulin resistance, beta-cell function, lipid levels, or insulin sensitivity when compared with placebo (103725,105887). Other clinical research in patients with PCOS shows that taking magnesium oxide orally, 250 mg daily for 10 weeks, improves subjective measures of quality of life, fatigue, and emotional functioning, but not objective measures such as alopecia, abnormal uterine bleeding, or acne, when compared with placebo (108965). A clinical study using a combination of magnesium 250 mg with vitamin E 400 mg daily for 12 weeks shows a modest reduction in insulin resistance, insulin levels, and triglyceride levels, but not other lipid levels, when compared with placebo (100264). It is unclear if these beneficial effects are due to magnesium, vitamin E, or the combination.
• Postoperative nausea and vomiting (PONV). It is unclear if intravenous (IV) magnesium is beneficial for PONV due to mixed results from clinical research. Details: A meta-analysis of 5 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium sulfate intraoperatively reduces PONV (114676). However, a meta-analysis of 20 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium perioperatively does not reduce the incidence of PONV (114678). A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery reduces the incidence of postoperative vomiting but not postoperative nausea when compared with control (113677). The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied.
• Postoperative recovery. It is unclear if intravenous (IV) magnesium is beneficial for postoperative recovery. Details: A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering IV magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce extubation time, time spent in the post-anesthesia care unit (PACU), or duration of hospital stay when compared with control (113677). Additionally, a meta-analysis of 3 different clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium intraoperatively does not reduce extubation time (114676).
• Postoperative sleep disturbance. It is unclear if oral magnesium is beneficial for postoperative sleep disturbances. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves sleep scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Postoperative sore throat. It is unclear if topical magnesium sulfate is beneficial for reducing sore throat pain after endotracheal intubation. Details: Preliminary clinical research in patients undergoing endotracheal intubation for surgery shows that using a gargle containing magnesium sulfate 20% with lidocaine, 20 minutes before anesthesia induction, is less effective for reducing sore throat pain than a gargle containing dexmedetomidine and lidocaine (112779). The study did not include a comparison to lidocaine alone.
• Pregnancy-related leg cramps. It is unclear if oral magnesium reduces leg cramps during pregnancy; evidence is conflicting. Details: One small clinical study in patients with pregnancy-related leg cramps shows that taking magnesium bisglycinate chelate 300 mg daily for 4 weeks reduces the frequency and intensity of leg cramps when compared with placebo (99318). A smaller clinical study in this population shows that taking a specific mixture of magnesium lactate and citrate (Nycoplus Magnesium) providing elemental magnesium 120 mg in the morning and 240 mg in the evening for 3 weeks reduces the frequency of cramps when compared with placebo (1194). However, not all research agrees. One small clinical study using this same supplement and dose for 2 weeks found no benefit when compared with placebo (17463). It is possible that a 2-week duration of treatment is too short to be beneficial. Finally, a meta-analysis of these studies and one other more recent clinical study shows that taking magnesium does not reduce the frequency or improve the resolution of pregnancy-related leg cramps when compared with placebo (105916). This analysis may not have been adequately powered to detect a difference between treatment groups.
• Pre-procedural sedation. It is unclear if intravenous magnesium is beneficial when administered in addition to other medications used for sedation during surgery. Details: A moderate-sized study of adults aged 65-79 years old undergoing endoscopic retrograde cholangiopancreatography (ERCP) shows that administering a single intravenous bolus of magnesium sulfate 40 mg/kg prior to the procedure reduces intraoperative propofol requirements by about 21% and reduces some peri-procedural adverse events including the incidence of respiratory depression and involuntary movement when compared with control. However, there were no differences in recovery time, hemodynamic parameters, or the incidence of hypotension, bradycardia, perioperative nausea or vomiting, lethargy, or arrythmias (111694). Another moderate-sized study in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce the need for medications used for anesthesia induction, intraoperative maintenance propofol requirements, or recovery time when compared with control. However, magnesium sulfate does seem to reduce the amount of remifentanil required for intraoperative anesthesia maintenance and increase norepinephrine requirements when compared with control (113677).
• Preterm labor. The use of magnesium sulfate to inhibit uterine contractions in preterm labor (tocolysis) is controversial. However, its use for the purpose of fetal neuroprotection for up to 48 hours is supported by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine. Details: Magnesium is given intravenously (IV) during preterm labor in an effort to improve fetal neurological outcomes, such as to reduce the risk of cerebral palsy and motor dysfunction in the infant (60915,60927,60931,61001,97485,103734,103754,114681). The typical dosage of magnesium sulfate is 4 grams infused IV over 10-30 minutes, followed by a maintenance infusion of 1-4 grams/hour for 48 hours or until birth. Use beyond 5-7 days has been associated with hypocalcemia and bone abnormalities in the fetus (15,12590,12594). Some meta-analyses of clinical research suggest that magnesium sulfate is more effective at delaying delivery by 48 hours when compared with oxytocin receptor blockers, nitrates, beta-mimetics, and/or placebo (20263,61021). However, an additional meta-analysis of several clinical studies shows that magnesium sulfate 4 or 6 grams IV is not more effective at delaying preterm labor by 48 hours when compared with nifedipine (115639). The reason for these discrepant findings are unclear, but may be related to the heterogenous methods between clinical trials, including dose and duration.
• Pseudoxanthoma elasticum (PXE). It is unclear if oral magnesium is beneficial for PXE. Details: Preliminary clinical research in patients with PXE shows that taking magnesium oxide 800 mg (500 mg of elemental magnesium) twice daily for one year tends to reduce calcification of elastic skin fibers when compared with placebo, but the effect is not statistically significant (101393). This study was limited by small size and insufficient power to detect smaller effects.
• Restless legs syndrome (RLS). It is unclear if oral magnesium is beneficial for RLS. Details: Some observational research has found that hypomagnesemia is associated with RLS; however, not all research agrees (8096,9472). Preliminary clinical research in adults with RLS who are beginning treatment with pramipexole shows that also taking magnesium oxide 250 mg orally daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052). Other low-quality clinical research in adults with RLS or periodic limb movement during sleep shows that taking magnesium 12.4 mmol orally in the evening for 4-6 weeks decreases movement and increases sleep when compared with baseline (9466). The validity of this finding is limited by the lack of a comparator group.
• Sarcopenia. It is unclear if oral magnesium is beneficial for the prevention or treatment of sarcopenia. Details: Population research in older adults has found that lower dietary intake of magnesium is associated with sarcopenia. However, the effect of magnesium supplementation on sarcopenia prevention or treatment has not been evaluated (110055). Magnesium has been evaluated in combination with other ingredients for treatment of sarcopenia. A small clinical study in elderly individuals with sarcopenia undergoing a diet and exercise program shows that taking a combination supplement containing magnesium 300 mg, carnosine, hydroxymethylbutyrate, lactoferrin, and sodium butyrate daily for 4 months increases muscle mass, as measured by the skeletal muscle index, and improves measures of muscle function, including handgrip muscle strength, chair test, and walking speed, when compared with placebo (114682). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Sepsis. It is unclear if intravenous magnesium is beneficial for sepsis. Details: A very large observational study in patients with sepsis and hypomagnesaemia or normomagnesemia in the intensive care unit (ICU) suggests that administering intravenous magnesium sulfate 2 or 4 grams within 24 hours of admission reduces 28-day all-cause mortality from 25% in patients who did not use magnesium sulfate to 20% in those who were administered magnesium sulfate, regardless of baseline serum magnesium level and other baseline characteristics. Administration of intravenous magnesium sulfate in this population may also reduce ICU mortality by 4%, in-hospital mortality by 3%, and the use of renal replacement therapy by 3% but also seems to increase the length of ICU and hospital stay when compared with patients who did not use magnesium sulfate (113676). The validity of these results is limited by the observational nature of the study.
• Sleep deprivation. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of magnesium 1350 mg, zinc 90 mg, and vitamin B6 31.5 mg for 3 nights at bedtime does not change sleep quality, subjective sleepiness, mood, or fatigue the next day when compared with placebo (113655).
• Stroke. Increased dietary magnesium may decrease stroke risk, and using a magnesium-containing salt substitute may improve neurological performance post-stroke. However, intravenous magnesium has not demonstrated benefit. Details: Most population research has found that increased dietary intake of magnesium is associated with decreased stroke risk and decreased mortality from stroke (9001,9002,90013,90030,90036,92107,103736). In patients who have had a stroke, a preliminary clinical study shows that using a salt substitute providing the Dietary Reference Intake (DRI) of magnesium and potassium for 6 months improves neurological performance when compared with using regular salt (97491). However, intravenous (IV) magnesium does not seem to be beneficial in patients who have had a stroke. Large prospective clinical trials show that IV magnesium given within 12 hours of acute stroke does not reduce mortality or disability in most patients when compared with placebo. However, one subgroup analysis suggested that IV magnesium might benefit patients with lacunar (non-cortical) stroke (13361,90021). IV magnesium also doesn't seem to reduce cardiovascular complications after acute stroke. A secondary analysis of a clinical trial in patients after ischemic and hemorrhagic stroke shows that giving IV magnesium does not reduce serious cardiac adverse events when compared with placebo (104393). Another secondary analysis of this trial shows that giving IV magnesium prior to arrival at the hospital and within 2 hours of a hemorrhagic stroke does not reduce hematoma volume on hospital arrival, hematoma expansion during hospital admission, or functional outcomes at 3 months (108733).
• Subarachnoid hemorrhage. Intravenous magnesium sulfate may reduce the risk of adverse outcomes in people with subarachnoid hemorrhage, but evidence is conflicting. Details: There is mixed evidence regarding the effect of magnesium sulfate in managing aneurysmal subarachnoid hemorrhage. One meta-analysis of clinical research shows that intravenous magnesium sulfate 64-144 mmol/day for 10-18 days reduces the risk of poor outcomes following aneurysmal subarachnoid hemorrhage, including death, vegetative state, or dependency, by 46% when compared with control (60932). Also, meta-analyses of clinical research show that intravenous magnesium reduces the risk of delayed cerebral ischemia by 27% when compared with placebo (60944,89398). However, these results were not confirmed in other meta-analyses (60973,90034).
• Thrombocytopenia. It is unclear if intravenous magnesium sulfate is beneficial in patients with thrombotic thrombocytopenic purpura (TTP). Details: Addition of intravenous magnesium sulfate as a 6-gram loading dose followed by 6 grams infused over 24 hours for 3 days, to standard treatment for TTP does not reduce the time to normalization of the platelet count, the incidence of TTP-related organ dysfunction, or the recurrence rate, when compared with standard treatment alone (112777). This study may have been underpowered to detect a difference.
• Urinary incontinence. Although there has been interest in using oral magnesium for urinary incontinence, there is insufficient reliable information about the clinical effects of magnesium for this purpose. More evidence is needed to rate magnesium for these uses.

(Read more about MAGNESIUM)

EFFECTIVE

• Manganese deficiency. Oral and intravenous manganese can prevent and treat manganese deficiency. Details: Taking manganese orally or intravenously is effective for preventing or treating manganese deficiency (15). However, the incidence of manganese deficiency is not well documented. Long-term home parenteral nutrition should provide no more than 55 mcg daily of manganese for adults or 1 mcg/kg daily (up to 50 mcg) of manganese for children unless clinically indicated (96416,99302). A clinical trial in children aged 8-14 months who are manganese deficient shows that taking manganese in addition to other vitamins and minerals in a 30 mL beverage six days per week for up to 14 months promotes growth when compared with placebo (19348).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal manganese is beneficial in patients with allergic rhinitis. Details: A small clinical study in patients with chronic allergic rhinitis shows that using an isotonic seawater nasal spray enriched with manganese (Sterimar Mn, Laboratori Baldacci) four puffs daily for 5 months, in addition to standard treatment with oral antihistamines, nasal corticosteroids, and nasal decongestants, reduces the number of acute exacerbations by about three when compared with the standard treatment alone (99416). However, the effect of the manganese in this product is unclear since nasal lavage with a plain saline nasal spray also helps in allergic rhinitis.
• Chronic obstructive pulmonary disease (COPD). Intravenous manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated for exacerbation of COPD shows that intravenous supplementation with manganese 0.4 mg, selenium 100 mcg, and zinc 2 mg daily may shorten the number of days spent on mechanical ventilation when compared with placebo (61432). It is unclear if these findings are due to manganese, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral intake of or environmental exposure to manganese decreases the risk of metabolic syndrome. Details: A meta-analysis of 12 observational studies suggests that increased dietary intake of manganese or higher levels of manganese in the serum, whole blood, or urine are not associated with a lower risk of metabolic syndrome when compared with lower manganese intake or laboratory values (112138).
• Obesity. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a specific combination product (7-Keto Naturalean, Enzymatic Therapy, Inc.) containing manganese 500 mcg, 7-oxo-DHEA 100 mg, L-tyrosine 100 mg, asparagus root extract 100 mg, choline bitartrate 50 mg, inositol 50 mg, copper gluconate 500 mcg, and potassium iodide 100 mcg daily for 8 weeks reduces body weight by around 1.5 kg and body mass index (BMI) by around 0.7 kg/m² when compared with placebo (61581).
• Osteoarthritis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with osteoarthritis of the knee and lower back show that taking a specific combination product (Cosamin DS, Nutramax Laboratories) containing manganese ascorbate 228-304 mg (about 31-41 mg of elemental manganese), glucosamine hydrochloride 1500-2000 mg, and chondroitin sulfate 1200-1600 mg daily for 4 months improves pain and ability to do activities of daily living when compared with baseline or placebo (4237,7169). The amount of manganese in the Cosamin DS formulation used in this study is considerably higher than the 1 mg of elemental manganese per 1500 mg of glucosamine hydrochloride in the current formulation. Since numerous studies show glucosamine with chondroitin without manganese might be effective for osteoarthritis, it is not possible to draw conclusions about the effects of manganese alone.
• Osteoporosis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal patients shows that taking manganese 5 mg in combination with elemental calcium 1000 mg, zinc 15 mg, and copper 2.5 mg daily for 2 years reduces spinal bone loss when compared with placebo (1994). Another small clinical study in females with osteopenia shows that taking a specific combination product (Vitrum Osteomag, Unipharm Inc.) containing manganese 1.8 mg, calcium 600 mg, vitamin D (cholecalciferol) 200 IU, magnesium 40 mg, zinc 7.5 mg, copper 1 mg, and boron 250 mcg twice daily for one year improves bone mineral density when compared with no treatment (36840). However, since numerous studies have demonstrated the efficacy of calcium plus vitamin D for osteoporosis, it is not possible to draw conclusions about the effects of manganese alone.
• Premenstrual syndrome (PMS). Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with PMS shows that taking manganese 1.0 mg or 5.6 mg in combination with calcium 587 mg or 1336 mg daily for about 24 weeks improves symptoms of PMS including pain, crying, loneliness, anxiety, restlessness, irritability, mood swings, depression, and tension (2004).
• Wound healing. Topical manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research has found that applying an alginate dressing containing manganese, calcium, and zinc to chronic wounds for 12 weeks is associated with improved wound healing when compared with previous treatments (61327). It is unclear if these findings are due to manganese, other ingredients, or the combination. More evidence is needed to rate manganese for these uses.

(Read more about MANGANESE)

LIKELY EFFECTIVE

• Molybdenum deficiency. Oral molybdenum is beneficial for the prevention and treatment of molybdenum deficiency. Details: Taking or consuming molybdenum can treat or prevent molybdenum deficiency (7135,16478). However, molybdenum deficiency is very rare.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using oral molybdenum for acne, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Asthma. Although there has been interest in using oral molybdenum for asthma, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Atopic dermatitis (eczema). Although there has been interest in using oral molybdenum for atopic dermatitis, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Cancer. Although there has been interest in using oral molybdenum for cancer, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Dental caries. Although there has been interest in using oral molybdenum for dental caries, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Esophageal cancer. It is unclear if oral molybdenum is effective for the prevention of esophageal cancer. Details: Observational studies suggest that low intake of molybdenum might be associated with an increased risk of esophageal cancer (16478,17205). However, it is not known if molybdenum supplements reduce the risk of developing esophageal cancer.
• HIV/AIDS. Although there has been interest in using oral molybdenum for HIV/AIDS, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Iron deficiency anemia. Although there has been interest in using oral molybdenum for iron deficiency anemia, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Liver disease. Although there has been interest in using oral molybdenum for liver disease, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Multiple sclerosis (MS). Although there has been interest in using oral molybdenum for MS, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Osteoporosis. Although there has been interest in using oral molybdenum for osteoporosis, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Sexual desire. Although there has been interest in using oral molybdenum for increasing sexual desire, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Vaginal candidiasis. Although there has been interest in using oral molybdenum for vaginal candidiasis, there is insufficient reliable information about the clinical effects of molybdenum for this purpose.
• Wilson disease. Although there has been interest in using oral molybdenum for Wilson disease, there is insufficient reliable information about the clinical effects of molybdenum for this purpose. More information is needed to rate molybdenum for these uses.

(Read more about MOLYBDENUM)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Actinic keratoses. It is unclear if oral or topical niacinamide is beneficial for reducing actinic keratoses. Research results are conflicting. Details: A large clinical trial in healthy Australian adults with actinic keratoses shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the number of actinic keratoses by 13% when compared with placebo. The difference between the 2 groups was observed as early as 3 months after starting niacinamide (93362). Additionally, a small clinical study in healthy, older Australian adults with actinic keratoses shows that taking niacinamide (Nature's Own, Virginia) 500 mg once or twice daily for 4 months reduces the total number of actinic keratoses by 29% and 35%, respectively, when compared with placebo (93365). However, a large clinical trial in solid organ transplant recipients in Australia shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 6 months does not reduce the number of actinic keratoses when compared with placebo (113559). Also, a small clinical trial in kidney transplant recipients with actinic keratoses and a history of nonmelanoma skin cancer shows that taking niacinamide 500 mg twice daily for 12 months does not decrease the number of actinic keratoses when compared with placebo (113682). The study may have been inadequately powered to detect a difference between groups. Two small clinical studies conducted in Brazil in elderly adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days or applying a cream containing niacinamide 5% twice daily for 56 days does not reduce the number of actinic keratoses when compared with placebo (107714,113684). Most studies were conducted in countries with high year-round ultraviolet radiation exposure, such as Australia and Brazil; results may not be readily extrapolated to populations in other geographic regions.
• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560). A moderate-sized clinical study in adults with mild atopic dermatitis (AD) shows that applying a specific niacinamide containing body emollient (Bioderma Atoderm PP Baume, Bioderma Cosmetics Trading Co., Ltd.) 250 grams weekly, applied twice daily for 28 days with or without pre-cleansing with a specific niacinamide containing gel wash (Atoderm Intensive Gel Moussant, Bioderma Cosmetics Trading Co., Ltd.), improves AD severity, itching, trans-epidermal water loss, skin water content, and dermatological quality of life when compared with a control emollient and water-only skin cleansing. Additionally, using both the niacinamide containing emollient and cleansing gel improves trans-epidermal water loss and skin water content sooner when compared with niacin containing emollient only (113681). However, the study may have been inadequately powered and too short in duration to detect additional differences between the 2 niacinamide groups.
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was first administered intravenously, providing niacinamide 200 mg, inosine 400 mg, riboflavin 40 mg, and succinate 2000 mg daily for 10 days, followed by an oral formulation providing niacinamide 100 mg, inosine 200 mg, riboflavin 20 mg, and succinate 1200 mg daily for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves melasma. Details: A small clinical study in female adults with melasma shows that applying a specific niacinamide 10% serum (Bo leda, Shanghai Ruizhi Medical Technology Co., Ltd) twice daily after skin cleansing for 16 weeks improves melasma area and severity, pigmented spots, and skin texture when compared with control. Both groups were also treated with salicylic acid 30% throughout the study (113683). Topical niacinamide has also been studied in patients with hyperpigmentation. A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Nonmelanoma skin cancer. It is unclear if oral or topical niacinamide reduces the risk of nonmelanoma skin cancer. Details: A meta-analysis of 4 clinical trials in adults shows that taking niacinamide 500 mg twice daily for 4-12 months does not reduce the risk of nonmelanoma skin cancer when compared with placebo. This analysis also shows no effect of niacinamide on the risk of basal cell carcinoma and squamous cell carcinoma (113560). However, there was high heterogeneity across the studies due to differences in patient populations and mixed results overall. Two studies included in the analysis show that niacinamide, including a specific niacinamide product (Nature's Own, Virginia), reduces the risk of nonmelanoma skin cancer in immunocompetent adults when compared with placebo (93362,93365). One was a large clinical trial that shows taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the rate of new nonmelanoma skin cancer by 23%, but it does not reduce the risk of not recurrent nonmelanoma skin cancers, when compared with placebo. However, this reduced risk appears to be transient. Follow up 6 months after niacinamide was discontinued showed no difference between groups (93362). The 2 other studies analyzed, including a large trial using a specific niacinamide product (Insolar, Blackmores), were conducted in transplant recipients showed no reduced risk of nonmelanoma skin cancer when compared with placebo (113560,113559). All studies were conducted in Australia; it is unclear if these results can be extrapolated to other geographical regions with different background ultraviolet radiation exposure and skin cancer rates. A previous meta-analysis of 5 clinical studies shows taking niacinamide 500-1000 mg daily for 6-12 months or applying niacinamide 1% twice daily for 6 months decreases the rate of basal cell and cutaneous squamous cell carcinomas by 54% and 52%, respectively when compared with control. Niacinamide was only administered topically in 1 of the 5 studies and only reduced risk of cutaneous squamous cell carcinoma (110497).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

EFFECTIVE

• Pantothenic acid deficiency. Taking pantothenic acid 5-10 mg daily is effective for treating and preventing pantothenic acid deficiency (15).

POSSIBLY INEFFECTIVE

• Radiation dermatitis. Topical dexpanthenol does not seem to be beneficial for preventing or treating radiation dermatitis. Details: Applying dexpanthenol, an analog of pantothenic acid, twice daily to areas of irradiated skin does not seem to reduce erythema, desquamation, itching, or pain following radiation treatment (7192). Also, applying dexpanthenol 0.5% cream (Bepanthen, Hoffmann LaRoche ) daily during radiation therapy and for 2 weeks after completing radiation therapy is less effective than methylprednisolone aceponate 0.1% cream (Advantan) at reducing radiation-induced skin irritation (67779).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral or topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In adults with mild to moderate acne, clinical research shows that taking a specific supplement (Pantothen, Avilan Marketing LLC) providing pantothenic acid 1.1 grams twice daily in addition to other B vitamins for 12 weeks modestly reduces total and non-inflammatory lesion counts when compared with placebo (105188). Also, in adolescents or young adults with mild to moderate acne, preliminary clinical research shows that topical application with a gel containing D-panthenol 4%, hydrogen peroxide 4%, and salicylic acid 0.5% once daily for 60 days modestly reduces acne lesions when compared with baseline (105189). The validity of this finding is limited by the lack of a comparator group.
• Alcoholism. Although there is interest in using oral pantothenic acid for improving recovery from alcoholism, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral pantothenic acid for allergic rhinitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Alopecia areata. Pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with diffuse hair loss shows that intramuscular administration of dexpanthenol 250 mg and biotin 5 mg once weekly for 6 weeks reduces hair fall count at weeks 1 and 8, but only increases hair density at week 1, when compared to baseline (111366). The validity of these findings is limited by the study's small size, short duration, and lack of comparator group.
• Anxiety. Although there is interest in using oral pantothenic acid for anxiety, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Asthma. Although there is interest in using oral pantothenic acid for asthma, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Athletic performance. Although there is interest in using oral pantothenic acid to improve athletic performance, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Oral pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some small outdated clinical studies in children diagnosed with hyperkinesis suggest that taking calcium pantothenate 1.2 grams, alone or in combination with niacinamide, ascorbic acid, and pyridoxine, does not improve symptoms of hyperactivity when compared with placebo (3351,9957). It is unclear what effects pantothenic may have, if any, in children with a modern diagnosis of ADHD.
• Atopic dermatitis (eczema). It is unclear if topical pantothenic acid is beneficial in infants or children with atopic dermatitis. Details: One preliminary clinical trial in infants and children with stable mild atopic dermatitis shows that topical application of an emollient containing panthenol (Bepanthen, SensiDaily, Bayer Consumer Care AG) for 3 months is as effective as a reference emollient for reducing symptoms and preventing a flare. However, the efficacy of the reference emollient (Stelatopia Emollient Cream, Mustela; Laboratoires Expanscience) is unclear based on available preliminary clinical research (105190).
• Autism spectrum disorder. Although there is interest in using oral pantothenic acid for autism spectrum disorder, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Carpal tunnel syndrome. Although there is interest in using oral pantothenic acid for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Cheilitis. Topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study in adults with mild-to-moderate cheilitis shows that applying a specific lip care product containing pantothenic acid and bisabolol (Eucerin Aquaphor SOS lip care) at least twice daily for 8 weeks reduces cheilitis severity scores by 5 points on a 12 point scale assessing erythema, scale, fissure, and inflammation when compared to baseline (114549). The validity of this finding is limited by the small study size and lack of a comparator group. Additionally, it is unclear if this effect is due to pantothenic acid, bisabolol, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral pantothenic acid for CFS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Conjunctivitis. Although there is interest in using oral or ocular pantothenic acid for conjunctivitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Constipation. It is unclear if oral or intramuscular dexpanthenol is beneficial for constipation. Details: Preliminary clinical research shows that administering dexpanthenol (Bepanthene), an analog of pantothenic acid, 400 mg orally or 500 mg intramuscularly daily for 5 days decreases the time to a bowel movement in patients with chronic or occasional constipation when compared with an oral placebo (67822).
• Dandruff. Although there is interest in using oral or topical pantothenic acid for dandruff, is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Depression. Although there is interest in using oral pantothenic acid for depression, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Diaper rash. Although there is interest in using topical pantothenic acid for diaper rash, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry eye. Although there is interest in using ocular pantothenic acid for dry eye, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry skin. It is unclear if topical dexpanthenol is beneficial for patients with dry skin. Details: A small, open-label study in healthy adults with dry skin shows that cleansing the skin with a dexpanthenol-containing liquid cleanser (DCLC, Bepanthen SensiControl Daily Gentle Body Wash) daily for 4 weeks increases stratum corneum hydration by 17% without affecting skin barrier function, pH, or microbiome when compared to baseline (111262). The validity of these findings is limited by the lack of blinding and a comparator group.
• Epilepsy. Although there is interest in using oral pantothenic acid for epilepsy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Eye trauma. It is unclear if ocular dexpanthenol is beneficial for eye trauma. Details: Some preliminary clinical research shows that using eyedrops containing dexpanthenol 5%, a derivative of pantothenic acid, two drops four times daily for 28 days following surgery for retinal detachment reduces eye pain and discomfort when compared with placebo drops (67783). However, using a specific dexpanthenol 5% ointment (Bepanthen) does not seem to improve corneal epithelial wound healing following phototherapeutic keratectomy when compared with placebo (67801).
• Heart failure. Although there is interest in using oral pantothenic acid for heart failure, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Herpes zoster (shingles). Although there is interest in using oral or topical pantothenic acid for shingles, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Insomnia. Although there is interest in using oral pantothenic acid for insomnia, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Laser skin resurfacing. It is unclear if topical dexpanthenol or pantothenic acid can reduce adverse effects after laser skin resurfacing procedures. Details: A preliminary clinical study shows that use of a dexpanthenol-containing ointment (Bepanthen Wound Healing Ointment, Bayer) once daily modestly reduces the diameter of lesions up to 3 days after fractional carbon dioxide laser resurfacing when compared with petroleum jelly (105743). Also, applying a specific cream (Cicaplast Baume B5 cream, L'Oreal) containing panthenol 5%, madecassoside, copper, zinc, and manganese to one side of the face for 28 days reduces decrustation time by approximately one day when compared with a control emollient. Redness and swelling were lower at 3 days, but there was no difference in pain and burning (105742). It is unclear if these effects are due to pantothenic acid, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral pantothenic acid for MS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Muscular dystrophy. Although there is interest in using oral pantothenic acid for muscular dystrophy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Nipple fissures. Although there is interest in using topical pantothenic acid for nipple fissures, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Obesity. Although there is interest in using oral pantothenic acid for obesity, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Pain (chronic). It is unclear if oral or topical pantothenic acid is beneficial for the management of various forms of chronic pain. Details: Although there is interest in using oral or topical pantothenic acid for various forms of chronic pain, including neuropathy and arthritis, there is limited information available about the clinical effects of pantothenic acid for this purpose. One review of preliminary clinical research found that calcium pantothenate does not reduce symptoms of arthritis in patients with rheumatoid arthritis or osteoarthritis (10433).
• Parkinson disease. Although there is interest in using oral pantothenic acid for Parkinson disease, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical pantothenic acid for poison ivy dermatitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Postoperative pain. It is unclear if oral pantothenic acid is beneficial for postoperative pain. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily reduces pain when compared with placebo. Postoperative pain was modestly reduced at 1, 3, 7, and 14 days after surgery (105191).
• Postoperative sore throat. It is unclear if pantothenic acid lozenges are beneficial for postoperative sore throat. Details: Preliminary clinical research shows that taking two lozenges containing dexpanthenol, an analog of pantothenic acid, 200 mg 30 minutes prior to general anesthesia reduces the incidence and severity of postoperative sore throat when compared with a benzydamine hydrochloride or placebo spray (67792).
• Pregnancy-related leg cramps. Although there is interest in using oral pantothenic acid for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral pantothenic acid for PMS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Respiratory tract infections. Although there is interest in using oral pantothenic acid for respiratory tract infections, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Rhinosinusitis. It is unclear if nasal dexpanthenol is beneficial for rhinosinusitis. Details: Preliminary clinical research shows that using a nasal spray (MarPlus) containing dexpanthenol, an analog of pantothenic acid, on the first, second, fourth, and sixth week after endoscopic sinus surgery reduces nasal discharge, but not other symptoms associated with chronic rhinosinusitis, when compared with saline nasal spray (67808).
• Skin irritation. It is unclear if topical dexpanthenol is beneficial for preventing or treating skin irritation due to sodium lauryl sulfate. Details: Preliminary clinical research shows that applying dexpanthenol (Bepanthol Handbalsam), an analog of pantothenic acid, twice daily for 26 days does not prevent sodium lauryl sulfate-induced skin irritation (67785). However, dexpanthenol may be effective for treating skin irritation caused by sodium lauryl sulfate. Use of an ointment containing dexpanthenol 1% to 5% twice daily for up to 30 days following skin exposure to sodium lauryl sulfate seems to reduce skin water loss, skin roughness, and skin inflammation when compared to control (67802,67806).
• Ulcerative colitis. Although there is interest in using oral or rectal pantothenic acid for ulcerative colitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Vertigo. Although there is interest in using oral pantothenic acid for vertigo, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Wound healing. Preliminary clinical research suggests that oral dexpanthenol might be beneficial for wound healing. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily improves wound healing when compared with placebo. Depending on the type of surgery, wound healing occurred in 2.3-2.9 times as many patients within 7 days of surgery, and in 13% to 35% more patients within 14 days, when compared with placebo (105191). More evidence is needed to rate pantothenic acid for these uses.

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EFFECTIVE

• Bowel preparation. Oral sodium phosphate is effective for cleansing the colon in preparation for colonoscopy; however, it is unclear whether sodium phosphate is as effective as polyethylene glycol (PEG) solution. Some products are approved by the US Food and Drug Administration (FDA) for this use. However, due to the potential for kidney damage, sodium phosphate is not recommended as first-line therapy. Details: Sodium phosphate tablets (OsmoPrep, Salix Pharmaceuticals; Visicol, Salix Pharmaceuticals) are FDA-approved for cleansing the colon in preparation for colonoscopy. Clinical research shows that using the OsmoPrep formulation can achieve an "excellent" or "good" response rate, which is defined as having 90% of the mucosa visible with only some or little suctioning needed, in 94% to 97% of patients (88133). Similarly, using the specific product Visicol has been shown to achieve an excellent or good response rate in 82% to 86% of patients (94674). Non-FDA-approved sodium phosphate products have also been investigated. One such product (Fleet Phospho-soda, C. B. Fleet Co.) has been shown to achieve adequate bowel cleansing in 23% to 89% of patients (93846,94673). Another sodium phosphate tablet preparation (Clicolon tablets, Korea Pharma Co.) has been shown to achieve adequate bowel cleansing in 63% to 93% of patients (93848,93850,93853). Excellent or good bowel cleansing was found in 98.6% of patients using a 32-tablet regimen of other sodium phosphate tablets (Quiklean, Universal Integrated Corporation) (107008). Reasons for the differences in the percentage of patients who achieve adequate bowel cleansing with the same sodium phosphate product may relate to the method used to analyze bowel cleansing, differences in diet followed during bowel cleansing, and demographic factors (93846,93848,93850,93853). Various preparations (OsmoPrep, Salix Pharmaceuticals; Visicol, Salix Pharmaceuticals; Clicolon tablets, Korea Pharma Co.; Quiklean, Universal Integrated Corporation) have been used which contain 1.102 grams of sodium phosphate monobasic monohydrate and 0.398 grams of sodium phosphate dibasic anhydrous. These products have been taken as 3-4 tablets with 8 ounces of water every 15 minutes for a total of 20 tablets the evening before colonoscopy, and 3-4 tablets with 8 ounces of water every 15 minutes for a total of 12-20 tablets the morning of a colonoscopy (88133,93848,93850,94674,107008). Also, sodium phosphate solution (Fleet Phospho-soda, C. B. Fleet Co.) containing sodium hydrogen phosphate 24.4 grams and disodium phosphate dodecahydrate 10.8 grams has also been used the morning and evening before the procedure (93846). Numerous publications have compared the bowel cleansing activity of sodium phosphate with PEG solution. When given as a split-overnight dosage, sodium phosphate is about as effective as PEG solutions in achieving adequate bowel cleansing. However, when day-before dosage is used, PEG is more effective for bowel cleansing than sodium phosphate (93861,93862,107008). Sodium phosphate and PEG may have different effectiveness depending on the colonic site assessed. When only trials assessing descending colon cleansing are considered, sodium phosphate is found to work similarly to PEG solutions. When only studies assessing ascending colon cleansing are considered, PEG is more effective for bowel cleansing than sodium phosphate (93861). Also, a large clinical trial in outpatients scheduled for non-sedated colonoscopy shows that receiving PEG resulted in an easier insertion and a less painful colonoscopy when compared with receiving sodium phosphate (104473). However, in patients with chronic constipation, sodium phosphate seems to be preferable. A meta-analysis of three small clinical studies in adults with chronic constipation shows that using sodium phosphate has an 87% greater chance of a successful bowel preparation when compared with using PEG (104472). Sodium phosphate is not recommended as first-line therapy for bowel preparation prior to colonoscopy due to the potential for kidney damage (93863,94672). In fact, one sodium phosphate preparation (Fleet Phospho-soda, C. B. Fleet Co.) that was previously approved as an over-the-counter supplement for bowel preparation in the US was withdrawn from the market for this indication in December 2008 due to concerns for phosphate-induced kidney disease (94672). Of the sodium phosphate products that are still approved by the FDA, current guidelines recommend that these products not be used for bowel cleansing in patients with kidney disease, pre-existing electrolyte disturbances, congestive heart failure, cirrhosis, ascites, or inflammatory bowel disease. Guidelines also recommend that caution should be used if these products are prescribed for patients who are elderly, hypertensive, or taking certain classes of drugs (94672). For small bowel preparation for endoscopy, a meta-analysis suggests that sodium phosphate is no more effective than fasting alone (93860).
• Hypophosphatemia. Oral or intravenous phosphate salts are effective for the prevention or treatment of hypophosphatemia. Some products are approved by the US Food and Drug Administration (FDA) for this use. Details: Taking sodium or potassium phosphate orally is effective for preventing and treating hypophosphatemia (15). Treating hypophosphatemia with oral phosphates requires monitoring of serum electrolyte levels to determine appropriate dosing (15). The FDA-approved intravenous (IV) product is also used for the correction of hypophosphatemia (8302,8303,88135). FDA-approved intravenous (IV) sodium phosphate or potassium phosphate 15-30 mmol is typically given over 2-12 hours. Higher doses have been used if needed to increase efficacy (8302,8303,88135).

LIKELY EFFECTIVE

• Constipation. Oral or rectal sodium phosphate is approved by the US Food and Drug Administration (FDA) as an ingredient in over-the-counter (OTC) products to treat constipation. Details: Sodium phosphate is an FDA-permitted ingredient of oral and rectal OTC products intended for the treatment of constipation (88107).
• Dyspepsia. Oral aluminum phosphate and calcium phosphate are approved by the US Food and Drug Administration (FDA) as ingredients in over-the-counter (OTC) antacids. Details: Aluminum phosphate and calcium phosphate are FDA-permitted ingredients of oral OTC products intended for use as antacids (88107).
• Hypercalcemia. Although other treatments are preferred, oral non-calcium phosphate salts are beneficial for treatment of mild to moderate hypercalcemia. Details: Taking phosphate salts (except calcium phosphate) orally is effective for treating mild to moderate hypercalcemia (88144,88145). Treating hypercalcemia with oral phosphates requires monitoring of serum electrolyte levels to determine appropriate dosing (15); other agents are now preferred (6479). Intravenous phosphates should be avoided due to the risk of calcium precipitation in vital organs (metastatic calcification) (15,88144,88145).

POSSIBLY EFFECTIVE

• Kidney stones (nephrolithiasis). Oral potassium phosphate seems to be beneficial for prevention of kidney stones in individuals with hypercalciuria. Details: Taking potassium phosphate orally may help prevent calcium oxalate kidney stones in patients with hypercalciuria (6470). Clinical research in adults with absorptive hypercalciuria and at high risk for stone formation shows that taking a specific slow-release potassium phosphate product (Uro-Phos-K, Mission Pharmacal), providing phosphate 620 mg orally twice daily for 4 days, reduces urinary calcium excretion by 35% to 40% (2208,2209). Potassium and sodium phosphate salts providing 1200-1500 mg of elemental phosphate daily have been used (2209,6470).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. The evidence is mixed as to whether oral sodium phosphate improves cycling or running performance. Most research suggests that oral calcium phosphate and potassium phosphate are not beneficial. Details: Clinical research shows that taking calcium phosphate or potassium phosphate orally does not improve running or cycling performance (2499,9300,8301). Evidence for the use of sodium phosphate to improve cycling performance is mixed. One very small clinical study shows that taking sodium phosphate as tribasic sodium phosphate dodecahydrate for 6 days before a 10-mile cycling trial increases mean power output by about 10% and decreases the time needed to complete the trial by 3% in trained male cyclists (88150). Other small clinical trials in trained cyclists show that taking the same form of sodium phosphate as 50 mg/kg of fat-free mass in four divided doses daily for 6 days modestly improves work, power output, and peak oxygen uptake and reduces heart rate during high-intensity cycling exercise when compared to baseline (93857,93858,93859,107007). However, conflicting research shows that taking a similar dosage of this form of sodium phosphate does not improve time trial performance, work accomplished relative to energy expenditure, power output, or oxygen uptake in trained cyclists (93855,93856,107007). Sodium phosphate has also been evaluated for improving running performance, with mixed findings. Two small clinical trials in female athletes show that tribasic sodium phosphate dodecahydrate 50 mg/kg of fat-free mass taken in four divided doses daily for 6 days moderately improves repeated sprint times when compared with placebo (93843,93844). However, taking the same dosage does not significantly improve sprint times in male athletes (93849). Also, sodium phosphate does not seem to improve endurance or aerobic capacity in treadmill tests (8301,93854). Reasons for the discrepancies regarding the effects of sodium phosphate on athletic performance are not entirely clear, but likely relate to the very small number of participants in the included trials.
• Diabetic ketoacidosis. Potassium phosphate infusion is not recommended as first-line therapy for adults with diabetic ketoacidosis. Details: Clinical research shows that intravenous infusion of potassium phosphate 8.5 mmol/hour (approximately 6 grams of phosphate over 24 hours) along with potassium chloride 12.5 mEq/hour provides no benefit over potassium chloride alone in adults with diabetic ketoacidosis (88149). Guidelines for the treatment of diabetic ketoacidosis in the both the US and UK do not recommend phosphate replacement for most patients. However, it may be considered in specific cases, such as cardiac dysfunction, anemia, respiratory depression, and serum phosphate concentrations below 1 mg/dL (107349,107350A).
• Osteoporosis. Calcium phosphate seems to be beneficial for bone density improvement; however, it does not seem to be more beneficial than calcium carbonate. Details: In postmenopausal adults with osteoporosis and low phosphate intakes, taking calcium 1800 mg daily as tricalcium phosphate for 12 months improves lumbar spine and hip densities. However, it is no more effective than taking the same amount of calcium as calcium carbonate (93847). The calcium products were used in combination subcutaneous teriparatide and oral vitamin D (cholecalciferol) 1000 IU daily.
• Refeeding syndrome. It is unclear if intravenous potassium phosphate or sodium phosphate is beneficial for prevention of refeeding syndrome. Details: Preliminary clinical research shows that giving intravenous sodium and potassium phosphates, 50 mmol (1.56 grams) phosphate over 24 hours, prevents the refeeding syndrome seen when restarting adequate nutrition after severe malnutrition or starvation when compared with historical controls (88148). More evidence is needed to rate phosphate salts for these uses.

(Read more about PHOSPHATE SALTS)

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Anxiety. It is unclear if oral riboflavin is beneficial for anxiety. Details: A large observational cohort study in adults suggests that a dietary riboflavin intake above 2.1 mg daily is associated with a 5% lower prevalence of anxiety when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg daily. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Cognitive function. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a combination supplement containing riboflavin 70 mg, other group B vitamins, ginkgo leaf, and bacopa daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population suggests that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Depression. It is unclear if oral riboflavin is beneficial for depression. Details: A large cross-sectional study in middle-aged adults suggests that dietary riboflavin intake above 2.1 mg daily is associated with an 8% lower prevalence of depression when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Diabetes. It is unclear if oral riboflavin reduces the risk of developing gestational diabetes. Details: A large prospective cohort study in pregnant adults shows that supplementation with riboflavin at doses over 2.5 mg daily during the first trimester and 2.1 mg daily in the second trimester is associated with a lower risk of developing gestational diabetes when compared with riboflavin doses under 1.1 mg daily. However, this effect was not found for dietary intake of riboflavin, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo. This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan suggests that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

LIKELY EFFECTIVE

• Selenium deficiency. Oral selenium is effective for the treatment and prevention of selenium deficiency. Details: Selenium supplementation is effective for reversing symptoms of selenium deficiency, as well as for preventing the development of selenium deficiency (4844,90357).

POSSIBLY EFFECTIVE

• Autoimmune thyroiditis. Oral selenium seems to improve autoimmune thyroiditis in adults, but the evidence of benefit in children is conflicting. Details: A meta-analysis of mostly small, low-quality clinical and observational studies in children and adults with Hashimoto thyroiditis shows that taking selenium 83 mcg, selenomethionine 50 mcg or 200 mcg, or selenium 83 mcg with myoinositol 600 mg daily for 3 to 6 months reduces thyroid peroxidase antibody (TPOAb) levels and thyroglobulin antibody (TgAb) levels after 6 months of treatment when compared with baseline or placebo. However, there was no change in thyroid antibody levels at 3 months, suggesting a longer duration of 6 months is needed to sufficiently reduce serum antibody levels. Additionally, subgroup analysis suggests that patients with higher baseline thyroid antibody levels might benefit more from selenium supplementation compared to those with lower baseline thyroid antibody levels (113645). The validity of these effects is limited by high heterogeneity between baseline thyroid antibody levels amongst the included studies. Additionally, clinical research in adults with thyroiditis shows that taking selenium up to 200 mcg daily in combination with levothyroxine reduces TPOAbs by about 6% to 30% more than placebo after 3-12 months of treatment (9797,17510,17511,17512,17513,17515,17516,97943,104424). Selenium also seems to improve measures of quality of life such as feelings of well-being and mood (17515). Doses under 200 mcg daily might not be as effective (17512); selenomethionine might be more effective than sodium selenite (97943). Some research shows that selenium might be more effective in patients with more severe disease activity and less effective in patients with only moderate disease activity (9797,17513,17515). Also, selenium might not reduce TPOAbs in patients newly diagnosed with thyroiditis not receiving concurrent levothyroxine (97943). There is no reliable evidence about the effect of selenium on thyroid function or thyroid morphology. Despite positive findings in adults, most clinical research in children suggests that taking selenium 50-200 mcg daily for 3-12 months does not significantly improve TPOAb, TgAb, or thyroid echogenicity (17514,90362).
• Kashin-Beck disease. Selenium seems to help prevent Kashin-Beck disease, but does not improve symptoms in patients with existing disease. Details: A meta-analysis of prospective studies conducted in China shows that adding salt enriched with selenium to the diet of healthy children for up to 4 years reduces the odds of developing Kashin-Beck disease by 84% when compared with the use of iodine salt. Additionally, in children with Kashin-Beck disease, adding salt enriched with selenium to the diet might help heal metaphyseal lesions (97945). However, selenium does not seem to improve symptoms in those with existing disease. A clinical trial in children with Kashin-Beck disease shows that selenium supplementation does not improve joint pain or mobility when compared with placebo (55941).
• Pre-eclampsia. Oral selenium might reduce the risk of pre-eclampsia in pregnant patients. Details: A meta-analysis of three low-quality clinical trials in pregnant patients shows that taking selenium 60-100 mcg daily for up to 6 months reduces the risk of pre-eclampsia by 72% when compared with placebo. Additionally, a meta-analysis of population research has found that the risk of pre-eclampsia is higher in pregnant patients with low selenium levels. Selenium levels were about 6.5 mcg/L lower in those who developed pre-eclampsia compared with those who did not (97946).

POSSIBLY INEFFECTIVE

• Asthma. Oral selenium does not seem to improve asthma symptoms. Details: Epidemiological research has found that plasma selenium concentration is not associated with asthma (74422). Also, clinical research in patients with asthma shows that taking selenium 100 mcg daily for 14-24 weeks does not improve symptoms, lung function, use of rescue inhalers, or quality of life when compared with placebo (74490,74387).
• Atopic dermatitis (eczema). Oral selenium-enriched yeast does not seem to improve eczema symptoms. Details: A small clinical study in patients with eczema shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not improve symptom severity when compared with placebo (74456).
• Cardiovascular disease (CVD). Most research shows that oral selenium does not reduce the risk of CVD. Details: Meta-analyses of clinical trials in patients with and without risk factors for CVD show that taking selenium alone or with other supplements for up to 8 years does not reduce the risk of CVD mortality or fatal and non-fatal CVD events (90360,97078). When reported, patients in these studies all had adequate plasma selenium levels at baseline (90360).
• Colorectal cancer. Oral selenium does not seem to prevent cancer of the colon and rectum. Details: Epidemiological research has found no association between serum concentrations of selenium and the risk of developing colorectal cancer (74321,97085). Also, meta-analyses of clinical research, as well as individual clinical trials, show that taking selenium 100-200 mcg daily, alone or in combination with other vitamins and minerals, does not reduce the risk of colorectal cancer when compared with control (16707,34676,90361,97092).
• Dyslipidemia. Most research shows that oral selenium supplementation does not improve cholesterol levels. Details: A meta-analysis of 11 clinical studies in adults with dyslipidemia shows that taking selenium 50-300 mcg daily for 8-24 weeks does not increase high-density lipoprotein (HDL) cholesterol levels or decrease total or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. Taking selenium might modestly improve triglyceride levels, but this improvement is unlikely to be considered clinically significant (99662). Another meta-analysis of 21 mostly small, low-quality clinical studies, some of which were included in the prior meta-analysis, shows that taking various forms of selenium may modestly decrease total cholesterol levels, but does not improve triglycerides, LDL, or HDL cholesterol when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which assessed various selenium dosing regimens and enrolled healthy patients or those with various cardiovascular and non-cardiovascular conditions.
• Low birth weight. Oral or intravenous selenium supplementation does not improve outcomes in low birth weight infants. Details: Low selenium levels have been documented in low birth weight infants. However, selenium supplementation, orally or intravenously, does not appear to improve most outcomes in low birth weight infants. Clinical research shows that administering selenium, either as 7-10 mcg/kg daily parenterally or 5 mcg/kg daily orally, does not improve oxygen dependency or reduce the risk of death in low birth weight infants when compared with placebo. However, supplementation decreases the incidence of sepsis by up to 33% (74288,97083).
• Lung cancer. Oral selenium does not reduce lung cancer risk in most patients. Details: While a large cohort study suggests that increased dietary intake of selenium is associated with a lower risk of lung cancer, supplemental selenium does not appear to have the same effect. Additionally, a meta-analysis of three large clinical trials of over 20,000 patients, including patients with resected stage I non-small-cell lung cancer, shows that taking selenium 200-400 mcg daily for up to 5 years does not reduce the risk of lung cancer when compared with control (92912,97092). A secondary analysis of one of these studies found that selenium supplementation might reduce lung cancer risk in people with selenium levels below 105 ng/mL (9798). Also, a large study in healthy Chinese patients shows no benefit of using selenium in combination with other nutrients for over 5 years when compared with control (34539).
• Nonmelanoma skin cancer. Oral selenium does not reduce the risk of nonmelanoma skin cancer and has been linked to increased risk in some patients. Details: Epidemiological research has found that higher selenium intake is not associated with a reduced risk of nonmelanoma skin cancer (97085). Furthermore, clinical research shows that taking selenium orally 200 mcg daily does not reduce the risk of basal cell carcinoma when compared with control (2664,10687). In addition, some evidence shows that daily selenium supplementation might increase the risk of squamous cell carcinoma and total non-melanoma skin cancer (10687).
• Prostate cancer. Oral selenium does not seem to reduce prostate cancer risk. Details: Population studies have found that higher serum or toenail selenium levels are associated with a decreased risk of prostate cancer (8734,8735,8736,92911,10263). However, clinical research does not support this finding. A meta-analysis of 5 large clinical trials of over 20,000 patients shows that selenium 200-400 mcg daily for up to 5 years does not reduce the risk of prostate cancer when compared with control (97092). A 7-14 year follow-up study of one of these trials shows there was still no reduction of prostate cancer risk (17688). Selenium has also shown no benefit when used in combination with other supplements. In a large-scale clinical study (SU.VI.MAX), taking selenium 100 mcg in combination with vitamin C, vitamin E, beta-carotene, and zinc did not reduce prostate cancer risk (14135). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and prostate cancer risk, stating that it is highly unlikely that selenium supplements reduce the risk of prostate cancer (102373).
• Psoriasis. Oral selenium does not seem to reduce psoriasis severity. Details: Clinical research shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not reduce the severity of psoriasis when compared with placebo (74460).
• Sepsis. Intravenous selenium does not appear to improve outcomes in septic adults. Details: Earlier meta-analyses of clinical trials in septic adults showed that parenteral administration of selenium, along with routine nutritional interventions, reduces the risk of mortality by 11% to 27% when compared with placebo (90347,92907,92910). However, a more recent meta-analysis, which includes a large, multi-center study of over 1000 cases, shows that parenteral selenium does not reduce mortality in septic adults at 28, 90, or 180 days when compared with placebo (99658). Enteral selenium with other nutrients has been studied for sepsis in children. Clinical research in children shows that taking enteral selenium 40-400 mcg daily with zinc, glutamine, and IV metoclopramide is no more effective than whey protein for reducing time to first episode of nosocomial infection or sepsis in the intensive care unit (ICU). However, the selenium combination treatment might reduce the risk for sepsis in immunocompromised pediatric patients (86095).

LIKELY INEFFECTIVE

• Bladder cancer. Despite promising initial research, oral selenium does not seem to prevent the development, recurrence, or progression of bladder cancer. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and bladder cancer risk based on two small studies. However, the FDA determined that it is highly uncertain that selenium supplements reduce the risk of bladder cancer (102373). Since then, most available research has not confirmed an association between selenium and bladder cancer risk. Epidemiological and clinical research suggests that selenium supplementation is not associated with a reduced risk of bladder cancer and does not prevent recurrence, slow progression, or improve overall survival in patients with bladder cancer (97085). One moderate-sized clinical study shows that taking selenium 200 mcg daily with or without vitamin E 200-400 IU daily for 7 years does not prevent bladder cancer in older males (90352). Another small clinical study shows that taking selenium yeast 200 mcg daily for 3 years does not prevent the recurrence of bladder cancer when compared with placebo in patients that had undergone a transurethral resection for non-invasive bladder cancer (97087). These findings are supported by another moderate-sized clinical study in adults with non-invasive bladder cancer which shows that taking selenium 200 mcg with or without vitamin E 200 IU daily for a median of 1.5 years does not prevent recurrence, slow bladder cancer progression, or improve overall survival when compared with placebo over a median follow-up period of 5.5 years (114116).
• Diabetes. Increased intake of selenium, either in the diet or as a supplement, is associated with an increased risk for developing type 2 diabetes. It is unclear if oral selenium is beneficial in patients with type 2 diabetes. Details: Observational research suggests that high serum selenium levels, high dietary selenium intake, and selenium supplementation are each linked to an increased risk of developing diabetes (97091,99661). Consuming more than the recommended dietary allowance (RDA) of selenium daily is associated with an increased risk of developing diabetes when compared with consuming less than the RDA (99661). However, the effect of short-term selenium supplementation in patients with diabetes is unclear. Two meta-analyses of clinical studies in adults with various health conditions show that taking supplemental selenium as selenium yeast, sodium selenite, or selenomethionine in doses of 100-960 mcg daily for 4 to 96 weeks reduces serum and fasting insulin levels and increases measures of insulin sensitivity but does not lower fasting blood glucose or glycated hemoglobin (HbA1c) when compared with placebo. Additionally, selenium supplementation does not reduce total or low-density lipoprotein (LDL) cholesterol or triglycerides but may improve high-density lipoprotein (HDL) cholesterol (110593). However, the validity of the findings from the meta-analyses is limited by the heterogeneity of the included studies, which enrolled healthy adults and patients with diabetes, gestational diabetes, cardiovascular disease, heart failure, obesity, polycystic ovary syndrome (PCOS), cancer, and Alzheimer disease.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral selenium reduces the risk of cognitive decline in older adults. Details: A cross-sectional study in elderly Americans has found that lower blood levels of selenium are associated with a greater risk of poor cognitive scores when compared with higher levels (104426).
• Alcohol-related liver disease. Although there is interest in using oral selenium for alcohol-related liver disease, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral selenium for allergic rhinitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Alzheimer disease. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with Alzheimer disease shows that taking selenium 200 mcg with a probiotic daily for 12 weeks improves cognitive function as measured by the Mini-Mental State Examination (MMSE) when compared with placebo. However, when selenium 200 mcg was taken alone, no improvement in cognitive function over placebo was found, so it is unclear whether the improvements in cognitive function are due to the probiotics or the combination of ingredients (113659). Another very small clinical study in adults with mild-to-moderate Alzheimer disease shows that taking supranutritional selenium 30 mg daily for 12 weeks does not change cognitive measures, cerebrospinal fluid biomarkers, or neuroimaging biomarkers of Alzheimer disease progression when compared with placebo or nutritional selenium doses. However, the control group showed worsened diffusivity imaging markers indicative of deterioration of axonal structure integrity, while no such decline was noted in supranutritional selenium neuroimaging (113660).
• Androgenic alopecia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing selenium, hydrolyzed collagen, taurine, cysteine, methionine, and iron (GFM Oral, Cantabria Labs) daily for 12 weeks daily along with conventional therapy, consisting primarily of finasteride or minoxidil, improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to selenium, other ingredients, or the combination.
• Arsenic poisoning. It is unclear if oral selenized yeast is beneficial for patients that were exposed to high levels of arsenic in the environment. Details: A small clinical study in Chinese people environmentally exposed to high concentrations of arsenic shows that taking selenized yeast providing 100-200 mcg of selenium daily for 14 months decreases the concentration of arsenic and symptoms of toxicity when compared with placebo (7831).
• Benign prostatic hyperplasia (BPH). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in men with BPH shows that taking selenium 240 mcg plus silymarin 570 mg daily for 6 months reduces lower urinary tract symptoms when compared with placebo (88155). Another clinical study in men with BPH shows that taking tamsulosin 0.4 mg plus a specific product containing selenium, saw palmetto, and lycopene (Profluss, Ayanda AS) daily for one year improves lower urinary tract symptoms and urodynamic parameters when compared with tamsulosin-alone (90354). It is unclear if these effects are due to selenium, other ingredients, or the combinations.
• Burns. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with burns on 46% of their body surface suggest that taking a combination of copper 2.5-3.1 mg, selenium 315-380 mcg, and zinc 26.2-31.4 mg daily reduces the incidence of hospital-acquired pneumonia, but does not seem to improve wound healing, hospital stay, or mortality, when compared with placebo (6520,74382). Another very small clinical study in burn patients suggests that taking copper 4.5 mg, selenium 190 mcg, and zinc 40 mg daily reduces the duration of hospitalization, but does not have an effect on recovery and wound treatment requirements, when compared with standard dietary doses of these nutrients (74485).
• Cancer. Selenium does not seem to reduce the risk of cancer in most people, but it might be beneficial in those with low selenium levels and in men. Details: Meta-analyses of clinical research and several clinical studies show that selenium supplementation does not reduce the incidence of cancer or cancer-related mortality when compared with control (14109,34538,74414,97078,97092). In clinical studies, selenium 100-400 mcg taken daily for 2-7.5 years with or without additional antioxidants did not reduce overall cancer risk (14109,34538,74414). However, most evidence did not assess baseline selenium levels. Other evidence suggests that selenium may have a benefit in men and in people with lower selenium levels. Epidemiological research has found that selenium intake at the recommended daily allowance (RDA) of 55 mcg or higher is associated with decreased cancer incidence and cancer mortality, especially in men (97085,103164). However, this research suggests that cancer risk was also influenced by age, body mass index, and smoking status (103164). Some clinical research also suggests that taking selenium might decrease the risk of cancer, when only men are considered (14109). An older meta-analysis of clinical research suggests that selenium was particularly beneficial in patients with lower baseline levels of selenium and in patients at high risk for cancer (90350). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim stating that consumption of selenium may produce anticarcinogenic effects and reduce the risk for certain forms of cancer. However, the FDA has determined that the evidence is limited and inconclusive (102374).
• Cataracts. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An ancillary clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for around 5.6 years does not reduce the risk of age-related cataracts in men when compared with placebo (92902).
• Cervical dysplasia. It is unclear if oral selenized yeast is beneficial for patients with cervical dysplasia of mild severity. Details: A small clinical study in patients with cervical intraepithelial neoplasia grade 1 (CIN1) shows that taking yeast containing selenium 200 mcg daily for 6 months resulted in regression of CIN1 in 88% of participants, compared with regression in only 55% of participants taking placebo (97944).
• Chemotherapy-induced nephrotoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-induced nephrotoxicity when compared with a placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral selenium for CFS, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Cirrhosis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with primary biliary cirrhosis shows that taking a combination of selenium, vitamin A, vitamin C, vitamin E, methionine, and coenzyme Q10 for 12 weeks does not improve fatigue or any other disease-related symptoms when compared with placebo (34494).
• Cisplatin-associated ototoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-associated hearing loss when compared with placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Colorectal adenoma. It is unclear if oral selenium prevents recurrence of adenomas in the colon and rectum. Details: A large clinical study in patients with a history of colorectal adenomas shows that taking a specific selenium supplement (SelenoExcell High Selenium Yeast, Cypress Systems) 200 mcg daily for about 33 months does not reduce adenoma recurrence when compared with placebo. However, in a sub-group of patients with advanced adenomas at baseline, selenium seems to reduce risk of recurrence by 18% when compared with placebo (97091). Some research also shows that taking selenium in combination with zinc, and vitamins A, C, and E reduces adenoma recurrence when compared with placebo (92903). It is not clear any benefit is due to selenium, other nutrients, or the combination.
• Congestive heart failure (CHF). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in elderly patients with heart failure living in Sweden shows that taking a specific selenium supplement (SelenoPrecise, Pharma Nord) 200 mcg plus a specific coenzyme Q10 supplement (Bio-Quinon, Pharma Nord) 200 mg daily for about 4 years reduces the risk of cardiovascular mortality by about 55% when compared with placebo (92904). The risk reduction seems to be most pronounced in patients with lower selenium levels (97906). Furthermore, at 10- and 12-year follow-ups, cardiovascular mortality in the treatment group continued to be 49% and 41% lower, respectively, when compared with placebo (96546,97466). It is unclear if the benefit can be attributed to selenium, coenzyme Q10, or the combination.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral selenized yeast is beneficial for patients undergoing CABG surgery. Details: A small clinical study in patients undergoing CABG surgery shows that taking selenium 200 mcg daily as selenium yeast for 4 weeks improves glycemic control, lipid levels, and markers of inflammation when compared with placebo (103163). It is not known whether this influences the outcome or complications of CABG surgery.
• Critical illness (trauma). Evidence on the use of intravenous selenium in critically ill patients is conflicting. Details: The most recent meta-analysis of 24 clinical trials in critically ill patients shows that intravenous selenium does not improve survival over 6 months, shorten hospital stay, or reduce intensive care unit (ICU) stay, infectious complications, development of acute kidney failure, or duration of mechanical ventilation when compared with control. Also, length of ICU stay was increased by about 4.5-fold in patients receiving selenium in doses of more than 1000 mcg daily (109086). These findings are similar to those of a meta-analysis of 21 randomized controlled trials in critically ill patients from 2016 which shows that intravenous selenium given alone or with other nutrients does not improve mortality, duration of hospital stay, or kidney function when compared with control (97090). However, another recent meta-analysis of 19 clinical trials in critically ill patients shows that intravenous selenium reduces total mortality by 14% and shortens hospital stay by about 2 days when compared with control, without affecting ICU stay, duration of mechanical ventilation, or mortality over 28 days (101345). The reasons for these discrepancies are not clear and do not seem to be completely explained by differences in doses or durations of selenium (109086). Some reasons for the discrepancies might include differing analytic methods used in meta-analyses, as well as variations in forms of selenium, concomitant treatments, and specific patient populations. One sub-analysis shows that, when limited to randomized controlled trials examining the effect of selenium supplementation in patients sustaining traumatic injury, the odds of mortality was reduced by about 26% and duration of ICU and hospital stay were modestly reduced. There was no effect on infectious complications (109090).
• Dementia. It is unclear if oral selenium prevents dementia or reduces symptoms. Details: Observational research has found that taking selenium 200 mcg daily for 4 years does not decrease the incidence of dementia in men 60 years or older (93570). However, the follow-up period may not have been long enough to reliably detect the effect of selenium on the development of dementia. Also, the screening method used to detect new cases of dementia may have failed to identify individuals presenting with only the initial symptomatic stages of the disease (93570,93571).
• Depression. It is unclear if oral selenium is beneficial for the treatment of prevention of depression. Details: A meta-analysis of observational research has found no difference in serum levels of selenium between patients with or without depression. In addition, serum levels of selenium do not correlate with depression scores (109091). A meta-analysis of clinical research shows that selenium supplementation, usually 100-200 mcg daily, modestly reduces symptoms of depression; however, at least one of the three studies included in this meta-analysis investigated the effects of selenium in patients with postpartum depression, specifically (109091). These meta-analyses are limited by the quality of included research and the small number of available studies.
• Diabetic nephropathy. It is unclear if oral selenium alleviates diabetic nephropathy symptoms. Details: A small clinical study in patients with diabetic nephropathy shows that taking selenium (Nature Made) 200 mcg daily for 12 weeks does not improve kidney markers such as blood urea nitrogen or serum creatinine when compared with placebo (97084).
• Dilated cardiomyopathy. There is limited evidence on the oral use of selenium in patients with Keshan disease and peripartum cardiomyopathy. Details: Observational research in patients with a specific type of dilated cardiomyopathy called Keshan disease and congestive heart failure has found that selenium supplementation is associated with a 61% decreased risk of cardiac death when compared with no supplementation (101346). A small clinical study in patients with peripartum cardiomyopathy and selenium deficiency shows that taking selenium 200 mcg daily for 3 months does not seem to improve heart failure symptoms or left ventricle systolic function, or prevent death, when compared with no treatment (104420).
• Esophageal cancer. Limited research suggests that oral selenium does not reduce esophageal cancer risk. Details: Low quality clinical research suggests that taking selenium supplements alone or with other vitamins does not decrease the risk of esophageal cancer when compared with control (4679,12185).
• Gastric cancer. Oral selenium has only been evaluated in combination with other ingredients and in a specific patient population; its effect when used alone and in other populations is unclear. Details: Population research in Chinese patients has found that high levels of selenium are associated with lower risk of gastric cancer and cancer mortality (97948). However, clinical research does not agree. A large clinical study in patients residing in China shows that taking selenium 37.5 mcg in combination with vitamin C 250 mg and vitamin E 100 IU twice daily for about 7.3 years does not reduce the risk of developing gastric cancer or precancerous gastric lesions when compared with placebo. This combination treatment was not associated with reduced gastric cancer incidence or mortality at the 14-year follow-up of this study (14447,51470). Another clinical study in healthy Chinese adults also shows that taking a combination of selenium 50 mcg, vitamin E 30 mg, and beta-carotene 15 mg daily for 5.2 years does not reduce the risk of gastric cancer when compared with control (4679). It is unclear if these findings are generalizable to populations in geographic locations other than China.
• Graves' ophthalmopathy. It is unclear if oral selenium is beneficial for Graves' ophthalmopathy. Details: A small clinical trial in adults with Graves' ophthalmopathy shows that taking selenium 100 mcg twice daily for 6 months is modestly beneficial for reducing disease activity, based on signs and symptoms including pain, swelling, and redness, when compared with placebo (109085).
• Hepatitis C. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with hepatitis C shows that taking a combination of selenium 200 mcg, vitamin C 500 mcg, and vitamin E 945 IU daily for 6 months does not have an effect on levels of alanine aminotransferase or viral load when compared with placebo (74377).
• HIV/AIDS. It is unclear if oral selenium improves outcomes in patients with HIV. Details: Clinical trials in HIV-positive men and women, most receiving anti-retroviral therapy (ART), shows that taking selenium 200 mcg daily for up to 2 years can reduce HIV-1 viral load, increase CD4 cell counts, and lower the risk of hospitalizations when compared with placebo (15266,74314). However, not all research agrees. Two small clinical trials in HIV-positive patients taking ART shows that taking selenium 100-200 mcg daily for 6-12 months does not reduce the risk for opportunistic infections and does not increase CD4 counts when compared with control (7830,104417). Furthermore, selenium does not seem to benefit patients that are not receiving conventional ART. A large clinical study in HIV-infected pregnant patients in Tanzania with poor access to ART shows that taking selenium 200 mcg daily with prenatal vitamins until 6 months after delivery, does not improve progression of HIV nor pregnancy outcomes when compared with no selenium supplementation (74419). Another large clinical study in HIV-infected and ART-naïve patients in Botswana shows that taking selenium 200 mcg daily for 24 months does not slow HIV progression when compared with placebo (92905).
• Hypertension. It is unclear if oral selenium improves blood pressure. Some evidence suggests selenium supplementation may slightly increase systolic blood pressure. Details: A meta-analysis of 5 small clinical studies in adults with various health conditions shows that taking selenium or selenium yeast 100-200 mcg/day for 6-12 weeks may increase systolic blood pressure by about 2 mmHg but does not impact diastolic blood pressure when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with preeclampsia, gestational diabetes, obesity, or heart failure. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
• Hyperthyroidism. It is unclear if oral selenium alleviates symptoms in patients with Graves' disease. Details: A small clinical study in patients with Graves' hyperthyroidism shows that taking sodium selenite 300 mcg daily in addition to treatment with methimazole for 24 weeks does not affect symptoms or recurrence rates when compared with placebo plus methimazole (97089). Oral selenium has also been studied in combination with other supplements. A small preliminary clinical trial in patients with newly diagnosed Graves' disease and low levels of selenium and vitamin D shows that taking selenium 100 mcg daily for 180 days along with vitamin D as cholecalciferol 7000 IU weekly for 270 days, in addition to methimazole, modestly reduces levels of serum free thyroxine and improves quality of life when compared with methimazole alone. However, taking selenium and vitamin D did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral selenium improves thyroid hormone balance in elderly individuals, pregnant patients, or patients with subclinical hypothyroidism. In patients with iodine deficiency, selenium supplementation may be harmful. Details: Low selenium levels or selenium deficiency seems to reduce conversion of thyroxine (T4) to triiodothyronine (T3). However, clinical research in healthy elderly patients is conflicting. Although one study shows that taking selenium 100 mcg daily for 3 months increases conversion of T4 to T3 when compared with placebo (17508), a larger study shows that taking selenium 100-300 mcg daily for 6 months does not impact conversion of T4 to T3 when compared with placebo (17509). Additionally, taking selenium can worsen hypothyroidism in people with iodine deficiency. People who are iodine- and selenium-deficient should not receive selenium supplements without concomitant iodine. In these individuals, selenium increases conversion of T4 to T3, but the thyroid gland lacks iodine to synthesize more T4 (1664,14563,14564,14565,17508). Selenium does not have a significant effect on thyroid function when iodine intake is adequate (1664,4844). In pregnant patients with hypothyroidism, clinical research shows that taking selenium does not reduce complications such as pre-eclampsia or preterm birth. However, selenium might improve postpartum thyroid function and decrease the risk of postpartum thyroiditis (17507). Also, taking selenium 200 mcg daily during pregnancy seems to reduce the risk of developing postpartum thyroid dysfunction and permanent hypothyroidism by 41% and 42%, respectively, when compared with placebo in euthyroid pregnant patients who are positive for thyroid peroxidase antibodies (74391). Selenium supplementation has also been studied for subclinical hypothyroidism. Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking selenium 83 mcg daily and myo-inositol 600 mg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared with baseline. Selenium and myo-inositol supplementation also reduced patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to selenium, myo-inositol, or the combination.
• Influenza. Although there is interest in using oral selenium for influenza, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Kidney failure. It is unclear if oral selenium is beneficial for improving lipid parameters in patients on hemodialysis. Details: Selenium levels may be low in patients undergoing chronic hemodialysis, and supplementation might be needed (1805,11053). However, clinical research in patients on hemodialysis shows that taking selenium daily for 3 months does not improve the lipid profile when compared with taking placebo (109095).
• Lichen planus. It is unclear if topical or oral selenium alleviates oral lichen planus symptoms. Details: A small clinical study in patients with oral lichen planus shows that applying a selenium hydrogel (selenomethionine 14 mcg/gram) twice daily for 6 weeks seems to significantly reduce pain at a 12 week follow-up, but not immediately after use, when compared with applying topical corticosteroids and antifungal agents 2-4 times daily. Taking oral selenium 200 mcg twice daily for 6 weeks seems to be no different than the topical corticosteroids and antifungal treatment at both time points (104422).
• Liver cancer. It is unclear if oral selenium reduces liver cancer risk. Details: Preliminary clinical research in China suggest that taking selenium 200 mcg daily for 2-5 years can reduce the incidence of liver cancer when compared with control (74389). The benefit of selenium on prevention of liver cancer in Western countries is unknown.
• Lymphedema. It is unclear if oral selenium reduces lymphedema complications. Details: Preliminary clinical research in patients with secondary lymphedema after breast cancer surgery shows that taking a sodium selenite solution 1000 mcg daily for 1 week followed by 300 mcg daily for 2 weeks and then 200 mcg daily for a total of 15 weeks might reduce recurrence of erysipelas, a type of bacterial skin infection, when compared with placebo (15334).
• Male infertility. It is unclear if oral selenium, used alone or in combination with other antioxidants, improves pregnancy or live birth rates for couples with idiopathic male infertility. Details: Meta-analyses of 2-3 clinical trials in males with infertility show that taking selenium, alone or in combination with other antioxidants, for 12-26 weeks modestly improves sperm count and motility, but does not improve sperm morphology, when compared with placebo. Pregnancy rates and live birth rates were only studied in one clinical trial each, with no statistical evidence of benefit (109094,111459). However, the included studies may have been inadequately powered to detect a difference between groups. Studies included in the analysis used selenium 26-200 mcg daily for 3-26 weeks, either alone or in combination with vitamin A 1 mg, vitamin C 10 mg, and vitamin E 15 mg; vitamin E 400 IU and folic acid 5 mg; lycopene 6 mg, vitamin E 400 IU, vitamin C 100 mg, zinc 25 mg, folate 0.5 mg, and garlic 1000 mg; or N-acetyl-cysteine 600 mg (74526,74493,102968,109094,111459). Selenium has also been evaluated in combination with other ingredients. A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing selenium 50 mcg, vitamin B12, L-carnitine, acetyl L-carnitine, citric acid, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus, AltaSigma) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. However, improvements in sperm morphology were lacking. Furthermore, patients with more severe varicocele seem to benefit most (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to selenium, other ingredients, or the combination.
• Mercury toxicity. It is unclear if oral selenium improves clearance of mercury and reduces symptoms of toxicity. Details: A small clinical trial in Chinese adults environmentally exposed to high concentrations of mercury shows that taking selenium-enriched yeast, containing selenium 100 mcg, daily for 3 months increases urinary excretion of mercury when compared with control (90351).
• Muscular dystrophy. There is limited evidence on the oral use of selenium in Duchenne muscular dystrophy. Details: Preliminary clinical research suggests that supplementation with sodium selenite 1 mg daily for 6 months does not improve disease activity in patients with muscular dystrophy (74455).
• Obesity. It is unclear if oral selenium is beneficial for weight reduction. Details: A small clinical study in adults with obesity shows that taking selenium 240 mcg daily and following a low-calorie diet for 3 months does not reduce body weight when compared with following a low-calorie diet alone (104416). Additionally, a very small clinical study in adults with overweight or obesity shows that taking L-selenomethionine 200 mcg and zinc gluconate 25 mg once daily for 8 weeks does not improve body mass index (BMI), total body fat, or fat free mass when compared with placebo (111448).
• Oral mucositis. It is unclear if oral selenium is beneficial for reducing oral mucositis in patients undergoing radiotherapy. Details: A small clinical study in patients with head and neck cancers shows that taking selenium 200 mcg twice daily for the duration of radiation therapy does not seem to reduce the incidence or severity of oral mucositis when compared with placebo (104421). It is unclear if other doses or routes of administration might be beneficial.
• Osteoarthritis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis shows that taking a specific selenium-containing combination supplement (Selenium-ACE) does not improve most clinical symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral selenium reduces ovarian cancer risk. Details: Epidemiological research has found that there is no association between dietary selenium intake and the risk of developing ovarian cancer (74342).
• Overall mortality. Although oral selenium does not seem to reduce overall mortality risk in most patients, it might have benefit in patients with low nutrient intake. Details: Meta-analyses of clinical research show that selenium supplementation, alone or in combination with other micronutrients, does not reduce all-cause mortality when compared with placebo (15305,90360,97078). Selenium might also not be beneficial when used in combination with non-nutrient supplements. An additional large clinical study in elderly patients in Sweden shows that taking selenium 200 mcg daily plus coenzyme Q10 100 mg twice daily for around 5 years does not reduce the risk of all-cause mortality when compared with placebo. The baseline selenium status of these patients is unclear (92904). Despite these results, some evidence suggests that selenium used with other nutrients might have benefit in patients with low nutrient intake. In a large clinical study, selenium in combination with zinc, vitamin C, vitamin E, and beta-carotene lowered all-cause mortality risk in men, but not women, when compared with control (14109). Researchers speculate that this result occurred because men have a lower intake of dietary antioxidants than women. Another large clinical study in Chinese patients with chronically low nutrient intake shows that taking selenium with beta-carotene and vitamin E decreases stroke mortality, cancer mortality, and total mortality when compared with control (2673).
• Pancreatic cancer. It is unclear if oral selenium reduces pancreatic cancer risk. Details: Some epidemiological research has found that increased selenium intake is associated with a 34% lower risk of pancreatic cancer (97093). However, other observational research has found no association (101342).
• Pancreatitis. Although there is interest in using oral selenium for pancreatitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Periodontitis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing selenium 30 mcg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, vitamin C, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal measures such as bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Polycystic ovary syndrome (PCOS). It is unclear if oral selenium is beneficial for PCOS. Details: Most available research addressing the effects of selenium on the hormonal, metabolic, and reproductive symptoms associated with PCOS is conflicting. Meta-analyses of small clinical studies and a small clinical study in adults with PCOS show that taking selenium 200 mcg daily for 8-12 weeks might reduce total testosterone and dehydroepiandrosterone (DHEA) levels but does not seem to improve other hormone levels when compared with placebo (109096,113653,113654,113657). Additionally, a small clinical study in patients with PCOS shows that taking selenium yeast or selenium (Nature Made) 200 mcg daily for 8 weeks reduces the severity of alopecia, acne, and hirsutism when compared with placebo (109096). Research is conflicting whether selenium improves lipid profiles, glycemic indices, insulin metabolism, or anthropometric measures (109096,110596,113642,113654,113657). The effect of selenium on pregnancy outcomes in patients with PCOS who are undergoing or candidates for in vitro fertilization (IVF) is unclear. A small clinical study in patients with PCOS shows that taking selenium (Nature Made) 200 mcg daily for 8 weeks results in a significantly higher pregnancy rate of 19%, compared with 3% in those taking placebo (109096). However, another very small clinical study of the same population and dosing regimen shows that selenium does not improve IVF outcomes including pregnancy rate, endometrial thickness, number of oocytes retrieved, fertilization rate, or number of embryos when compared with placebo (113640). Selenium has also been studied in combination with other ingredients. A small clinical study in adults with PCOS shows that taking selenium 200 mcg daily for 12 weeks, along with a combination probiotic product, modestly improves subjective scores of depression, anxiety, and stress when compared with placebo. Taking this combination also modestly reduces total testosterone levels and subjective ratings of hirsutism when compared with placebo (99659). It is unclear if these effects are due to selenium, the probiotic, or the combination.
• Postoperative recovery. It is unclear if intravenous sodium selenite reduces morbidity and mortality in cardiac surgery patients. Details: A very large clinical study in adults undergoing high-risk cardiac surgery with cardiopulmonary bypass or cardioplegic arrest shows that administering intravenous high-dose sodium selenite 2000 mcg/L perioperatively, 2000 mcg/L immediately postoperatively, and then 1000 mcg/L daily in the intensive care unit (ICU) for up to 10 days does not increase the number of days alive or the number of days without persistent organ dysfunction over 30 days after surgery when compared with placebo. Additionally, intravenous sodium selenite does not reduce 30-day or 6-month mortality, intensive care unit (ICU) or hospital length of stay, or hospital readmission rates when compared with placebo (113651).
• Postpartum depression. It is unclear if oral selenium is beneficial for postpartum depression. Details: A meta-analysis of two observational studies has found that a high selenium intake is associated with a modestly reduced risk of postpartum depression. The effect of selenium supplementation on symptoms of postpartum depression is unclear. One moderate-sized clinical trial included in this publication shows that taking selenium reduces symptoms of postpartum depression (109091).
• Pregnancy-induced hypertension. It is unclear if oral selenium reduces the development of hypertension during pregnancy. Details: A small clinical study in pregnant patients shows that drinking a dietary liquid containing selenium 100 mcg daily for 6-8 weeks seems to decrease the incidence of pregnancy-induced hypertension when compared with placebo (74481).
• Premature rupture of membranes (PROM). It is unclear if oral selenium during pregnancy prevents PROM. Details: One clinical trial shows that taking selenium 100 mcg daily from the first trimester of pregnancy until delivery significantly reduces the incidence of PROM to 13%, compared to 34% with placebo (109097).
• Radiation-induced diarrhea. It is unclear if oral selenium reduces diarrhea in patients receiving radiation therapy for cancer. Details: A small clinical study in patients with cervical or endometrial cancer shows that taking selenium 500 mcg on days of radiation therapy and 300 mcg on days without radiation therapy reduces the incidence of radiation-induced diarrhea to 20.5%, compared to 44.5% in the control group not taking selenium. This benefit appears to be more pronounced in patients receiving a larger (>1302 mL) planning target volume of radiation (90355).
• Rheumatoid arthritis (RA). It is unclear if oral selenium reduces RA symptoms. Details: A small clinical study in patients with RA suggests that taking selenized yeast, providing selenium 200 mcg, daily for 90 days does not improve objective measures of RA when compared with placebo. However, there might be small improvements in quality of life measures (9763). Another small clinical study in Iranian patients with moderate to severe RA shows that taking selenium 200 mcg twice daily for 12 weeks in addition to standard treatment reduces patient-reported disease activity, difficulty in performing activities of daily living, and pain severity but does not change the number of tender or swollen joints, erythrocyte sedimentation rate, or disease activity as measured by Disease Activity Score of 28 Joints (DAS28) when compared with placebo (113648).
• Schizophrenia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with schizophrenia shows that taking a combination of selenium (Nature Made) 200 mcg and a combination probiotic mixture (LactoCare, Zisttakhmir Company) daily for 12 weeks modestly improves general positive and negative symptoms of schizophrenia, but not positive or negative scores, when compared with placebo. There were also modest improvements in levels of high-sensitivity C-reactive protein (CRP), fasting glucose, insulin resistance, and insulin sensitivity, but not lipid parameters (109087).
• Seborrheic dermatitis. It is unclear if topical selenium disulfide shampoo is beneficial for seborrheic dermatitis. Details: A very large observational study in adults with dandruff or seborrheic dermatitis suggests that applying selenium disulfide-based shampoo 2-3 times weekly for 4 weeks improves scalp condition and reduces flaking, erythema, and irritation when compared to baseline (113652). The validity of the results is limited by the observational nature of the study and lack of comparator group. A small clinical study in adults with moderate-to-severe seborrheic dermatitis shows that applying selenium disulfide-based 1% shampoo to the scalp once weekly for 8 weeks after a 2-week treatment with corticosteroid and salicylic acid combination therapy reduces relapse rate, erythema, pruritis, adherent dandruff, and total dandruff but does not improve non-adherent dandruff when compared with a placebo shampoo (113646).
• Statin-induced myopathy. Small clinical studies suggest that oral selenium may not improve symptoms of myopathy in patients taking statins. Details: Small clinical studies in patients with statin-induced myopathy suggests that taking selenium (SelenoPrecise, Pharma Nord) 200 mcg daily with or without coenzyme Q10 for 3 months does not improve myopathy symptoms when compared with placebo (92908,92909).
• Stroke. It is unclear if intravenous selenium improves neurological outcomes following a stroke. Details: A small clinical trial in patients with a recent first ischemic stroke shows that intravenous sodium selenite pentahydrate (Selenase, Biosyn, Arzenitmittel GmbH) 2000 mcg after admission and then 1000 mcg daily for 5 days modestly improves some, but not all, measures of neurological deficits when compared with placebo (109088). Another small clinical trial in patients with a recent ischemic stroke shows that the same intervention improves some neurological outcome measures on day 7 or at an earlier discharge, but benefits were not maintained at 3 months (109093). The effects of oral selenium on neurological outcomes following a stroke have not been investigated.
• Subarachnoid hemorrhage. Intravenous selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in adults with aneurysmal subarachnoid hemorrhage shows that administering intravenous selenium 800 mcg and acetylcysteine 1000 mg twice daily starting within 24 hours of admission for 14 days reduces total days spent in the intensive care unit but does not change neurological outcomes, time to reach target sedation, duration of hospital stay, or need for tracheostomy when compared with intravenous placebo. Additionally, no change in radiological outcomes including hematoma or perihematomal edema volume, midline shifting, or the incidence of radiological vasospasm, angioplasty for vasospasm, or hydrocephalus was observed when compared with placebo (113644). It is unclear whether this effect is due to selenium, acetylcysteine, or the combination.
• Succinylcholine-induced myalgia. It is unclear if oral selenium is beneficial for preventing succinylcholine-induced postoperative myalgia. Details: Clinical research in patients receiving succinylcholine for a sinuscopy shows that taking a single dose of selenium 200 mcg 2 hours before anesthesia induction modestly decreases the incidence of postoperative myalgia at 24 hours. In those taking selenium, 95% of patients had no postoperative myalgia, compared with 77.5% of those taking placebo. Postoperative analgesia requirements were also modestly reduced; however, there was no difference in overall pain or the incidence of muscle twitching (109089).
• Thyroid cancer. It is unclear if oral selenium reduces the risk of thyroid cancer in most patients. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and thyroid cancer risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer (102373). More recent observational research in postmenopausal individuals using data from the Women's Health Initiative has found that selenium intake at or above the recommended daily allowance from dietary sources or supplements is not associated with a decreased risk of thyroid cancer (110590).
• Ulcerative colitis. It is unclear if oral selenium is beneficial for ulcerative colitis. Details: A small clinical study in Iranian adults with mild-to-moderate ulcerative colitis shows that taking selenomethionine 200 mcg daily for 10 weeks in addition to standard therapy improves disease activity and quality of life and increases the percentage of patients with clinical improvement and clinical remission when compared with placebo (113643). Selenium has also been evaluated in combination with other ingredients. A clinical study in patients with ulcerative colitis shows that taking a liquid supplement containing a combination of selenium, fish oil, fructo-oligosaccharides, acacia, vitamin E, and vitamin C daily for 6 months does not improve disease activity scores when compared with placebo. However, taking the combination supplement seems to reduce the need for oral prednisone for symptom control (13757). More evidence is needed to rate selenium for these uses.

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POSSIBLY EFFECTIVE

• Osteoporosis. Higher dietary intakes of silicon in males and premenopausal females seem to be associated with higher bone mineral density (BMD), but it is unclear whether silicon supplements reduce the risk of osteoporosis. Details: Males and premenopausal females who have dietary intakes of silicon of at least 40 mg daily seem to have higher BMD than those with lower intakes. This could reduce the risk of osteoporosis (10470,12425). However, it is unclear if silicon supplements can reduce the risk for osteoporosis. Silicon intake has also been evaluated in postmenopausal females. Clinical and population-based research suggests that higher silicon intake does not seem to benefit postmenopausal females in general, although it may benefit those on hormone replacement therapy (10470,12425,75118,92135). Bone loss in postmenopausal females is primarily due to bone resorption. Silicon seems to affect only bone formation (12425).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral silicon is beneficial in patients with aging skin. Details: A small preliminary clinical study in healthy volunteers aged 40-60 years shows that taking a specific product (Exsynutriment by Biotec) containing organic silicon 600 mg in hydrolyzed marine collagen once daily, 15 minutes before breakfast, for 90 days improves skin firmness, hydration, and texture, but not wrinkles, brightness, or softness, when compared with placebo (100837).
• Alzheimer disease. Although there has been interest in using oral silicon for Alzheimer disease, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Androgenic alopecia. Although there has been interest in using oral silicon for androgenic alopecia, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral silicon for CVD, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Dental peri-implantitis. It is unclear if oral silicon is beneficial in patients with peri-implantitis. Details: A small, preliminary clinical study in patients aged 18-75 with peri-implantitis shows that a specific choline-stabilized orthosilicic acid product (BioSil, Bio Minerals NV) containing silicon 5 mg and choline 100 mg, taken twice daily for 12 months, does not improve markers of inflammation and periodontal disease (i.e. probing pocket depth, bleeding on probing) when compared with placebo (110028). However, this study may not have been adequately powered to detect a difference between groups. More evidence is needed to rate silicon for these uses.

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LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

(Read more about SODIUM)

EFFECTIVE

• Thiamine deficiency. Oral thiamine prevents and treats thiamine deficiency syndromes. Details: Thiamine deficiency is treated with oral thiamine 5-30 mg daily as a single dose or in divided daily doses for one month. For severe deficiency, thiamine up to 300 mg daily can be used (15).Thiamine deficiency can occur in people with malabsorption conditions such as alcohol use disorder, cirrhosis, and gastrointestinal diseases; in those with inadequate intake due to anorexia, nausea, and vomiting; and in those with increased requirements, including pregnancy, increased carbohydrate intake, increased physical activity, hyperthyroidism, infection, and liver disease. However, deficiency is rare with these conditions (15). The elderly might also be at increased risk for subclinical thiamine deficiency (11076).
• Wernicke-Korsakoff syndrome (WKS). Parenteral thiamine is effective for treating symptoms of WKS. Details: Parenteral administration of thiamine 5-200 mg daily for 2 days decreases the risk of developing WKS and decreases symptoms of WKS in acute alcohol withdrawal. Between 30% and 80% of alcoholics are suspected to have thiamine deficiency (11075). An optimal dose for treating WKS has not been established; however, early research suggests that a 200 mg intramuscular dose may be more effective than lower doses (11075). In contrast, a moderate-sized clinical trial in adults with a history of heavy alcohol use who were asymptomatic or symptomatic for WKS shows that there is no benefit to administering high doses (300 mg 3 times daily) compared with medium (100 mg 3 times daily) or low (100 mg daily) doses of parenteral thiamine on cognitive or neurological functioning (111690). The study may have been inadequately powered to detect a difference between groups.

POSSIBLY EFFECTIVE

• Dysmenorrhea. Oral thiamine might reduce pain in some patients with dysmenorrhea. Details: A clinical study in adolescent Iranian females with dysmenorrhea shows that taking thiamine 100 mg alone or along with fish oil 500 mg daily for 2 months moderately reduces pain intensity and duration when compared with placebo (89341). Another preliminary clinical study in Indian females 12-21 years of age with moderate to severe primary dysmenorrhea shows that taking thiamine 100 mg daily for 90 days eliminates pain in 87% of participants when compared to baseline (77820). The validity of this finding is limited by the lack of a placebo group. Furthermore, available research was conducted in India and Iran, so it is unclear if these findings are generalizable to other geographic locations.

POSSIBLY INEFFECTIVE

• Coronary artery bypass graft (CABG) surgery. Intravenous thiamine does not seem to improve outcomes after CABG surgery. Details: A small clinical study in adults undergoing CABG surgery with cardiopulmonary bypass shows that giving intravenous thiamine 200 mg immediately prior to surgery and immediately after surgery does not improve clinical outcomes or lactate levels when compared with placebo (97010). Larger doses of thiamine also don't seem to be beneficial. Another small clinical study in patients receiving CABG with cardiopulmonary bypass shows that giving thiamine 600 mg intravenously on the day of surgery, and 400 mg daily for three postoperative days, does not improve postoperative outcomes when compared with placebo (103000).
• Heart failure. Most research suggests that oral or intravenous thiamine does not improve outcomes in patients with heart failure. Details: Observational research suggests that having heart failure is associated with 2.5-fold increased odds of having thiamine deficiency, possibly because of diuretic use, intestinal malabsorption, and metabolism changes. However, it is unclear if thiamine supplementation is beneficial. A meta-analysis of 2 small clinical trials in adults with systolic heart failure and unclear thiamine status shows that thiamine 200-300 mg given orally or by IV for 7-28 days improves left ventricular ejection fraction (LVEF) by 3% when compared with control (97012). However, other meta-analyses and clinical studies in adults with heart failure with or without thiamine deficiency show that taking intravenous, intramuscular, or oral thiamine 100-500 mg daily does not improve LVEF fraction, left ventricular end-diastolic volume, dyspnea, mortality, hospitalization, or exercise tolerance when compared with placebo or control (103002,111682,111686,111688).
• Mosquito repellent. Oral thiamine does not seem to repel mosquitos. Details: Clinical research in healthy volunteers shows that taking thiamine does not improve mosquito repellency when compared with taking vitamin C as a control (18016).
• Sepsis. Intravenous or oral thiamine, alone or in combination with vitamin C and hydrocortisone, does not seem to reduce mortality or prevent organ failure in sepsis or septic shock. Details: Multiple meta-analyses of small clinical studies in patients with septic shock show that intravenous or oral thiamine 100-500 mg 2-3 times daily for 3-7 days is no better than placebo for improving mortality, end-organ damage, number of ventilator-free days, and duration of intensive care unit (ICU) stay (105443,107717,107727,111689). One meta-analysis suggests that administration of thiamine alone increases the risk of mortality in these patients (111689). Subgroup analyses including only higher quality studies also fail to show a benefit of thiamine (107717). Another recent small clinical trial in patients with septic shock shows that receiving the same dose of intravenous thiamine does not increase vasopressor-free days when compared with placebo (105441). Intravenous thiamine 200 mg every 12 hours has also been evaluated in combination with intravenous vitamin C 1.5-2 grams and hydrocortisone 50-200 mg every 6-12 hours for 4-10 days (HAT therapy). While some retrospective research found HAT therapy to be beneficial (100315,102980,111689), high-quality, prospective clinical research has shown no benefit (105447,109956,111689). Meta-analyses in patients with sepsis and septic shock shows that receiving HAT therapy does not improve mortality, kidney injury, number of ventilator-free days, or ICU length of stay when compared with control (102129,104027,104028,104032,102998,105447,109956,111642,111689). Additionally, the meta-analyses suggest that HAT therapy does not reverse shock or improve sequential organ failure assessment (SOFA) scores (109556,111642). However, one meta-analysis found that HAT therapy shortened the duration of vasopressor use when compared with placebo (111642). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for immediate memory scores and development of posttraumatic stress disorder, HAT therapy was less beneficial when compared with placebo (111299).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral or intravenous thiamine is beneficial for treating or preventing AKI. Details: Observational research in adults admitted to the intensive care unit (ICU) with AKI has found that treatment with thiamine (dose unspecified) within the first 48 hours of admission is associated with 39% lower odds of in-hospital mortality and 28% higher odds of kidney function recovery when compared with patients that did not receive thiamine. Receiving thiamine was also associated with a 0.5-day reduction in ICU length of stay (107719).
• Anxiety. Although there is interest in using oral thiamine for anxiety, there is insufficient reliable information about the clinical effects of thiamine for this purpose.
• Cardiac arrest. It is unclear if intravenous thiamine reduces the risk of death after resuscitation from cardiac arrest. Details: A small clinical study in adults resuscitated from cardiac arrest shows that receiving intravenous thiamine 100 mg every 8 hours for 7 days does not reduce 28-day mortality when compare with a normal saline placebo (105442).
• Cardiovascular disease (CVD). It is unclear if oral thiamine is beneficial for treating or preventing CVD. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 16% increased odds of developing angina or myocardial infarction when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on CVD have not been studied (107725).
• Cataracts. Small studies suggest that increased dietary thiamine might help prevent cataracts. Details: Observational research has found that a high dietary intake of thiamine 10 mg daily is associated with 40% lower odds of nuclear cataracts (6378). Other population research has found that higher dietary intake of thiamine is associated with a modestly reduced risk of age-related lens opacification (14301).
• Cervical cancer. It is unclear if oral thiamine reduces the risk of developing cervical cancer. Details: Epidemiological research has found that increasing intake of thiamine from dietary and supplemental sources, along with folic acid, riboflavin, and vitamin B12, is associated with a lower odds of precancerous cervical lesions (11074).
• Child development. It is unclear if supplementing breastfeeding females with oral thiamine improves infant neurocognitive development. Details: Preliminary clinical research shows that supplementing breastfeeding females with oral thiamine, 1.2-10 mg daily for 22 weeks, starting at 2 weeks postpartum, does not improve most cognitive or neurodevelopmental scores in the child when compared with placebo. However, one subgroup analysis suggests that thiamine supplementation may improve language scores (107726).
• Cognitive function. Oral thiamine has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing thiamine hydrochloride 50 mg, other group B vitamins, bacopa, and ginkgo daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of the combination supplementation on measures of attention in those with an optimal diet at baseline (111334). It is unclear if these findings are due to thiamine, other ingredients, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if intravenous or oral thiamine improves clinical outcomes in patients hospitalized with COVID-19. Details: A small observational study of adults admitted to the intensive care unit with COVID-19 has found that treatment with intravenous or oral thiamine 100 mg daily for an average of 7 days is associated with a 63% reduction in the odds of death within 30 days when compared with control. However, there was no associated reduction in duration of hospitalization or mechanical ventilation (107721). In addition, a small observational study of adults with encephalopathy that were mechanically ventilated secondary to COVID-19 has found that taking thiamine 500 mg three times daily orally for 5 days improves neurological manifestations, including ophthalmoparesis and ataxia, when compared with baseline. The validity of this study is limited by the lack of a comparator group (107722).
• Critical illness (trauma). It is unclear if oral or intravenous thiamine is beneficial in patients with critical illness. Details: A meta-analysis of critically ill patients shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days does not affect the need for mechanical ventilation, duration of hospital stay, or mortality when compared with control (107727).
• Delirium. It is unclear if oral or intravenous thiamine helps to prevent or treat delirium. Details: In critically ill patients, a meta-analysis of clinical research shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days reduces the odds of developing delirium by 42% when compared with control (107727). However, some observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001). In non-critically ill, hospitalized adults with altered mental status, retrospective, observational research has also found that administration of oral or intravenous thiamine is not associated with improved cognitive function or reduced in-hospital mortality when compared with control (107723). Preliminary clinical research in adults undergoing an allogeneic hematopoietic stem cell transplant also shows that administering thiamine 200 mg three times a day intravenously for 7 days does not prevent delirium or shorten duration of delirium when compared with placebo (107718).
• Dementia. It is unclear if oral thiamine is beneficial for the prevention of dementia. Details: Observational research in patients with alcohol use disorder has found that taking thiamine is associated with a 24% to 46% lower risk of developing dementia when compared with not taking thiamine (102999).
• Depression. It is unclear if oral thiamine is beneficial in patients with depression. Details: Meta-analyses of population research in adults has found that high dietary consumption of thiamine is associated with a 10% to 31% lower risk of having depression when compared with low dietary consumption of thiamine. However, this research did not evaluate the effects of thiamine supplementation on depression (107133,107725). One small clinical study in adults with major depressive disorder shows that taking thiamine 300 mg daily in conjunction with fluoxetine 20 mg daily leads to greater improvements in depressive symptoms at 6 weeks when compared to fluoxetine with placebo. This benefit was no longer present at 12 weeks. This suggests that thiamine may accelerate improvement in symptoms during initiation of fluoxetine therapy (97013).
• Diabetes. It is unclear if oral thiamine is beneficial for type 2 diabetes or gestational diabetes. Details: A meta-analysis of 6 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not reduce glycated hemoglobin (HbA1c), fasting blood glucose, or postprandial blood glucose when compared with placebo (111681). A large, prospective cohort study in adults without type 2 diabetes suggests that the risk of new-onset diabetes is minimized in adults consuming thiamine 0.75-1.10 mg daily from the diet, while lower and higher thiamine intake levels are associated with an increased risk of new-onset diabetes (111685). Thiamine has also been studied for preventing gestational diabetes. A large, prospective cohort study in pregnant adults suggests that higher supplementation with thiamine during the first and second trimesters is associated with a lower risk of gestational diabetes when compared with lower levels of total thiamine intake. However, this effect was not found for dietary intake of thiamine, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic nephropathy. It is unclear if oral thiamine is beneficial for diabetic nephropathy. Details: A small clinical study in patients with early-stage diabetic nephropathy and microalbuminuria shows that taking thiamine 100 mg three times daily for 3 months decreases urinary albumin excretion, but does not affect glomerular filtration rate (GFR), when compared with placebo (16556).
• Diabetic neuropathy. Although there is interest in using oral thiamine for diabetic neuropathy, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Dry eye. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with dry eye suggests that adding unspecified doses of thiamine and mecobalamin to treatment with daily artificial tears and corticosteroid drops might slightly improve overall symptoms when compared with only artificial tears and corticosteroid drops for 1 month. There were no differences between groups at 2 months (105444). This finding is limited due to incomplete reporting and a lack of adjustment for multiple hypothesis testing.
• Dyslipidemia. It is unclear if oral thiamine is beneficial for treating or preventing dyslipidemia. Details: A meta-analysis of 3 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not improve low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides when compared with placebo (111681). Observational research in Korea suggests that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with 10% higher odds of developing dyslipidemia when compared with sufficient dietary thiamine intake. However, the effects of thiamine supplementation on dyslipidemia have not been studied (107725).
• Emergence delirium. It is unclear if intravenous thiamine helps to prevent emergence delirium in patients after surgery. Details: One clinical study in adults in the intensive care unit (ICU) after gastrointestinal surgery shows that receiving intravenous thiamine 200 mg daily for 3 days is associated with up to 84% lower odds of emergence delirium on the first two days, but not on the third day, when compared with a normal saline control (105440).
• Fatigue. It is unclear if oral thiamine is beneficial in patients with fatigue. Details: A small clinical crossover study in patients with chronic fatigue and inflammatory bowel disease (IBD) shows that taking thiamine 600-1800 mg daily for 20 days reduces fatigue scores when compared with placebo (105438). Taking oral thiamine 300 mg daily for an additional 12 weeks did not seem to affect fatigue scores when compared with placebo. However, an observational follow-up study found that those who self-continued thiamine for an additional 24 weeks after the study ended reported lower fatigue scores when compared with those who did not self-continue thiamine (107720).
• Glaucoma. Although there is interest in using oral thiamine for glaucoma, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Herpes zoster (shingles). It is unclear if subcutaneous thiamine is beneficial in patients with shingles. Details: A small clinical trial shows that receiving subcutaneous thiamine 100 mg injections six times weekly for 4 weeks reduces itching by at least 30% in 67% of patients with herpes zoster. However, thiamine does not appear to significantly reduce pain in most patients (90396).
• Hypertension. It is unclear if oral thiamine is beneficial in treating or preventing hypertension. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 5% increased odds of developing hypertension when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on hypertension have not been studied (107725).
• Impaired glucose tolerance (prediabetes). It is unclear if oral thiamine is beneficial in patients with prediabetes. Details: A very small clinical trial in patients with prediabetes shows that taking thiamine 100 mg by mouth three times daily for 6 weeks modestly decreases 2-hour postprandial plasma glucose levels when compared to baseline and decreases fasting blood glucose levels when compared with placebo (91168).
• Kidney failure. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary, low-quality, clinical research in adults with kidney failure undergoing regular hemodialysis shows that taking oral thiamine 90 mg daily with folic acid 30 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if this effect is due to thiamine, folic acid, or the combination.
• Migraine headache. It is unclear if dietary thiamine is beneficial for the prevention or treatment of migraine headache. Details: A large, retrospective, cross-sectional study suggests that higher dietary intake of thiamine is associated with lower odds of severe headache or migraine, especially in females (111684). The validity of these effects is limited by the subjective outcome measures and retrospective study design.
• Pneumonia. It is unclear if thiamine is beneficial for patients with pneumonia. Details: A large retrospective cohort study in adults hospitalized with pneumonia and active alcohol use disorder suggests that parenteral administration of thiamine is associated with reduced 14-day mortality and more frequent discharges home, but not a shorter length of stay or fewer ICU transfers, when compared with no thiamine use. Furthermore, parenteral thiamine doses above 200 mg do not appear to improve mortality but may be associated with longer length of stay and less frequent discharges home when compared with low oral doses of thiamine or parenteral thiamine at doses under 200 mg (111679). The validity of these effects is limited by the retrospective study design.
• Ventilator-associated pneumonia (VAP). It is unclear if oral or parenteral thiamine is beneficial for patients with VAP. Details: A retrospective study in adults with VAP in the intensive care unit (ICU) suggests that supplementation with intravenous or oral thiamine may be associated with reduced ICU and in-hospital mortality (111683). The validity of these effects is limited by the retrospective study design. More evidence is needed to rate thiamine for these uses.

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EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143). Furthermore, a very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve neurodevelopment as measured by language, motor, socioemotional, or cognitive scores at 12 months old and may worsen early motor performance at 8-12 weeks when compared with placebo. However, the negative effects on motor performance resolved by 6 and 12 months of age (112431).
• Child growth. Oral vitamin B12 taken by pregnant adults does not seem to be beneficial for infant growth. Details: A very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve the infant's linear growth, length, or weight at 12 months of age (112431).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Hypotension. It is unclear if oral vitamin B12 is beneficial for treating hypotension. Details: A meta-analysis of 3 observational studies in patients hospitalized with hypotension secondary to cardiac surgery vasoplegia suggests that administration of intravenous vitamin B12 (hydroxocobalamin) is associated with an 8 mmHg higher mean arterial pressure (MAP) at 1 hour but no change in vasopressor dosage at 1 hour or mortality rate when compared with methylene blue (112264). The validity of these findings is limited by the inclusion of only retrospective studies.
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Mastalgia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin B12 as methylcobalamin 100 mg, gamma-linolenic acid, and vitamin C daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

(Read more about VITAMIN B12)

EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50% and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9308,9400,9405,9409). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing vitamin B6 (pyridoxine), nicotinamide, azelaic acid, zinc, copper, and folic acid for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared to baseline (90800). The validity of these findings is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B6 (pyridoxine) 50 mg, vitamin B12 1000 mcg, and folic acid 2.5 mg daily reduces the risk for AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Angioplasty. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B6 (pyridoxine) 10 mg, folic acid 1 mg, and vitamin B12 400 mcg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6 (pyridoxine), and vitamin B12 followed by oral administration of folic acid 1.2 mcg, vitamin B6 (pyridoxine) 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B6, other ingredients, or the combination.
• Antipsychotic-induced metabolic side effects. It is unclear if oral vitamin B6, as an adjunct to progesterone, is beneficial in patients with antipsychotic-induced amenorrhea. Details: A small clinical study in females with antipsychotic-induced amenorrhea shows that taking vitamin B6 80 mg three times daily for 1 month plus intramuscular progesterone daily for 5 days increases levels of estradiol and follicle stimulating hormone, reduces prolactin levels, and increases the rate of clinical efficacy, defined as the normalization of menstruation and improvement in endocrine indicators, by 14% when compared with progesterone alone (110457).
• Anxiety. It is unclear if oral vitamin B6 is beneficial in patients with anxiety. Details: Clinical research in college students shows that taking vitamin B6 100 mg daily for one month does not reduce anxiety scores when compared with placebo (110453). However, because a diagnosis of anxiety was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with anxiety.
• Asthma. It is unclear if oral vitamin B6 is beneficial in patients with asthma. Details: Preliminary clinical studies show that taking vitamin B6 (pyridoxine) 200-300 mg daily may improve symptoms of asthma in some patients, but not others, when compared with placebo (7064,7065). Studies have yielded conflicting results, with some research suggesting that it may only be beneficial in children with severe asthma (7065). Additionally, some research suggests that theophylline may lower vitamin B6 levels, although it is unclear if vitamin B6 supplementation is beneficial (4522,7066,9503).
• Atherosclerosis. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with intermediate risk for coronary heart disease shows that taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunga) containing vitamin B6 12.5 mg, aged garlic extract 250 mg, vitamin B12 100 mcg, folic acid 300 mcg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral vitamin B6 is beneficial in patients with eczema. Details: A small clinical study in children with eczema shows that taking vitamin B6 (pyridoxine hydrochloride) 50 mg daily for 4 weeks does not reduce symptoms such as redness and itchiness when compared with placebo (83090).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin B6 is beneficial for ADHD. Details: A small crossover study in children with ADHD shows that taking vitamin B6 600 mg, niacinamide and ascorbic acid 3 grams, and calcium pantothenate 1.2 grams daily for 6 weeks does not improve behavior scores when compared with placebo (9957).
• Autism spectrum disorder. Although there is interest in using oral vitamin B6 for autism, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Bipolar disorder. It is unclear if oral vitamin B6 is beneficial in patients with bipolar disorder. Details: A small clinical trial in patients with type 1 bipolar disorder who are taking lithium and experiencing an acute episode of mania shows that taking vitamin B6 80 mg daily for 8 weeks does not improve cognitive function or the severity of mania when compared with placebo. Cognitive function was reduced in patients taking vitamin B6; any effect on sleep was unclear (107132).
• Cancer. It is unclear if oral vitamin B6 reduces overall cancer risk. Details: Population research has found that higher dietary intake of vitamin B6 is associated with a 22% reduced risk of cancer, including esophageal, pancreatic, gastric, colorectal, and breast cancer. However, when dietary and supplemental vitamin B6 intake is considered, the inverse association between vitamin B6 and cancer risk is weaker and limited to fewer tumor sites. Furthermore, a meta-analysis of 9 clinical studies shows that taking vitamin B6 3-100 mg orally daily for 2-7.3 years, in combination with vitamin B12 and folate, does not reduce the risk of cancer in patients with cardiovascular disease or kidney failure (96164).
• Cardiovascular disease (CVD). Oral vitamin B6, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly lower the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B6 in combination with folic acid and/or vitamin B12 does not seem to help with secondary prevention of death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, some research shows that taking vitamin B6 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). Additionally, it is unclear which specific combination of B vitamins is optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cognitive function. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing vitamin B6, ginkgo leaf, bacopa, and other B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B6 reduces the risk of colorectal cancer. Details: A meta-analysis of observational studies suggests that the highest dietary intake of vitamin B6 is associated with a 20% reduced risk of colorectal cancer when compared with the lowest dietary intake. However, this association was not shown in subgroup analyses of studies conducted in Australia, Europe, or North America (111600). The validity of this analysis is limited by the heterogeneity of the included studies.
• Dental caries. There is limited evidence on the oral use of vitamin B6 for dental decay during pregnancy. Details: Meta-analyses of limited clinical research show that taking vitamin B6 (pyridoxine), 25 mg daily or a single dose of 100 mg orally or intramuscularly, may reduce the risk of dental decay during pregnancy when compared with placebo (83046,96166).
• Depression. It is unclear if oral vitamin B6 reduces the risk of developing depression or improves symptoms of depression. Details: Clinical research in healthy college students shows that taking vitamin B6 100 mg daily for one month does not reduce depression scores when compared with placebo (1104453). However, because a diagnosis of depression was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with depression. Whether vitamin B6 reduces the risk of developing depression is also unclear. A meta-analysis of population research has found that the highest dietary intake of vitamin B6 is associated with a 19% lower risk of depression when compared with the lowest intake. However, sub-analyses suggest that this association is only relevant in females and not males (107133). In one individual population study in community dwelling older adults included in the analysis, the consumption of at least 1.71 mg of vitamin B6 daily from food was associated with a 43% reduction in the likelihood of becoming depressed when compared with the consumption of 1.33 mg or less daily in females. However, there was no association between vitamin B6 levels and risk of depression in males, and the finding in females was no longer significant when adjusted for total energy intake, since foods rich in vitamin B6 are energy-dense (96168). Another observational longitudinal study in healthy adults starting oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 40% lower risk of depression when compared with no supplementation (90789). Most available studies are cross-sectional in nature, making any conclusions related to causation difficult.
• Diabetes. It is unclear if oral vitamin B6 is beneficial in patients with type 2 diabetes or gestational diabetes. Details: Observational research in Chinese adults with type 2 diabetes has found that dietary intake of vitamin B6 in the highest quartile is associated with 53% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with vitamin B6 intake in the lowest quartile (110452). Small clinical studies in patients with gestational diabetes and vitamin B6 deficiency shows that taking vitamin B6 (pyridoxine) 100 mg daily for 2 weeks improves glucose tolerance and blood glucose levels when compared with baseline (82967,83088). However, there is concern that these findings were confounded by dietary alterations. This benefit was not observed in a subsequent small case series in patients with gestational diabetes (22380).
• Diabetic neuropathy. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research suggests that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate) for 24 weeks does not improve neural dysfunction based on vibration perception when compared with placebo in patients with diabetic neuropathy. However, taking this combination appears to modestly improve neuropathy symptoms and quality of life related to mental functioning when compared with placebo (90375).
• Dysmenorrhea. It is unclear if oral vitamin B6 is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research shows that taking vitamin B6 (form not specified) 200 mg daily reduces pain associated with dysmenorrhea when compared with placebo. However, taking vitamin B6 in combination with magnesium does not reduce pain when compared with placebo (77388).
• Fibromyalgia. It is unclear if oral vitamin B6 is beneficial in patients with fibromyalgia. Details: A small clinical study in patients with fibromyalgia shows that taking vitamin B6 80 mg daily for 8 weeks does not improve pain, disease severity, anxiety, depression, or quality of life when compared with placebo (110454).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral vitamin B6 is beneficial in children with gastroenteritis. Details: A small clinical study in children aged 6 months to 12 years with acute viral gastroenteritis shows that taking vitamin B6 (form not specified) does not improve symptoms of dehydration or the frequency of vomiting when compared with placebo (90793).
• Helicobacter pylori. It is unclear if oral vitamin B6 is beneficial for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy does not improve eradication rates when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Hypertension. It is unclear if oral vitamin B6 reduces blood pressure. Details: One small clinical study in patients with essential hypertension shows that taking vitamin B6 (pyridoxine hydrochloride) 5 mg/kg daily for 4 weeks can reduce systolic and diastolic blood pressure when compared with baseline (83091). The validity of this finding is limited by the lack of a control group.
• Hypertriglyceridemia. It is unclear if oral vitamin B6 reduces triglyceride levels. Details: Preliminary clinical research shows that vitamin B6 (form not specified) 50 mg daily for 12 weeks does not reduce triglyceride levels in people with hypertriglyceridemia when compared with placebo. However, vitamin B6 appears to decrease total cholesterol and high-density lipoprotein (HDL) cholesterol by approximately 9% in these patients (59028).
• Infertility. Although there is interest in using oral vitamin B6 for infertility, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Insomnia. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults with self-reported sleep difficulty shows that taking a specific product (LZ Complex3, Sanofi Consumer Healthcare Pty Ltd.) containing vitamin B6, zizyphus extract, hops extract, hydrolyzed milk protein (Lactium), and magnesium oxide nightly, 30 minutes before bed, for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo. However, due to the large improvement seen in both the treatment and placebo groups, the effectiveness of this product is unclear (95971).
• Isoniazid-induced neuropathy. It is unclear if oral vitamin B6 prevents the development of neuropathy in patients taking isoniazid. Details: Preliminary clinical research in patients taking isoniazid for tuberculosis shows that taking vitamin B6 (pyridoxine) 6 mg daily reduces the development of neuropathy when compared with control (83068).
• Lactation. It is unclear if oral vitamin B6 helps to suppress postpartum lactation. Details: A meta-analysis of two small clinical trials shows that taking vitamin B6 (pyridoxine) 400-600 mg daily for 6-7 days postpartum does not suppress lactation when compared with no treatment (83047).
• Levetiracetam-induced side effects. While some conflicting evidence exists, several small, low-quality studies suggest that oral vitamin B6 (pyridoxine) may reduce some neuropsychiatric adverse effects related to the use of levetiracetam. Details: In an analysis of case reports, retrospective studies, and a single low-quality prospective study, improvement in levetiracetam-associated neuropsychiatric symptoms occurred in approximately 73% of patients taking pyridoxine (107137). A more recent preliminary clinical trial in children ages 1-17 years shows that taking pyridoxine 10 or 15 mg/kg daily as needed based on symptoms improves behavioral side effects associated with levetiracetam by a small amount when compared with low-dose pyridoxine 0.5 mg/kg daily used as placebo (107124). Also, observational research in children ages 9 months to 14 years has found that taking vitamin B6 is associated with improved behavior and a 44% lower risk of levetiracetam discontinuation when compared with no vitamin B6 supplementation (110455). Some observational research in adults with levetiracetam-associated irritability has found that taking vitamin B6 is associated with an improvement in irritability in 45% of patients when compared to baseline (107129). However, a small clinical trial in adults with epilepsy shows that taking pyridoxine 40 mg daily for 3 weeks does not improve levetiracetam-related psychiatric adverse effects when compared with placebo (110456). This study may have been underpowered to detect differences between groups. Pyridoxine doses used in the studies above have ranged from 50-400 mg daily in children and 40-600 mg daily in adults (107124,107129,107137,110456).
• Lung cancer. It is unclear if dietary or oral vitamin B6 reduces lung cancer risk. Details: Epidemiological research has found that higher serum levels of vitamin B6 in male smokers is associated with a lower risk of lung cancer (9454). Also, people with blood levels of vitamin B6 in the top quartile have a modestly lower risk of lung cancer when compared with those whose levels are in the lowest quartile. The association is stronger for males and for people who have smoked (97999). However, other epidemiological research found that increased dietary intake of vitamin B6 is not associated with a reduced risk of lung cancer (96164).
• Menopausal symptoms. Although there is interest in using oral vitamin B6 for menopausal symptoms, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Motion sickness. Although there is interest in using oral vitamin B6 for motion sickness, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Nausea and vomiting. It is unclear if oral vitamin B6 is beneficial for nausea and vomiting in patients taking oral contraceptives or antibiotics for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding. An observational longitudinal study in healthy females taking oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 43% reduced risk of nausea when compared with no supplementation (90789).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B6 for patients with NAFLD. Details: A small clinical trial in patients with NAFLD shows that taking vitamin B6 (pyridoxine) 30 mg three times daily for 12 weeks does not reduce levels of liver transaminases or plasma lipids when compared with baseline. However, hepatic fat accumulation was modestly reduced (107130). The validity of this study is limited by the lack of a comparator group.
• Obesity. It is unclear if oral vitamin B6 in beneficial in overweight or obese individuals. Details: A small clinical trial in females with a body mass index (BMI) of at least 25 kg/m² shows that taking vitamin B6 as pyridoxine 80 mg daily for 8 weeks reduces fat mass and improves insulin resistance and triglyceride levels by a small amount when compared with placebo. Although some other anthropometric and metabolic indices were improved when compared with baseline, there was no effect of pyridoxine on body weight, visceral adiposity, or other endpoints when compared with placebo (107131).
• Overall mortality. It is unclear if oral vitamin B6 reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of vitamin B6 in the highest quintile is associated with a 12% to 21% lower risk of all-cause mortality and a 31% to 44% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary vitamin B6 intake (110451).
• Pancreatic cancer. It is unclear if oral vitamin B6 reduces the risk of pancreatic cancer. Details: Observational research has found that higher dietary intake of vitamin B6 is associated with a 37% lower risk of developing pancreatic cancer when compared with lower intake (104927).
• Postpartum depression. It is unclear if oral vitamin B6 is beneficial in patients with postpartum depression. Details: Preliminary clinical research in individuals considered at increased risk for postpartum depression, but without clinical depression, shows that taking vitamin B6 80 mg daily from the 28th week of pregnancy until birth, and then 40 mg daily for one month, reduces symptoms of depression 1.5 months after birth when compared with baseline (measured during the third trimester) and when compared with placebo. However, it is unclear if any of the patients included in the study developed postpartum depression, as there were no changes in overall symptoms in patients taking placebo (107126).
• Proton pump inhibitor-induced gastrointestinal (GI) symptoms. It is unclear if oral vitamin B6 is beneficial for proton pump inhibitor-induced GI symptoms. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Restless legs syndrome (RLS). It is unclear if oral vitamin B6 is beneficial in patients with RLS. Details: A small clinical study in adults with RLS who are beginning treatment with pramipexole shows that also taking vitamin B6 40 mg daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052).
• Schizophrenia. It is unclear if oral vitamin B6 is beneficial for patients with treatment-resistant schizophrenia. Details: Clinical research in male patients with treatment-resistant schizophrenia who are on a consistent antipsychotic dose shows that adding vitamin B6 300 mg twice daily for 16 weeks modestly improves psychotic symptoms and some measures of cognitive performance when compared with adding aripiprazole 5 mg twice daily (107128). More research is needed to determine if these benefits are clinically relevant.
• Seizures. It is unclear if oral vitamin B6 is beneficial for preventing seizures in patients with glycosylphosphatidylinositol (GPI) deficiency. Details: Observational case series in a small number of children and young adults with GPI deficiency has found that taking vitamin B6 20-30 mg/kg daily for 3-12 months is associated with some reduction in seizure frequency in 9 of 13 patients. However, no patient reached seizure freedom (107125,107135). In one case series, treatment for 12 months was associated with modest developmental improvements in almost all patients (107135). The study patient populations were slightly different in terms of age and underlying genetic causes for GPI deficiency.
• Sickle cell disease. Oral vitamin B6 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B6 4.2-6 mg, vitamin B12 4.2-6 mcg, and folic acid 700 mcg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B6, either alone or with other B vitamins, is beneficial for stroke prevention. Details: There is some debate about whether supplementation with homocysteine-lowering B vitamins, including vitamin B6, can reduce the risk of stroke. A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, another meta-analysis of three clinical trials including 9900 patients with a history of stroke shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% when compared with placebo, although this finding was determined to have a low level of certainty. Based on two clinical trials, there was also a 17% reduced risk of vascular death and an 11% reduction in the combined risk of stroke, myocardial infarction, and vascular death (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis shows that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Exposure to low, but not high amounts, of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tardive dyskinesia. It is unclear if oral vitamin B6 prevents tardive dyskinesia in patients taking neuroleptic drugs. Details: A small clinical study in patients taking neuroleptic drugs for schizophrenia shows that taking vitamin B6 (form not specified) 400 mg daily seems to improve Parkinsonian, dystonic, and dyskinetic symptoms when compared with placebo (8558).
• Tourette syndrome. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing vitamin B6 2.8 mg and L-theanine 200 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups.
• Vincristine-induced neuropathy. Oral vitamin B6 has only been evaluated in combination with pyridostigmine; its effect when used alone is unclear. Details: A small clinical study in children ages 11 months to 13 years with neuropathy due to vincristine treatment for acute lymphoblastic leukemia, shows that taking vitamin B6 150 mg/m2 and pyridostigmine 3 mg/kg twice daily for 3 months is associated with reduced severity of sensory and motor neuropathy when compared with baseline (104928). The validity of this finding is limited by the lack of a control group. More evidence is needed to rate vitamin B6 for these uses.

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EFFECTIVE

• Vitamin C deficiency. Oral or intramuscular vitamin C is effective for preventing or treating vitamin C deficiency. Details: Administering vitamin C orally or intramuscularly prevents and treats vitamin C deficiency, including scurvy. Vitamin C administration can reverse complications of scurvy within 2 days to 3 weeks (4844). In newborns with transient tyrosinemia due to vitamin C deficiency, oral or intramuscular vitamin C can correct this condition (15).

POSSIBLY EFFECTIVE

• Anemia of chronic disease. Oral vitamin C seems to improve markers of anemia in patients on hemodialysis. Details: Meta-analyses of clinical research in hemodialysis patients with anemia shows that treatment with vitamin C 200-300 mg three times weekly for 3-6 months increases hemoglobin levels by approximately 0.9 grams/dL, increases transferrin saturation by about 8%, and decreases the required recombinant human erythropoietin dose by 17 U/kg weekly when compared with standard care (83447,83475).
• Atrial fibrillation. Oral and intravenous vitamin C seems to help prevent atrial fibrillation after cardiac surgeries. Details: Meta-analyses of clinical research show that taking vitamin C prior to and after cardiac surgery reduces the risk of postoperative atrial fibrillation by 27% to 53%. Most studies administered vitamin C at doses of 1-2 grams orally daily for 1-3 days prior to cardiac surgery, followed by 1-2 grams in two divided doses daily for 4-5 days after cardiac surgery. Some studies provided vitamin C intravenously at similar doses, but oral vitamin C seems to be more effective (91233,96703,96705). Despite these findings, a meta-analysis of clinical research conducted only in the U.S. does not support the benefit of vitamin C for reducing postoperative atrial fibrillation (96703). These differences may be related to lifestyle factors such as nutrition, as well as differences in hospital treatments. Vitamin C has also been studied in combination with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with evidence of benefit (90701).
• Bowel preparation. Powdered vitamin C is approved for use as part of a polyethylene glycol-based bowel preparation for colonoscopy. Details: Clinical research shows that treatment with 2 liters of oral solution containing polyethylene glycol (PEG) plus vitamin C achieves a similar quality of bowel cleansing as treatment with 4 liters of PEG when administered on the evening prior to colonoscopy or when administered in a split-dose regimen. Patients given 2 liters of PEG plus vitamin C solution also have better adherence and experience fewer adverse events, such as nausea, vomiting, or abdominal bloating, compared to patients treated with 4 liters of PEG solution without vitamin C (90413,90415,90420,90424,90428). This treatment also appears to be effective and tolerable in elderly patients aged 60-79 years, including those with poor bowel habits and a high number of comorbidities (108085). Other clinical research in older adults undergoing bowel preparation for colonoscopy also shows that taking 1 liter of PEG plus vitamin C (CleanViewAL, Taejoon Pharm) results in similar quality of bowel cleansing overall and per segment with similar tolerability and adverse effects as sodium picosulfate 170 mL plus magnesium citrate or oral sulfate solution alone (111297,112476). The most common PEG plus vitamin C preparation used in clinical research is MoviPrep (Norgine BV), which contains macrogol 3350 100 grams, sodium sulfate 7.5 grams, sodium chloride 2.7 grams, potassium chloride 1 gram, vitamin C 4.7 grams, and sodium ascorbate 5.9 grams per liter of solution (90413,90415,90424). In the U.S., MoviPrep is approved by the Food and Drug Administration (FDA) for bowel preparation prior to a colonoscopy.
• Cataracts. Dietary and supplemental intake of vitamin C may reduce the risk of developing cataracts. Details: Population research suggests that people with the highest total intake of vitamin C have about a 19% reduced risk of developing cataracts when compared with those with the lowest total intake, with the most benefit observed for nuclear cataracts (96711). Additionally, another observational study shows that higher supplemental intake of vitamin C over 10 years is associated with a 60% reduction in the incidence of nuclear and cortical cataracts (4208). Other population research suggests that individuals with the highest blood levels of vitamin C have a 33% lower odds of developing age-related cataract, but any benefit is limited to Asian populations (90944). An umbrella review of meta-analyses also shows that dietary intake of vitamin C is associated with a 27% lower odds of cataract development (112095). However, a prospective clinical study shows that a combination of vitamin C, vitamin E, and beta-carotene does not prevent age-related loss of vision from cataracts in well-nourished people with an average supplementation duration of 6.3 years (7304).
• Common cold. Oral high-dose vitamin C might modestly shorten and reduce cold symptoms; however, taking vitamin C prophylactically does not seem to prevent the development of a cold. Details: There is substantial controversy about the effectiveness of vitamin C for treating the common cold (1969,1989,7100,9835,9836). The majority of evidence shows that taking high doses of vitamin C orally might decrease the duration of cold symptoms by 1-1.5 days in some patients (1966,1967,1968,1987,6458,7102,9832,83487). However, other studies have found no effect with doses up to 3 grams daily (9833). A meta-analysis of clinical research in healthy children and adults shows that taking vitamin C 1-4 grams daily for one week to 5 months reduces cold severity by 13%, limits absences from daily activities, and improves the duration of severe symptoms, but does not reduce the duration of mild symptoms, when compared with placebo (113665). Vitamin C has also been investigated for preventing the common cold. A meta-analysis of clinical research suggests that vitamin C supplementation decreases the incidence of cold in individuals exposed to physical stress, but not in the general population (83487). Other research suggests vitamin C may be more effective for treating cold symptoms in children than in adults. Also, there may be a dose-dependent response; doses of at least 2 grams daily seem to work better than 1 gram doses (9834). Taking vitamin C supplements prophylactically does not decrease the risk of catching a cold (1966,1967,1968,1987,3042,6458,7101,9832). Dietary intake of vitamin C also does not seem to affect the risk of getting a cold (10780).
• Complex regional pain syndrome. Most research shows that taking oral vitamin C after a distal radius (i.e. wrist) fracture or surgery seems to reduce the risk of developing complex regional pain. However, it is unclear if oral vitamin C is beneficial in reducing the risk of complex regional pain in other orthopedic surgeries. Details: Although some research has found no benefit in patients with distal radius (i.e. wrist) fractures (90411,96702), most clinical research shows that taking vitamin C 500 mg daily, and possibly doses of up to 1500 mg daily, for 45-50 days beginning immediately after fracture can reduce the risk of developing complex regional pain syndrome (2045,16302,96700,96706). Reasons for discrepancies are unclear but might relate to differences in diagnostic criteria for complex regional pain syndrome (96702). Research in patients undergoing various orthopedic surgeries has also shown benefit with the use of vitamin C for the prevention of complex regional pain syndrome; however, some findings are conflicting. (90422,108076,115613). One meta-analysis of clinical research in patients undergoing ankle, foot, or wrist surgery shows that taking vitamin C 500-1000 mg for 42-50 days following surgery reduces the rate of complex regional pain syndrome, and may improve pain following ankle or foot surgery, when compared with placebo (108076). The validity of these findings is limited by the high heterogeneity of included trials. An additional meta-analysis of clinical research in patients undergoing a broader variety of orthopedic surgery types (i.e., ankle, foot, knee, shoulder, wrist) shows that taking vitamin C 500 to 1500 mg does not reduce the incidence of complex regional pain syndrome (115613). The reasons for these discrepant findings are unclear but may relate to the inclusion of a wide range of orthopedic surgeries.
• Exercise-induced respiratory infections. High-dose oral vitamin C seems to reduce the risk of respiratory infections associated with strenuous exercise. Details: Some preliminary clinical research suggests that prophylactic use of vitamin C in doses of 600 mg to 1 gram daily for 3-8 weeks before heavy physical exercise, such as a marathon, might prevent upper respiratory infections that sometimes follow heavy exercise (9831,83370). More recently, high doses of vitamin C have been studied. A large clinical study in army recruits undergoing basic military training shows that taking vitamin C 6 grams daily for one month reduces the odds of getting a cold by 20% when compared with placebo (102975).
• Hypercholesterolemia. Oral vitamin C seems to reduce lipid levels in patients with hypercholesterolemia. Details: A meta-analysis of clinical research in patients with hypercholesterolemia shows that taking vitamin C 500 mg daily for at least 4 weeks reduces low-density lipoprotein (LDL) cholesterol by about 8 mg/dL and reduces triglycerides by about 20 mg/dL when compared with control (83445).
• Hypertension. Oral vitamin C seems to modestly reduce blood pressure in patients with hypertension, but some evidence is conflicting. Details: Vitamin C seems to modestly reduce systolic blood pressure (SBP), without meaningful effects on diastolic blood pressure (DBP) (2044,9822,13162,83483,102974). A meta-analysis of 13 clinical trials in patients with hypertension, with or without other comorbidities, shows that taking a median dose of vitamin C 500 mg daily for 8 weeks reduces SBP but not DBP by about 5 mmHg. Some of the studies used vitamin C in combination with other supplements, such as vitamin E and magnesium. When studies assessing vitamin C alone were analyzed, the magnitude of reduction in SBP decreased (83483). A newer meta-analysis of small clinical studies in patients with essential hypertension shows that taking vitamin C 200 mg or more daily reduces SBP by about 4 mmHg and DBP by about 2 mmHg (102974). However, this newer analysis omitted numerous relevant studies and included studies with normotensive patients and those without an adequate control, limiting the validity of its findings. In contrast, a network meta-analysis of small, low-quality clinical studies comparing five different vitamins in adults with essential hypertension shows that vitamin C does not reduce SBP, DBP, mean 24-hour SBP, mean 24-hour DBP, or heart rate when compared with placebo and when indirectly compared with vitamin B2, vitamin D, vitamin E, and folic acid. However, the included studies were of low quality and high heterogeneity, particularly in dosing, limiting the validity of the results (113668).
• Laser skin resurfacing. Topical vitamin C seems to reduce erythema occurring after cosmetic laser skin resurfacing procedures intended to reduce scars and wrinkles. Details: There is some evidence that an aqueous formulation of topical vitamin C can decrease the degree and duration of erythema following cutaneous carbon dioxide laser resurfacing for scar and wrinkle removal (1959).
• Lead toxicity. Dietary vitamin C seems to lower concentrations of lead in the blood. Details: Observational research has found that consuming more vitamin C from dietary sources is associated with lower blood concentrations of lead. People who consumed at least 340 mg of vitamin C daily as part of the diet had lower blood lead levels than those who consumed less than 100 mg vitamin C daily (3097,3098,3099).
• Nitrate tolerance. Oral vitamin C might prevent nitrate tolerance in some patients. Details: Small clinical studies show that taking vitamin C orally seems to prevent the development of nitrate tolerance in patients taking sublingual nitroglycerin. There is some evidence that short-term vitamin C supplementation can prevent tolerance to the vasodilatory effects of nitrates (1441,1961).
• Postoperative pain. Oral or intravenous vitamin C might prevent acute postoperative pain following certain surgeries. It is unclear if vitamin C reduces chronic postoperative pain. Details: A meta-analysis of 7 small clinical studies in adults undergoing elective surgery shows that receiving perioperative vitamin C, either as 1 gram orally, 2-3 grams intravenously, or 50 mg/kg intravenously, modestly reduces acute pain and opioid requirements for up to 24 hours when compared with control (105457). Most surgeries were laparoscopic and included cholecystectomy, colectomy, hysterectomy; two non-laparoscopic surgeries included uvulopalatopharyngoplasty with tonsillectomy and major abdominal surgery (90418,99840,105457). A meta-analysis of clinical trials in adults undergoing noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, kidney transplantation) shows that administering perioperative vitamin C, either orally or intravenously, reduces postoperative intravenous morphine requirements at 2, 24, and 48 hours after surgery and improves pain scores at 2, 6, and 24 hours after surgery when compared with placebo. The dose of vitamin C did not appear to impact outcomes. However, when only laparoscopic surgeries are included, perioperative vitamin C does not improve pain or morphine use when compared with placebo (108087). Use of vitamin C perioperatively has also been evaluated in other surgery types with generally similar outcomes. A moderate-sized clinical study in adults undergoing total hip arthroplasty shows that intravenous vitamin C 3 grams perioperatively reduces 24-hour post-operative morphine use and subjective pain scores when compared with placebo; however, these improvements do not appear to be clinically significant (115500). The validity of these results is limited by a short follow-up period. Additionally, a small observational study in adults undergoing surgery for wisdom tooth extraction shows that taking vitamin C 500 mg three times daily for 7 days in addition to standard treatment reduces pain 24, 48, and 72 hours after surgery when compared with control (113664). However, a moderate-sized clinical study in adults undergoing transurethral resection of a bladder tumor under general anesthesia shows that administering intravenous vitamin C 1 gram after induction of anesthesia reduces the incidence and severity of catheter-related bladder discomfort immediately after surgery and at 1 and 2 hours postoperatively, but not 6 hours, when compared with placebo. Further, vitamin C does not reduce postoperative pain scores or analgesic requirements when compared with placebo (111645). Vitamin C has also been evaluated for reducing chronic pain after surgery. Clinical research in patients undergoing surgery for foot or ankle trauma shows that taking vitamin C 500 mg orally twice daily postoperatively for 6 weeks reduces pain scores when compared with placebo at 2 weeks and 6 weeks. The mean total amount of diclofenac used for pain relief over the 6-week period is also reduced, from 5.7 grams with placebo to 3.4 grams with vitamin C (102131).
• Wrinkled skin. Topical vitamin C might reduce the appearance of existing wrinkles. Details: Topical preparations containing vitamin C seem to improve the appearance of wrinkled skin. Some evidence shows that vitamin C 3% applied for 12 weeks might reduce facial wrinkles (14008). A small clinical study shows that applying a dissolving microneedle patch containing vitamin C 5.6% every 4 days for 12 weeks to crow's feet on one side of the face reduces wrinkles when compared to control treatment applied on the other side of the face (98780). Other clinical research in females aged 30-60 years shows that applying an oil-soluble cream containing the vitamin C derivative tetra-isopalmitoyl ascorbic acid 1%, 2%, or 3% to the periorbital area twice daily for 8 weeks reduces visual wrinkle grading when compared with placebo. A dose analysis shows greater improvements in wrinkle parameters, average wrinkle depth, and mean depth with the lower concentration, while greater improvements in maximum roughness and maximum depth are observed with the higher concentration (108072). This study only included individuals defined as having Fitzpatrick skin type III or IV; it effects on other skin types is unclear. Preparations containing vitamin C in combination with other ingredients have also been investigated. A small low-quality trial in females with moderately photodamaged and hyperpigmented facial skin shows that applying a moisturizer with vitamin C 30%, vitamin E, and coenzyme Q10 once daily in the morning, along with applying retinol 0.5% once daily or once every other day for 12 weeks, seems to improve skin tone, photodamage, and wrinkles when compared to baseline (99085). In another small trial, a topical preparation containing vitamin C 10% as L-ascorbic acid along with acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months improves fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). It is unclear if the beneficial effects of these products are due to vitamin C, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Acute bronchitis. Oral vitamin C doesn't seem to improve symptoms of acute bronchitis. Details: A clinical study in adults with acute bronchitis shows that taking vitamin C orally 500 mg on day 1, then 250 mg on days 2 through 5 (similar to an azithromycin regimen) doesn't seem to have any effect on quality of life or bronchitis duration when compared with azithromycin (9827).
• Asthma. Oral vitamin C doesn't seem to prevent asthma or improve lung function. Details: Although some observational research has found that some patients with asthma might have lower serum vitamin C levels (5873), other observational research found that increased dietary vitamin C intake is not associated with a reduced risk of asthma or improved lung function (15006,34567). In addition, clinical research shows that supplemental intake of vitamin C does not reduce asthma symptoms, improve lung function, or reduce the use of inhaled steroids in asthma patients (90409).
• Atherosclerosis. Oral vitamin C does not seem to reduce the progression of atherosclerosis. Details: A clinical study shows that taking a specific combination product containing slow-release vitamin C 250 mg and vitamin E 136 IU (CellaVie, Ferrosan A/S) twice daily modestly slows the 3-year progression of atherosclerosis of the carotid artery in males, but not females. This result persisted at a 6-year follow-up of this study (1918,10473). However, when this form of vitamin C is used alone, it does not slow the 3-year progression of atherosclerosis of the carotid artery (1918).
• Bladder cancer. Oral vitamin C does not reduce the risk of bladder cancer or mortality from bladder cancer. Details: Epidemiological research has found that supplemental vitamin C intake is not associated with mortality rate in patients with bladder cancer (9839). A secondary analysis of a large clinical trial, the Physicians' Health Study II, in healthy men aged at least 50 years also shows that taking vitamin C 500 mg daily alone or with vitamin E 400 IU daily for up to 10 years does not reduce the risk of developing bladder cancer or bladder cancer-related deaths when compared with placebo (90097).
• Cardiovascular disease (CVD). Oral vitamin C does not seem to be beneficial for either primary or secondary CVD prevention. Details: Vitamin C does not seem to be beneficial for primary prevention of CVD. Some population research has found that higher supplemental vitamin C or dietary vitamin C has been associated with a reduced risk of developing CVD (10358,14108,109779), while other observational research has found no benefit (34566,10358,14108). However, meta-analyses of clinical research in healthy patients show that vitamin C supplementation does not prevent CVD or coronary heart disease when compared with control (97308,104025). In 2004, the American Heart Association stated that current evidence does not justify use of antioxidants such as vitamin C for reducing the risk of CVD (12142). Evidence is also negative for secondary prevention in people with coronary heart disease. Population studies have found that higher serum vitamin C was associated with no effect or decreased CVD mortality from CVD (3910,5878). A meta-analysis of two large clinical trials shows that vitamin C supplementation does not reduce CVD events or CVD mortality when compared with control (97308).
• Colorectal cancer. Oral vitamin C does not seem to prevent colorectal cancer. Details: Population research has found that dietary vitamin C intake is not associated with a reduced risk of developing colon cancer. When total vitamin C intake from food and supplements is considered, there is a modest association (34600). However, most clinical trials show that supplemental vitamin C, alone or along with other antioxidants, does not reduce the risk of colorectal cancer development, colorectal cancer or adenoma recurrence, or colorectal cancer-related mortality (34580,34581,34594,90097,90089,92903).
• Fetal and premature infant mortality. Oral vitamin C does not seem to prevent neonatal death. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of neonatal death (83472,96707).
• Fractures. Oral vitamin C does not seem to improve fracture healing. Details: Clinical research shows that taking vitamin C 500 mg daily for 50 days following an acute distal radial fracture does not improve physical function, symptoms, or healing rates when compared with placebo (90411).
• Helicobacter pylori. Oral vitamin C does not seem to improve eradication of H. pylori. Details: Most clinical research shows that treatment with vitamin C, alone or in combination with vitamin E, does not improve the eradication rate of H. pylori when taken with a standard eradication regimen when compared with the eradication regimen alone (83476,90094).
• Hereditary motor and sensory neuropathy. Oral vitamin C does not seem to improve neuropathy in these patients. Details: In a meta-analysis of five studies in patients with Charcot-Marie-Tooth disease type 1A, taking vitamin C 1-4 grams orally daily for 1 year did not improve neuropathy when compared with placebo (99084). Continuing vitamin C 4 grams daily for 2 years also does not improve neuropathy in these patients (90419).
• Interferon-related retinopathy. Oral vitamin C does not seem to improve retinopathy associated with interferon therapy. Details: A small clinical study in patients with chronic hepatitis C receiving interferon therapy shows that taking vitamin C 600 daily orally does not seem to reduce the risk of retinopathy from interferon therapy when compared with control (10355).
• Leukemia. Oral vitamin C does not seem to reduce the risk of leukemia or mortality from leukemia. Details: A large clinical trial in men aged at least 50 years shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing leukemia or leukemia-related deaths when compared with placebo (90097).
• Low birth weight. Oral vitamin C does not seem to reduce the risk of infants being born with a low birth weight. Details: Meta-analyses of clinical research show that maternal use of oral vitamin C alone or with other supplements does not reduce the risk of giving birth to infants with low birth weight when compared with control (83450,83472).
• Lung cancer. Oral vitamin C does not seem to reduce the risk of lung cancer. Details: Two meta-analyses of clinical research suggest that taking vitamin C, alone or in combination with vitamin E, does not reduce the incidence of lung cancer or lung cancer-related mortality (34528,34632). Also, a clinical study in females shows that taking supplemental vitamin C 500 mg daily, with or without vitamin E and beta carotene, is associated with an INCREASED risk of lung cancer when compared with placebo (34580). However, another large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests that moderate dietary intake of vitamin C around 500 mg daily is protective against lung cancer, but higher doses of vitamin C might increase the risk of lung cancer (112096).
• Melanoma. Oral vitamin C does not seem to reduce the risk of melanoma. Details: Clinical research shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing melanoma or melanoma-related deaths when compared with placebo in men aged at least 50 years (90097).
• Miscarriage. Oral vitamin C does not seem to reduce the risk of miscarriage. Details: A meta-analysis of clinical research shows that taking vitamin C alone or with other supplements does not reduce the risk of miscarriage when compared with control (94820).
• Overall mortality. Oral vitamin C does not reduce overall mortality. Details: Although population research suggests that higher dietary intake and higher plasma vitamin C levels are associated with a reduced risk of mortality from all causes (3910,109779), vitamin C supplementation does not seem to affect overall mortality. Meta-analyses of clinical research show that taking vitamin C supplements does not reduce overall mortality when compared with control (34622,111641). Clinical studies of vitamin C used in combination with vitamin E, beta carotene, and/or selenium and zinc, also show no benefit for overall mortality (9817,14109).
• Pancreatic cancer. Oral vitamin C does not seem to prevent pancreatic cancer. However, it is unclear if intravenous vitamin C is beneficial for treatment of pancreatic cancer. Details: Observational research has found that increased dietary vitamin C intake is associated with up to a 30% reduced risk of pancreatic cancer (99083,99086). However, clinical research shows that supplemental vitamin C 500 mg daily does not reduce the risk of pancreatic cancer in females (34580). Also, taking vitamin C in combination with beta-carotene plus vitamin E does not reduce the risk of pancreatic cancer (12185,34581). While research suggests oral vitamin C may not prevent pancreatic cancer, intravenous vitamin C is being explored in the treatment of pancreatic cancer. A small, open-label clinical study in adults with stage IV pancreatic ductal adenocarcinoma shows that administration of intravenous vitamin C 75 grams three times weekly throughout each cycle of chemotherapy increases median overall survival and progression free survival by approximately 8 months and 2 months, respectively, when compared with chemotherapy alone (115499). The validity of these results is limited by potential overestimation of treatment effects, influenced by small sample size, differences in chemotherapy doses, and early study termination.
• Pre-eclampsia. Oral vitamin C does not seem to prevent pre-eclampsia. Details: Despite some early positive research in high-risk pregnancies, the majority of meta-analyses and clinical studies show that taking vitamin C alone or with vitamin E or other supplements does not reduce the risk of pre-eclampsia when compared with control. There is even some concern that vitamin C supplementation may increase the risk of gestational hypertension (3236,83450,83472,83474,96707).
• Preterm labor. Oral vitamin C does not seem to prevent preterm labor. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of preterm labor when compared with control (83450,83472,96707).
• Prostate cancer. Oral vitamin C does not seem to prevent prostate cancer. However, it is unclear if intravenous vitamin C is beneficial for the treatment of prostate cancer. Details: A large-scale clinical study (The SU.VI.MAX study) shows that a combination of vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg, taken daily for an average of 8 years, does not reduce the risk of prostate cancer overall. However, it might reduce the risk of prostate cancer in those who have normal PSA levels. It does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). Another large scale study (Physician's Health Study II) shows that taking vitamin C 500 mg daily for an average of 8 years does not significantly reduce the risk of prostate cancer when compared with placebo (16708). Similarly, results from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial seem to show that supplemental or dietary intake of vitamin C does not reduce the risk of prostate cancer when compared to individuals not taking vitamin C (14124). While research suggests oral vitamin C may not prevent prostate cancer, intravenous vitamin C is being explored in the treatment of prostate cancer. A small clinical study in adults with metastatic castration-resistant prostate cancer shows that administration of intravenous vitamin C 1 gram/kg twice weekly in combination with docetaxel for up to 24 weeks does not reduce prostate-specific antigen (PSA) by 50% or more when compared with docetaxel alone (115611). This study may have been underpowered to show a difference between groups.
• Radiation dermatitis. Topical vitamin C does not seem to prevent radiation dermatitis in cancer patients. Details: A small clinical study shows that applying a 10% vitamin C solution does not appear to protect from radiation dermatitis when applied to the scalps of patients treated with radiation for intracranial tumors (789).
• Small for gestational age (SGA). Oral vitamin C does not seem to reduce SGA. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of small for gestational age birth when compared with control (83450,83472).
• Stillbirth. Oral vitamin C does not seem to prevent stillbirth. Details: Meta-analyses of clinical research show that maternal use of vitamin C alone or with other supplements does not reduce the risk of stillbirth when compared with control (83472,96707).

LIKELY INEFFECTIVE

• Coronavirus disease 2019 (COVID-19). Oral vitamin C, even at high doses, does not seem to speed recovery from COVID-19 in non-hospitalized patients. Most studies show that oral or intravenous vitamin C given to patients hospitalized with COVID-19 does not improve organ function or survival, but the evidence is conflicting. It is unclear whether vitamin C is beneficial for long COVID. Details: A clinical study in adult outpatients with confirmed COVID-19 shows that taking oral vitamin C (ascorbic acid) 8000 mg in 2-3 divided doses daily, alone or with zinc gluconate 50 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). The study was terminated prior to complete enrollment due to futility and apparent lack of effect from vitamin C and/or zinc supplementation. Limitations of this study include a lack of placebo control and blinding. Additionally, this study has been criticized for methodologic concerns (106624). Another small clinical trial in adult outpatients with confirmed COVID-19 shows that taking vitamin C 1000 mg daily for 14 days does not improve symptoms or quality of life when compared with placebo (109462). Vitamin C has also been evaluated in patients hospitalized with COVID-19. A very large analysis of two multinational clinical studies in critical and non-critical adults hospitalized with COVID-19 shows that administering intravenous vitamin C 50 mg/kg every 6 hours for 96 hours does not improve organ support-free days or survival and has a high probability of futility and worsened outcomes when compared with placebo (113666). Individual prospective and retrospective studies in critically ill patients hospitalized with COVID-19 in various countries have found that administering vitamin C, either enterally as 500-1000 mg daily or intravenously as 8-24 grams daily or 50 mg/kg daily, does not significantly reduce in-hospital or short-term mortality, hospital length of stay, or end-organ failure when compared with control groups receiving standard care alone. Additionally, all but one study found no change in the need for mechanical ventilation (105458,105465,106937,106938,108075,108079,108081). However, a meta-analysis and some small individual studies have found that vitamin C is modestly beneficial for patients hospitalized with COVID-19. A meta-analysis of 10 clinical trials and 9 observational studies in patients hospitalized with COVID-19 shows that receiving oral or intravenous vitamin C daily reduces the odds of in-hospital mortality by 41% when compared with control. When only clinical trials were considered, the odds of in-hospital mortality were decreased by 56%; however, this reduction was only identified in studies using vitamin C 10 grams daily or less. Conversely, supplementation with vitamin C increased the length of intensive care unit (ICU) stay by nearly 2 days and did not impact length of hospital stay or reduce the need for mechanical ventilation, liver injury, or cardiac injury (109955). Similarly, a meta-analysis of 8 clinical studies in primarily hospitalized patients with moderate to severe COVID-19 shows that vitamin C administered orally or intravenously decreases the risk of all-cause mortality by 16% when compared with control (114488). Additionally, a small study found a small improvement in survival when compared with standard care; however, the overall survival rate in this study was low (108075). Another clinical study in patients hospitalized in Turkey with COVID-19 shows that adding high-dose intravenous sodium ascorbate 50 mg/kg to a treatment regimen of hydroxychloroquine, azithromycin, and zinc may improve recovery time, with 57% and 39% of patients achieving total recovery at day 15 in the vitamin C and control groups, respectively (108071). However, the validity of this trial is limited due to unclear reporting. Vitamin C has also been evaluated in combination with other ingredients in patients with long COVID. Preliminary clinical research in adults with long COVID and persistent fatigue shows that taking a specific combination product containing vitamin C 500 mg and L-arginine 1.66 grams (Bioarginina C, Farmacetici Damor) for 28 days increases 6-minute walk test distance by 10% and reduces self-reported fatigue when compared with placebo (110390). However, it is unclear whether these effects are due to vitamin C, L-arginine, or the combination.
• Sepsis. Intravenous vitamin C, alone or in combination with thiamine and/or hydrocortisone, does not prevent organ failure, reduce intensive care or hospital length of stay, or reduce mortality in sepsis or septic shock. Details: Observational research suggests that patients with septic shock are more likely to have low plasma levels of vitamin C (100317). However, three randomized clinical trials in patients with sepsis or septic shock show no benefit with intravenous vitamin C, with or without thiamine, for improving organ function and preventing organ failure when compared with control treatment (102130,104027,114489). A small clinical study in patients with septic shock shows that intravenous vitamin C 50 or 150 mg/kg daily for 4 days does not improve organ dysfunction or failure rates, duration of hospital or intensive care unit (ICU) length of stay, duration of mechanical ventilation, or mortality rate when compared with placebo (114489). Another clinical study in patients with septic shock shows that administering an intravenous bolus of vitamin C 1000 mg followed by a continuous infusion of 250 mg/hour for 96 hours, starting within 24 hours of vasopressor initiation, does not improve 28-day or ICU mortality when compared with placebo. A subgroup analysis shows that the addition of corticosteroids does not affect outcomes in either group (108078). This study may have been inadequately powered to detect a difference between groups. Also, a larger clinical trial in adults with sepsis receiving vasopressor therapy in the ICU shows that intravenous administration of vitamin C 50 mg/kg every 6 hours for up to 4 days increases the risk of death or persistent organ dysfunction at day 28 by 14% to 21% when compared with placebo. There were no differences in mortality at 6 months (109459,111643). Vitamin C has also been frequently studied in patients with sepsis and septic shock in a specific combination regimen (HAT therapy) which includes intravenous vitamin C 1.5-2 grams with hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours. While some retrospective research has found HAT therapy to be beneficial in sepsis (100315,102980), high quality, prospective clinical research has not confirmed these findings (105447,106620,109956). Several meta-analyses of randomized controlled trials and small clinical studies in patients with sepsis or septic shock show that intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, does not reduce short- or long-term mortality, ICU or hospital length of stay, kidney injury, or duration of mechanical ventilation, but modestly improves duration of vasopressor use and procalcitonin clearance, when compared with placebo or standard care. These analyses also show mixed results with respect to improvement in sequential organ failure assessment (SOFA) scores within 72 hours (105447,106620,106935,108073,109460,111298,111300,111301,111642,112479). Most studies included in the analyses administered HAT therapy for 2-10 days and compared it with normal saline control or with hydrocortisone alone (102129,102998,104027,104028,104032,105446). Although some subgroup analyses suggests that intravenous vitamin C alone in patients with sepsis may improve short-term mortality (106620,111298), other meta-analyses have not shown this benefit in subgroup analyses (111300). In addition, meta-analyses have identified significant publication bias (111298,111300). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for some domains, HAT therapy was worse when compared with placebo (111299). Studies evaluating intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, in mixed critically ill populations have also shown mixed findings. Four meta-analyses of randomized controlled trials and observational studies show that intravenous vitamin C does not have a significant effect on the length of hospital stay, mortality at 1 month, ICU mortality, use of invasive ventilation, use of renal replacement therapy, organ function, or incidence of kidney injury when compared with placebo or standard care. The meta-analyses reach conflicting conclusions on whether intravenous vitamin C reduces the risk of in-hospital mortality, 30-day mortality, and the duration of ICU stay. When only data from low risk-of-bias clinical trials are considered, the effects of intravenous vitamin C on mortality at any point are no longer significant (106933,106934,109957,113663). However, a subgroup analysis in one of these analyses suggests that intravenous vitamin C as monotherapy, or in doses of at least 10 grams daily, may improve overall mortality (106934). Vitamin C also does not appear to benefit complications from sepsis, such as vasoplegic shock. A small clinical study in adults in the ICU with vasoplegic shock mostly secondary to sepsis and requiring moderate vasopressor support shows that administering intravenous vitamin C as sodium ascorbate 1.5 grams every 6 hours for 5 days or until cessation of vasoactive therapy does not reduce the duration of vasopressors, vasopressor dose, hospital or ICU length of stay, or mortality outcomes when compared with placebo (112475).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atrophic acne scars. It is unclear if applying topical vitamin C after microblading improves atrophic acne scars. Details: A clinical study in adults with mild to severe atrophic acne scarring shows that applying a serum containing vitamin C 17% to the face after a once-monthly home microblade treatment for 4 months improves the appearance of acne scars at month 5 when compared with baseline (108086). Although this study enrolled a control group that used topical insulin in place of vitamin C, no between-group statistical comparisons were conducted, limiting the validity of this study.
• Age-related macular degeneration (AMD). It is unclear if dietary vitamin C or oral vitamin C taken in combination with other ingredients prevents AMD. Details: An umbrella review of meta-analyses shows that increased dietary intake of vitamin C is associated with 21% higher odds of developing AMD (112095). A population study suggests that vitamin C intake is associated with increased odds of developing age-related maculopathy (9823). However, other population studies have found no association between dietary or supplemental vitamin C intake and the risk of developing AMD (14007,14257). When taken in combination with other ingredients, most clinical and population research shows that taking vitamin C 500 mg along with other antioxidants such as vitamin E 400 IU, beta-carotene 15 mg, and/or elemental zinc 80 mg reduces the risk of visual acuity loss by 23% to 27%, progression to advanced AMD at 5 years by 25% to 32%, and AMD overall (7303,7304,11326,14257,90069). The antioxidant plus zinc combination seems to reduce the risk of progression to advanced AMD in these patients more than taking the antioxidants without zinc (7303,90069). More evidence is needed to determine what role, if any, vitamin C intake has on the risk of developing AMD.
• Aging skin. Topical vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Albuminuria. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking vitamin C 1250 mg plus vitamin E 680 IU daily for 4 weeks can reduce the excretion of albumin by about 19% when compared with placebo in patients with type 2 diabetes (10434).
• Allergic rhinitis (hay fever). It is unclear if oral vitamin C is beneficial in patients with hay fever. Details: Epidemiological research has found that higher vitamin C plasma levels are not associated with a decreased risk of allergic rhinitis (15200). However, clinical research shows that some forms of vitamin C might help. In one small clinical study, intranasal vitamin C administered three times daily for 2 weeks reduces nasal secretions, nasal blockage, and edema in up to 74% of patients with perennial allergic rhinitis (15201). Another small clinical study in patients with seasonal allergic rhinitis shows that taking a single oral dose of vitamin C 2 grams reduces bronchial responsiveness to histamine at one hour after ingestion (15202). However, in another small study in patients with seasonal allergic rhinitis taking vitamin C orally in doses up to 4 grams daily for 3 days does not appear to suppress cutaneous or nasal response to histamine when compared to placebo (15203).
• Alzheimer disease. It is unclear if dietary vitamin C helps to prevent this condition. Details: Most epidemiological research has found that dietary intake of vitamin C is associated with a 17% reduced risk of developing Alzheimer disease (4636,9824,10131,13165,90082).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral vitamin C helps to prevent ALS. Details: Observational research has found that increased dietary or supplemental intake of vitamin C is not associated with risk of developing ALS (90412).
• Anthracycline cardiotoxicity. Although there is interest in using oral vitamin C for anthracycline-induced cardiac toxicity, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Aspirin-associated gastric damage. It is unclear if oral vitamin C helps to prevent gastric damage caused by aspirin. Details: Some clinical research shows that vitamin C 480 mg might prevent gastric damage associated with taking aspirin 400 mg by decreasing blood loss and preventing decreased gastric blood flow (10357). However, a small clinical study in healthy patients shows that taking vitamin C 500 mg as ascorbic acid with aspirin 600 mg actually increases gastrointestinal permeability to a greater extent than either ingredient taken alone (98781).
• Athletic performance. It is unclear if oral vitamin C improves athletic performance. Details: Although some small preliminary clinical studies suggest that vitamin C might improve certain biomarkers during exercise (82922), a meta-analysis of small clinical trials in older and younger adults shows that taking vitamin C 500-1000 mg daily, with or without vitamin E, does not improve endurance, lean mass, or muscle strength when compared with placebo (102973). A more recent, small clinical study in recreationally trained males shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg daily for 10 weeks while participating in a resistance training program does not improve measures of muscle strength when compared with placebo (109959).
• Atopic disease. It is unclear if dietary vitamin C helps to prevent atopic disease. Details: Population research has found that higher intake of vitamin C is not associated with a reduced risk of eczema, wheeze, IgE-mediated food allergy, or allergic sensitization (90098).
• Attention deficit-hyperactivity disorder (ADHD). Small clinical studies suggest that high-dose oral vitamin C may not improve symptoms in patients with ADHD. Details: Some research suggests that taking megadose vitamins, including vitamin C, does not improve ADHD symptoms (9957,9958,9959). However, other preliminary clinical research shows that taking 25 mg of vitamin C in combination with flaxseed oil providing alpha-linolenic acid 200 mg twice daily might improve measures of attention, impulsivity, restlessness, and self-control in children with ADHD when compared with baseline (14443). It is not clear if these effects are due to vitamin C, flaxseed oil, or the combination.
• Autism spectrum disorder. It is unclear if oral vitamin C is beneficial in patients with autism spectrum disorder. Details: One small clinical study shows that taking vitamin C 8 grams per 70 kg daily for 10 weeks modestly reduces autism symptom severity in school children when compared with placebo (83604).
• Bleeding. It is unclear if intravenous vitamin C can reduce bleeding after total abdominal hysterectomy. Details: A small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery reduces postoperative hemorrhage volume by around 40 mL when compared with placebo (109465).
• Brain tumor. It is unclear if oral vitamin C helps to prevent brain tumors. Details: Population research has found that vitamin C intake is associated with a 14% reduced risk of glioma. This risk reduction was more prevalent in America compared to other geographic locations (98782).
• Breast cancer. It is unclear if oral vitamin C helps to prevent breast cancer, its recurrence, or breast cancer-related mortality. Details: Some epidemiological research has found that dietary vitamin C is associated with a reduced risk of breast cancer (1444,10823,10824). However, other epidemiological research has found no association with dietary or supplemental vitamin C (10825,10826,108080). One cohort study found no association between breast cancer risk and total, dietary, or supplemental vitamin C, regardless of dose, treatment duration, or formulation (single ingredient or combination product). Additionally, hormone and menopausal status did not appear to impact risk. Vitamin C intake might be associated with a reduced risk in individuals with a family history of breast cancer in first-degree relatives (108080). In patients with breast cancer, supplemental or dietary intake of vitamin C might be associated with a reduced risk of mortality. A meta-analysis of results from population research shows that vitamin C supplementation following breast cancer diagnosis is associated with a 15% lower risk of breast cancer-related mortality when compared with no supplementation (90416). A large, observational study in patients with breast cancer undergoing radiation therapy has found that vitamin C supplementation does not reduce the risk of breast cancer recurrence over a period of 5 years when compared with no supplementation. Although the vitamin C group had notably less aggressive tumor types, recurrence-free survival was similar in both vitamin C and control groups (108082). The validity of these findings is limited due to unknown doses of vitamin C and the inclusion of various breast cancer subtypes.
• Burns. Small studies suggest that intravenous vitamin C may modestly improve symptoms in patients with severe burns. Details: A small clinical study in patients with severe burns shows that administering vitamin C intravenously (IV) 66 mg/kg hourly over 24 hours, as part of fluid resuscitation using lactated ringer solution, reduces wound edema and the volume of fluid needed when compared with fluid resuscitation alone (83145). A retrospective review of adults hospitalized with severe burns has found that those who receive a continuous IV infusion of at least 10 grams of vitamin C within 2 days of admission have an in-hospital mortality rate of 46%, compared with 58% for those who do not receive vitamin C (102128).
• Cancer. It is unclear if oral or intravenous vitamin C helps to prevent cancer or cancer-related mortality. Details: Some population research has found that DIETARY intake of vitamin C is linked with a lower risk of cancer and cancer-related mortality (3910,5878,10819,109779). However, clinical research shows that taking vitamin C SUPPLEMENTS does not reduce the risk for cancer (10819,14109,34580,90097). In people with cancer, although some clinical research has shown that taking high-dose vitamin C supplements can improve survival rates (9809,96704), other clinical research has not shown this benefit (4842,4843). In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that some scientific evidence suggests that antioxidant vitamins, such as vitamin C, may reduce the risk of certain forms of cancer. However, the FDA has determined that there is little scientific evidence supporting this claim (102334). Preliminary clinical research has also evaluated vitamin C supplements in patients with cancer. High-dose oral vitamin C, 10 grams daily, in patients with advanced cancer does not seem to improve survival or decrease disease progression (4842,4843,106617). However, preliminary clinical research suggests high doses of vitamin C, given intravenously, might have a beneficial effect on some outcomes, including survival rate in some patients with cancer (9809,96704,106617). However, there is no benefit to other patients studied in the case reports and this has not been tested in well-designed clinical trials (9809,96704).
• Cardiac arrest. It is unclear if intravenous vitamin C is beneficial for patients after cardiac arrest. Details: A small clinical study conducted in Slovenia in adult survivors of out-of-hospital cardiac arrest shows that administering intravenous vitamin C 1.5 grams every 12 hours for 8 consecutive doses, with the first dose administered within 6 hours of resuscitation, in addition to standard care protects against arrhythmias and reduces the length of intensive care unit (ICU) stay when compared with placebo and standard care. However, intravenous vitamin C does not appear to protect against neurological or myocardial injury, reduce the need for mechanical ventilation, reduce the duration of hospital stay, or increase survival when compared with placebo (113667).
• Carpal tunnel syndrome. Vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamins C, E, B1, B2, B6, and B12, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and turmeric twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to vitamin C, other ingredients, or the combination.
• Cervical cancer. It is unclear if oral vitamin C helps to prevent cervical cancer. Details: Observational research has found that higher vitamin C intake is associated with a 33% to 42% reduced odds of cervical neoplasm. Increasing vitamin C intake by 50 mg daily is associated with an 8% reduced odds of cervical neoplasm (34609,98771).
• Child growth. Some clinical research in pregnant smokers suggests that taking vitamin C during pregnancy may improve pulmonary function in the offspring from birth to 6 years of age. Details: A meta-analysis of 4 data sets from one large clinical study in pregnant adults who smoke at least one cigarette daily shows that taking supplemental vitamin C 500 mg daily during pregnancy reduces lower airway resistance and improves lung capacity of the offspring at 0, 3, 12, and 60 months of age, but does not improve airway obstruction, when compared with control (113670). Additionally, one of the clinical studies included the meta-analysis shows that taking vitamin C during pregnancy lowers the occurrence of wheezing in offspring at 4-6 years of age (114496,114497).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin C for CFS, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Colistin-induced nephrotoxicity. It is unclear if intravenous vitamin C helps to prevent nephrotoxicity from colistin. Details: A small clinical study shows that intravenous administration of vitamin C 2 grams every 12 hours along with colistin for around 9-10 days does not prevent nephrotoxicity when compared with colistin therapy alone (99839). However, this study was limited by a lack of statistical power to detect differences between the study groups.
• Contrast induced nephropathy. It is unclear if oral vitamin C helps to prevent contrast-induced nephropathy (CIN). Details: Some clinical research shows that taking vitamin C before and after coronary angiography reduces the risk of developing CIN by 33% to 55% when compared with placebo in patients with renal dysfunction (12234,90421). However, other clinical evidence published since 2012 suggests that vitamin C given orally and/or intravenously before and after angiography does not reduce the risk of CIN compared with control in high-risk patients with chronic renal insufficiency or diabetes (91232,91236,90410,90425). Reasons for the discrepancies are not entirely clear. However, it is possible that the lack of significant benefit from vitamin C in the latter studies results from the fact that incidences of CIN have become less common than in the past due to avoidance of dehydration, use of smaller catheters, and use of contrast agents with reduced nephrotoxicity (90429).
• Coronary artery bypass graft (CABG) surgery. It is unclear if intravenous vitamin C helps to improve patient outcomes after CABG surgery. Details: A small clinical study shows that giving vitamin C 5 grams intravenously (IV) before anesthesia induction and 5 grams in the cardioplegia solution used during surgery shortens the length of stay in the intensive care unit (ICU) by about 8 hours (102127). However, some limited research suggests that IV vitamin C does not resolve cardiac surgery complications. A small clinical study in patients with vasoplegia after receiving CABG and other cardiac surgeries shows that receiving IV vitamin C 1.5 grams every 6 hours after being admitted to the ICU does not improve vasoplegia when compared with control (102981).
• Delirium. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001).
• Dental plaque. It is unclear if vitamin C in a chewing gum helps to reduce dental plaque formation. Details: A small clinical study in patients with calculus shows that chewing 10 pieces of gum, each containing 60 mg of vitamin C, daily for 3 months reduces the formation of dental calculus, visible plaque, and the number of bleeding sites when compared not chewing gum (83303). The validity of this finding is limited by a lack of placebo group.
• Depression. It is unclear if oral vitamin C is beneficial for the treatment or prevention of depression. Details: A small clinical study in children and adolescents shows that taking vitamin C 500 mg orally twice daily in combination with fluoxetine 10-20 mg daily for 6 months reduces most symptoms of major depressive disorder when compared with taking fluoxetine alone (90404). However, a small clinical study in adults shows that taking vitamin C up to 1000 mg daily for 2 months does not improve the response rate or decrease symptoms of depression in adults also taking citalopram when compared with citalopram alone (96708). Reasons for these conflicting results may relate to the age of the patients, study duration, or differences in antidepressant medication being taken. One clinical guideline also provisionally recommends against the use of oral vitamin C to treat patients with depression based on low-quality evidence (110318). Some research has also evaluated vitamin C intake for the prevention of depression. A secondary analysis of pre- and peri-menopausal adults enrolled in the Study of Women's Health Across the Nation (SWAN) program suggests that vitamin C intake is inversely associated with depressive symptoms. This association persisted regardless of age, race, physical activity, body mass index, antidepressant use or menopausal status (108083). The validity of these findings is limited due to the secondary nature of this study; additionally, follow-up time is unclear.
• Diabetes. It is unclear if oral vitamin C prevents diabetes. Some low-quality research suggests that vitamin C might improve glycemic control in patients with diabetes. Details: Population research has not found a link between dietary vitamin C and the risk of developing type 2 diabetes (14004). However, low certainty clinical research has found some benefit of taking vitamin C supplements for glycemic control. Two meta-analyses of several small, heterogeneous clinical studies in patients with type 2 diabetes show that taking vitamin C 200-3000 mg daily for 2-48 weeks reduces fasting blood glucose by approximately 11 mg/dL (112478) and glycated hemoglobin (HbA1c) by an average of 0.5% when compared with placebo, standard treatment, or no treatment (105461,112478). Subgroup analyses suggest that durations of supplementation longer than 12 weeks show greater glycemic benefit, and although one meta-analysis suggests there is no dose-response relationship (105461), another meta-analysis suggests that doses of vitamin C 1000 mg and higher are most beneficial for improving glycemic indices (112478). Some research has evaluated the effects of vitamin C supplementation on the lipid profile in patients with diabetes, with mixed findings. One meta-analysis of 17 small clinical studies shows that taking vitamin C 200-3000 mg daily for 2 to 48 weeks improves levels of triglycerides and total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that study durations of at least 12 weeks show greater benefit (106621). However, two other meta-analyses in patients with diabetes, one of 16 small heterogenous clinical studies and one of 11 small clinical studies, show no clinically important improvement in lipid levels after vitamin C supplementation (105461,105464).
• Dry mouth. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical trial in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 100 IU and vitamin C 500 mg twice daily for an average of 3 months improves dry mouth when compared to baseline (99080). The validity of these results is limited by the lack of comparison with a control group.
• Endometrial cancer. Increased dietary vitamin C has been linked to reduced risk of endometrial cancer. Details: Population research has found that intake of vitamin C from dietary sources is associated with a slightly decreased risk of endometrial cancer when compared with control. However, this benefit is not observed when results from a prospective cohort study are assessed (34578).
• Endometriosis. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with endometriosis and pelvic pain shows that taking vitamin C 1000 mg and vitamin E 800 IU daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo. Vitamin C and vitamin E supplementation also reduces some biochemical markers of oxidative stress when compared with placebo (106622). Additionally, a meta-analysis of 4 other, mostly small clinical studies in patients with endometriosis shows that taking vitamin C 1000 mg and vitamin E 800-1200 IU daily for 6-8 weeks reduces chronic pelvic pain and improves dysmenorrhea and dyspareunia when compared with placebo (114491).
• Endoscopy-associated adverse effects. It is unclear if a topical vitamin C spray reduces mucosal irritation in patients undergoing Lugol chromoendoscopy. Details: A small clinical trial in patients receiving a Lugol chromoendoscopy shows that spraying a vitamin C 2% solution after the application of the Lugol iodine 2% solution reduces the severity of mucosal irritation, heartburn, and pain when compared with using a normal saline spray after the Lugol iodine 2% solution (104030).
• Esophageal cancer. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research has found that higher dietary intake of vitamin C is associated with reduced odds of esophageal adenocarcinoma. A 50 gram increase in dietary vitamin C intake is associated with a 13% reduced odds of esophageal cancer (34551,98770). However, a meta-analysis of clinical research shows that taking a vitamin C supplement in combination with beta-carotene and vitamin E does not reduce the risk of esophageal cancer (34581).
• Exercise-induced asthma. Small clinical studies suggest that oral vitamin C may modestly improve symptoms in patients with exercise-induced asthma. Details: A meta-analysis of the available clinical research shows that vitamin C supplementation might reduce exercise-induced breathlessness when compared with placebo or control. However, the available research is of poor quality, and no clear conclusions can be drawn regarding its benefits for exercise-induced asthma (90409).
• Exercise-induced muscle damage. It is unclear if oral vitamin C is beneficial in exercise-induced muscle damage. Details: A small clinical study in healthy females shows that taking vitamin C 1000 mg before moderate intensity cycling does not prevent muscle damage when compared with placebo (99837). Another small clinical study in endurance-trained runners shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve other markers of exercise-induced muscle damage when compared with placebo (109961).
• Gallbladder disease. It is unclear if oral vitamin C reduces the risk of gallbladder disease. Details: Cross-sectional epidemiological evidence has found that vitamin C supplementation and increased vitamin C serum levels are associated with a decreased risk of developing gallbladder disease in females, but not males (5877).
• Gastric cancer. It is unclear if dietary or supplemental vitamin C reduces the risk of gastric cancer. Details: Most population research has not found an association between DIETARY intake of vitamin C and gastric cancer risk (9194,10822,10819,90083). Also, clinical research shows that taking vitamin C supplements in combination with other antioxidants does not reduce the risk of gastric cancer or precancerous gastric lesions (14447,34581,90085). However, some research suggests that it might be associated with a reduced risk for specific forms of gastric cancer (9838,90083). One clinical study shows that taking vitamin C orally 500 mg daily for 6 months after eradication of Helicobacter pylori infection decreases the incidence of precancerous changes in stomach tissue when compared with no treatment (10359). Also, other clinical research shows that taking vitamin C orally 1 gram daily helps promote the regression of precancerous gastric lesions in people at high risk for gastric cancer (2579). In 2009, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that vitamin C supplements may reduce the risk of gastric cancer. However, the FDA has concluded that it is highly uncertain that vitamin C supplements actually reduce the risk of gastric cancer (102332).
• Gastritis. There is limited evidence on the oral use of vitamin C in omeprazole-induced corpus gastritis. Details: A small clinical study shows that taking vitamin C orally 1200 mg daily along with omeprazole decreases corpus gastritis associated with omeprazole therapy in patients with H. pylori infection (10360).
• Gout. It is unclear if oral vitamin C helps to prevent or manage gout. Details: Population research in men has found that taking vitamin C 500-1500 mg daily from the diet and/or supplements is associated with up to a 34% reduced risk of gout when compared with less than 250 mg daily (16755). Also, men who ingest over 500 mg of vitamin C daily from the diet and supplements have serum uric acid levels that are slightly lower than men who consume less than 90 mg daily (16820). However, taking supplemental vitamin C 500 mg daily for 8 weeks does not seem to lower serum uric acid levels in patients who already have gout (90423).
• Hearing loss. There is limited evidence on the intravenous use of vitamin C in idiopathic sudden sensorineural hearing loss. It is unclear if dietary vitamin C intake can affect the risk of hearing loss. Details: A small clinical study in patients with idiopathic sudden sensorineural hearing loss shows that receiving intravenous high-dose vitamin C 200 mg/kg daily in combination with steroid therapy for 10 days, followed by oral vitamin C 2000 mg daily for 30 days, increases recovery rate two-fold and modestly improves hearing threshold levels when compared with receiving steroid therapy only (90417). In addition, population research in females has found that high dietary intake of vitamin C is associated with a 22% increased risk of developing self-reported hearing loss over a 22-year period when compared with low intake (109807).
• Heart transplant complications. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of vitamin C 500 mg and vitamin E 400 IU, taken twice daily for 1 year starting within the first 2 years after cardiac transplant, reduced the progression of vasculopathy as measured by intravascular ultrasonography (IVUS) when compared with placebo. This suggests that the combination may help slow the progression of CAV (82826).
• Hepatitis C. It is unclear if oral vitamin C is beneficial in patients with hepatitis C. Details: A small clinical study in patients with confirmed hepatitis C shows that taking vitamin C 1000 mg daily with conventional therapy (sofosbuvir plus daclatasvir) for 4 weeks improves serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and albumin when compared with conventional therapy alone (109463).
• HIV/AIDS. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, low-quality study in men with HIV shows that taking vitamin C 250 mg daily in combination with vitamin A, beta-carotene, vitamin E, selenium, and coenzyme Q10 does not improve viral load, although it seems to improve markers of oxidative stress when compared to baseline. However, a 1000 mg dose of vitamin C, as well as higher doses of the other antioxidants, do not seem to provide any additional effect (9830).
• HIV transmission. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in HIV-positive mothers shows that taking vitamin B, vitamin C, and vitamin E daily during pregnancy and while breast-feeding for 20 weeks seems to reduce child mortality and HIV transmission through breast milk when compared with taking vitamin A (9801).
• Hyperphosphatemia. Intravenous vitamin C might be beneficial for reducing phosphate levels in patients with end-stage renal disease. Details: A small clinical study in hemodialysis patients with elevated phosphorus levels suggests that administering vitamin C 500 mg intravenously three times weekly for 8 weeks reduces phosphorus levels about seven-fold when compared with placebo (90414).
• Idiopathic interstitial pneumonia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with idiopathic pulmonary fibrosis, a form of idiopathic interstitial pneumonia, shows that taking a combination of vitamin C 250 mg every other day, vitamin D 50,000 IU daily, and vitamin E 200 IU daily for 12 weeks improves some, but not all, measures of lung function and reduces markers of inflammation and oxidative stress when compared to baseline (109464). The validity of these findings is limited by a lack of placebo control group.
• Infertility. It is unclear if oral vitamin C is beneficial in anovulatory females. Details: A very small clinical study suggests that taking vitamin C 400-1000 mg daily might improve fertility, resulting in ovulation and pregnancy in some anovulatory females, when compared to baseline (14018). The validity of these findings is limited by the small study size and lack of a comparator group. However, a very large observational study suggests that there is no association between dietary vitamin C intake and in-vitro fertilization (IVF) outcomes including good oocyte quality, embryo transfer success rates, clinical pregnancy rates, and successful term pregnancy rates in subfertile couples who are candidates for IVF (112097).
• Male infertility. It is unclear if oral or intravenous vitamin C is beneficial in males with infertility. Details: A meta-analysis of three small, low-quality clinical trials in males with infertility shows that taking vitamin C up to 1000 mg daily for up to 12 weeks can improve sperm count, motility, and vitality, but does not seem to increase semen volume or sperm concentration, when compared with control (109461). It is unclear if vitamin C can increase pregnancy rates, as these studies did not assess this outcome. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing vitamin C 90 mg, zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296).
• Mastalgia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin C 100 mg, vitamin B12, and gamma-linolenic acid daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Melasma. It is unclear if topical vitamin C is beneficial in patients with melasma. Details: A small clinical study in patients with bilateral symmetrically distributed facial melasma shows that applying 0.5 mL of vitamin C (Cosmotech, Alpha Medical Cosmotech) following dermapen microneedling every 2 weeks for 6 weeks is similarly effective to tranexamic acid for improving melasma severity and pigmented, but not vascular, findings on dermoscopic examination (106939). Additionally, a small clinical study in adults with melasma shows that applying 1 to 2 mL of 20% vitamin C solution following dermapen microneedling every 2 weeks for 8 weeks does not improve the degree of pigmentation when compared with topical metformin but does improve the degree of pigmentation when compared to baseline (115610).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin C is beneficial in patients with NAFLD. Details: A clinical study in patients with NAFLD shows that taking vitamin C 250 mg, 1000 mg, or 2000 mg daily for 12 weeks improves some biochemical markers of liver health and glucose metabolism when compared with baseline. However, the improvement from baseline was similar between groups (106942).
• Nonalcoholic steatohepatitis (NASH). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests vitamin C in combination with vitamin E might improve hepatic fibrosis in patients with NASH. However, it does not seem to decrease liver inflammation (14005).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin C reduces the risk of developing diffuse large B-cell lymphoma. Details: In one population study, higher dietary or supplemental intake of vitamin C was associated with a reduced risk of diffuse large B-cell lymphoma, a type of non-Hodgkin lymphoma, when compared with lower intake in postmenopausal adults (90945).
• Oral cancer. It is unclear if oral vitamin C reduces the risk of developing oral cancer. Details: Population research has found that higher dietary intake of vitamin C is associated with a reduced risk of oral cancer (10821). However, clinical research has not shown benefit with oral vitamin C supplements. A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Oral leukoplakia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not improve leukoplakia symptoms or reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Osteoarthritis. It is unclear if dietary vitamin C reduces the risk of developing osteoarthritis. Details: Observational research has found that increased vitamin C from dietary sources is associated with a reduced risk of cartilage loss and disease progression in people with osteoarthritis (5881).
• Osteoporosis. It is unclear if dietary vitamin C improves bone density or reduces fracture risk in patients at risk for osteoporosis. Details: Some cross-sectional observational research in postmenopausal patients without a history of smoking or estrogen use has found that higher serum vitamin C levels are associated with lower bone mineral density (9828). However, other observational research in a larger population of adults at risk for osteoporosis has found that higher dietary vitamin C intake is not associated with fracture risk (104415).
• Ovarian cancer. Dietary vitamin C might not affect the risk of ovarian cancer. Details: Epidemiological research has found that dietary vitamin C intake is not linked with ovarian cancer risk (9193,102977).
• Pancreatitis. It is unclear if intravenous vitamin C is beneficial in patients with acute pancreatitis. Details: A small meta-analysis of clinical studies in patients with acute pancreatitis shows that intravenous vitamin C does not improve the odds of developing organ failure when compared with placebo or no intervention. Intravenous vitamin C seems to reduce hospital stay, but not in-hospital mortality (106941).
• Parkinson disease. Dietary vitamin C might not affect the risk of developing this condition. Details: Observational research has found that moderate or high dietary intake of vitamin C is not associated with a reduced risk of Parkinson disease (83316).
• Periodontitis. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if dietary vitamin C reduces the risk of periodontitis. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing vitamin C 100 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation, among others, when compared with placebo (111708). It is unclear if these effects are due to vitamin C, other ingredients, or the combination. There is also interest in whether dietary vitamin C intake impacts the risk of periodontitis. Observational research in US adults has found that individuals with dietary intake of vitamin C in the third quartile, but not the second or fourth quartiles, have lower odds of periodontitis when compared with vitamin C intake in the lowest quartile. Furthermore, the investigators identified a non-linear relationship between vitamin C intake and periodontitis risk, suggesting that individuals with intakes either much lower or much higher than 158 mg daily are at increased risk of developing periodontitis (109958).
• Peripheral arterial disease (PAD). It is unclear if dietary vitamin C helps to reduce the risk of developing PAD. Details: In females, epidemiological evidence has found that dietary intake of vitamin C of 142 mg daily or greater is associated with a 36% reduced risk of PAD when compared with lower intake levels of less than 80 mg daily (10130).
• Physical performance. It is unclear if oral vitamin C helps to improve physical performance and muscle strength in older people. Details: Population research has found that higher intake of dietary vitamin C is associated with improved physical performance and muscle strength in elderly people (14006). In contrast, a small clinical study in elderly men undergoing strength training shows that taking vitamin C 1000 mg and vitamin E 258IU daily for 12 weeks does not increase strength, and might even attenuate increases in muscle mass, when compared with strength training alone (96701).
• Pneumonia. It is unclear if oral or intravenous vitamin C helps to prevent or treat pneumonia. Details: A meta-analysis of 6 clinical studies in adults with community-acquired pneumonia shows that oral or intravenous vitamin C does not reduce overall mortality, hospital or intensive care unit length of stay, or the risk of mechanical ventilation when compared with control (114490). The interpretation of these results is limited by significant heterogeneity of the included studies. An earlier meta-analysis of two small, low-quality clinical studies in children shows that vitamin C does not seem to reduce the risk of pneumonia when compared with a control (104033).
• Postoperative recovery. It is unclear if oral or intravenous vitamin C improves postoperative recovery. Details: Meta-analyses of clinical research show that oral or intravenous vitamin C can shorten the duration of hospitalization after cardiac surgery when compared with control (91233,96703). However, other research shows no decrease in intensive care unit (ICU) or hospital stay with vitamin C supplementation (96705), while another clinical study in patients undergoing cardiac surgery with extracorporeal circulation shows that intravenous vitamin C administered during surgery and 48 hours after surgery reduces ICU stay and re-admission rates, wound infection, and hospital mortality, but not length of hospital stay, when compared with control (114492). A meta-analysis of 37 clinical trials in adults undergoing low- to high-risk noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, or kidney transplantation), shows that receiving perioperative vitamin C, either orally or intravenously, does not improve duration of hospitalization or overall mortality when compared with control (108087).
• Postoperative pulmonary complications. It is unclear if intravenous vitamin C improves postoperative pulmonary complications. Details: A large, single-blind clinical study in patients with recent cardiac surgery with extracorporeal circulation shows that parenteral administration of vitamin C 50 mg/kg intraoperatively and 50 mg/kg every 6 hours for the next 48 hours, followed by oral vitamin C 2000 mg daily until 1-week post-discharge, reduces the incidence of postoperative pulmonary complications (PPC) by 22% and improves PPC severity scores when compared with control. Specifically, vitamin C reduces the incidence of pneumothorax, pleural effusion, pneumonia, and re-intubation and may ameliorate lung damage as suggested by higher Horowitz index when compared with control (114492). A small clinical trial in patients undergoing low-risk cardiac surgery shows that receiving intravenous vitamin C 1 gram 10 minutes after anesthesia might slightly reduce the rate of postoperative pulmonary complications when compared with receiving a saline injection (104034).
• Postoperative swelling. It is unclear if vitamin C reduces postoperative swelling after dental surgery. Details: A small observational study in adults undergoing surgery for wisdom tooth extraction shows that taking vitamin C 500 mg three times daily for 7 days in addition to standard treatment reduces swelling 7 days after surgery when compared with control. However, vitamin C does not seem to reduce swelling 3 days after surgery when compared with control, suggesting that longer durations are needed for anti-inflammatory effects (113664).
• Premature rupture of membranes (PROM). Oral vitamin C seems to reduce the risk of PROM in some patients; however, the addition of oral vitamin E seems to negate any benefit. Details: A meta-analysis of clinical research shows that taking vitamin C alone decreases the risk of both term and preterm PROM by 45% and 34%, respectively, when compared with placebo or control (96707). Another meta-analysis of clinical research shows that taking vitamin C during pregnancy decreases the risk of PROM by 43% and preterm PROM by 33%, but does not decrease the risk of term PROM, when compared with a control. While vitamin C was studied in doses of 100, 500, and 1000 mg daily, the decreased risk of PROM was only observed in studies of 100 mg daily (114493). A moderate-sized clinical study in patients with a history of PROM shows that taking vitamin C 100 mg daily, starting at 14 weeks' gestation, increases the gestational age at recurrent PROM by around 1 week and increases the gestational age at birth by around 1.3 weeks when compared with placebo (109960). Additionally, a meta-analysis of observational studies suggests that vitamin C levels in the blood tend to be lower in patients with PROM, particularly preterm PROM (114493). Taking vitamin C in combination with vitamin E, however, does not seem to reduce the risk of term or preterm PROM; some research suggests that it might even increase the risk of non-preterm PROM (83472,96707). However, other research shows that taking vitamin C 1000 mg plus vitamin E 400 IU daily, beginning at 24 to 34 weeks gestation and continuing until delivery, may help increase the latency period until delivery by 5 days and increase gestational age at delivery by almost 1 week when compared with placebo in patients with preterm PROM (90078).
• Pressure ulcers. It is unclear if oral vitamin C, when used alone or in combination with other ingredients, can improve the healing of pressure ulcers. Details: A small clinical study in institutionalized patients with pressure ulcers shows that taking vitamin C 500 mg twice daily for 12 weeks does not improve wound closure or increase healing rates when compared with vitamin C 10 mg twice daily (83617). Oral vitamin C has also been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients with pressure ulcers shows that administering an oral nutritional supplement enriched with vitamin C, L-arginine, and zinc improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, vitamin C, L-arginine, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Radiation proctopathy. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with chronic radiation proctitis shows that vitamin C 500 mg plus vitamin E 400 IU three times daily might improve symptoms when compared with baseline (9825). The validity of these findings is limited by the lack of a comparator group.
• Renal cell carcinoma. It is unclear if increased dietary intake of vitamin C helps to reduce the risk of renal cell carcinoma. Details: Population research has found that increased dietary intake of vitamin C is associated with a 12% reduced risk of renal cell carcinoma (98779).
• Respiratory tract infections. It is unclear if oral vitamin C is beneficial for preventing respiratory tract infections or reducing the duration of these infections. Details: A meta-analysis of clinical research in children and adults shows that, when compared with placebo, oral vitamin C supplementation reduces the average number of symptomatic days per individual, but does not reduce the average symptom days per respiratory episode. Also, vitamin C intake does not reduce the incidence or severity of respiratory disease or improve recovery in hospitalized patients with respiratory tract infections (108077). The validity of this trial is limited by the high heterogeneity of included studies, which evaluated various vitamin C regimens, ranging from 100 mg to 8 grams daily, as preventive therapy or as an adjuvant to active treatment. A clinical study in children aged 3-10 years shows that taking vitamin C 50 mg in combination with a specific product (Lab4) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis daily for 6 months reduces the incidence of cough and sore throat by 16% and 20%, respectively, when compared with placebo. However, it did not improve total symptoms, nasal congestion, nasal discharge, or sneezing. Also, aside from a 33% reduction in the average number of days with a sore throat, daily supplementation does not reduce the duration of individual symptoms or total symptoms (106943). It is unclear if these effects are due to vitamin C, the probiotics, or the combination.
• Restless legs syndrome (RLS). It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in hemodialysis patients with RLS shows that taking vitamin C 200 mg daily, alone or in combination with vitamin E 400 mg, for 8 weeks reduces the severity of RLS when compared with placebo (90093). More research is needed to determine if vitamin C is beneficial in treating RLS that is not associated with hemodialysis.
• Sunburn. Topical and oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin C orally in combination with vitamin E seems to prevent ultraviolet (UV) radiation-induced erythema (sunburn) (4715,4716). Vitamin C in combination with high dose oral RRR-alpha-tocopherol (natural vitamin E) seems to protect against skin inflammation after exposure to UV radiation (4715). Also, applying topical vitamin C in combination with topical vitamin E and melatonin seems to provide modest photoprotective effects when used prior to UV exposure. However, it has no effect when used during or after UV exposure (4713,4714).
• Stress. It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in healthy adults shows that taking vitamin C 3000 mg daily for 14 days modestly reduces blood pressure and subjective stress response to psychological stress when compared with placebo (10353).
• Stroke. Observational research has found that although taking vitamin C supplements does not seem to be beneficial, eating more vitamin C-rich food is linked with reduced risk of stroke. Details: Lower plasma levels of vitamin C have been associated with increased stroke risk (90408). Additionally, population research has found that higher dietary intake of vitamin C is associated with a 8% to 19% reduction in stroke risk when compared to lower intake (90408,109779). This reduction appears to be dose-dependent, with each 100 mg/day increase in dietary vitamin C intake associated with about a 17% reduction (90408). However, taking vitamin C supplements has not been found to be associated with reduced stroke risk (1449,90408).
• Tetanus. It is unclear if intravenous vitamin C helps to reduce symptoms of tetanus. Details: A low quality clinical trial in children and young adults with tetanus shows that intravenous vitamin C 1 gram daily along with conventional treatment reduces fatality when compared to control (21539).
• Tooth extraction. It is unclear if oral vitamin C is beneficial for reducing pain or improving healing after tooth extraction. Details: A small clinical study in healthy patients aged 14-41 years who are undergoing bilateral premolar extraction shows that taking vitamin C 200 mg three times daily, beginning immediately after extraction and continued for 10 days, improves pain on days 1-3, and may reduce mesio-distal wound size between days 1 and 7, when compared with placebo, but not when compared with vitamin C 500 mg three times daily. A dose of 500 mg three times daily did not improve pain scores or extraction wound healing when compared with placebo (108084). The validity of this trial is limited by the short duration of treatment; additionally, this study did not report baseline vitamin C levels.
• Urinary tract infections (UTIs). Although there is interest in using oral vitamin C for UTIs, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Vascular dementia. It is unclear if oral vitamin C reduces the risk of vascular dementia. Details: Population research has found that supplemental intake of vitamin C and vitamin E is associated with a reduced risk of vascular dementia in Japanese-American men (4636). However, when cases in which dementia was diagnosed prior to the study are excluded from data analysis, intake of vitamin C and vitamin E is not associated with a reduced risk of vascular dementia in these patients (9824).
• Wound healing. It is unclear if oral vitamin C improves the healing of chronic foot ulcers. It is also unclear if intravenous vitamin C improves healing of surgical wounds after total abdominal hysterectomy. Details: A very small clinical study in adults with chronic foot ulcers shows that taking slow-release vitamin C 500 mg daily for 8 weeks seems to result in a median of 100% ulcer healing, compared with a median of 14% ulcer healing in patients taking glucosamine 1000 mg daily (105456). This finding is limited due to the small and heterogeneous patient population, which included patients with diabetes, vascular disease, and/or vitamin C deficiency. Another small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery does not reduce the rate of surgical site infection or wound dehiscence when compared with placebo (109465). However, this study may not have been adequately powered to detect differences between groups. More evidence is needed to rate vitamin C for these uses.

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EFFECTIVE

• Familial hypophosphatemia. Oral vitamin D in combination with phosphate is effective for bone disorders in patients with familial hypophosphatemia. Details: Taking calcitriol or dihydrotachysterol orally in combination with phosphate supplements is effective for treating bone disorders in people with familial hypophosphatemia (11818).
• Hypoparathyroidism. Oral vitamin D increases serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism. Details: Vitamin D2 (ergocalciferol) is effective in high doses for increasing serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism (11820). Also, taking vitamin D (form unspecified) or calcitriol postoperatively is effective for preventing hypocalcemia in people with hypoparathyroidism due to thyroidectomy (39045).
• Osteomalacia. Oral vitamin D is effective for osteomalacia. Details: Oral calcifediol is effective for treating osteomalacia secondary to liver disease (hepatic osteodystrophy) and anticonvulsant-induced osteomalacia. Vitamin D2 (ergocalciferol) is effective for osteomalacia due to malabsorption syndromes, Fanconi syndrome, and corticosteroid-induced osteomalacia (11819,11821).
• Renal osteodystrophy. Oral calcitriol prevents renal osteodystrophy in patients with chronic renal failure. Details: Taking calcitriol orally manages hypocalcemia and prevents renal osteodystrophy in patients with chronic renal failure undergoing dialysis (11823).
• Rickets. Oral vitamin D prevents and treats rickets. Details: Vitamin D is effective for preventing and treating rickets, a consequence of vitamin D deficiency. Calcitriol should be used in patients with renal failure (11824). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to prevent nutritional rickets in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). A large clinical study in pregnant adults shows that taking vitamin D 28,000 IU weekly from the second trimester up to 6 months post-partum decreases the risk of biochemical rickets by about 84% in the offspring at 6-12 months of age when compared with placebo. However, taking vitamin D 4200, 16,800, or 28,000 IU weekly from the second trimester to delivery does not decrease the risk of rickets in the offspring when compared with placebo (114503).
• Vitamin D deficiency. Oral vitamin D prevents and treats vitamin D deficiency. Details: Vitamin D is effective for preventing and treating vitamin D deficiency using a wide range of doses and dosing frequencies (7555,16888,16891,17476,115590). Optimal blood levels of 25-hydroxyvitamin D for maintaining bone density is controversial; however, it is typically estimated that blood levels of 20-100 ng/mL are needed. Toxicity usually does not occur until levels exceed 150 ng/mL (17476,93945). Vitamin D also alleviates symptoms and syndromes associated with vitamin D deficiency. Administering vitamin D2 (ergocalciferol) intramuscularly or orally seems to help treat severe proximal myopathy associated with severe vitamin D deficiency. Several case reports suggest vitamin D therapy can provide prompt relief of muscle weakness and restore mobility (11923,84348,84687).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral vitamin D prevents corticosteroid-induced osteopenia and osteoporosis. Details: Taking calcifediol, cholecalciferol, calcitriol, or alfacalcidol orally prevents corticosteroid-induced osteopenia and osteoporosis (7555,83933). Vitamin D3 metabolites, including calcitriol and alfacalcidol, seem to be more effective at preventing bone loss compared to cholecalciferol in these patients, although the vitamin D3 metabolites seem to be inferior to bisphosphonates (83955). Furthermore, taking activated vitamin D or other forms of vitamin D alone or along with calcium improves bone mineral density in people with corticosteroid-induced osteoporosis (38493,38581).
• Osteoporosis. Adequate intake of vitamin D in conjunction with adequate calcium intake helps to prevent the progression of osteoporosis. It might also reduce the risk of a first fracture in some patients. However, its place in the prevention of secondary fracture is unclear. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate vitamin D intake of 800-1000 IU daily along with adequate calcium intake for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake, with a target serum vitamin D level of 30 ng/mL (109425). In the US, foods that contain at least 120 IU vitamin D can be labelled with a health claim regarding the relationship between adequate vitamin D intake and a reduced risk for osteoporosis (97001). However, vitamin D supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Clinical research shows that vitamin D3 (cholecalciferol) and calcium can decrease postmenopausal bone loss, improve bone density, help prevent osteoporosis, and decrease the risk of fractures (10932,12926,12930,12934,12952) (38973,39015,39026,84003,113584). According to one analysis, taking oral vitamin D3 700-800 IU daily with or without calcium reduces fracture risk in ambulatory and institutionalized elderly people (12933). Other analyses suggest that taking vitamin D as cholecalciferol, ergocalciferol, calcifediol, calcitriol, or alfacalcidol with or without calcium can reduce the risk of all fractures by up to 17%, nonvertebral fractures by up to 49%, and hip fractures by up to 30% in older adults. However, the incidence of vertebral fractures does not appear to be reduced with vitamin D supplementation (38942,38970,38973,39015,39026,84660,109053). Despite the majority of research showing benefit, some studies have not found a positive effect of vitamin D on fracture risk. Some analyses of clinical evidence, including patients with and without osteoporosis, show that taking vitamin D3 or vitamin D2 (ergocalciferol) alone does not reduce fracture risk, suggesting that adequate calcium intake is needed for any benefit to be realized (39015,84471). Also, some evidence suggests that vitamin D3 400 IU daily is not effective for the prevention of osteoporotic fractures in elderly nursing home residents (109053). Another clinical trial found that taking vitamin D3 800 IU daily with calcium 1200-1500 mg daily for 2 years does not increase bone mineral density (BMD) in Black postmenopausal adults. This may be due to the fact that Black females have a lower rate of bone remodeling, an increased calcium absorption efficiency, and reduced calcium excretion when compared with other ethnic groups; therefore, supplementation with vitamin D3 and calcium might not be as beneficial in these patients (16878). There is concern that vitamin D might not be effective for secondary prevention of fractures in elderly patients. A meta-analysis of clinical studies, including many studies cited above, and a large clinical study in elderly adults with a previous osteoporotic fracture show that taking vitamin D3 400-4000 IU daily or as a single dose up to 500,000 IU orally or injected annually with or without calcium 480-1200 mg daily for up to 5 years does not reduce the risk of hip, vertebral, or other fractures when compared with placebo or no treatment (13073,112486). Another study also shows that taking vitamin D3 800 IU and calcium 1000 mg daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (under 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). However, these studies have been criticized for failing to measure vitamin D levels and low adherence to study protocol (12931). Also, one of these studies did not use a placebo control (12929). Taking alfacalcidol orally seems to maintain BMD in prostatic carcinoma patients at risk for osteoporosis when treated with luteinizing hormone-releasing hormone analogue (LHRH-a). Alfacalcidol maintains, but does not increase, BMD in these patients (6360).
• Psoriasis. Topical vitamin D or vitamin D analogues improve symptoms of psoriasis. This benefit is not seen with oral vitamin D. Details: Topical application of vitamin D in the form of calcitriol or other vitamin D analogues, such as calcipotriene, maxacalcitol, and paricalcitol, effectively treats plaque psoriasis in some patients, including those with chronic plaque psoriasis (11822,84325). Applying topical vitamin D or its analogues in combination with topical corticosteroids such as betamethasone seems to be more effective for treating plaque psoriasis than either agent used alone (22283,82572,84325,84536,84647). Despite evidence that patients with psoriasis have low baseline serum levels of vitamin D, taking oral vitamin D does not seem to prevent psoriasis, improve symptoms, or reduce the severity of psoriasis in general (11822,22283,82572,84325,84536,84647,98193,108426,112481,112482). An analysis of a large clinical study in older adults with mild psoriasis shows that taking a vitamin D3 (cholecalciferol) loading dose of 200,000 IU followed by vitamin D3 100,000 IU monthly for 1 year does not affect the severity or spread of psoriasis when compared with placebo (98193).

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Some research suggests that oral vitamin D reduces symptoms of allergic rhinitis in children and adults. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention of allergic rhinitis in the child. Details: Preliminary clinical research in adults with allergic rhinitis and vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 8 weeks along with cetirizine improves overall symptom severity when compared with placebo and cetirizine. This improvement was not significant at 4 weeks, suggesting that symptom improvement might not occur until vitamin D has been adequately replenished (102120). Another moderate-sized clinical study conducted in China in adults with moderate to severe allergic rhinitis and vitamin D levels at the low end of the normal range shows that taking vitamin D 800 IU daily for 4 weeks along with mometasone nasal spray improves runny nose, itchy nose, and nasal congestion but does not reduce sneezing when compared with placebo and mometasone (112483). In children aged 5-15 years, 4 small- or moderate-sized clinical trials show that taking vitamin D 800 IU or 1000 IU daily for 1-6 months modestly reduces symptoms such as nasal congestion and rhinorrhea when compared with placebo or no supplementation (109728). It is unclear whether these children had vitamin D deficiency at baseline. Vitamin D supplementation during pregnancy has also been evaluated. A meta-analysis of three large clinical studies shows that prenatal vitamin D supplementation does not reduce the risk of the child developing allergic rhinitis when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Coronavirus disease 2019 (COVID-19). Clinical research suggests that vitamin D deficiency is associated with greater risk for and severity of COVID-19 infection. Research of varying quality has evaluated the use of vitamin D supplementation in adults with COVID-19 infection, suggesting that it does not reduce overall mortality, but may reduce the risk of intubation and admission to the intensive care unit (ICU). It is unclear whether any benefits are correlated to baseline vitamin D status. Details: Clinical and observational research suggests that prophylactic vitamin D supplementation may reduce the risk for and severity of COVID-19 infection in people with vitamin D deficiency or insufficiency at baseline. An umbrella review of meta-analyses summarizing data from 9 observational studies suggests that vitamin D deficiency is associated with an increased risk for COVID-19 infection and a greater severity of illness when compared with control (114583). Additionally, a separate meta-analysis of 12 observational studies conducted early in the COVID-19 pandemic suggests that low baseline vitamin D status (25-hydroxyvitamin D levels below 30 ng/mL) is associated with a greater risk of severe COVID-19 pneumonia and mortality when compared with higher levels. However, patients with lower vitamin D levels were also more likely to have baseline hypertension and cardiovascular disease (107206). While earlier meta-analyses suggested that vitamin D supplementation did not prevent COVID-19 (109040,112488), a larger and more recent meta-analysis of 5 clinical studies conducted in healthcare workers, of whom 85-94% had vitamin D insufficiency or deficiency, shows that taking vitamin D reduces the odds of developing a COVID-19 infection by about 80% when compared with control. A separate meta-analysis of 2 clinical studies in the general population found no correlation between vitamin D supplementation and risk of COVID-19 infection; however, the people in these studies had adequate vitamin D levels at baseline (113590). The benefits of vitamin D prophylaxis in people with sufficient vitamin D levels is unclear. Clinical studies have evaluated the use of vitamin D supplementation in hospitalized adults with COVID-19, assessing hospital length of stay (LOS), the risk of ICU admission, and rate of intubation. Although meta-analyses conducted in the first year of the COVID-19 pandemic did not identify an association between vitamin D supplementation and any of these outcomes (107206,109733,112490), more recent meta-analyses suggest benefit in certain populations. Meta-analyses of clinical studies in adults with COVID-19 show that vitamin D supplementation may be correlated with a modest reduction in hospital LOS in certain patients when compared with placebo or a lower dose of vitamin D. Subgroup analyses suggest that this reduction may be limited to patients with non-severe disease and those aged 60-65 years and older (115575,115578). Additionally, more recent meta-analyses of clinical studies show that vitamin D supplementation reduces the risk of admission to the ICU when compared with control, although the odds ratio varies depending on the analysis conducted (112488,112490,115578). Similarly, meta-analyses of observational studies suggest that vitamin D supplementation is associated with a reduced odds of ICU admission when compared with control (113590,115578). Also, meta-analyses of clinical studies show that vitamin D supplementation modestly reduces the risk of intubation when compared with control (112488,115578). Meta-analyses of observational studies, as well as studies conducted early in the COVID-19 pandemic, originally suggested a potential reduction in mortality with the use of vitamin D supplementation during hospitalization (109040,114583,115578). However, more recent meta-analyses of prospective clinical studies do not support this finding. A meta-analysis of 19 clinical studies in adults with moderate to severe COVID-19 shows that vitamin D supplementation does not reduce mortality when compared with placebo or standard care, when controlling for heterogeneity. Additionally, a subgroup analysis of 13 clinical studies administering high-dose vitamin D does not show a reduction in mortality (115576). Other meta-analyses of clinical studies also show that vitamin D supplementation does not reduce mortality when compared with control, regardless of baseline vitamin D status (114488,115578). In most studies that provided vitamin D to hospitalized patients, oral doses ranged from 1000-25,000 IU daily for 1-3 weeks, 10,000-25,000 weekly for up to 6 weeks or until hospital discharge, or as a single 140,000-600,000 IU dose. In some studies, vitamin D 200,000-500,000 IU was administered intramuscularly as a single dose. Cholecalciferol was the most common form administered. However, some studies used calcitriol or calcifediol (107206,107208,109040,109733,112488,112490,113590,114583,115575,115578). Overall, the validity of the findings from meta-analyses is limited by the significant heterogeneity of the included studies, which enrolled patients of varying age, disease severity, and baseline vitamin D status, and implemented highly variable vitamin D supplementation protocols. The relationship between vitamin D levels and COVID-19 has also been evaluated in pregnant adults. A meta-analysis of observational research suggests that, while lower vitamin D levels are not associated with an increased risk of COVID-19, the presence of severe COVID-19 symptoms during pregnancy may be correlated to lower vitamin D levels when compared with non-severe COVID-19 symptoms (112025). Vitamin D has also been evaluated for post-COVID-19 symptoms. A clinical study in adults with vitamin D deficiency, as well as fatigue and neuropsychiatric symptoms for at least one month post-COVID-19, shows that taking vitamin D 60,000 IU weekly for 8 weeks modestly improves fatigue, anxiety, and some aspects of cognitive function, but not symptoms of depression, when compared with placebo (115580). It is unclear if the improvements in anxiety and cognitive function were clinically significant. Additionally, it is unclear if vitamin D supplementation is beneficial in adults with adequate baseline vitamin D levels.
• Dental caries. Some research suggests that oral vitamin D reduces the risk of dental caries in children. Details: A meta-analysis of clinical research suggests that vitamin D3 (cholecalciferol) reduces the risk of cavities by 49%, and vitamin D2 (ergocalciferol) reduces the risk by 36% when compared with placebo in infants, children, and adolescents (84690). The validity of this finding is limited by the heterogeneity of the included trials. Also, clinical research shows an inverse correlation between cord blood vitamin D status and the number of decayed primary teeth in the infant at 12 months of age (104620). However, this same research shows that taking two oral prenatal doses of vitamin D2 50,000 IU during pregnancy does not prevent dental caries in the infant at 12 months of age or increase vitamin D levels in the cord blood (104620).
• Heart failure. Limited research suggests that oral vitamin D reduces the risk of developing heart failure in some patients. However, vitamin D does not seem to improve outcomes in patients that have already developed heart failure. Details: Population research has found that vitamin D levels below 15 ng/mL are associated with increased risk of developing heart failure (16615). A meta-analysis of 17 trials, including the landmark Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, shows that vitamin D reduces the risk of heart failure by 21% compared to not taking vitamin D in patients 60 years or older (91343). This finding is limited because none of the included trials were designed to determine effects on cardiovascular outcomes. In contrast, a secondary analysis of data from the Women's Health Initiative trial shows that taking vitamin D 400 IU with calcium 1000 mg daily is not associated with a reduced risk of heart failure in postmenopausal adults. However, a subgroup analysis of that trial shows that taking vitamin D plus calcium is associated with a 37% lower risk of developing heart failure in postmenopausal adults classified as low-risk for heart failure at baseline. It is speculated that high-risk patients might not benefit from vitamin D plus calcium due to negative interactions with medications used to manage cardiovascular risk factors in this group (97307). While vitamin D might be associated with a reduced risk of developing heart failure, most evidence suggests that vitamin D is not beneficial in patients already diagnosed with heart failure. In one small clinical trial, taking vitamin D3 50,000 IU weekly along with calcium citrate 800 mg daily for 6 months was not associated with an improvement in 6-minute walk test, timed get up and go test (TGUG), electrocardiographic variables, or health status when compared with placebo in adults with heart failure; mortality was not evaluated (97299,97300). In another clinical trial, taking vitamin D3 2000 IU daily did not decrease the risk of mortality when compared with placebo in New York Heart Association (NYHA) class 2 heart failure patients (16620).
• Hyperparathyroidism-related bone loss. Limited evidence suggests that oral vitamin D is beneficial in patients with this condition. Details: Taking vitamin D3 (cholecalciferol) orally seems to help decrease secondary hyperparathyroidism and bone turnover in females. In one study, supplementation with vitamin D3 increased serum levels of 25-hydroxyvitamin D, reduced levels of parathyroid hormone, and decreased production of markers of bone turnover (3463).
• Respiratory tract infections. Clinical research shows that oral vitamin D supplementation reduces the risk for respiratory tract infections (RTIs) in children but not in adults or older adults. Some clinical practice guidelines recommend vitamin D supplements or fortified foods for children to potentially lower the risk of RTIs. It is unclear if oral vitamin D is beneficial for the treatment of RTIs. Details: Prenatally, increased levels of vitamin D during pregnancy have been associated with a lower incidence of childhood RTIs (98197). However, two meta-analyses of small clinical studies and one meta-analysis of large clinical studies show no effect of prenatal vitamin D supplementation on the incidence of infant or childhood RTIs, including lower RTIs, when compared with control. Results related to risk of wheeze are conflicting (95910,95912,108438). In children, most research shows that vitamin D supplementation reduces the risk of RTIs. A meta-analysis of clinical trials in children aged 1-16 years shows that taking vitamin D decreases the odds of having an RTI by about 29% when compared with control, although this study also identified a high likelihood of publication bias (105721). Daily or weekly vitamin D doses seem to be more beneficial than single bolus doses, although the largest meta-analysis failed to confirm this result (84689,93766,105721). One clinical study in preterm Black infants shows that taking vitamin D3 (cholecalciferol) 200 IU daily and then 400 IU daily until 6 months of age does not affect the rate of RTIs, but does reduce wheeze by 11%, when compared with a normal diet without vitamin D supplementation (98191). This study may not have been powered to detect a difference in RTIs between groups. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to potentially lower the risk of RTIs in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). In adults, vitamin D supplementation does not seem to reduce the risk of RTIs. Observational research in adults has found that low levels of vitamin D are associated with worsened RTI complications, and even increased mortality in older adults ages 50-75 years (103659). However, meta-analyses of prospective clinical trials in adults show that taking vitamin D supplements 300-4000 IU daily for 7 weeks to 5 years or taking vitamin D 30,000-100,000 IU monthly or 96,000-120,000 IU every 2 months for 1-5 years does not reduce the odds of developing an RTI or severe respiratory complications, such as emergency department utilization, hospitalization, and death, when compared with placebo. These results were similar in subgroup analyses evaluating overall vitamin D dose and baseline vitamin D status (84689,105721,114506). The largest single clinical trial, conducted in adults at least 60 years of age, shows that taking vitamin D3 (cholecalciferol) 60,000 IU once monthly for up to 5 years reduces the duration of total and severe respiratory symptoms by approximately 0.5 days, but does not reduce the incidence of respiratory illness or hospitalization, when compared with placebo (105726,110825). When adults and children are evaluated together, vitamin D supplementation does not seem to reduce the risk of respiratory infections. Two large meta-analyses of 40 clinical studies in both children and adults shows that taking vitamin D does not reduce the risk of acute RTIs. While subgroup analyses suggest a potential modest reduction in risk of acute RTIs in studies not exceeding 4 months' duration and with daily supplementation of 400-1200 IU during winter, spring, and autumn, these findings are limited by the low quality of the evidence and publication bias (108435,115582). Vitamin D has also been evaluated for the treatment of RTIs. A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D improves outcomes (e.g., sputum conversion, survival rate, therapeutic success, need for intensive care admission) by a small, but not clinically relevant, amount. In subgroup analyses, these beneficial effects only persisted in studies considered to be of low quality (108436). The validity of these findings is limited by publication bias.
• Tooth retention. Oral vitamin D with calcium seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking vitamin D3 (cholecalciferol) 700 IU daily along with calcium citrate malate 500 mg daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Most research shows that taking vitamin D with or without calcium does not reduce the risk of CVD or CVD complications. There is some speculation that there might be modest benefit in the elderly, but more research is needed to confirm. Details: Population research has found that low vitamin D levels, especially those below 15 ng/mL, are associated with an increased risk of developing CVD (15630,16618,93944,113588). However, taking vitamin D supplements does not seem to prevent CVD. The majority of evidence from clinical research, population research, and meta-analyses shows that vitamin D supplementation, with or without calcium, does not reduce the risk of mortality, myocardial infarction, cardiac-related hospitalizations, or stroke when compared with placebo in patients with or without CVD risk factors (91343,97296,97305,97308,98902,98916,99762,109729,110811,110827)(112021,112022,113588). The most reliable evidence comes from two meta-analyses of mainly high-quality clinical research investigating the effect of supplementation with vitamin D alone or with calcium for at least 1 year. These analyses show that vitamin D does not reduce major adverse cardiovascular events, stroke, CVD mortality, or all-cause mortality, regardless of baseline vitamin D level, vitamin D dosage, sex, formulation, or concomitant calcium supplementation (99762,109729). One large clinical trial in individuals at increased CVD risk shows that taking vitamin D as cholecalciferol 60,000 IU monthly modestly INCREASES the risk of CVD- and presumed CVD-related mortality (110827). The effect of vitamin D supplementation in elderly adults on CVD outcomes has also been evaluated. In some research, taking vitamin D 700-1000 IU daily shows a trend towards lower CVD events and reduced risk of major adverse cardiovascular events in elderly patients (11931,98916,99762). However, another study in adults aged 70 years or older without a history of cardiovascular events and who are vitamin D replete at baseline shows that taking vitamin D 2000 IU daily for 3 years does not decrease the risk of coronary heart disease, heart failure, stroke, or hypertension when compared with placebo (113581). Larger, high-quality trials with prespecified primary outcomes are needed to determine whether or not vitamin D supplementation reduces CVD risk in elderly populations.
• Critical illness (trauma). Taking vitamin D 540,000 IU as a single oral dose does not reduce death or hospital stay in critically ill patients. However, limited research suggests that taking a smaller dose of vitamin D long-term might have a modest benefit. Details: The most robust evidence to date shows that correcting vitamin D levels in critically ill patients with vitamin D deficiency does not reduce mortality rate or duration of hospital stay. A large, multicenter clinical study in critically ill patients with vitamin D deficiency shows that administering a single, enteral dose of vitamin D 540,000 IU does not reduce 90-day all-cause mortality, duration of hospital stay, ventilator-free days, or other clinical outcomes when compared with placebo (103656). A previous meta-analysis of clinical research showed that vitamin D supplementation administered for a duration of 7 days or up to 6 months reduces the risk of death by 30% in critically ill hospitalized patients (95913). However, included studies were of low methodological quality, had high heterogeneity, assessed patients with and without vitamin D deficiency, and used variable vitamin D dose regimens and administrations methods (95913,95914).
• Fractures. Most evidence shows that oral vitamin D alone does NOT prevent factures in people who do not have osteoporosis. Some research shows that taking vitamin D with calcium prevents fractures; however, more research is needed to determine who is most likely to benefit. Details: Clinical research shows that taking vitamin D alone does not seem to prevent fractures in older adults. Most adults in these studies did not have osteoporosis, although osteoporosis status was unclear in some research (10140,12933,14282,38970,39015,84660,95822,97296,102145,104619)(109059,110827). However, several meta-analyses suggest that taking higher doses of vitamin D (about 800 IU daily) in combination with calcium might reduce overall fracture risk in older patients (38942,38970,39015,84660,102145,110809). One meta-analysis of clinical research in community- or long-term care-living males and females at least 65 years of age shows that taking vitamin D 800 IU daily in combination with calcium reduces the risk of hip and non-vertebral fractures by 25% and 20%, respectively, compared with placebo (110809). However, discrepancies exist which are possibly related to the dose and form of calcium used in combination with vitamin D and/or the patient population. Some research shows that taking vitamin D 800 IU daily in combination with calcium 1200 mg daily as tricalcium phosphate reduces fracture risk by up to 31% while taking vitamin D with calcium carbonate does not reduce fracture risk (12929,14282,16878,110809). Some individual clinical studies in postmenopausal females aged 50-79 years show that taking vitamin D plus calcium daily for 2-7 years does not prevent fractures when compared with placebo (14282,16878). Other confounding variables include the possible additional effects of hormonal therapy when given with calcium to postmenopausal adults and/or the inclusion of institutionalized patients with unclear osteoporotic status (95822,97296). Most research shows that taking vitamin D in combination with omega-3 fatty acids does not prevent fractures. A large clinical study shows that taking vitamin D 2000 IU daily alone or with omega-3 fatty acids 1 gram daily and/or strength training three times weekly does not prevent fractures in adults over 70 years of age when compared with placebo (104619). Another large clinical trial shows that taking vitamin D 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, over approximately 5 years does not prevent overall fractures, nonvertebral fractures, or hip fractures in adults over 50 (males) or 55 (females) years old when compared with placebo. Although the osteoporosis status of the population was unclear, findings were consistent in adults at high fracture risk based on use of osteoporosis medications and/or a history of fragility fractures (109059). As of April 2018, the US Preventative Services Task Force (USPSTF) recommends against supplementing with vitamin D 400 IU daily or less along with calcium 1000 mg daily or less for preventing primary fractures in community-dwelling postmenopausal adults. The USPSTF also concludes that there is insufficient evidence to determine whether supplementing with doses of vitamin D greater than 400 IU daily along with calcium doses greater than 1000 mg daily is safe or effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture (95695). For information on patients WITH osteoporosis, refer to the Osteoporosis discussion. There is limited research available regarding the effects of vitamin D supplementation for fracture prevention in children. Preliminary research in children aged 2 to 17 years with vitamin D insufficiency and one or more previous fractures shows that taking vitamin D 2000 IU daily with calcium 600 mg daily for 6 months modestly reduces the risk of forearm fractures over 12 months compared with children not given vitamin D or calcium (110820).
• Hypertension. Overall, vitamin D does not seem to prevent or lower high blood pressure in most patients; however, it may lower blood pressure in hypertensive patients with vitamin D deficiency. Details: Although population research has found that lower vitamin D levels are associated with a higher risk of developing hypertension, clinical research shows vitamin D supplementation does not prevent hypertension (15630). A large clinical trial in postmenopausal adults shows that taking vitamin D3 400 IU with calcium 1000 mg daily does not reduce the risk of developing hypertension (16714). Most meta-analyses and clinical trials in patients with existing hypertension show that vitamin D supplementation does not lower blood pressure when compared with placebo, regardless of vitamin D formulation, dose, or duration of supplementation (16714,91340,96405,103657,104619,113583,113668). However, a meta-analysis of 5 clinical studies in patients with hypertension and vitamin D deficiency shows that supplementation with vitamin D reduces systolic and diastolic blood pressure by about 7 mmHg and 3 mmHg, respectively, when compared with placebo (100895). Another meta-analysis of 11 clinical trials in patients over 60 years of age with hypertension and vitamin D deficiency shows that taking vitamin D supplements significantly reduces systolic, but not diastolic, blood pressure when compared with placebo, especially in trials lasting more than 8 weeks where the total dose of vitamin D is above 400,000 IU (113592). An individual clinical study in patients with hypertension and vitamin D deficiency or insufficiency shows that taking vitamin D 50,000 IU weekly or 1000 IU daily reduces systolic blood pressure by about 6 mmHg and mean arterial pressure by about 4 mmHg, but does not affect diastolic blood pressure, when compared to baseline (108440).
• Prostate cancer. Oral vitamin D does not appear to affect prostate cancer progression or cancer-related mortality. Details: A meta-analysis of three clinical trials shows that vitamin D supplementation does not affect prostate cancer progression as measured by prostate-specific antigen (PSA), or mortality in patients with prostate cancer (99770).
• Psychosis. Oral vitamin D does not seem to improve symptoms in patients with a functional psychotic disorder. Details: A clinical study in adults with a functional psychotic disorder shows that taking oral vitamin D3 (cholecalciferol) 20,000 IU monthly for 6 months has no effect on total positive and negative syndrome scale score (PANSS) when compared with placebo. The majority of patients included in this study were deficient in vitamin D at baseline (107226).
• Tuberculosis. Oral vitamin D seems to be ineffective for reducing the severity of tuberculosis or mortality from tuberculosis. Limited research suggests that vitamin D may have small benefits in newly diagnosed patients receiving tuberculosis treatment for the first time. Details: Although population research has found that tuberculosis is associated with vitamin D deficiency, most clinical research shows that taking vitamin D does not improve clinical outcomes in people with tuberculosis infection. Meta-analyses and individual clinical studies show that taking vitamin D as a single 100,000 IU dose, or as 400 IU daily for 2 months, along with standard care does not improve tuberculosis severity or reduce the risk of mortality in children or adults with tuberculosis, regardless of their baseline vitamin D levels (82570,82475,98913,103655,103668,104022). However, some research has identified modest benefits in newly diagnosed patients receiving anti-tuberculosis treatment for the first time. A meta-analysis of clinical research in this population shows that taking vitamin D at a dose of 1000 IU daily or 600,000 IU monthly modestly increases the odds of sputum smear conversions by 1.2-fold, but does not improve the time to sputum smear conversions, when compared with placebo (98235). A small clinical study in treatment-naïve adults with low levels of serum vitamin D shows that taking calcitriol 0.25 mcg twice daily for up to 6 months, starting with anti-tuberculosis treatment initiation, decreases the time to sputum smear conversion and 50% lesion absorption by about 3 days when compared with not taking vitamin D (109045). Additionally, a small clinical study in children aged 6-18 years with vitamin D insufficiency receiving standard treatment for newly diagnosed pulmonary tuberculosis shows that taking vitamin D 1000 IU daily reduces the duration of fever and cough by 1 and 2 weeks, respectively, when compared with placebo (108437).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral vitamin D is beneficial for acne. Details: A small clinical trial in patients with acne and vitamin D deficiency shows that taking cholecalciferol 1,000 IU daily for 2 months reduces the number of inflammatory lesions by about 35%, compared with 6% in those taking placebo. There was no effect on the total or non-inflammatory lesion count (106127). Other preliminary clinical research shows that taking alfacalcidol (One Alpha, LEO Company, Denmark) 0.25 mcg daily for 3 months modestly improves acne severity when compared with taking placebo (106128). In addition, population research has found that individuals with acne have modestly lower vitamin D levels than healthy controls. The odds of vitamin D deficiency were approximately three times higher in patients with acne when compared with healthy controls (106105).
• Age-related cognitive decline. It is unclear if oral cholecalciferol is beneficial for preventing age-related cognitive decline. Details: Pooled results of two large clinical sub-studies in community-dwelling adults aged 60 years or older show that taking cholecalciferol 2000 IU daily for 2-3 years has no effect on cognitive decline when compared with placebo. A subgroup analysis in Black patients suggests a modest effect of vitamin D when compared with placebo (108428).
• Alzheimer disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Some population research has found that lower serum concentrations of vitamin D are associated with higher risk of Alzheimer disease, and also with decreased cognition. People with Alzheimer disease seem to have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without Alzheimer disease (84672,103666). However, other population research has found that vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) is not associated with increased risk of Alzheimer disease (100899).
• Asthma. Oral vitamin D might reduce asthma exacerbations in adults and children with mild, but not severe or persistent, asthma. Vitamin D supplementation during pregnancy or the first 6 months of an infant's life does not seem to prevent the development of asthma later in infancy or childhood. Details: Population research in patients with asthma suggests that low vitamin D levels are associated with an increased risk of exacerbations and increased need for medication therapy (94693). However, findings from clinical research are mixed. Some meta-analyses of clinical trials in adults and children with asthma show that taking vitamin D for 3 months to 1 year reduces the rate of asthma exacerbations by 31% to 38% when compared with control (92690,94686,115584). However, other meta-analyses show that vitamin D supplementation does not reduce the risk of asthma exacerbations when compared with placebo (109728,109732,110833). The reasons for this discrepancy are not clear. However, some clinical research suggests that vitamin D supplements might only prevent asthma in people with non-persistent asthma (92690,94685,94686,94688,104020). Also, many studies are small and do not represent patients with severe asthma exacerbations (92690,94687). Baseline levels of vitamin D may play a role. A clinical study in children aged 6-16 years with persistent asthma and low vitamin D levels shows that taking vitamin D 4000 IU daily for 48 weeks does not reduce severe asthma exacerbations when compared with placebo (104020). However, a meta-analysis including this study shows that taking vitamin D does reduce risk of asthma exacerbations in children with low baseline vitamin D levels (109728). Additionally, two meta-analyses show that taking vitamin D seems to modestly improve pulmonary function when compared with placebo (109732,115584). Vitamin D doses have varied, with oral doses of 200-4000 IU daily, 1000-14,000 IU once weekly, 60,000 IU once monthly, 120,000 IU every 2 months, 100,000 IU 14 days apart, or 100,000 to 600,000 IU as a bolus dose followed by 400-4000 IU daily (92690,94686,104020,109728,110833,115584). Vitamin D supplementation for the prevention of asthma in infants has also been evaluated. A meta-analysis of 4 large clinical studies shows that taking vitamin D 400-1200 IU daily for the first 6 months of life does not reduce the risk of asthma or wheezing at 6-30 months of age when compared with control (112031). Vitamin D supplementation during pregnancy has also been evaluated (97306,99763,102146,112031). A meta-analysis of 3 large clinical studies shows that taking vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy reduces the risk of recurrent wheezing by 23% but does not reduce the risk of asthma diagnosis within the first 3-6 years of life when compared with vitamin D 400 IU daily (112031). Some research suggests that the dose of vitamin D plays a role. A meta-analysis shows that prenatal vitamin D 800 IU daily reduces the odds of wheeze or asthma by 32%, while lower or higher vitamin D doses were not beneficial (103661).
• Athletic performance. It is unclear if oral vitamin D is beneficial for athletic performance. Details: One small clinical trial in athletes shows that taking vitamin D 20,000 or 40,000 IU once weekly for 2 doses does not affect performance on vertical jumps, sprints, or leg and bench presses when compared with placebo (98188). Another small clinical trial in professional rugby players shows that taking vitamin D3 (cholecalciferol) 50,000 IU once every two weeks over 12 weeks does not improve sprinting speed or the ability to perform bench presses, bench pulls, and chin-ups when compared with placebo (98189). Also, most research shows that taking vitamin D does not improve measures of cardiorespiratory fitness. One small study in young males undergoing resistance training shows that taking vitamin D 8000 IU daily for 12 weeks does not improve cardiorespiratory fitness compared with taking placebo (110812).
• Atopic dermatitis (eczema). Most research shows that oral vitamin D reduces eczema severity in children. However, most research shows that oral vitamin D, taken during pregnancy or infancy, does not prevent eczema in the child. Details: A meta-analysis of eight moderate-quality clinical trials in children shows that taking vitamin D, most commonly 1000-2000 IU daily for 4-12 weeks, modestly reduces severity of eczema when compared with placebo (109728). Most of the children in these studies were also given conventional medications. Oral vitamin D has also been evaluated for eczema prevention. A meta-analysis of two clinical studies shows that consuming vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy is not associated with a reduced risk for eczema in children during the first 3 years of life when compared with vitamin D 400 IU daily (97306). Another meta-analysis of five large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing eczema when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Atrial fibrillation. It is unclear if oral vitamin D is beneficial for preventing atrial fibrillation. Details: A large clinical trial in adults without cardiovascular disease shows that taking vitamin D 2000 IU daily for an average of 5 years does not reduce the incidence of atrial fibrillation when compared with placebo or fish oil 840 mg daily (105209). However, observational research in postmenopausal adults with osteoporosis found that vitamin D supplementation is associated with a lower occurrence of atrial fibrillation when compared with not taking vitamin D (98922). Also, one large observational study in vitamin D-deficient patients with no history of atrial fibrillation has found that vitamin D supplementation for at least 6 months is associated with up to a 16% decreased risk of atrial fibrillation when compared with not taking vitamin D. There were also modest improvements in atrial fibrillation-free survival. In males 65 years and older with hypertension or diabetes at baseline, blood levels of at least 30 ng/mL following vitamin D supplementation were associated with decreased risk of atrial fibrillation; a post-supplementation blood level of 21-29 ng/mL was not associated with decreased risk (109043).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin D is beneficial for ADHD. Details: A small clinical trial in children 5-12 years of age with ADHD and vitamin D insufficiency shows that taking vitamin D 2000 IU daily along with methylphenidate for 8 weeks seems to improve parental ratings of evening, but not morning or overall, symptoms of inattentiveness and impulsivity when compared with methylphenidate alone. Vitamin D insufficiency was defined as levels less than 30 ng/mL (98196). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive use in children with ADHD, especially those with insufficient intake or skin exposure to sunlight (110318).
• Autism spectrum disorder. It is unclear if oral vitamin D is beneficial for autism spectrum disorder. Details: A small clinical study in children aged 2.5-8 years with autism spectrum disorder shows that taking vitamin D 2000 IU daily for 12 months modestly reduces irritability and hyperactivity when compared with placebo (99767).
• Autoimmune thyroiditis. It is unclear of oral vitamin D improves outcomes in patients with Hashimoto's thyroiditis. Details: A meta-analysis of 12 clinical trials in patients with Hashimoto's thyroiditis shows that taking vitamin D for at least 12 weeks increases free triiodothyronine (T3) and thyroxine (T4) levels, and reduces levels of thyroid stimulating hormone, thyroglobulin antibody, and anti-thyroid peroxidase antibody, when compared with placebo or no treatment (113593).
• Back pain. It is unclear if oral vitamin D is beneficial for reducing chronic low back pain. Details: A meta-analysis of 10 clinical studies in adults with chronic low back pain shows that taking vitamin D does not reduce pain scores when compared with placebo, regardless of baseline vitamin D status or duration of supplementation. Oral vitamin D dosages used in these studies included 400-4000 IU daily for 1-6 months, 50,000 IU once weekly for 8 weeks, or 150,000-300,000 IU as a single dose. Intramuscular dosages ranged from 150,000-300,00 IU as a single dose (115588).
• Bacterial vaginosis. It is unclear if oral vitamin D is beneficial for bacterial vaginosis. Details: Preliminary clinical research in females at high risk for sexually transmitted disease shows that taking vitamin D along with standard therapy for bacterial vaginosis does not reduce the prevalence of bacterial vaginosis when compared with placebo. Patients in this study had been treated with metronidazole 500 mg orally twice daily for 7 days along with vitamin D3 (cholecalciferol) 50,000 IU each week for 4 weeks and then every 4 weeks for the remaining 20 weeks (91348).
• Bariatric surgery complications. It is unclear if vitamin D supplementation after bariatric surgery attenuates any bone health-related complications. Details: Clinical research in adults who had undergone bariatric surgery shows that vitamin D supplementation in doses of 800-7900 IU daily improves vitamin D status when compared with placebo. It is unclear if vitamin D supplementation in these doses for 1 year improves parathyroid hormone levels or bone mineral density or reduces fracture risk (115589).
• Breast cancer. It is unclear if oral vitamin D is beneficial for the prevention of breast cancer. Details: Some population research evaluating intake of calcium plus vitamin D suggests that higher vitamin D intake is not associated with a reduced risk of breast cancer in premenopausal or postmenopausal adults (15631). Similarly, a large observational study in females with a biological sibling with breast cancer has found that taking vitamin D recently or prior to enrollment is not associated with a reduced risk of breast cancer when compared with nonrecent vitamin D use or never taking vitamin D, respectively (107215). However, other research found that higher vitamin D intake is associated with a 17% reduced risk of breast cancer in premenopausal and perimenopausal, but not postmenopausal, adults (39001). Observational research has also examined the association between blood levels of vitamin D and risk of developing breast cancer. A meta-analysis found that those with serum levels of about 52 ng/mL had a 50% lower risk of developing breast cancer when compared with those with serum levels of less than 13 ng/mL. This high serum level of vitamin D corresponds to a high dose of about 4000 IU daily (16049). Other observational research has found that baseline vitamin D levels of more than 20 ng/mL are associated with a 48% reduced risk of developing breast cancer over approximately 9 years in Latina females in the US when compared with levels below 20 ng/mL; however, this association was not present in Black females (109058). Despite the contradictory findings from observational research, results from clinical research are generally negative. Evidence from one large-scale clinical trial (Women's Health Initiative) shows that postmenopausal adults who take vitamin D3 (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years do not have a significantly reduced risk of developing breast cancer (16715,98895). Also, a meta-analysis of two large-scale clinical trials, which did not include the Women's Health Initiative trial, shows that taking vitamin D 800-1000 IU daily, alone or with calcium, for 3-4 years does not reduce the incidence of breast cancer in postmenopausal adults, although there was a trend towards reduced risk with higher doses of vitamin D supplementation (97301). While vitamin D and calcium supplementation during the intervention period of the Women's Health Initiative trial was not associated with a reduced risk of developing breast cancer or ductal carcinoma in situ (DCIS), a precursor to breast cancer, a secondary post-hoc analysis of the data shows that supplementation reduces the risk of developing DCIS by 18% over a median follow-up of 19 years (107216). Additional research is needed regarding an optimal dose of vitamin D, timing of initiation, and whether any benefit is affected by menopausal status.
• Bronchopulmonary dysplasia. Limited research suggests that vitamin D deficiency is linked with bronchopulmonary dysplasia in the infant. Details: Observational research has found that vitamin D deficiency at birth is associated with about a 2-fold increased odds of developing bronchopulmonary dysplasia (104021). However, it is unclear if vitamin D supplementation is beneficial.
• Cancer. Vitamin D does not seem to reduce overall cancer risk. However, some research shows that vitamin D might slightly reduce the risk of metastatic cancer and cancer-related mortality. Details: There is interest in vitamin D for cancer PREVENTION, as observational research suggests that higher vitamin D intake and higher 25-hydroxyvitamin D levels are associated with a lower risk of cancer (111150). While individual clinical trials evaluating vitamin D for cancer have produced inconsistent findings, most meta-analyses and clinical trials show that taking vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) alone or with calcium does not significantly reduce the risk of developing cancer (15629,91344,93943,97296,98916,104024,104618,110811). However, vitamin D supplementation might reduce the risk of metastatic cancer and cancer-related mortality. A large clinical trial shows that taking vitamin D3 2000 IU daily for a median of 5.3 years slightly reduces the risk of advanced metastatic or fatal cancers when compared with placebo (104618). Additionally, meta-analyses of several large clinical trials show that taking vitamin D 400-4000 IU daily, with or without calcium, for 1-7 years reduces the risk of cancer-related mortality by 12-13% when compared with control, while intermittent bolus dosing of vitamin D at high doses for 1-5 years does not appear to reduce the risk of cancer-related mortality (104024,111149). The role of vitamin D in cancer TREATMENT is unclear. A meta-analysis of clinical and observational research suggests that supplementation of vitamin D after a cancer diagnosis is associated with a modest improvement in overall survival, but not progression-free or cancer-specific survival (109726). Doses used in clinical research ranged between 1200 IU and 8000 IU daily or 100,000 IU every 50 days, after surgery and/or during treatment (99195,99196,109726). Other clinical research in patients with luminal gastrointestinal cancers shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse when compared with placebo (99195). It is unclear which, if any, types or stages of cancer respond best to vitamin D, and what dose of vitamin D is optimal.
• Child growth. It is unclear if oral vitamin D is beneficial for improving infant growth or bone structure. Details: Meta-analyses and individual clinical trials show that vitamin D supplementation during pregnancy modestly increases length at birth and bone mineral density at up to 7 years of age when compared with control, usually placebo or vitamin D 400 IU daily. However, there was no effect on length in the infant up to one year of age, weight at birth or up to one year of age, head circumference at birth or up to 6 years of age, bone mineral content at up to 6 years of age, or neonatal bone mineral density, bone mineral content, bone area, or femur or humoral length (98198,109737,112028,115585). In the available research, vitamin D was taken in doses of 200 IU to 4400 IU daily, 4200 IU to 50,000 IU weekly, 50,000 IU every 2 weeks, or 60,000 IU every 4-8 weeks, starting from the early to late stages of pregnancy and usually continued until birth (98198,109737,115585).
• Chronic kidney disease (CKD). It is unclear if oral vitamin D is beneficial in patients with CKD. Most research suggests that it does not reduce the risk for adverse cardiovascular events. Details: Population research in patients on dialysis has found that vitamin D levels less than 17.8 ng/mL are associated with a higher risk of all-cause mortality compared with higher levels (16619). A meta-analysis and individual clinical studies show that vitamin D and vitamin D analogues decrease parathyroid hormone (PTH) levels and urine protein levels in people with CKD (84376,84377,84628,98233,98236). However, taking vitamin D does not appear to decrease the risk of death or parathyroidectomy in CKD patients (84376,84377). Also, taking vitamin D increases the risk for hypercalcemia and hyperphosphatemia in this patient population (84376,84377,98236). Vitamin D has also been evaluated for the prevention of cardiovascular events in adults with CKD. Observational research has found that vitamin D deficiency in patients with CKD is associated with adverse cardiovascular events. However, vitamin D supplementation does not seem to be beneficial. One clinical study shows that taking paricalcitol, an active form of vitamin D, titrated to maintain adequate serum calcium levels, for 48 weeks does not affect the size of the left ventricle or heart function when compared with placebo (98233). Other clinical research in Japanese patients on hemodialysis for CKD shows that adding alfacalcidol, another active form of vitamin D, 0.5 mcg daily to standard treatment for 4 years does not affect mortality or cardiovascular events such as myocardial infarctions, stroke, aortic dissection, and others compared to standard treatment only (98920). Also, a large clinical trial in patients with CKD shows that taking vitamin D as cholecalciferol 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, does not affect major cardiovascular events or invasive cancer when compared with placebo (110811). Vitamin D has also been evaluated for musculoskeletal health in adults with CKD. A small clinical study shows that taking cholecalciferol 4000 IU daily, with or without physical activity, for 3 months improves bicep strength, but not back flexibility or aerobic fitness capacity, when compared with baseline. In patients taking cholecalciferol in combination with physical activity, musculoskeletal health was similar when compared with cholecalciferol alone (108431). However, this study was inadequately powered to detect a difference between groups, and it is unclear if the improvement from baseline differed between groups. Vitamin D has also been evaluated for the improvement of iron status in adults with CKD and secondary hyperparathyroidism. Clinical research shows that taking Vitamin D as cholecalciferol (Vitamin D3 Forte Renapharma) 8000 IU daily for 12 weeks does not improve iron status compared with taking placebo. However, a sub-analysis shows that hemoglobin levels are modestly improved in patients with a low Vitamin D status at baseline suggesting that Vitamin D might improve iron availability in these patients (110819).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin D is beneficial for COPD; benefits may be limited to patients with severe vitamin D deficiency. Details: Population research has found an association between low vitamin D levels and reduced lung function, increased risk of developing COPD, and worsening COPD severity (17685,96401). However, 3 meta-analyses of clinical research in adults with COPD show that, overall, oral vitamin D does not have beneficial effects on mortality, rate of COPD exacerbations, pulmonary function, or most measures of symptom severity when compared with placebo (109732,112485,115586). A subgroup analysis suggests that any benefits of vitamin D supplementation may be limited to patients with severe vitamin D deficiency (25-hydroxyvitamin D levels below 25 nmol/L) at baseline (115586).
• Cognitive function. It is unclear if oral vitamin D is beneficial for cognitive function. Details: Population research has found that low vitamin D levels are associated with worse cognitive performance and cognitive decline when compared to high vitamin D levels in healthy adults (84672,95916). However, the effect of vitamin D supplementation on cognitive function is unclear. One small meta-analysis of clinical research shows that vitamin D supplementation does not improve cognitive function (95916). However, the included trials evaluated a widely heterogeneous study population and utilized variable measures of cognitive function.
• Cognitive impairment. It is unclear if oral vitamin D is beneficial for older adults with mild cognitive impairment. Details: A small clinical study in older adults with mild cognitive impairment shows that taking vitamin D3 10,000 IU three times weekly for 20 weeks in addition to exercise and cognitive training does not improve cognitive function when compared with placebo and exercise with or without cognitive training. However, most participants had sufficient serum vitamin D levels at baseline (112489).
• Colorectal cancer. It is unclear if oral vitamin D is beneficial for the treatment or prevention of colorectal cancer. Details: Epidemiological research has found that a higher serum vitamin D level is associated with decreased risk of mortality and increased survival in patients with colorectal cancer (16101,99196). However, it is unclear whether vitamin D supplementation improves survival in patients with colorectal cancer, as research has generally involved small populations and results are somewhat conflicting. A subgroup analysis of one clinical study shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse or death, death due to any cause, or relapse over 5 years when compared with placebo in patients with colorectal cancer (99195). However, this subgroup may have been underpowered to detect between-group differences. Another small clinical trial in patients with advanced or metastatic colorectal cancer shows that taking high-dose vitamin D 8000 IU daily during the first cycle of chemotherapy, and then 4000 IU daily for subsequent cycles, does not increase median progression-free survival when compared with taking vitamin D 400 IU daily. However, patients taking high-dose vitamin D were 36% less likely to experience disease progression or death during follow-up when compared with patients taking the lower dose of vitamin D (99196). This latter result suggests that high-dose vitamin D supplementation might be beneficial for patients with advanced or metastatic colorectal cancer, but larger, multicenter studies are needed to confirm. The role of vitamin D in colorectal cancer prevention has also been investigated. A meta-analysis of epidemiological research has found that a higher serum vitamin D level is associated with a decreased colorectal cancer risk; however, sub-analyses suggest that this association only occurs in females, not males (109740). Most studies have evaluated vitamin D supplements in combination with calcium; the effects of vitamin D supplementation alone are unclear. One meta-analysis of clinical research suggests that taking vitamin D plus calcium is not associated with a decreased incidence of colorectal cancer in people with a low baseline risk of colorectal cancer (39042). Another meta-analysis of clinical research shows that vitamin D supplementation, with or without calcium, does not reduce the incidence of colorectal cancer or colorectal adenomas (109730). Additionally, a large clinical trial suggests that postmenopausal adults who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290,98895). One clinical study shows that taking calcium supplements reduces the risk of colorectal adenomas, but not in people with lower than average vitamin D levels (12118).
• Crohn disease. Limited evidence suggests that vitamin D reduces relapses in patients with Crohn disease. Details: A meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). The validity of these findings is limited by the heterogeneity of the included studies.
• Dementia. It is unclear if oral vitamin D is beneficial for dementia. Details: Population research has found that patients with any type of dementia have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without dementia (84672). However, it is unclear if vitamin D supplementation is beneficial.
• Depression. It is unclear if oral vitamin D is beneficial for treating depression. Vitamin D does not seem to prevent the development of depression. Details: The role of vitamin D in the treatment of depression is unclear. Earlier meta-analyses of clinical research show that vitamin D supplementation does not improve overall symptoms of depression. However, some subgroup analyses suggest that vitamin D may be beneficial for improving the symptoms of depression in people with clinically significant symptoms, as well as those with baseline vitamin D deficiency (97295,97298). More recent meta-analyses of several clinical trials, that include some of the same studies, show that vitamin D modestly improves symptoms of depression in adults; however, subgroup analysis suggests that vitamin D does not improve depressive symptoms in older adults (110832,112786). These analyses are mixed over whether baseline vitamin D status affects results (110832,112786) and one of these analyses shows no evidence that the type of depression affects findings (110832). Another meta-analysis of generally small clinical trials in patients with type 2 diabetes and depression shows that taking vitamin D modestly improves depressive symptoms when compared with placebo or no intervention (110814). Although, results of an individual clinical trial in patients with type 2 diabetes are in contrast (108423). The evaluated research implemented one-time doses of 150,000-500,000 IU, as well as daily and weekly doses ranging between 400-5000 IU daily or 5000-100,000 IU weekly for 6 weeks to 2 years, with the most evidence of benefit related to one-time high doses. Cholecalciferol was the most common form of vitamin D used (97295,97298,108423,110814,110832,112786). Significant heterogeneity between studies and the wide variability in dosing strategies limit the validity of these findings, as well as identification of an effective dose or target population. Vitamin D has also been evaluated for the prevention of depression. One large clinical study (VITAL-DEP) in healthy patients 50 years and older shows that taking vitamin D 2000 IU daily for about 5.3 years does not prevent depression or depressive symptoms, or improve mood, when compared with placebo (103670). An analysis of a cohort of patients from the VITAL-DEP trial also shows that taking vitamin D 2000 IU daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores in patients with subthreshold depression or risk factors for late-life depression when compared with placebo (112032). In addition, a meta-analysis of several clinical studies suggests that vitamin D supplementation does not prevent depression based on subgroup analysis of patients without depression at baseline (112786). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive or monotherapy use in patients with depression, especially those with insufficient intake or skin exposure to sunlight (110318).
• Diabetes. Oral vitamin D might improve glycemic indices in some patients with type 2 diabetes and gestational diabetes. It is unclear if oral or intramuscular vitamin D is beneficial for the prevention of type 1 or gestational diabetes. Details: Most meta-analyses of mainly small clinical trials show that vitamin D supplementation is beneficial for measures of glycemic control in adults with diabetes. However, the best evidence of benefit is in people with baseline vitamin D deficiency. Five meta-analyses of clinical studies in patients with type 2 diabetes show that vitamin D supplementation reduces glycated hemoglobin (HbA1c) by 0.2% to 0.3%, and improves serum insulin, fasting blood glucose, and measures of insulin resistance when compared with control (96403,110822,112487,115581,115583). Supplemental vitamin D seems to be most beneficial in patients with baseline vitamin D deficiency or insufficiency (96403,107210,110822,112487,115581). Furthermore, correlation analysis suggests an inverse relationship between serum vitamin D levels and serum insulin, fasting blood glucose, and measures of insulin resistance (112487). In most clinical studies vitamin D supplementation ranged from 1000-6000 IU daily, 20,000-60,000 IU weekly, or 100,000-400,000 IU once over 8-48 weeks (96403,107210,110822,115581,115583). Most analyses exhibited significant heterogeneity related to vitamin D dosing regimen, geographic location, and patient population. However, one meta-analysis of clinical research in patients with diabetes shows that vitamin D improves HbA1c, insulin resistance, and insulin measures in studies lasting less than 6 months, but not in studies lasting longer than 6 months (99764). An additional meta-analysis suggests that most evidence of benefit is associated with doses of more than 2000 IU daily for 4-12 weeks (110822). Another meta-analysis suggests that benefits may be greater in adults with less severe obesity and a shorter duration of type 2 diabetes (115583). Vitamin D has been evaluated for the prevention of type 1 diabetes. There is preliminary evidence that daily vitamin D supplementation (form not specified) in infants during the first year of life is associated with a reduced incidence of type 1 diabetes development later in life (10139). Also, a meta-analysis of population studies has found that vitamin D supplementation in early childhood is associated with a 29% reduced risk of developing type 1 diabetes later in life (84225). Vitamin D has been evaluated in adults with gestational diabetes, yielding conflicting findings. One clinical trial shows that oral vitamin D 50,000 IU every 4 weeks modestly reduces levels of insulin, as well as measures of insulin resistance, with no effect on fasting blood glucose (106125), whereas other clinical research shows that this same dosing regimen modestly reduces levels of fasting blood glucose and HbA1c, with no effect on insulin measures (106126). A separate clinical study shows that taking oral vitamin D 500 IU twice daily in yogurt modestly improves all measures of glycemic indices (101775). Additionally, a large clinical trial shows that taking oral vitamin D 1600 IU daily modestly reduces fasting blood glucose when compared with vitamin D 400 IU daily (112020). Some clinical research also shows that oral vitamin D modestly improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with control (106125,110823), although not all research agrees (106126). Also, a meta-analysis of clinical research shows that taking oral vitamin D reduces the risk of premature birth and neonatal hospitalization by approximately 63% and 62%, respectively (110823). A meta-analysis of 5 small clinical studies shows that taking oral vitamin D 400-1000 IU daily for 6 weeks or 50,000 IU twice over 6 weeks along with calcium decreases fasting plasma glucose and serum insulin when compared with placebo (115579). One small clinical study shows that giving vitamin D 300,000 IU as a single intramuscular injection at 24-28 weeks' gestation does not affect HbA1c (106124). Vitamin D has also been evaluated for the prevention of gestational diabetes. A Cochrane analysis of one large clinical study shows that taking vitamin D during pregnancy does not lower the risk of gestational diabetes when compared with no supplementation (114587). In addition, a meta-analysis of population studies suggests that there is a U-shaped association between serum vitamin D levels and the risk of developing gestational diabetes, with 25-hydroxyvitamin D levels of 40-90 nmol/L associated with the lowest risk (106109). A meta-analysis of clinical research in adults with insulin resistance during pregnancy, but not gestational diabetes, shows that taking vitamin D at varying doses for 6-26 weeks modestly decreases measures of insulin resistance when compared with placebo (110821). However, this study did not evaluate whether vitamin D prevented the development of gestational diabetes in these patients. Vitamin D has also been evaluated in combination with other ingredients. One study evaluated vitamin D in combination with eicosapentaenoic acid (EPA) 360 mg plus docosahexaenoic acid (DHA) 240 mg twice daily, suggesting that this combination improves glycemic markers when compared with taking vitamin D alone (106122). Other clinical research in patients with gestational diabetes shows that taking vitamin D with omega-3 fatty acids 8,000 mg twice daily for 6 weeks modestly improves glycemic indices when compared with placebo (106114). However, it is unclear if these effects are due to vitamin D, other ingredients, or the combination.
• Diabetic foot ulcers. It is unclear if oral vitamin D is beneficial for diabetic foot ulcers. Details: A meta-analysis of clinical research in patients with diabetic foot ulcers shows that taking vitamin D modestly reduces ulcer size and improves glycemic and lipid indices when compared with placebo (110835). This meta-analysis is limited by the availability of three small clinical trials, as well as the heterogeneous doses of vitamin D in the included studies.
• Diabetic nephropathy. Limited evidence suggests that vitamin D improves some markers of kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical studies in patients with diabetic nephropathy shows that taking vitamin D or its analogs reduces inflammatory markers and protein in the urine, but does not affect measures of kidney function such as serum creatinine or glomerular filtration rate, when compared to control (99771).
• Diabetic retinopathy. It is unclear if oral vitamin D is beneficial in diabetic retinopathy. Details: There is weak evidence from observational research suggesting a link between vitamin D deficiency and diabetic retinopathy (112095). However, clinical research addressing the effectiveness of vitamin D supplementation for treatment or prevention of diabetic retinopathy is lacking.
• Dysmenorrhea. Limited evidence suggests that oral vitamin D reduces pain in patients with dysmenorrhea. Details: A meta-analysis of 9 small clinical studies in patients with dysmenorrhea shows that taking vitamin D in doses ranging from 5000 IU daily to 300,000 IU monthly modestly reduces pain when compared with control (112029). However, the validity of these findings is limited by a high degree of heterogeneity across the studies, including differences in blinding and control interventions, vitamin D doses and frequency of supplementation, and baseline vitamin D levels. Another small clinical study in adolescent patients with dysmenorrhea shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces pain when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
• Erectile dysfunction (ED). It is unclear if oral vitamin D is beneficial for ED. Details: Although some data suggest ED is associated with low serum 25-hydroxy-vitamin D levels, preliminary research in males aged 60-84 years shows that taking vitamin D 60,000 IU once monthly for up to 5 years does not prevent or improve ED when compared with placebo (113580).
• Exercise-induced muscle damage. Small studies suggest that vitamin D does not improve exercise-induced muscle damage. Details: A meta-analysis of 6 small studies shows that taking vitamin D before and/or during exercise does not improve circulating levels of creatine kinase, lactate dehydrogenase, or myoglobin when compared with placebo (107218).
• Fall prevention. The role of vitamin D in fall prevention is confusing and controversial. Most clinical research shows that taking vitamin D 800-1000 IU daily decreases the risk of falls, with effects most apparent with daily over intermittent dosing and in those with vitamin D deficiency or insufficiency. Taking vitamin D at doses higher or lower than this may be associated with increased risk of falls. Details: Higher serum levels of vitamin D have been associated with improved lower-extremity function in elderly adults (15636). Clinical research in older adults shows that taking vitamin D or vitamin D analogues, with or without calcium, reduces the number of people who have a fall by up to 19% (39038,84215,84374,84539,94130,104023,113595,114504). Other research shows that vitamin D, with or without calcium, reduces number of falls by 19% to 50% (11939,16275,84404,93941,109053). The beneficial effect does not appear to depend on the form of vitamin D used (ergocalciferol, cholecalciferol, calcitriol, or alfacalcidol) (39038,84374,113595). Multiple meta-analyses of clinical research show that taking vitamin D leads to a decreased rate of falls in patients with low baseline levels of vitamin D, but not in those with adequate vitamin D levels (84670,84684,109053,114504). One meta-analysis also suggests that taking vitamin D as cholecalciferol up to 1000 IU daily reduces fall risk by up to 19%, whereas higher doses do not reduce fall risk (109053). Also, daily dosing, but not intermittent dosing, seems to be associated with a reduced risk of falling (109053,114504). Similarly, another meta-analysis of clinical research shows that taking vitamin D 800-1000 IU daily, with or without calcium, lowers the risk of falls by about 15-26% when compared with placebo, no treatment, or calcium alone. However, taking vitamin D 500 IU or less daily and vitamin D 1100 IU or more daily, with or without calcium, is not associated with a lower risk of falls and may even increase the risk of falls by 22-44% (114504). Despite the above meta-analyses, other clinical research shows that vitamin D does not reduce the risk of falling (84404,84670), the rate of falls overall (84670,93942), or the rate of injurious falls (93942) in elderly patients (93942). One study in adults over 70 years of age with a history of falling found that taking high-dose vitamin D, either as 60,000 IU monthly or 24,000 IU plus calcifediol 300 mcg monthly, increased both the risk of falling and the mean number of falls compared to a lower dose of 24,000 IU monthly (93940). One meta-analysis of 20 trials including nearly 30,000 patients shows that taking vitamin D, with or without calcium, does not reduce the risk of falling in elderly patients, regardless of baseline 25-hydroxyvitamin D levels, level of 25-hydroxyvitamin D achieved with treatment, duration of treatment, or residential status of the patients (91342). While a meta-analysis of 10 trials in nearly 6,000 patients shows that taking vitamin D 700-1000 IU daily with calcium 1000-2000 mg daily reduces the risk of falling in the elderly by 12% when compared with placebo or no treatment, a meta-analysis of 21 trials in nearly 52,000 patients shows that vitamin D alone is only associated with a reduced risk of falls in patients with baseline vitamin D levels of less than 50 nmol/L when compared with placebo or no treatment (107224). The 2018 US Preventative Services Task Force (USPSTF) guidelines for fall prevention acknowledges this research by recommending AGAINST vitamin D supplementation for fall prevention in community dwelling adults 65 years of age and older who do not have osteoporosis or vitamin D deficiency (95703). The reasons for the disparate study results may have to do with the way in which clinical trials have reported outcomes. Clinical trials assessing the effect of vitamin D on fall risk may report results as the number of patients who experience one or more falls, the total number of falls, or the rate of falls per individual. This can affect ultimate conclusions and, in some cases, can be misleading. For example, when studies report on only the total number of falls, it is unclear if vitamin D reduces the rate of falls across the study population, or if it only reduces falls in a small subset of patients. Also, analyses of research suggest that the size of the clinical study appears to affect the trial results. Most trials showing significant reductions in fall risk have been small and of short duration (91342,94132); whereas larger and longer-term studies tend to show no benefit (13073,84399).
• Fetal and premature infant mortality. Taking vitamin D during pregnancy might reduce the risk of fetal or early infant death. Details: A meta-analysis of clinical research shows that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal death by 31% when compared with not supplementing with vitamin D. A sub-analysis shows that this benefit was limited to doses of up to 4000 IU daily (109055). However, a Cochrane review suggests that the evidence linking vitamin D supplementation to a lower risk of fetal or neonatal death is very uncertain (114587). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of intra-uterine and neonatal mortality, preeclampsia, preterm birth, and small for gestational age (SGA) birth. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Fibromyalgia. A small clinical study suggests that vitamin D might improve pain in patients with fibromyalgia. Details: A small clinical study in fibromyalgia patients with low vitamin D levels shows that taking vitamin D3 (cholecalciferol) 1200-2400 IU daily seems to reduce pain, but not mood or quality of life, when compared with placebo (91349).
• Food allergies. It is unclear if prenatal or infant oral vitamin D supplementation reduces the risk of developing food allergies. Details: A meta-analysis of two large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing food allergies when compared with low-dose vitamin D or no intervention (108438).
• Frailty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of frailty in older adults. Details: Frailty involves a combination of muscle loss and weakness, with exhaustion and reduced ability for physical activity. Some observational research has found that low vitamin D status is associated with frailty occurrence. However, clinical research in community dwelling older adults shows that taking vitamin D as 1000 IU, 2000 IU, or 4000 IU daily for 24 months does not prevent frailty or attenuate the worsening of frailty when compared with low-dose vitamin D 200 IU daily. Baseline vitamin D status did not affect these findings. Also, a sub-analysis suggests that vitamin D 2000 IU might increase frailty; however, only a small number of participants were randomized to this dose (109046). Other clinical research in community dwelling adults at least 70 years of age shows that taking cholecalciferol 2000 IU daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo. However, when taken in combination with omega-3 fatty acids 1 gram daily and a home exercise program, the odds of becoming pre-frail is reduced by 39% (110829).
• Generalized anxiety disorder (GAD). A small clinical study suggests that vitamin D may modestly improve anxiety in patients with GAD. Details: A small clinical study in patients with GAD shows that taking vitamin D 50,000 IU once weekly for 3 months, in addition to taking an antidepressant and an anxiolytic, moderately reduces anxiety scores when compared with taking these medications alone (103654).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral vitamin D is beneficial for improving outcomes in patients receiving HSCT. Details: A small clinical study in patients who have undergone an autologous HSCT shows that taking calcitriol 0.25 mcg three times daily for 30 days can reduce the time to absolute lymphocyte count recovery, but does not affect time to recovery of absolute neutrophil and platelet counts, when compared with placebo (103665).
• Hepatitis C. Low levels of vitamin D have been associated with an inadequate response to hepatitis C therapy. Adding vitamin D to standard therapy for hepatitis C may improve viral response, especially in specific genotypes. Details: A small clinical trial in patients with hepatitis C genotypes 2-3 receiving standard therapy with PEG-interferon and ribavirin shows that adding vitamin D 2000 IU daily for 24 weeks results in 95% of patients achieving undetectable levels of hepatitis C RNA, compared to only 77% of patients treated with standard therapy alone (98917). Another small clinical study in patients with hepatitis C genotype 1b receiving the same standard therapy shows that adding vitamin D 1000 IU daily for 16 weeks results in about 79% of patients achieving undetectable levels of hepatitis C RNA, compared to about 55% of patients treated with standard therapy alone. The TT genotype seems to be especially susceptible to vitamin D supplementation, while TG/GG genotype does not seem to be susceptible (98923).
• HIV/AIDS. It is unclear if oral vitamin D is beneficial for improving bone mineral density (BMD) in children and young adults with HIV. Details: Vitamin D deficiency and hyperparathyroidism are common in children and young adults with HIV. A meta-analysis of two clinical trials in this population shows that taking cholecalciferol for 12 months does not improve spine BMD when compared with placebo. Also, an analysis of two clinical trials shows that taking doses of 1600 IU to 4000 IU daily does not improve spine BMD when compared with taking doses of 400-800 IU daily. However, taking higher dose vitamin D has a small beneficial effect on total BMD when compared with taking lower doses. There was no improvement on parathyroid hormone levels (110824). This meta-analysis is limited by the availability of small clinical trials, as well as the heterogeneous doses of vitamin D used in the included studies.
• Hyperlipidemia. Although population research has found that higher vitamin D levels are associated with improved lipid levels, it is unclear if vitamin D supplementation is beneficial. Clinical research results are conflicting. Details: Population research has found that higher vitamin D levels are associated with lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels when compared with lower vitamin D levels (15630,98919). However, supplementation might not be beneficial. A meta-analysis of small clinical studies suggests that taking vitamin D as cholecalciferol, ergocalciferol, alfacalcidol, or calcitriol slightly increases LDL cholesterol, but does not affect total cholesterol, triglycerides, or HDL cholesterol, when compared with placebo (84642). The validity of these findings is limited by the variability in patient populations, vitamin D dose and formulation, and study duration. Also, none of the included studies were prospectively designed to test the effect of vitamin D on lipid levels. Another meta-analysis of clinical studies in a mixed population of healthy adults and adults with metabolic disease shows that taking vitamin D 1400-50,000 IU weekly with calcium 500-2000 mg daily results in very modest improvements in total cholesterol, triglyceride, and HDL cholesterol levels, but not LDL or very low-density lipoprotein (VLDL) cholesterol levels, when compared with placebo. Subgroup analyses suggest that effects are more pronounced in people with metabolic disease (107227). The validity of these findings is limited by the heterogeneity of the included studies, which persisted throughout subgroup analyses.
• Hyperthyroidism. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research suggests that serum vitamin D levels are decreased in patients with newly diagnosed Graves' disease. A small preliminary clinical trial in patients with newly diagnosed Graves' disease taking methimazole and low levels of selenium and vitamin D shows that taking vitamin D as cholecalciferol for 270 days, in combination with selenium for the first 180 days, modestly reduces levels of serum free thyroxine and improves quality of life when compared with no vitamin D or selenium. However, taking vitamin D and selenium did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral vitamin D is beneficial in the treatment of subclinical hypothyroidism. Details: Preliminary clinical research in patients with vitamin D deficiency and subclinical hypothyroidism shows that taking vitamin D 50,000 IU weekly for 2-12 weeks decreases mean thyroid stimulating hormone levels by about 20% when compared with placebo, or by 3.55 mIU/L when compared to baseline (107213,113589).
• Ichthyosis. It is unclear if oral vitamin D is beneficial in patients with inherited ichthyosis. Details: A small clinical study in patients with congenital non-syndromic ichthyosis shows that taking vitamin D 2000 IU daily for 24 weeks reduces the clinical severity of disease at 12 weeks, but not 24 weeks, when compared with baseline. When compared with patients taking acitretin 0.5 mg/kg daily, results were similar at both 12 and 24 weeks, but it is unclear if the improvement from baseline differed between groups (108441).
• IgA vasculitis. It is unclear if oral alfacalcidol is beneficial in children with IgA vasculitis. Details: A clinical study in children with IgA vasculitis shows that taking alfacalcidol 0.25 mcg daily along with vitamin C, rutin, dipyridamole, cimetidine, calcium, and glucocorticoids for 4 weeks improves rates of recurrence and incidence of kidney damage when compared with those receiving the same regimen without alfacalcidol. Alfacalcidol also improves cellular immune function and reduces levels of inflammatory biomarkers (107212).
• Irritable bowel syndrome (IBS). It is unclear if oral vitamin D is beneficial for IBS; the available research is conflicting. Details: Although some meta-analyses show that taking vitamin D is moderately more effective than placebo for improving IBS symptom severity and quality of life, other analyses disagree. Doses of vitamin D have included 50,000 IU weekly or every 2 weeks or 2000-4000 IU daily for up to 6 months (109041,109054,109057). The reasons for these discrepancies might be attributed to the inclusion criteria related to the individual trials, the small sample sizes, and varied dosing strategies used in the available research.
• Kidney transplant. It is unclear if oral cholecalciferol is beneficial for improving allograft function or preventing non-skeletal complications in kidney transplant recipients. Details: Following a kidney transplant, patients are at increased risk of vitamin D insufficiency and related outcomes. A large clinical trial shows that taking a high dose of cholecalciferol for 2 years does not reduce the composite risk of developing type 2 diabetes, major cardiovascular events, or cancer, or death when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). The effect of a high dose of vitamin D on these outcomes individually is not clear. However, taking vitamin D does not seem to improve allograft function. A clinical study in kidney transplant recipients shows that taking cholecalciferol 4000 IU daily, beginning 1-month posttransplant and continuing for 11 months, has no effect on allograft function when compared with placebo (108425).
• Kidney transplant-related bone loss. Oral vitamin D might be beneficial for preventing bone loss associated with kidney transplantation. Details: A large clinical trial shows that taking a high dose of cholecalciferol for 2 years modestly reduces the odds of a fracture by 76% when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). A prespecified secondary analysis of a clinical study in patients at 1-month post-kidney transplant from a living donor in Japan shows that taking vitamin D (cholecalciferol) 4000 IU daily for months 1-12 posttransplant reduces whole blood parathyroid hormone levels by 15%, but does not alter levels of tartrate-resistant acid phosphatase 5-b or bone-specific alkaline phosphatase, when compared with placebo. The greatest effects on parathyroid hormone levels are observed in those with more severe vitamin D deficiency, hypocalcemia, and more preserved kidney function. Vitamin D supplementation also attenuates changes in bone mineral density (BMD) at the lumbar spine, but not the distal radius, from prior to transplant. Patients taking vitamin D had a loss of only 0.2%, compared with a loss of 2% in those receiving placebo. The greatest effects are observed in those with osteoporosis or osteopenia (107220). Conversely, a small clinical trial shows that taking calcitriol (1,25-dihydroxyvitamin D3) 0.25 mcg daily in combination with calcium carbonate 500 mg daily does not decrease bone loss associated with kidney transplantation. However, calcitriol might reduce osteoclast suppression, help maintain trabecular bone volume and wall thickness, and improve axial BMD (4823).
• Impaired glucose tolerance (prediabetes). Taking vitamin D might slow prediabetes progression to diabetes in people with low baseline levels of vitamin D or in people achieving high levels of vitamin D following supplementation. It is unclear if vitamin D supplementation is beneficial in people with prediabetes and sufficient vitamin D levels. Details: Observational research has found that low vitamin D levels are linked with a higher risk of prediabetes and higher dietary vitamin D is linked with a lower chance of developing diabetes (84594,103669). Meta-analyses and individual clinical studies in patients with prediabetes and unclear or sufficient vitamin D levels show that vitamin D supplementation might improve some glycemic indices, but does not seem to prevent progression of prediabetes to diabetes (84594,91347,99769,108421). However, a more recent meta-analysis of 3 clinical studies designed to evaluate the preventative effects of oral vitamin D shows that taking it in the form of cholecalciferol 4000 IU daily or 20,000 IU weekly or eldecalcitol 0.75 mcg daily reduces the risk of developing diabetes with an absolute risk reduction of 3.3% over 3 years when compared with placebo. However, the actual risk reduction is highly dependent on vitamin D status. Patients achieving the highest serum vitamin D levels have absolute 3-year risk reductions of 11.4% to 18.1% (110810). In patients with vitamin D deficiency and prediabetes, vitamin D might improve beta-cell function, suggesting reduced disease progression (99768,107210). One clinical study in adults with vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 3 months, and then monthly for 3 months, modestly improves insulin resistance and beta-cell function as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but does not affect fasting or postprandial glucose levels when compared with placebo (99768). Further, a meta-analysis of randomized controlled trials in patients with vitamin D deficiency and prediabetes shows that oral vitamin D at a median dose of 50,000 IU weekly for 26 weeks modestly improves fasting blood glucose and some markers of islet function, but not postprandial blood glucose or glycated hemoglobin (HbA1c) levels, when compared with control. Additionally, a significantly greater proportion of patients receiving vitamin D supplementation regressed from prediabetes to normal glucose status (107210). A meta-analysis of clinical studies in overweight or obese children and adolescents shows that high doses of vitamin D, 4000 IU daily or higher for 12-52 weeks, reduce HOMA-IR and C-reactive protein levels, but do not affect body weight, cholesterol, or parathyroid hormone (113596). A study in females with vitamin D deficiency and prediabetes shows that taking vitamin D 60,000 IU weekly for 8 weeks, followed by a maintenance dose of 200 IU daily, has no effect on the incidence of type 2 diabetes at 2 years (107211). Clinical practice guidelines from the Endocrine Society conditionally recommend, with moderate certainty of evidence, empiric vitamin D supplementation in addition to lifestyle modification for adults with high-risk prediabetes to reduce the risk of progression to diabetes. Empiric vitamin D supplementation is defined as vitamin D from supplements or fortified food above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Infant development. It is unclear if giving oral vitamin D in doses above the recommended dietary allowance during infancy is beneficial for improving neurodevelopment. It is also unclear if oral vitamin D during pregnancy is beneficial for improving cognitive development in the offspring. Details: Clinical research shows that giving vitamin D 1200 IU daily to healthy term infants of Northern European ethnicity starting at 2 weeks of age does not improve measures of neurodevelopment at 2 years of age when compared with giving the standard dose of vitamin D 400 IU (106121). Overall, the evidence from population research is mixed as to whether vitamin D status during gestation is associated with infant developmental outcomes. However, some population research has found that increased vitamin D status during pregnancy is associated with improved anthropomorphic and neurodevelopmental outcomes (104621,105724). Two meta-analyses of observational research show that low vitamin D status during pregnancy is associated with reduced head circumference and cognitive development scores, and higher odds of the offspring developing autism and attention deficit hyperactivity disorder (105724,105725). However, one meta-analysis suggests these risks may be limited to those with very low vitamin D status (serum level < 12 ng/mL) (105724). Multiple meta-analyses show that vitamin D status during pregnancy does not appear to affect motor development (105724,105725). In one observational study, plasma vitamin D concentrations in the second trimester of pregnancy was associated with increased IQ scores in the offspring at age 4-6 years. Each 10 ng/mL increase in vitamin D levels was associated with a 1.17-point increase in IQ (104621). In contrast, clinical research shows that taking vitamin D3 2800 IU daily during the third trimester does not improve neurodevelopmental outcomes in the first 6 years of life when compared to taking lower doses of 400 IU daily (104623).
• Infertility. It is unclear if oral or intramuscular vitamin D is beneficial in females with infertility. Details: Observational research in females undergoing in vitro fertilization suggests no association between dietary vitamin D intake and oocyte quality, successful embryo transfer, clinical pregnancy rate, or term pregnancy rate (112097). Additionally, a meta-analysis of clinical research in females with infertility shows that, although there was no effect of taking vitamin D on implantation rate or miscarriage, taking vitamin D increases the odds of clinical pregnancy by 49% when compared with placebo. However, sub-analyses of clinical and observational research found that benefits on clinical pregnancy rates were limited to populations with vitamin D insufficiency, but not vitamin D deficiency, and for doses between 1000 to 10,000 IU daily for 30-90 days (110818). Most studies included in the analysis used oral vitamin D; however, intramuscular vitamin D was used in one cohort study. A smaller meta-analysis of clinical studies in females with infertility and vitamin D insufficiency undergoing IVF shows that taking vitamin D increases the rate of chemical pregnancy by 50%, but has no effect on the clinical pregnancy rate (108432).
• Lichen planus. It is unclear if oral vitamin D is beneficial for lichen planus. Details: A small clinical study in patients with oral lichen planus and vitamin D deficiency or insufficiency shows that taking vitamin D 60,000 IU weekly in combination with systemic steroids for 1 month reduces pain severity and improves healing of lesions when compared with systemic steroids alone (114586). The validity of the study is limited by the lack of a placebo.
• Low birth weight. It is unclear if oral vitamin D can reduce the risk for low birth weight; the available evidence is conflicting. Details: A meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with lower birth weight and increased odds of SGA births. However, these risks have not been demonstrated in those with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Most research also shows that vitamin D supplementation during pregnancy reduces the risk of low birth weight. A meta-analysis of three clinical trials shows that supplementation with vitamin D 800-1000 IU daily starting between 27 and 32 weeks' gestation, or 200,000 IU administered as a single dose or in two divided doses during the seventh and eighth month of pregnancy, reduces the risk of delivering a low birth weight infant by 60% (84659). Other meta-analyses of clinical research show that supplementation with vitamin D during pregnancy results in a 31% to 60% reduced risk of low birth weight and a 103 gram greater average birth weight when compared with placebo or no intervention (99766,114587). However, some meta-analyses show that vitamin D supplementation during pregnancy does not reduce the risk of low birth weight when compared with no supplementation (95910,109055). One meta-analysis that included studies that did not directly measure birth weight shows no effect of vitamin D supplementation during pregnancy on the rate of low birth weight, despite showing an increase in overall birth weight of about 58 grams (95910).
• Lung cancer. It is unclear if oral vitamin D prevents lung cancer or improves lung cancer prognosis. Details: A small meta-analysis of randomized controlled trials and observational research has found that high intake of vitamin D is associated with a 10% reduction in the risk of developing lung cancer when compared with low vitamin D intake. In terms of prognosis, high vitamin D intake is associated with improvements in both overall survival and relapse-free survival (107217).
• Male infertility. It is unclear if oral cholecalciferol is beneficial in males with infertility. Details: A small clinical study in males with infertility shows that taking cholecalciferol 2500 IU daily for 6 months modestly improves progressive sperm motility, sperm concentration, and sperm morphology when compared with baseline (108427). The validity of these findings is limited by the lack of a comparator group.
• Melanoma. It is unclear if oral vitamin D is beneficial in patients with melanoma. Details: A meta-analysis of 14 observational studies suggests that vitamin D deficiency is associated with a 45% greater risk of melanoma when compared with normal vitamin D levels (112027). However, a small clinical study in patients with newly resected stage II melanoma shows that taking vitamin D3 100,000 IU every 50 days for 3 years does not improve disease-free survival when compared with placebo. Most patients in this study had vitamin D deficiency or insufficiency at baseline (106113).
• Metabolic syndrome. It is unclear if oral vitamin D is beneficial for preventing or treating metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking vitamin D 50,000 IU weekly for 16 weeks does not affect most metabolic or anthropometric factors when compared with placebo, although there was a modest decrease in triglyceride levels (106123). However, almost all of the individuals in this study were vitamin D deficient or insufficient, and many remained in that category even after supplementation. It is unclear if vitamin D supplementation is beneficial in vitamin D sufficient patients with metabolic syndrome. There is conflicting evidence about the association between vitamin D and metabolic syndrome (14265,16713,98234). Some population research has found that higher vitamin D levels are associated with a lower risk of metabolic syndrome, while other research found no association (14265,16713). Furthermore, a small clinical trial in patients with metabolic syndrome shows that taking vitamin D 20,000 IU or 40,000 IU weekly for 8 weeks does not affect metabolic risk factors when compared with placebo (98234).
• Migraine headache. It is unclear if oral vitamin D reduces the frequency of migraine. Details: A meta-analysis of three small high-quality clinical studies in patients with migraine shows that taking vitamin D 2000 or 4000 IU daily for 12-24 weeks or 500,000 IU weekly for 2 months reduces the frequency of migraines by 2-3 attacks monthly when compared with usual care or placebo (108439).
• Miscarriage. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing vitamin D 50 mcg, alpha-lipoic acid, hyaluronic acid, magnesium, and vitamin B6 daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to vitamin D, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo for the control group.
• Multiple sclerosis (MS). Although vitamin D supplementation has been linked with a lower risk of developing MS, taking oral vitamin D supplements does not seem to reduce MS relapses. Details: Vitamin D deficiency appears to be linked to the risk of MS development and progression. Population research suggests that long-term supplementation with vitamin D 400 IU is associated with a 40% lower risk of MS in females. The effect seems to be dose-dependent. Consumption of at least 400 IU daily, mainly in the form of a multivitamin supplement, appears to have the greatest protective effect (11356). Additional population research in over 7 million people suggests that higher levels of calcifediol are associated with a lower risk of developing MS. In white adults, for every 20 ng/mL increase in vitamin D levels, there appears to be a 41% decrease in MS risk. However, this was not found in black and Hispanic adults (15159). Vitamin D supplementation has also been examined in patients with MS. Population research suggests that taking vitamin D supplements and the maintenance of optimal blood levels of vitamin D are associated with a reduction in the development of new areas of demyelination detected by magnetic resonance imaging (MRI) over 24 months. However, there are no correlations between vitamin D consumption or vitamin D blood levels and clinical outcomes (110816). Also, vitamin D supplementation does not seem to impact MS relapses or most symptoms in patients with MS. Meta-analyses of preliminary clinical research show that vitamin D supplementation does not affect the rate of MS relapses, overall symptoms, disability scores, or the number of MS nerve lesions detected by MRI, regardless whether the vitamin D was low-dose or high-dose (98192,98914,106119,113586). However, one meta-analysis of 6 small clinical studies shows that taking vitamin D for 8-96 weeks slightly improves fatigue scores when compared with placebo (112024). These analyses are limited by the small size and heterogeneity of most of the included studies and variability in dosing and duration of vitamin D regimens.
• Muscle strength. It is unclear if oral vitamin D improves muscle strength in middle aged or older adults with low or sufficient levels of vitamin D. The available research is conflicting. Details: Clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not increase muscle strength when compared with placebo (11814,104619,108429). In patients 40-80 years of age with low vitamin D levels, taking vitamin D3 100,000 IU (2500 mcg) once, followed by 20,000 IU (500 mcg) weekly for 4 months, does not improve muscle strength when compared with placebo (103658). Similarly, meta-analyses of clinical research show that vitamin D does not increase grip strength, muscle mass, global muscle strength, or back extensor strength when compared with control (91341,113595). However, some research has found some benefit with the use of vitamin D supplements. One meta-analysis shows that taking vitamin D increases grip strength after menopause when compared with placebo or low-dose vitamin D, although a sub-analysis shows that beneficial effects are limited to individuals aged 60-69 years, when vitamin D is taken without calcium, when baseline vitamin D levels are at least 30 ng/mL, or when the treatment consists of the vitamin D analog alfacalcidol. This suggests heterogeneity between studies (109048). Another meta-analysis in elderly adults shows that taking vitamin D as calcifediol 10-30 mcg daily for a median of 24 weeks modestly improves hand grip strength and leg extension, but not leg flexion, when compared with baseline (109042). Also, some individual clinical research in older adults with low levels of vitamin D at baseline shows that taking vitamin D3 800 IU daily or vitamin D2 (ergocalciferol) 1000 IU daily for 12 months in combination with calcium 1000 mg daily modestly improves lower extremity or hip strength by 8% to 23% when compared with calcium alone (38915,84530).
• Myalgia. It is unclear if oral vitamin D is beneficial for reducing myalgia associated with obesity. Details: Preliminary clinical research in obese individuals with vitamin D deficiency who are on a low-calorie diet shows that taking vitamin D 50,000 IU weekly, alone or in combination with an aerobic exercise program three times weekly for 12 weeks, modestly reduces muscle pain when compared with only aerobic exercise three times weekly (106118).
• Myelodysplastic syndromes. It is unclear if oral vitamin D is beneficial for patients with myelodysplastic syndromes. Details: A small observational study in patients with myelodysplastic syndromes has found that taking calcitriol or calcifediol orally is associated with slowed disease progression (11825).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral or intramuscular vitamin D is beneficial in children or adults with NAFLD. Details: Although findings from individual research are mixed, one meta-analysis of mainly small clinical trials in patients with NAFLD shows that vitamin D modestly improves insulin resistance and serum alanine aminotransferase (ALT) levels, with no effect on serum aspartate aminotransferase (AST) levels. Most studies included in the analysis used oral vitamin D 1000 IU daily or 50,000 IU weekly or biweekly for 3-6 months and compared with placebo; however, one study used a single intramuscular injection of vitamin D 600,000 IU compared with lifestyle modifications (109056). Vitamin D has also been evaluated in combination with fish oil. A clinical study in adults with NAFLD shows that taking oral vitamin D3 1680 IU daily in combination with fish oil or fish oil alone for 3 months improves serum ALT levels similarly to a control group (107186). Vitamin D has also been evaluated for use in children with NAFLD. One clinical study in children with obesity and biopsy-proven NAFLD shows that taking oral vitamin D3 2000 IU daily for 6 months with a hypocaloric diet improves liver histopathology in terms of steatosis, lobular inflammation, and NAFLD activity score at 6 months, but not hepatocyte ballooning or fibrosis, when compared with baseline. These improvements were not seen in the group receiving placebo with a hypocaloric diet, but it is unclear if the improvement from baseline differed between groups (107222).
• Nonmelanoma skin cancer. It is unclear if oral vitamin D is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking vitamin D3 1000 IU daily for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking vitamin D3 with calcium 1200 mg daily as calcium carbonate reduces the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but has no effect on the risk of basal cell carcinoma. Vitamin D taken alone has no effect on the risk for either type of cancer (104622).
• Obesity. The evidence for the use of oral vitamin D in obesity is conflicting and unclear. Details: Population research has found that people with lower vitamin D levels are significantly more likely to be obese when compared to people with higher vitamin D levels (15630). Also, a large-scale, high-quality clinical trial in postmenopausal adults taking calcium 1000 mg plus vitamin D3 (cholecalciferol) 400 IU daily for 3 years shows that these patients are more likely to lose weight and maintain their weight when compared with those taking placebo. This beneficial effect is mainly seen in females who have inadequate intake of calcium, less than 1200 mg/day, before starting a calcium supplement (15604). However, other evidence suggests that vitamin D alone does not improve weight loss. One clinical trial shows that taking vitamin D3 2000 IU/day without calcium for 12 months does not increase weight loss when compared with placebo in overweight and obese postmenopausal adults who are deficient in vitamin D at baseline (91345).
• Orthostatic hypotension. It is unclear if oral vitamin D is beneficial for prevention of orthostatic hypotension. Details: A secondary analysis of a clinical study in older patients with vitamin D insufficiency who are at an increased risk for falls shows that taking vitamin D 1000-4000 IU daily for up to 2 years has no effect on the risk of orthostatic hypotension or orthostatic symptoms when compared with those receiving vitamin D 200 IU daily (107223).
• Osteoarthritis. It is unclear if oral vitamin D is beneficial for osteoarthritis. Details: The evidence for the use of vitamin D in osteoarthritis is conflicting. Some clinical research shows that taking vitamin D3 (cholecalciferol) 2000 IU daily, or at a higher dose to reach serum vitamin D levels over 36 ng/mL, for 2 years does not reduce knee pain or loss of cartilage when compared with placebo in patients with symptomatic osteoarthritis (84688). However, another clinical study shows that taking vitamin D3 daily for 10 days and then vitamin D3 60,000 IU monthly for 12 months modestly reduces pain and improves function when compared with placebo in patients with osteoarthritis and vitamin D insufficiency (98199). It is possible that higher doses of vitamin D have an effect on osteoarthritis, while lower doses do not. Due to this conflicting and low-quality evidence, the American College of Rheumatology (ACR) recommends against the use of vitamin D for any form of osteoarthritis (102114).
• Otitis media. It is unclear if oral vitamin D is beneficial in patients with otitis media. Details: The relationship between vitamin D status and otitis media is unclear. Population research has found that having otitis media is associated with lower blood levels of vitamin D; however, lower vitamin D levels were not associated with greater risk of otitis media (98194).
• Overactive bladder. It is unclear if oral vitamin D is beneficial for overactive bladder in children or adults. Details: A large clinical trial in older males shows that taking vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the odds of weekly overactive bladder when compared with placebo. In males with low baseline serum vitamin D, taking vitamin D reduces the odds of overactive bladder at 5 years by 49%, including 34% reduced odds of overactive bladder with urinary incontinence and 81% reduced odds of overactive bladder without incontinence. However, urinary incontinence while sleeping or napping was increased (109738). Vitamin D has also been evaluated for overactive bladder in children with low vitamin D levels. A large, single-blind clinical study in children with overactive bladder without urinary incontinence, and with vitamin D insufficiency or deficiency, shows that taking vitamin D 2400 IU daily for 8 weeks with standard urotherapy reduces voiding frequency by about 3 or 4 voids daily when compared with standard urotherapy, with or without solifenacin 5 mg daily (115574,115591). Standard urotherapy was defined in this study as medical education, timed voiding, and pelvic floor muscle training.
• Overall mortality. Taking oral vitamin D alone does not seem to reduce mortality; however, there is some evidence that taking certain forms of vitamin D with calcium might have a modest benefit. Details: While higher vitamin D levels have been associated with a small reduction in mortality when compared with lower vitamin D levels (98187), clinical research shows that taking vitamin D does not reduce the risk of mortality. A comprehensive meta-analysis shows that vitamin D supplementation alone does not reduce all-cause mortality when compared to control (100900). However, giving vitamin D with calcium may modestly reduce the risk of mortality. Meta-analyses show a 4% to 9% reduced risk of mortality when trials of vitamin D alone and vitamin D with calcium are pooled together (16102,97296,98186,112022). Finally, some research suggests that the type of vitamin D supplementation might influence the results. A meta-analysis of clinical research found that vitamin D3 (cholecalciferol) with or without calcium reduces mortality risk by 6%, while alfacalcidol, calcitriol, and vitamin D2 (ergocalciferol) do not have benefit (84595,98186). Other clinical research suggests that vitamin D supplementation in older adults may reduce the risk of all-cause mortality by about 4%, with an estimated effect size of 6 fewer deaths per 1000 individuals. This finding informed the 2024 Endocrine Society Clinical Practice Guidelines on vitamin D for the prevention of disease in the general population. The Endocrine Society conditionally recommends, with moderate certainty of evidence, empiric vitamin D supplementation from fortified foods or vitamin D-containing supplements in the general population aged 75 years and older to potentially lower the risk of mortality. Empiric vitamin D is defined as vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status. For empiric supplementation and for those who have indications for vitamin D treatment or supplementation, daily lower-dose versus intermittent higher doses was suggested (114502).
• Pain (chronic). It is unclear if oral vitamin D is beneficial for chronic pain. Details: A meta-analysis of clinical research in patients with chronic pain shows that taking vitamin D for 1-24 months produces a 43% greater decrease in pain score when compared with placebo. However, the final follow-up pain score is similar for both groups (96402). The effect of vitamin D on pain based on pain-related diagnosis, vitamin D status, or dose is unknown.
• Parkinson disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Population research found that higher levels of vitamin D are associated with milder Parkinson disease symptoms, while deficiency is associated with increased risk of Parkinson disease (97000,99772). One small study shows that taking vitamin D3 (cholecalciferol) 1200 IU daily for one year might modestly slow the progression of Parkinson disease based on the Hoehn and Yars staging criteria. However, there was no improvement in disease severity according to the more widely used Unified Parkinson Disease Rating Stage (UPDRS). The UPDRS includes measures of activities of daily living and non-motor symptoms. Vitamin D had no effect on most quality of life measures (95915).
• Periodontitis. It is unclear if oral vitamin D is beneficial for periodontal disease. Details: A meta-analysis of mostly observational research suggests that vitamin D levels are not associated with an increased or decreased risk of periodontitis (112026). Other population research suggests that higher blood levels of vitamin D may be associated with a reduced risk of periodontal disease in adults 50 years of age or older. However, this association was not found for adults younger than 50 years (15634).
• Physical performance. It is unclear if oral vitamin D improves muscle strength in elderly adults. Details: Some clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not improve physical performance when compared with placebo (11814,104619,108429). Also, results from one meta-analysis of clinical research in postmenopausal females with low levels of vitamin D shows that taking vitamin D does not improve the timed up and go test when compared with placebo or low-dose vitamin D (109048). One meta-analysis that included studies specifically evaluating the use of calcifediol in older adults shows a large benefit on gait speed; however, only one study included in the analysis used this endpoint and other measures of physical performance were not affected (109042).
• Pneumonia. High-dose oral vitamin D does not reduce pneumonia severity in children. Details: Although vitamin D supplementation might prevent respiratory tract infections in children, it might not prevent recurrent pneumonia. A small clinical study in children under 5 years of age with recurrent pneumonia and variable vitamin D blood levels shows that taking vitamin D 300,000 IU quarterly for 1 year does not reduce respiratory infections, severity of pneumonia, hospital admissions, or disease complications when compared with placebo (103667). However, it's unknown if vitamin D supplementation using lower and more frequent doses, or supplementation in patients with vitamin D deficiency, might be beneficial. Some observational research has found that having vitamin D deficiency is linked to a higher risk for developing community-acquired pneumonia (CAP) (102118). For information on other respiratory infections, refer to the Respiratory Tract Infection discussion.
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin D improves pregnancy rates and outcomes, clinical symptoms, metabolic parameters, or hormone levels in patients with PCOS. Details: Observational research in adults with infertility, PCOS, and insulin resistance suggests that normal vitamin D levels are associated with better embryo quality and increased pregnancy rate when compared with vitamin D deficiency or insufficiency (100834). It is unclear if supplementation with vitamin D improves pregnancy rates in patients with PCOS. A meta-analysis of several mostly low-quality clinical studies in patients with PCOS and vitamin D deficiency at baseline shows that intramuscular or oral vitamin D 200-10,000 IU daily for up to 24 weeks in addition to fertility treatment improves pregnancy rates and reduces premature miscarriage and premature delivery, but does not impact the incidence of pregnancy complications including gestational hypertension or gestational diabetes, when compared with control. This analysis also suggests vitamin D supplementation improves certain IVF-related outcomes including ovulation rate, fertilization rate, and number of mature oocytes (112787). An earlier meta-analysis of clinical research shows that taking vitamin D 400-12,000 IU daily for 2-6 months improves follicular development when compared with placebo. Taking vitamin D in combination with metformin 1500 mg daily also appears to increase the number of regular menstrual cycles by 85% when compared with metformin alone, but without an effect on follicular development (96404). However, a meta-analysis of 3 clinical studies shows that combining vitamin D with metformin probably does not improve menstrual cycle regulation when compared with metformin alone (113594). The effect of vitamin D on the hormonal and metabolic profiles of patients with PCOS has also been evaluated. An umbrella review of up to 15 meta-analyses of clinical studies in patients with PCOS shows that taking vitamin D 2000-8500 IU daily for 6.5-13.5 weeks reduces levels of serum triglycerides, total and low-density lipoprotein (LDL) cholesterol, and total testosterone, but not body mass index (BMI) or insulin levels, when compared with placebo (115577). A separate meta-analysis of 9 clinical studies, not included in the umbrella review, shows that combining vitamin D with metformin reduces insulin resistance, BMI, and testosterone levels when compared with metformin alone (113594). Additionally, a small clinical study in adults with PCOS and vitamin D deficiency or insufficiency shows that taking vitamin D 2000 IU daily in combination with diet and exercise for 12 weeks reduces insulin resistance, BMI, waist to hip ratio, serum triglyceride levels, and total and LDL cholesterol levels when compared with diet and exercise alone (114580). The interpretation of the results in this clinical study is limited by the lack of a placebo control.
• Post-stroke fatigue. It is unclear if oral vitamin D is beneficial for post-stroke fatigue. Details: A retrospective study in patients with post-stroke fatigue and vitamin D deficiency suggests that vitamin D (cholecalciferol) 600 IU daily is associated with improvements in fatigue severity at months 1 and 3 when compared with control. Neurologic disability also showed improvement at 3 months, but not at 1 month, when compared with control. It is unclear if improvements from baseline differed between groups (107225).
• Pre-eclampsia. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention or treatment of pre-eclampsia. Details: While some clinical research suggests that taking vitamin D during pregnancy does not reduce the risk of pre-eclampsia (113585,114587), clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small for gestational age (SGA) birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Precocious puberty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of precocious puberty. Details: A meta-analysis of 43 mostly observational studies from China suggests that vitamin D deficiency or insufficiency is associated with 2.25-fold greater odds of precocious puberty when compared with normal vitamin D levels. Taking vitamin D 200-1000 IU daily for 3-12 months along with a gonadotropic-releasing hormone analog (GnRHa) is associated with lower luteinizing hormone, follicle-stimulating hormone, and estradiol levels and reduced bone age when compared with GnRHa therapy alone (112019). Another meta-analysis of 15 studies, mainly from China and with high heterogeneity and publication bias, suggests that there is a negative correlation between serum 25-hydroxy-vitamin D concentrations and precocious puberty, and that vitamin D deficiency increases the risk of precocious puberty by about 53% (113578).
• Pregnancy-induced hypertension. It is unclear if oral vitamin D is beneficial for patients with gestational hypertension. Details: Meta-analyses of two low-quality clinical trials show that vitamin D supplementation during pregnancy does not reduce the risk for gestational hypertension when compared with control (95910,114587).
• Prematurity. It is unclear if taking vitamin D during pregnancy prevents respiratory complications in preterm neonates. Details: A large clinical study in pregnant patients with gestational age less than 34 weeks and at risk of preterm delivery shows that a single intramuscular injection of vitamin D 50,000 IU within 72 hours before delivery decreases the risk of respiratory distress syndrome treated by surfactant in the neonate by about 2.25-fold and increases the 5th minute APGAR scores, but not 1st minute APGAR scores, gestational age, neonatal intensive care unit admission, length of hospital stay, or delivery method, when compared with no treatment (114581).
• Premenstrual syndrome (PMS). It is unclear if oral vitamin D is beneficial in patients with PMS. Details: Observational research has found that increasing dietary intake of vitamin D above 706 IU daily is linked to a reduced risk of developing PMS when compared with consuming 112 IU daily (13094). Furthermore, a clinical study shows that taking vitamin D 400 IU daily in combination with calcium 1000 mg daily can decrease the severity of PMS symptoms (16869). Another clinical study in adolescent females with PMS shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces PMS symptoms when compared to baseline (98912). A small clinical study in young adults with PMS and vitamin D deficiency shows that taking vitamin D 50,000 IU every 2 weeks for 16 weeks reduces psychological symptom scores by 54% and physical symptom scores by 39% when compared with placebo (113582).
• Preterm labor. It is unclear if oral vitamin D is beneficial for preterm labor. Details: Vitamin D deficiency, defined as serum levels less than 20 ng/mL, during pregnancy has been associated with a 25% greater risk of preterm birth (95911). The risk seems to be especially prominent in those with darker colored skin (103662). However, meta-analyses of clinical research show that vitamin D supplementation during pregnancy does not reduce the risk of a preterm birth when compared with no supplementation with vitamin D (84659,95910,109055,114587). The effect vitamin D specifically in vitamin D-deficient patients is still unclear. Some small, heterogeneous, and low-quality studies show that vitamin D supplementation might reduce the rate of preterm birth in vitamin D-deficient patients (84659,95910). Additional studies are needed to determine the effect of vitamin D supplementation on the risk of preterm birth. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preterm birth, small for gestational age (SGA) birth, preeclampsia, intra-uterine mortality, and neonatal mortality. Empiric vitamin D supplementation iss defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral vitamin D may not improve symptoms in patients with RA. Details: Population research has found that higher intake of vitamin D from foods or supplements is associated with a lower risk of developing RA (12206,98200). However, a meta-analysis of two small clinical trials shows that vitamin D supplementation does not reduce pain or recurrence of RA when compared with placebo (98190).
• Rhinosinusitis. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking 1 or 2 sachets of a specific combination product (Flogostop Forte, Humana Italia) containing vitamin D 600 IU, black currant, Boswellia serrata, and bromelain along with a nasal corticosteroid daily for 15-30 days reduces symptoms of nasal hyperemia and rhinorrhea when compared with corticosteroid nasal spray alone (111501). It is unclear if these findings are due to vitamin D, other ingredients, or the combination.
• Sarcopenia. It is unclear if oral vitamin D is beneficial in older adults with sarcopenia. Details: A meta-analysis of randomized trials in older adults with sarcopenia shows that taking vitamin D3 (cholecalciferol) 100-800 IU daily, with protein 10-44 grams daily or amino acids 2.5-6 grams daily, for 2-6 months moderately improves muscle strength, but not muscle mass or walking speed, when compared with placebo (105727). The validity of this study is limited by high heterogeneity and an unreported baseline vitamin D status. Similarly, a small network meta-analysis of randomized trials shows that taking vitamin D 500-1600 IU daily or 2500-5000 IU weekly with protein 20-80 grams daily or amino acids 3-32 grams daily with and without exercise for 3-18 months increases hand grip strength and shortens time to chair-stand, respectively, but not gait speed or lower-limb mass when compared with usual care (107221). It is unclear if these effects are due to vitamin D, protein/amino acid supplementation, exercise, or the combinations.
• Schizophrenia. It is unclear if oral vitamin D is beneficial for schizophrenia. Details: Based on preliminary clinical evidence, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is not recommended for adjunctive use in patients with schizophrenia (110318). A moderate-sized clinical study in patients with schizophrenia shows that taking a specific combination product (BioZenD, Tak Gen Zist Pharmaceutical Company) containing vitamin D 400 IU in combination with a blend of probiotics (Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, Limosilactobacillus reuteri, Lacticaseibacillus paracasei, Bifidobacterium longum, Bacillus coagulans) 2 x 10⁹ CFU daily for 12 weeks improves cognitive function scores but does not improve the severity of positive and negative schizophrenia symptoms when compared with placebo (114582). It is unclear if this effect is due to vitamin D, the probiotics, or the combination.
• Sciatica. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary research in adults up to 45 years of age with discogenic sciatica shows that taking cholecalciferol 800 IU with alpha-lipoic acid, acetyl-L-carnitine, and resveratrol daily for 30 days, in combination with a 20-session rehabilitation protocol, improves pain, disability, and quality of life when compared with the supplements alone or the rehabilitation protocol alone (112933).
• Seasonal affective disorder (SAD). One small study suggests that a large dose of oral vitamin D can improve symptoms of SAD. Details: A small clinical study in patients with SAD suggests that a single dose of vitamin D2 (ergocalciferol) 100,000 IU improves symptoms after one month when compared to baseline (83791). The validity of this finding is limited by the lack of a control group.
• Seborrheic keratosis. It is unclear if topical vitamin D analogues improve symptoms of seborrheic keratosis. Details: Preliminary clinical research suggests that topical ointments containing activated vitamin D in the form of tacalcitol, calcipotriol or maxacalcitol, applied for 3-12 months, can reduce tumor volume by at least 40% in 75% of patients with seborrheic keratosis. Additionally, over 30% of patients seem to experience complete tumor resolution or a reduction in tumor volume of at least 80% (84033). The validity of this finding is limited by the lack of a control group.
• Sexual dysfunction. One small study suggests that injecting a large dose of vitamin D might improve sexual function. Details: A small clinical study in females with vitamin D deficiency and sexual dysfunction shows that receiving an intramuscular injection of vitamin D as cholecalciferol 300,000 IU once at baseline and a second time 4 weeks later improves sexual function at 4 and 8 weeks when compared with placebo (100896).
• Sickle cell disease. One small study suggests that oral vitamin D reduces pain and improves quality of life in children with sickle cell disease with vitamin D insufficiency or deficiency. Details: A small clinical study in children with sickle cell disease shows that taking vitamin D3 (cholecalciferol) 40,000-100,000 IU weekly for 6 weeks reduces days with pain and improves physical activity and quality of life for up to 6 months when compared with placebo. Of the children included in the study, 82.5% had vitamin D insufficiency, while 52.5% were deficient in vitamin D (98918). It is unclear if vitamin D is effective for patients with sickle cell disease who have adequate levels of vitamin D.
• Small for gestational age (SGA). It is unclear if oral vitamin D can reduce the risk for SGA births; the available evidence is conflicting. Details: Two meta-analyses of clinical research show no effect of vitamin D on the risk of SGA birth (84659,109055). However, one meta-analysis shows a 40% reduction in the risk of SGA births with vitamin D supplementation (95910). Also, one meta-analysis shows that when vitamin D supplementation is initiated before the 20^th week of gestation, the risk of SGA is reduced by 54% (109055). Most individual clinical trials are small and heterogeneous. Also, the formulation of vitamin D and/or vitamin D status at baseline may explain part of the discrepant findings. For example, a meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with increased odds of SGA births. This association does not seem to be present with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Clinical practice guidelines from the Endocrine Society conditionally recommend, with low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of SGA births, as well as preeclampsia, intra-uterine mortality, preterm birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Statin-induced myalgia. It is unclear if oral vitamin D is beneficial for patients with statin-induced myalgia. Details: Observational research has found that taking oral vitamin D supplements is associated with decreased symptoms of myalgia in patients taking statin drugs. In a small case series, patients who discontinued statins due to myalgia were able to resume statin therapy after starting vitamin D supplements. The majority of patients with myalgia were found to be vitamin D deficient, with vitamin D levels less than 12 ng/mL at baseline (16829). An observational study has also found that administering 50,000 units of vitamin D2 (ergocalciferol) once a week for 12 weeks reversed symptoms of myalgia in 92% of statin treated patients with low serum vitamin D levels of less than 32 ng/mL (16831).
• Stroke. Although low vitamin D levels are associated with higher risk of stroke, taking vitamin D supplements does not seem to reduce stroke risk. Details: Population research has found that low vitamin D levels are associated with an increased risk of stroke. Furthermore, increased dietary intake of vitamin D is associated with a reduced risk of stroke (15630,16618,93944,97303,106106). However, clinical research shows that vitamin D supplementation does not reduce stroke risk. Several meta-analyses and randomized controlled trials show that taking vitamin D alone or with calcium does not reduce the risk of stroke in patients with or without cardiovascular disease risk factors (16616,91343,97296,97308,106106,112022). It is difficult to draw firm conclusions from these studies, as they did not assess whether patients had adequate vitamin D levels at baseline. It is unclear if vitamin D supplementation might prevent strokes in patients with vitamin D deficiency.
• Sunburn. Although there is interest in using oral vitamin D for the treatment of sunburns, there is insufficient reliable information about the clinical effects of vitamin D for this purpose.
• Systemic lupus erythematosus (SLE). It is unclear if oral vitamin D is beneficial in patients with SLE. Details: While some observational research has found that adults with SLE are more likely to have vitamin D deficiency than healthy controls (102119), a small cross-sectional study in females has found no association between serum levels of 25-hydroxyvitamin D, SLE disease activity, and the presence or absence of lupus nephritis (107214). A meta-analysis of three small clinical studies shows that taking vitamin D3 (cholecalciferol) 2000 IU daily or 50,000 IU weekly seems to reduce anti-dsDNA positive, a marker of disease activity, when compared with placebo in patients with SLE (98190). However, the clinical significance of this finding is unclear. A small clinical trial in females with SLE shows that taking vitamin D3 5000 IU daily for 12 weeks modestly improves overall disease activity, but not quality of life, when compared with placebo (109735).
• Thyroid cancer. It is unclear if oral vitamin D is beneficial in patients with thyroid cancer. Details: Observational research in patients undergoing thyroidectomy for differentiated thyroid cancer suggests that taking vitamin D daily for at least 6 months after surgery is associated with a 38% lower risk of all-cause mortality and a 33% lower risk of total cancer-related mortality when compared with no vitamin D supplementation at around 10 years' follow-up. However, vitamin D does not appear to be linked to a lower risk of thyroid cancer-related mortality in these patients (112018).
• Ulcerative colitis. Limited evidence suggests that vitamin D may be beneficial in patients with ulcerative colitis. Details: A meta-analysis of mainly small clinical trials in patients treated with mesalazine shows that taking vitamin D for up to 24 weeks modestly increases clinical efficacy and reduces disease score when compared with mesalazine alone (109044). Also, a meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). These findings are limited because of the heterogeneity of the included studies.
• Upper respiratory tract infection (URTI). It is unclear if oral vitamin D is beneficial for dementia. Details: A large clinical trial shows that taking vitamin D 2800 IU daily, starting at gestational week 24 and continuing until one week after birth, reduces the risk of the child developing croup by 3 years of age by 40% when compared with olive oil as placebo. This risk reduction did not change after adjusting for the use of omega-3 fatty acids 2.4 grams daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Urinary incontinence. Limited evidence suggests that vitamin D may be beneficial in middle-aged, but not older, adults with urinary incontinence. Details: Clinical research in middle-aged premenopausal females with stress urinary incontinence and low vitamin D status shows that taking vitamin D 5000 IU once weekly for 12 weeks has a moderate to large beneficial effect on the severity of incontinence and quality of life when compared with placebo. Kegel exercises were performed by all participants (109736). However, vitamin D supplementation does not seem to be beneficial for reducing urinary incontinence in older adults. In older females and males, a large clinical trial shows that vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the incidence or progression of urinary incontinence when compared with placebo (109738,109741). In older males with low vitamin D status, vitamin D supplementation may actually increase some types of incontinence (109738).
• Urinary tract infections (UTIs). It is unclear if oral vitamin D is beneficial for the prevention of UTIs in children. Details: A meta-analysis of 13 small observational studies in children suggests that lower levels of vitamin D are associated with 2.8-fold greater odds of UTI when compared with higher vitamin D levels. Further, this analysis shows that vitamin D deficiency in children is linked to 5.5-fold greater odds of UTI when compared with normal vitamin D levels (112030).
• Urticaria. It is unclear if oral vitamin D is beneficial for the prevention or treatment of urticaria. Details: A meta-analysis of population research has found that having urticaria is associated with a slightly lower vitamin D blood level and a greater likelihood of vitamin D deficiency when compared with individuals without urticaria. In addition, a meta-analysis of 6 clinical trials shows that taking vitamin D at an average daily dose of at least 4100 IU has a modest effect on the severity of urticaria symptoms (106115). Pooled data from 2 clinical studies in adults with chronic urticaria shows that taking vitamin D for 12 weeks, either as cholecalciferol 60,000 IU every 2 weeks or as alfacalcidol, 0.25 mcg once daily, reduces pruritus severity when compared with placebo (115587).
• Uterine fibroids. Low vitamin D status is associated with uterine fibroids and some clinical research suggests that taking vitamin D may modestly decrease the size of uterine fibroids. Details: Two meta-analyses of 5 clinical studies in premenopausal adults with uterine fibroids shows that taking vitamin D, either 50,000 IU weekly or biweekly for 8-12 weeks or 1000 IU daily for 1 year, decreases fibroid size when compared with placebo or no treatment (113577,115573). One of the meta-analyses found a 5.7% difference in fibroid size between vitamin D and control (115573). Observational research also suggests that vitamin D status is associated with uterine fibroids. Specifically, meta-analyses of a total 23 observational studies suggest that individuals with uterine fibroids have lower serum vitamin D levels and a 3.7-times higher odds of vitamin D deficiency (115573).
• Vaginal atrophy. It is unclear if oral vitamin D is beneficial for vaginal atrophy. There is limited evidence on the topical use of vitamin D in vaginal atrophy in postmenopausal adults or patients taking tamoxifen. Details: A small cross-sectional study in postmenopausal adults has found that taking a vitamin D supplement for at least one year improves the maturation index of superficial vaginal wall cells when compared with those who do not take vitamin D. However, symptoms of vaginal atrophy were not different between groups (16879). Vitamin D has also been evaluated for vaginal atrophy due to tamoxifen. A small clinical trial in females with breast cancer using tamoxifen shows that receiving vitamin D 1000 IU vaginal suppositories daily for 8 weeks improves maturation index of vaginal walls and self-reported symptoms when compared with placebo (99773).
• Vertigo. It is unclear if oral vitamin D is beneficial in patients with vertigo. Details: An analysis of observational research suggests that lower serum levels of vitamin D are associated with a higher risk of benign paroxysmal positional vertigo (BPPV) when compared with higher vitamin D levels (114579). However, it is unclear if vitamin D supplementation can reduce the risk of BPPV in individuals with low vitamin D levels. Vitamin D has been evaluated in combination with other ingredients for the treatment of BPPV. A large clinical study in adults with recurrent BPPV shows that taking vitamin D 400 IU and calcium 500 mg twice daily for one year reduces the risk of recurrence by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 4 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination.
• Vitiligo. Although there is interest in using oral vitamin D for vitiligo, there is insufficient reliable information about the clinical effects of vitamin D for this condition.
• Warts. Although there is interest in using topical vitamin D derivatives for warts, there is insufficient reliable information about the clinical effects of vitamin D for this condition. More evidence is needed to rate vitamin D for these uses.