California Grown Spirulina 500 mg [Discontinued] by The Vitamin Shoppe

POSSIBLY EFFECTIVE

• Hypertension. Oral blue-green algae seem to modestly reduce blood pressure in patients with hypertension. Details: Some small clinical studies show that blue-green algae can decrease blood pressure in patients with hypertension (97206,99654). A meta-analysis of five small clinical trials in patients with hypertension, type 2 diabetes, or chronic pain shows that taking spirulina blue-green algae 1-8 grams daily for up to 12 weeks reduces systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure (DBP) by 7 mmHg when compared with placebo. The effect size was larger in patients with hypertension and in those treated for at least 12 weeks (109964). Another small clinical study shows that taking spirulina blue-green algae (A. maxima) 4.5 grams daily for 6 weeks decreases blood pressure in adults with hypertension, with the number of subjects fulfilling the criteria for hypertension decreasing from 45% to 14% when compared to baseline (18297). A more recent clinical study in patients with hypertension shows that consuming a salad dressing containing 2 grams spirulina blue-green algae daily for 8 weeks reduces SBP by around 6 mmHg and DBP by around 4 mmHg when compared to baseline. While overall reduction in blood pressure with spirulina dressing was larger when compared with patients consuming a control dressing, the study groups were heterogenous at baseline, limiting the validity of any statistical comparisons between groups (109965).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if oral blue-green algae are beneficial in allergic rhinitis. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 2 grams daily for 6 months, improves self-rated scores for sneezing, nasal discharge, nasal congestion, and itching when compared with placebo in adults with allergic rhinitis (18300).
• Antiretroviral-induced insulin resistance. It is unclear if oral blue-green algae are beneficial for insulin resistance due to antiretrovirals. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 19 grams daily for 2 months increases insulin sensitivity by about 225% when compared to baseline in patients with antiretroviral-induced insulin resistance (75944). The validity of this finding is limited by the lack of a comparator group.
• Anxiety. Although there has been interest in using oral blue-green algae for anxiety, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Arsenic poisoning. It is unclear if oral blue-green algae are beneficial for chronic arsenic toxicity. Details: Preliminary clinical research in people living in areas of Bangladesh with high arsenic levels in drinking water shows that taking a combination of an alcoholic extract of spirulina blue-green algae 250 mg and zinc 2 mg orally twice daily for 16 weeks, in addition to use of filtered drinking water, increases urinary arsenic excretion, reduces hair arsenic levels, and improves skin manifestations of chronic arsenic toxicity when compared with placebo plus filtered water (18301).
• Athletic performance. Most research suggests that oral blue-green algae are not beneficial for improving athletic performance; however, the available studies are small. Details: AAlthough some research disagrees, most small or preliminary clinical trials show that taking spirulina blue-green algae does not improve athletic performance in trained or untrained adults. One study shows that, when compared with placebo, taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks has no effect on exercise output during a 30-minute elliptical trainer workout in active males (97203). In elite rugby players, taking spirulina blue-green algae (Algae Green Value) 5.7 grams daily for 7 weeks does not improve jump or sprint performance or body composition when compared to placebo (104567). In healthy untrained males, a small study shows that taking spirulina blue green algae 6 grams daily for 7 days does not increase the time to fatigue related to arm cycling following a 30-minute submaximal exercise bout (104566). In male recreational runners, spirulina blue-green algae (A. platensis) 2 grams three times daily for 4 weeks was not associated with any change in exercise intensity during a 2-hour treadmill jogging period. However, sprinting time to exhaustion following the 2-hour jog increased from 2.05 minutes to 2.7 minutes (18306). Also, a study of athletes and non-athletes shows that taking spirulina blue-green algae (Parry Nutraceuticals) 2 grams daily for 8 weeks has a small effect on isometric muscle strength, but not muscle endurance, when compared with placebo (104568).
• Attention deficit-hyperactivity disorder (ADHD). Oral blue-green algae have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 3 mL of a specific combination of spirulina blue-green algae, peony, ashwagandha, gotu kola, bacopa, and lemon balm (Nurture and Clarity, Tree of Healing-LD) diluted in 50-60 mL of water three times daily for 4 months improves ADHD scores when compared with placebo in previously untreated children aged 6-12 years (19272). It is unclear if this effect is due to blue-green algae, other ingredients, or the combination.
• Beta-thalassemia. It is unclear if oral blue-green algae are beneficial in beta-thalassemia. Details: In children with beta-thalassemia, preliminary clinical research shows that taking spirulina blue-green algae (GNC Natural Brand Spirulina, General Nutrition Corporation) 250 mg/kg daily, up to a maximum dose of 4 grams daily, for 3 months reduces the percentage of children requiring blood transfusion during an interval of less than 2 weeks from 66% to 40%. There were also improvements in red blood cell count and levels of hemoglobin, ferritin, and liver function enzymes (104569). However, the validity of these findings is limited by the lack of a comparator group.
• Blepharospasm. It is unclear if oral blue-green algae are beneficial when used in conjunction with botulinum toxin injections. Details: Preliminary clinical research shows that taking a specific product containing the blue-green algae species Aphanizomenon flos-aquae (Super Blue-Green Algae, Cell Tech) 1500 mg per day orally for 6 months in addition to botulinum toxin-A injections does not reduce eyelid spasms when compared with botulinum toxin-A alone in people with essential blepharospasm or Meige syndrome (14842).
• Cancer. Although there has been interest in using oral blue-green algae for cancer, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral blue-green algae for CVD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Cognitive Impairment. It is unclear if oral blue-green algae are effective for improving cognitive impairment. Details: A small clinical study in patients aged 60 or older with mild cognitive impairment shows that taking blue-green algae extract 1 gram 3 times daily for 12 weeks slightly improves some components of cognitive function testing related to visual learning, memory, and vocabulary when compared with placebo (112001). However, the validity of these findings is limited by lack of adjustment for multiple comparisons, which may explain the discrepant results with the other components of the cognitive function tests.
• Depression. Although there has been interest in using oral blue-green algae for depression, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Diabetes. It is unclear if oral blue-green algae are beneficial in diabetes. Details: A meta-analysis of seven small clinical studies in patients with type 2 diabetes shows that taking spirulina blue-green algae 0.8-14 grams daily for 6-12 weeks reduces fasting blood glucose and improves total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, but does not affect low-density lipoprotein (LDL) cholesterol, when compared with placebo. There was no reduction in glycated hemoglobin (HbA1c); however, all but two of the studies lasted less than 12 weeks, limiting the validity of the findings related to HbA1c (109970).
• Dyslipidemia. It is unclear if oral blue-green algae are beneficial in dyslipidemia. Details: Several clinical studies in patients with normal or elevated cholesterol levels show that doses of spirulina blue-green algae (A. platensis, A. maxima, A. fusiformis) ranging from 1-10 grams daily for 1-6 months may reduce total cholesterol by 8% to 27%, low-density lipoprotein (LDL) cholesterol by 10% to 65%, and triglycerides by 0% to 23%; and increase high-density lipoprotein (HDL) cholesterol by 0% to 66% (18297,18298,18299,91705,91708,91710,91717,102689). However, the validity of these studies is limited by methodological weaknesses and heterogeneous population characteristics. A meta-analysis of 23 small studies, several of which were in patients with type 2 diabetes or obesity, shows that taking blue-green algae 0.8-10 grams for 4 to 24 weeks modestly improves levels of LDL, HDL, triglycerides, and total cholesterol when compared with placebo or no treatment (112004). The interpretation of these findings is limited by the high heterogeneity of the included studies which enrolled patients of varying health status and employed various study designs.
• Dyspepsia. Although there has been interest in using oral blue-green algae for dyspepsia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Exercise-induced muscle soreness. It is unclear if oral blue-green algae are effective for the prevention of exercise-induced muscle soreness. Details: A small clinical study in recreationally trained males shows that taking spirulina blue-green algae 2 grams three times daily does not reduce delayed onset muscle soreness after eccentric exercise when compared with placebo (109967).
• Hepatitis C. Evidence for the use of oral blue-green algae in hepatitis C is conflicting. Details: One clinical study in adults with chronic hepatitis C who are unresponsive to interferon treatment shows that taking spirulina blue-green algae (A. platensis) 500 mg orally three times daily for 6 months is associated with greater improvements in alanine aminotransferase (ALT) levels than taking silymarin 140 mg three times daily. Complete virological response rates were 13% with blue-green algae and 3% with silymarin, although this difference was not statistically significant (63247). However, in another study in people with chronic hepatitis B or C, liver function enzyme levels worsened after one month of treatment with oral spirulina blue-green algae (18304).
• HIV/AIDS. It is unclear if oral blue-green algae are beneficial for people with HIV/AIDS who do not have access to antiretrovirals. Details: One clinical study in adults with untreated HIV shows that taking spirulina blue-green algae (A. platensis) powder 5-10 grams daily for 3-6 months does not affect CD4 counts, viral load, or weight gain in patients with HIV (75927,91707). However, in one study, the incidence of opportunistic infections, respiratory disease, gastrointestinal symptoms, and fatigue was 43% for patients taking spirulina blue-green algae, compared to 70% for patients taking placebo (91707).
• Iron deficiency anemia. Although there has been interest in using oral blue-green algae for iron deficiency anemia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Lichen planus. It is unclear if oral blue-green algae are beneficial in patients with oral lichen planus. Details: A small clinical study in patients with oral lichen planus shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks along with application of triamcinolone acetonide 0.1% oral paste three times daily for 1 week reduces pain and lesion size when compared with only triamcinolone acetonide three times daily for 8 weeks (109963).
• Malnutrition. Evidence for the use of oral blue-green algae in malnutrition is conflicting. Details: Some clinical research in severely undernourished children shows that adding spirulina blue-green algae (A. platensis) 5 grams orally twice daily for 8 weeks to a traditional diet results in an average daily weight gain of 25 grams, compared with only 15 grams for those given the traditional diet alone. Similarly, giving blue-green algae 10 grams twice daily for 8 weeks in addition to a misola diet (millet, soy, peanut kernel, sugar, and salt) results in an average daily weight gain of 34 grams, compared with only 20 grams for children given the misola diet alone (18308). However, a small clinical study in malnourished children aged 3 months to 3 years shows that giving spirulina blue-green algae 5 grams daily for 3 months in addition to a traditional diet fails to increase weight gain more than the traditional diet alone (18309). Similarly, a moderate-size crossover study in preschool-aged children in Cambodia shows that taking blue-green algae 2 grams 5 times a week during the first hour of school for 8 weeks does not improve weight gain or height but may reduce the proportion of children with anemia when compared with placebo (112002). The interpretation of these findings is limited by the high rate of patients lost to follow-up and the lack of statistical adjustment for confounding factors, such as parasitism and home diet.
• Memory. Although there has been interest in using oral blue-green algae for memory, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Menopausal symptoms. It is unclear if oral blue-green algae are beneficial for improving symptoms of menopause. Details: A preliminary clinical study shows that taking a product containing the blue-green algae species Aphanizomenon flos-aquae (Klamin, Nutrigea) 1.6 grams daily for 8 weeks reduces anxiety and depression when compared with placebo in menopausal adults aged 50-60 years. The treatment has no effect on vasomotor symptoms or hormone levels (18310).
• Mental alertness. It is unclear if oral blue-green algae are beneficial for reducing mental fatigue. Details: A preliminary clinical study shows that taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks improves performance on a mathematical based mental fatigue test in healthy men when compared with placebo. Subjective improvement in mental alertness over placebo was also reported (97203).
• Metabolic syndrome. It is unclear if oral blue-green algae are beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking spirulina blue-green algae (Spirulysat, AlgoSource), providing phycocyanin 20 mg, daily for 12 weeks improves triglyceride levels, but does not reduce body mass index, waist circumference, blood pressure, glycemic indices, or other lipid levels, when compared with placebo (109971).
• Nonalcoholic fatty liver disease (NAFLD). Although there has been interest in using oral blue-green algae for NAFLD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Obesity. Evidence for the use of blue-green algae in obesity is conflicting. Details: Small, low-quality clinical trials have shown mixed results in people with obesity (18295,91717,97205,99655,99703,102688). When results are analyzed together, there is evidence of a very small benefit for both body weight and plasma lipid levels. Two meta-analyses show that taking spirulina blue-green algae may increase weight loss by up to 1.85 kg when compared with placebo (102690,104565). A greater effect is seen in patients with obesity when compared with overweight patients. In addition, there is a small effect on fat loss (102690). However, there is evidence from two studies lasting longer than 12 weeks that taking blue-green algae may slightly increase BMI (104565). A meta-analysis of small clinical trials also shows that taking spirulina blue-green algae reduces fasting blood sugar and total cholesterol levels by a small amount when compared with placebo, but has no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels, in patients with obesity (102689). When combined with an exercise program, taking spirulina blue-green algae increases weight loss by 1.4 kg and improves exercise tolerance and total, LDL, and high-density lipoprotein (HDL) cholesterol levels when compared with exercise alone (99655,102688). Doses have included a specific product containing the spirulina blue-green algae species A. fusiformis (Multinal, New Ambadi Estate Pvt. Ltd.) 1 gram twice daily or four times daily for 3 months (91717) or spirulina blue-green algae 2 grams daily for 3 months, or 4.5 grams daily for 6 weeks, alone or in combination with exercise (97205,99655,102688).
• Oral leukoplakia. It is unclear if oral blue-green algae are beneficial for oral leukoplakia in tobacco chewers. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. fusiformis) orally 1 gram daily for 12 months produces regression of precancerous oral leukoplakia lesions in 45% of tobacco chewers, compared to only 7% of those receiving placebo. Regression rates appear to be highest in those with homogeneous lesions and lowest in those with ulcerated or nodular lesions (15782).
• Periodontitis. It is unclear if injecting blue-green algae into periodontal pockets is beneficial in periodontitis. Details: Preliminary clinical research shows that injecting a 4% w/v gel prepared from spirulina blue-green algae into periodontal pockets of adults with chronic periodontitis, after scaling and root planing, is associated with a decrease in probing pocket depth of 1.57 mm after 120 days, compared with only 0.84 mm in patients receiving scaling and root planing alone (91709).
• Premenstrual syndrome (PMS). Although there has been interest in using oral blue-green algae for PMS, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Stress. Although there has been interest in using oral blue-green algae for stress, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Ulcerative colitis. It is unclear if oral blue-green algae are beneficial in patients with ulcerative colitis. Details: A small clinical study in patients with ulcerative colitis shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks improves quality of life scores and reduces stress and sleep disturbances when compared with placebo. However, there was no effect on most measures of sleep quality, mood, and fatigue (109969).
• Wound healing. Although there has been interest in using oral blue-green algae for wound healing, there is insufficient reliable information about the clinical effects of blue-green algae for this condition. More evidence is needed to rate blue-green algae for these uses.

(Read more about BLUE-GREEN ALGAE)

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.

(Read more about CALCIUM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical chlorophyll is beneficial in patients with acne. Details: Preliminary clinical research in young adults with acne shows that applying facial sheets (VIRTA-Healer, Aseptica) containing chlorophyll to one side of the face for 30 minutes twice weekly, in combination with light-emitting diode (LED) irradiation, improves acne severity and reduces acne counts by 32% more than LED irradiation alone after 2 weeks of treatment (93893).
• Allergic rhinitis (hay fever). It is unclear if oral chlorophyll is beneficial in patients with allergic rhinitis (hay fever). Details: Preliminary clinical research in adults with allergic rhinitis shows that taking oral chlorophyll 0.7 mg daily for 12 weeks reduces the use of rescue medications after 8 weeks, but does not improve symptoms or quality of life, when compared with placebo (97934).
• Colostomy odor. Although there has been interest in using oral chlorophyll for colostomy odor, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Constipation. Although there has been interest in using oral chlorophyll for constipation, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Genital herpes. Although there has been interest in using topical chlorophyll for genital herpes, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Halitosis. Although there has been interest in using oral chlorophyll for halitosis, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Herpes zoster (shingles). Although there has been interest in using topical chlorophyll for herpes zoster (shingles), there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Nonmelanoma skin cancer. Although there has been interest in using topical or intravenous chlorophyll for nonmelanoma skin cancer, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Obesity. Although there has been interest in using oral chlorophyll for obesity, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose.
• Pancreatitis. It is unclear if oral chlorophyll is beneficial in patients with pancreatitis. Details: Preliminary observational research in patients with chronic relapsing pancreatitis suggests that administering chlorophyll 5-20 mg intravenously divided 1-2 times daily for 1-2 weeks modestly improves pain and other symptoms of pancreatitis when compared to baseline (1324). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. Although there has been interest in using oral chlorophyll for wound healing, there is insufficient reliable information about the clinical effects of chlorophyll for this purpose. More evidence is needed to rate chlorophyll for these uses.

(Read more about CHLOROPHYLL)

POSSIBLY EFFECTIVE

• Diabetic neuropathy. Clinical research suggests that oral GLA may improve nerve function and symptoms of diabetic neuropathy in patients with type 1 and type 2 diabetes. Details: Two clinical trials in patients with type 1 or type 2 diabetes and diabetic neuropathy show that taking GLA 360-480 mg daily for 6-12 months improves measures of nerve function and symptoms of neuropathy, including muscle weakness, impaired tendon reflexes, and impaired sensation, when compared with placebo (1984,8926). GLA seems to be more effective in patients with better glucose control when compared with patients with poor glucose control (8926).

POSSIBLY INEFFECTIVE

• Atopic dermatitis (eczema). Most research suggests that oral GLA does not improve the symptoms or severity of atopic dermatitis in children and adults. Details: A meta-analysis of 11 small clinical studies in children and adults with atopic dermatitis shows that taking GLA from borage oil or evening primrose oil does not improve the severity of atopic dermatitis when compared with placebo oils. Adult doses in these studies ranged from 132-720 mg daily for 3-24 weeks. Child doses ranged from 90-480 mg daily for 3-16 weeks (13758). Also, a more recent clinical study in adults with mild-to-moderate atopic dermatitis shows that taking a food product containing GLA 200 mg daily for 12 weeks does not improve skin hydration, itching, or redness when compared with a control (92868). Conversely, one small open-label clinical trial in infants with atopic dermatitis shows that taking GLA 3 grams daily for 4 weeks might reduce redness, itching, and use of antihistamines when compared to baseline (51042). The validity of these findings is limited by a lack of placebo control.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of randomized controlled trials evaluating GLA, fish oil, and antioxidants, provided as a specific enteral formula (Oxepa, Abbott Nutrition) or a combination supplement given as a bolus, shows that there is no effect on overall all-cause mortality or ventilator- or ICU-free days when compared with generally isonitrogenous and isocaloric control formulas. A subgroup analysis of lower quality research shows that there may be a modest benefit for patients with a higher risk of mortality (105250). Two more recent meta-analyses have yielded similar results. Although most of the studies included in these meta-analyses investigated the use of Oxepa, some studies investigating other sources of enteral or intravenous fish oil were also included (105248,105249). In one of these analyses, some low- to very low-quality evidence suggests that use of Oxepa modestly reduces mortality at 28 days, as well as ICU length of stay and duration of mechanical ventilation (105248). However, these benefits were not found in the second meta-analysis (105249). It is unclear if GLA, when used alone, is beneficial in patients with ARDS.
• Asthma. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with asthma shows that taking 10 grams of a medical food emulsion providing GLA 0.75 grams with eicosapentaenoic acid (EPA) 0.5 grams, or 15 grams of a medical food emulsion providing GLA 1.13 grams with EPA 0.75 grams, daily for 4 weeks does not improve self-reported overall symptoms of asthma and bronchodilator use at 2 or 4 weeks when compared with placebo. Another small clinical study shows that taking medical food EFF1009, providing GLA 0.75 grams and EPA 0.5 grams, daily for 4 weeks modestly reduces bronchodilator use and improves quality of life and symptoms such as wheezing when compared to baseline (105251). The validity of this finding is limited by the lack of a comparator group and a high dropout rate.
• Attention deficit-hyperactivity disorder (ADHD). Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in drug-naïve children ages 6 to 12 years with mild to moderate ADHD shows that taking GLA 60 mg in combination with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily for 12 months results in some small beneficial effects on inattentive symptoms when compared with placebo. However, these changes are unlikely to be clinically useful. Also, there was no change in blood levels of fatty acids (111058). The effect of GLA itself is unclear from this study.
• Autism spectrum disorder. Although there has been interest in using oral GLA for autism spectrum disorder, there is insufficient reliable information about the clinical effects of GLA for this purpose.
• Back pain. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in patients with back pain due to compressive radiculopathy syndrome shows that taking GLA 360 mg and alpha-lipoic acid 600 mg daily for 6 weeks while undergoing rehabilitation therapy reduces pain intensity and improves disability status when compared with rehabilitation therapy alone (20489). It is unclear if these findings are due to GLA, alpha-lipoic acid, or the combination.
• Breast cancer. It is unclear if oral GLA is beneficial in patients with breast cancer. Details: A small clinical study in patients with various stages of endocrine-sensitive breast cancer shows that taking GLA 2.8 grams daily along with tamoxifen for 6 weeks seems to improve the response to tamoxifen when compared with tamoxifen alone (5902).
• Hyperlipidemia. Although there has been interest in using oral GLA for hyperlipidemia, there is insufficient reliable information about the clinical effects of GLA for this purpose.
• Hypertension. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with modestly elevated diastolic blood pressure (DBP) shows that taking a combination of GLA 0.12 grams plus eicosapentaenoic acid (EPA) 0.48 grams does not reduce DBP when compared with olive oil (13771). However, another small clinical study in patients with hypertension shows that taking 4 grams of an oil preparation rich in GLA, EPA, and docosahexaenoic acid (DHA) daily for 6 weeks reduces DBP when compared with sunflower seed oil (51022). It is unclear if these findings are due to GLA, other ingredients, or the combination.
• Mastalgia. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical trial in patients with mastalgia shows that taking GLA 100 mg daily in combination with vitamin C and vitamin B12 as methylcobalamin for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with taking placebo (111059).
• Menopausal symptoms. Although there has been interest in using oral GLA for menopausal symptoms, there is insufficient reliable information about the clinical effects of GLA for this purpose.
• Pressure ulcers. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute lung injury shows that taking a specific enteral emulsion (Oxepa, Ross Laboratories) providing GLA from borage oil along with fish oil and vitamins A, C and E for 7 days does not improve the healing of existing pressure ulcers when compared with a control enteral formula. Although the number of pressure ulcers in the group given the GLA-containing formula was lower when compared with the control formula, these patients also had fewer pressure ulcers at baseline and no statistical comparison was conducted. The clinical significance of this finding is unclear (105252).
• Psoriasis. Although there has been interest in using oral GLA for psoriasis, there is insufficient reliable information about the clinical effects of GLA for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral GLA for RA, there is insufficient reliable information about the clinical effects of GLA for this purpose.
• Rosacea. It is unclear if oral GLA is beneficial in patients with rosacea. Details: A small clinical study in adults with rosacea shows that taking GLA (Evoprim) 320 mg daily along with minocycline 50 mg twice daily for 8 weeks improves patient satisfaction and measures of skin hydration and increases the rate of treatment success, defined as an investigator global assessment score of 1 or lower, indicating clear or minimal symptoms, by 2-fold when compared with placebo plus minocycline (107927).
• Scleroderma. It is unclear if oral GLA is beneficial in patients with scleroderma. Details: A small clinical study in patients with scleroderma shows that taking GLA (dose unknown) for 6 months does not reduce symptoms of scleroderma when compared with placebo (1977).
• Ulcerative colitis. Oral GLA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with ulcerative colitis shows that taking a combination of GLA 1.6 grams, eicosapentaenoic acid (EPA) 270 mg, and docosahexaenoic acid (DHA) 45 mg daily for 12 months does not reduce symptoms when compared with placebo (51013). More evidence is needed to rate GLA for these uses.

(Read more about GAMMA-LINOLENIC ACID (GLA))

EFFECTIVE

• Anemia of chronic disease. Oral and intravenous iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that intravenous iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, intravenous iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of intravenous or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidelines from the British Society of Gastroenterology recommend treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. The guidelines recommend ferrous sulfate, fumarate, or gluconate as one tablet daily. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels are normalized (110193). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, intravenous or intramuscular iron were also used (104684). Intravenous iron has also been evaluated for the prevention of postoperative anemia. A large clinical trial in adult cardiology patients without pre-operative anemia or iron deficiency shows that a single intravenous administration of ferric carboxymaltose 1000 mg 24-72 hours before on-pump cardiac surgery reduces the number of red cell units transfused by about 5-fold, reduces the number of patients requiring transfusion by about 1.7-fold, and improves levels of hemoglobin, serum ferritin, iron, transferrin, and transferrin saturation by 4 days postoperative when compared with placebo. Additionally, improvement in hemoglobin was maintained at 6 weeks after surgery (113902).
• Pregnancy-related iron deficiency. Oral iron is effective for preventing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 20-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 62% to 100% (20122,20123,20124,110180,110188). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188). However, in patients with anemia during pregnancy, a meta-analysis of clinical research shows that intravenous iron sucrose and ferric carboxymaltose were more effective than oral ferrous sulfate for improving hemoglobin levels (110185).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600). Most studies included in the analyses evaluated daily iron supplementation, with a few studies assessing iron taken 4-6 times weekly (110181,112600). In contrast, a large clinical trial in schoolchildren in Ethiopia shows that taking iron supplements, providing 42 mg of elemental iron, once weekly for 11 months does not improve working memory, nonverbal intelligence, planning, or problem-solving, and may even worsen one measure of attention and concentration when compared with placebo (113904). These discrepant findings may be related to differences in frequency of dosing (daily vs. weekly) and baseline demographics; only 20% and 4% of children in this study had iron deficiency and iron deficiency anemia, respectively.
• Heart failure. Intravenous iron seems to be effective for improving recovery in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). A number of large clinical trials and meta-analyses of clinical research in patients with heart failure show that administering intravenous iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599,113900,113901). A meta-analysis of 3 large clinical trials in patients with heart failure shows that ferric carboxymaltose, administered intravenously at baseline and then 6 weeks or 6 months later, reduces the rate heart failure-related hospitalizations by 16% when compared with placebo (113901). Some individual clinical trials have used intravenous ferric carboxymaltose 200 mg or iron sucrose 200 mg in patients with mild or moderate heart failure and iron deficiency (17498,91179) while others administered 1500 mg every 6 months (113900,113901). Guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron improves symptoms and quality of life in patients with functional iron deficiency related to CHF (110193). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or intravenous ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of intravenous ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Intravenous iron sucrose has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral iron does not seem to improve athletic performance. Details: A meta-analysis of clinical research in adults of childbearing age shows that iron supplementation improves some exercise performance measures, such as maximal oxygen uptake capacity, but not others, such as time until exhaustion and energy consumption, when compared with control (91184). Another meta-analysis of clinical research in patients with iron deficiency without anemia shows that iron supplementation improves subjective measures of fatigue, but does not improve exercise time to exhaustion or other measures of physical capacity (104684). A small clinical study in healthy children shows that taking iron supplements or consuming food providing iron 30-200 mg daily for 1-2 months improves running performance when compared with placebo. This was demonstrated by reductions of heart rate of 6.6 to 8 beats per minute during the running exercise. One preliminary study included in this analysis also showed that iron supplementation improved treadmill endurance time (20140).
• Child growth. Oral iron does not seem to be beneficial for child growth. Details: Meta-analyses of mainly preliminary clinical research show that oral iron supplementation, at doses averaging 2-80 mg or 1-10 mg/kg elemental iron daily for up to 52 weeks, does not increase growth rate in children (20131,20132,20133,95434).
• Preterm labor. Oral iron does not seem to prevent preterm labor and may actually increase the risk in malaria-endemic regions. Details: A meta-analysis of results from five clinical studies shows that maternal intake of iron as ferrous sulfate 20-60 mg daily for 14-26 weeks starting in the second trimester of pregnancy does not affect the length of gestation or increase birthweight of the infant (95434). In females from a malaria-endemic area who have never been pregnant before, another clinical study shows that taking ferrous gluconate 60 mg and folic acid 2.8 mg weekly, starting before conception and continuing to the first antenatal visit, may more than double the risk of preterm birth, defined as a delivery under 37 weeks gestation, when compared with folic acid alone (100969). Some research suggests that the adverse outcome in this latter study may be explained by a rise in hepcidin levels in pregnant patients with malaria. Hepcidin is a hormone that regulates iron absorption and distribution, and malaria can upregulate hepcidin. High levels of hepcidin can decrease iron absorption, stimulate inflammatory processes, and cause progesterone withdrawal, leading to preterm labor (102863).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron 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 one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: Three small clinical studies in children with ADHD and iron deficiency shows that taking oral iron improves some measures of ADHD after 1-3 months of treatment when compared with baseline or placebo. These studies used ferrous sulfate 5 mg/kg daily, ferrous sulfate 80 mg daily, ferrous fumarate 200 mg daily for children weighing up to 30 kg, or ferrous fumarate 400 mg daily for children weighing more than 30 kg (1093,16013,110191).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, preliminary clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with intravenous iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that intravenous iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

(Read more about IRON)

EFFECTIVE

• Hypokalemia. Oral or intravenous potassium can treat and prevent hypokalemia. Details: Administering potassium orally or intravenously is effective for treating and preventing hypokalemia (15,107970). Oral potassium 20 mEq (780 mg of elemental potassium) is typically taken once daily to prevent hypokalemia (15,95010). Oral potassium 40-100 mEq (1560-3900 mg of elemental potassium) is typically taken in 2-5 divided doses daily to treat hypokalemia (95010). Doses should be limited to 40 mEq (1560 mg of elemental potassium), and the total dose should not exceed 200 mEq (7800 mg of elemental potassium) in 24 hours (95010). Potassium supplementation and route of administration should be individualized based on serum potassium level and patient status (15,107970).

LIKELY EFFECTIVE

• Hypertension. Oral potassium, via dietary intake or supplementation, reduces blood pressure. Details: Population research has found that higher dietary potassium consumption is associated with a lower risk of developing hypertension (1310,8817,69512). Additionally, most clinical research shows that potassium, taken orally as part of the diet or as a supplement, reduces systolic blood pressure by about 3-9.5 mmHg and diastolic blood pressure by about 2-6.4 mmHg in patients with or without hypertension (3385,92104,92106,95624,107974). In most of these studies, daily intake of potassium typically ranged from about 1500-7800 mg, with the most common intake being about 2340-2540 mg daily (92104,95624). However, some research shows that taking potassium does not lower systolic or diastolic blood pressure (69541,69550,107966). Differences in the patient populations, potassium intake, and salt intake could have contributed to the conflicting results. Potassium seems to be more effective for people with hypertension, low potassium levels, high daily sodium intake, and for Black adults (3384,3385,3386,92104,92106). Some research also shows that the greatest blood pressure-lowering effects of potassium occur at doses of about 3900-7800 mg daily (95624). A meta-analysis of clinical trials using a novel computational technique to assess both potassium intake and excretion suggests that the optimal blood pressure reduction occurs when taking about 1500 mg supplemental potassium daily or an overall intake of 4500-6500 mg potassium daily (105448). This analysis is limited by the heterogeneity and short duration of the included trials. There is also interest in utilizing low-sodium, high-potassium food substitutes to treat hypertension. Research shows that using salt substitutes containing 25% to 30% potassium chloride reduces systolic and diastolic blood pressure by 3-4.6 mmHg and 1 mmHg, respectively, when compared with regular table salt (107971,107976). In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines recommending that patients with hypertension consume 3500-5000 mg of potassium daily (95680). This intake of potassium is expected to lower systolic blood pressure by about 4-5 mmHg in patients with hypertension and by about 2 mmHg in normotensive patients (3385). Although potassium supplements and dietary potassium both seem to be beneficial, the guidelines recommend getting potassium from dietary sources, since potassium-rich diets are usually heart-healthy (95680). Additionally, the US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Kidney stones (nephrolithiasis). Oral prescription potassium citrate reduces the risk of kidney stone recurrence. It is unclear if non-prescription potassium citrate would be beneficial. Details: The American Urological Association (AUA) recommends potassium citrate therapy for patients with recurrent calcium stones and low urinary citrate, those with recurrent calcium or calcium oxalate stones without current metabolic abnormalities, and those with uric acid or cystine stones. The citrate component reduces urine calcium excretion and increases urine citrate and urine pH, which in turn alleviates crystal growth, formation, and aggregation. Sodium citrate may also be used to prevent stone recurrence; however, due to sodium's propensity to increase urine calcium excretion, potassium citrate remains the preferred salt formulation (107972). It is important to note that potassium citrate supplements are not equivalent to prescription potassium citrate products. Dose and duration of treatment is determined by a healthcare professional and individualized based on a patient's urinary citrate levels (107975,107989). Serum potassium levels should be monitored prior to starting potassium citrate, within 2 weeks of treatment initiation, and every 12 months (107975).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Eating foods high in potassium and low in sodium might reduce the risk of cardiovascular disease. It is unclear if taking potassium supplements has the same benefit. Details: Large population studies in adults without prior CVD have found that higher dietary potassium intake is associated with a lower risk of cardiovascular events (109395,109399). One study found that daily potassium intake of about 3300 mg is associated with a 13% reduction in CVD risk when compared with intake of about 1920 mg (109399). The other study found that each additional 1000 mg of daily urinary potassium excretion, which is a marker of dietary intake, is associated with an 18% reduction in CVD risk (109395). Another observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Stroke. Eating foods high in potassium and low in sodium might reduce the risk of stroke. It is unclear if taking potassium supplements has the same benefit. Details: Higher dietary intake of potassium seems to be associated with a lower risk of stroke. Population research has found that increasing dietary potassium intake by 1-1.5 grams daily is associated with up to a 20% reduced risk of stroke (92105,92107). Some population research has found that higher supplemental intake of potassium is associated with a 29% reduced risk of ischemic stroke. However, supplemental potassium intake is not found to be associated with a lower risk of hemorrhagic or total stroke (92107). An observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental hypersensitivity. It is unclear if topical potassium improves dental hypersensitivity. Details: One meta-analysis of clinical research shows that using a dentifrice containing 5% potassium nitrite reduces dentin sensitivity when compared with a dentifrice that does not contain potassium nitrite (69549). Other clinical research published in a systematic review shows that potassium-containing toothpastes might reduce dentin sensitivity more than controls that do not contain potassium. However, these toothpastes might be less effective than other active toothpastes, such as those containing sodium monofluorophosphate, and the effect may result from a placebo effect, since the mechanism of action of potassium is unclear (69456).
• Diabetes. It is unclear if increasing dietary potassium reduces the risk of diabetes. Details: A meta-analysis of 7 large population studies has found that consuming dietary potassium 3300-3500 mg daily is associated with a 20% reduction in the risk of diabetes when compared with consumption below 1000 mg daily. Results were similar when studies that measured potassium intake with a dietary questionnaire were analyzed separately from those that measured intake based on urinary potassium excretion (110776). However, the validity of this finding is limited by the heterogeneity of the included studies. Furthermore, despite use of data from various databases, most studies included in the analysis were conducted by the same author.
• Impaired glucose tolerance (prediabetes). It is unclear if oral potassium improves glycemic control in prediabetes. Details: A small clinical study in Black patients with prediabetes shows that taking extended-release potassium (Klor-Con M10, Cardinal Health) 40 mEq daily as potassium chloride for 3 months does not improve glucose tolerance when compared with placebo. Although fasting glucose levels were slightly reduced in the potassium group when compared with placebo, both groups experienced a worsening of glucose intolerance, with no change in insulin levels or glycated hemoglobin (98533).
• Osteoporosis. Although there is interest in using oral potassium for osteoporosis, there is insufficient reliable information about the clinical effects of potassium for this condition.
• Physical performance. It is unclear if oral potassium improves physical performance in older adults. Details: Observational research in older adults has found that decreased dietary potassium intake and increased dietary sodium intake over 5 years is associated with worsened physical performance (105450).
• Systemic lupus erythematosus (SLE). It is unclear if oral potassium is beneficial in patients with SLE. Details: Observational research in patients with SLE has found that increased dietary potassium intake is not associated with improvements in disease activity scores or markers of cardiovascular disease, including lipid levels and blood pressure, when compared with low dietary potassium intake. However, higher potassium intake does seem to reduce the odds of having elevated levels of C-reactive protein, a marker of inflammation, in these patients (109397). More evidence is needed to rate potassium for these uses.

(Read more about POTASSIUM)

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)

POSSIBLY EFFECTIVE

• Osteoarthritis. Intra-articular injection of superoxide dismutase may reduce pain in patients with osteoarthritis of the knee. It is unclear if oral superoxide dismutase is beneficial in these patients. Details: Two clinical studies in patients with osteoarthritis of the knee show that intra-articular administration of superoxide dismutase 16 mg every 1-2 weeks for 3-6 weeks reduces pain for up to 3-6 months after initiation of treatment when compared with placebo or methylprednisolone (2228,2229).
• Rheumatoid arthritis (RA). Intra-articular injection of superoxide dismutase may reduce knee stiffness, flexion, and pain in patients with RA affecting the knees. It is unclear if oral superoxide dismutase is beneficial in these patients. Details: Three small clinical studies in patients with RA show that intra-articular administration of superoxide dismutase 4 mg weekly for up to 6 weeks improves knee stiffness, flexion, and pain for up to 12-24 weeks after initiation of treatment when compared with methylprednisolone or aspirin (2230,2231,2232).

LIKELY INEFFECTIVE

• Myocardial infarction (MI). Intravenous superoxide dismutase may not confer additional benefits in patients with acute MI undergoing thrombolysis or coronary angioplasty. Details: Clinical studies in patients undergoing thrombolysis or coronary angioplasty for acute MI show that intravenous administration of superoxide dismutase does not improve reperfusion or left ventricular function when compared with placebo (2241,2243).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). It is unclear if subcutaneous superoxide dismutase can prevent bronchopulmonary dysplasia in neonates with ARDS. Details: A small clinical study in neonates with ARDS shows that subcutaneous administration of superoxide dismutase 0.25 mg/kg twice daily until ventilator support is no longer required reduces the risk of bronchopulmonary dysplasia by around 70% when compared with placebo. For every two neonates treated with subcutaneous superoxide dismutase, one additional case of bronchopulmonary dysplasia is prevented. Also, superoxide dismutase can reduce the incidence of wheezing and pneumonia in these infants (2242).
• Aging. Although there has been interest in using oral superoxide dismutase to prevent the signs and symptoms of aging, there is insufficient reliable information about the clinical effects of superoxide dismutase for this purpose.
• Aging skin. Although there has been interest in using oral superoxide dismutase to prevent and treat aging skin, there is insufficient reliable information about the clinical effects of superoxide dismutase for this purpose.
• Burns. Although there has been interest in using topical superoxide dismutase for burns, there is insufficient reliable information about the clinical effects of superoxide dismutase for this purpose.
• Corneal ulceration. It is unclear if ophthalmic superoxide dismutase is beneficial in patients with noninfectious corneal ulceration. Details: A case series of 19 patients with noninfectious corneal ulcers found that application of a specific lecithinated superoxide dismutase 0.1% ophthalmic solution for at least 2 weeks reduces ulcer size and improves healing in most patients (14815). However, the validity of these findings is limited by a lack of control group.
• Diabetic neuropathy. Oral superoxide dismutase has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with diabetic neuropathy shows that taking a specific combination product (ALA600SOD, Alfa Wassermann) providing superoxide dismutase 140 IU and alpha-lipoic acid 600 mg daily for 4 months improves pain by 18% when compared to baseline. Small improvements in motor and sensory nerve conduction were also reported (20488). Another small clinical study in patients with diabetic neuropathy shows that taking a specific combination product (Combinerv, Libytec Pharmaceuticals) providing superoxide dismutase 10 mg, alpha-lipoic acid 570 mg, acetyl-L-carnitine 300 mg, and vitamin B12 250 mcg daily for 12 months improves pain scores by 16% when compared with placebo. Taking this combination product also improved diabetic quality of life scores and some measures of nerve conduction when compared with placebo (105502). It is unclear if these effects are due to superoxide dismutase, other ingredients, or the combination.
• Interstitial cystitis. It is unclear if injecting superoxide dismutase into the bladder wall is beneficial in patients with interstitial cystitis. Details: A small, uncontrolled clinical study in patients with radiation-induced or interstitial cystitis shows that administration of superoxide dismutase 4-12 mg as an injection into the bladder wall every 4-6 weeks for up to 6 treatments improves pain, urinary urgency, incontinence, bladder capacity, and micturition frequency when compared to baseline (2233). The validity of these findings is limited by a lack of control group.
• Male infertility. Oral superoxide dismutase has only been evaluated in combination with other ingredients; its effect when used alone is unclear for male infertility. Details: A moderate-size cross-sectional, propensity-score matched study in males with idiopathic infertility suggests that taking a combination product containing superoxide dismutase, hydroxytyrosol, and carnosol (FertiPlus SOD, Idipharma) for 3 months modestly improves progressive sperm motility, sperm morphology, and sperm DNA fragmentation index but does not affect semen volume or sperm concentration when compared with control (112091). However, it is unclear if this effect is due to superoxide dismutase, other ingredients, or the combination.
• Neck pain. Oral superoxide dismutase has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with chronic neck pain shows that taking a specific combination product (ALA600SOD, Alfa Wassermann) containing superoxide dismutase 140 IU and alpha-lipoic acid 600 mg daily for 2 months, along with physiotherapy, reduces neck pain when compared with physiotherapy alone. In addition to improvements in pain scores at rest and during movement, 81% of patients receiving the combination product reported their pain to be "much improved" or "slightly improved", compared with just 29% of patients receiving physiotherapy alone. For every two patients treated with this supplement plus physiotherapy, one additional patient will report pain improvement over physiotherapy alone (90440).
• Obesity. Oral superoxide dismutase has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in obese patients shows that taking superoxide dismutase 400 IU with Saccharomyces bouldardii 5 billion colony forming units twice daily for 60 days does not reduce body weight, body mass index, or measures of hunger and satiety when compared with placebo (106848).
• Pneumonia. It is unclear if intravenous superoxide dismutase is beneficial in patients with pneumonia. Details: A small clinical study in patients with idiopathic interstitial pneumonia shows that intravenous infusion of lecithinized superoxide dismutase 40 or 80 mg daily for 28 days does not improve lung function when compared with placebo (95212).
• Radiation fibrosis. It is unclear if topical superoxide dismutase is beneficial in patients with radiation fibrosis. Details: A small clinical trial in patients with post-radiation fibrosis following treatment for head and neck cancer shows that applying ¼ teaspoon of topical superoxide dismutase (Sodermix cream, Life Science Investments) twice daily for 3 months does not improve symptoms of fibrosis when compared with placebo (101080).
• Radiation-induced cystitis. It is unclear if injecting superoxide dismutase into the bladder wall is beneficial in patients with radiation-induced cystitis. Details: A small, uncontrolled clinical study in patients with radiation-induced or interstitial cystitis shows that administration of superoxide dismutase 4-12 mg as an injection into the bladder wall every 4-6 weeks for up to 6 treatments improves pain, urinary urgency, incontinence, bladder capacity, and micturition frequency when compared to baseline (2233). The validity of these findings is limited by a lack of control group.
• Stress. It is unclear if oral superoxide dismutase is beneficial in patients with stress. Details: A small clinical study in healthy individuals shows that taking a specific melon extract (Extramel, Bionov), providing superoxide dismutase 140 IU, daily for 12 weeks slightly reduces stress when compared with placebo. Stress scores were reduced by 6.6%, compared with a 2.6% reduction with placebo (95211). It is unclear if this difference would be considered clinically significant.
• Vitiligo. It is unclear if oral superoxide dismutase is beneficial in patients with vitiligo. Details: A small clinical study in patients with non-segmental vitiligo shows that taking a gliadin-protected formulation of superoxide dismutase (Glisodin, Isocell Laboratory) 500 mg twice daily for 12 weeks followed by 250 mg twice daily for 12 weeks along with twice-weekly phototherapy improves the degree of re-pigmentation when compared with placebo plus phototherapy (106849). More evidence is needed to rate superoxide dismutase for these uses.

(Read more about SUPEROXIDE DISMUTASE (SOD))

EFFECTIVE

• Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

POSSIBLY EFFECTIVE

• Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
• Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
• Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
• Measles. High-dose vitamin A, at recommended age-specific doses, seems to reduce mortality in children with measles under 2 years of age. Additionally, vitamin A may reduce the incidence of measles in children up to 5 years of age who are at risk for vitamin A deficiency. Details: Vitamin A deficiency is a known risk factor for severe measles, as well as measles-related morbidity and mortality. The use of vitamin A supplementation for the treatment of measles has been studied mostly in resource-limited countries with increased risk for vitamin A deficiency. However, measles infection has also been shown to deplete vitamin A stores, leading to recommendations for vitamin A supplementation in acute measles, regardless of geographic location (115976). Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502). However, a sub-analysis of 3 studies that utilized a higher dose of 200,000 IU orally daily for two days, in children under 2 years of age who were hospitalized with measles, shows that this dosing regimen reduces the relative risk of mortality by about 60% when compared with placebo (82373,82502). Additionally, vitamin A supplementation in children with measles may reduce the risk of some complications, such as croup (82373). Most studies in these analyses were conducted in regions with high measles case-fatality rates; the benefit of vitamin A supplementation in regions with lower case-fatality rates, such as the United States, is unclear. Based on these data, the World Health Organization (WHO) recommends treatment with vitamin A, using age-specific doses, for all children with acute measles (115966). The American Academy of Pediatrics (AAP) also recommends the administration of age-specific doses to all children with measles, regardless of severity, as follows: 200,000 IU daily for 2 days in children at least one year of age, 100,000 IU daily for 2 days in children 6-12 months of age, and 50,000 IU daily for 2 days in children under 6 months old. In children with clinical symptoms of vitamin A deficiency, an additional age-specific dose is recommended 2-6 weeks later (115977). Vitamin A supplementation has also been studied in apparently healthy children living in regions at high risk for vitamin A deficiency. A meta-analysis of 6 clinical studies shows that taking vitamin A reduces the incidence of measles in children ages 6 months to 5 years. These studies provided vitamin A supplementation either as a single high dose or as three high doses over one year. In 3 studies, vitamin A was given in conjunction with measles vaccination; vaccination status was not provided for the other studies (109755). The WHO and AAP do not recommend the use of vitamin A for measles prevention. Instead, routine measles vaccination is recommended. Additionally, for people over 6 months of age with recent measles exposure who are unimmunized or insufficiently immunized, immediate measles vaccination is recommended (115966,115977).
• Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
• Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
• Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). Meta-analyses including 8-18 clinical studies show that vitamin A supplementation reduces all-cause mortality by about 12%-26% in children 6 months to 5 years of age (82559,95055,115748), but does not seem to reduce mortality in neonates or children 1-6 months of age (115748). Notably, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which involved one million preschool children and was included in one of the previously discussed meta-analyses, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
• Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
• Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
• Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
• Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A meta-analysis of 6 clinical studies including a total of 352 females over 30 years of age with mild to moderate photodamage shows that applying stabilized retinol 0.1% to the face once or twice daily for 8-12 weeks reduces overall photodamage when compared with placebo. Retinol also reduced uneven skin tone, brown spots, wrinkles and fine lines on the forehead, cheek, and undereye, and crow's feet. Five of the six studies used a split-face design, with each participant serving as their own control. Skin assessments were performed by a single dermatologist in all six studies (114500).

POSSIBLY INEFFECTIVE

• Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
• Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
• Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
• Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
• Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
• Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
• Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.

LIKELY INEFFECTIVE

• Head and neck cancer. Oral vitamin A taken for 2 years does not seem to improve survival or prevent head and neck cancer recurrence. Details: A large clinical study n patients with a history of head and neck cancer shows that taking vitamin A as retinyl palmitate 300,000 IU daily for 1 year, and followed by 150,000 IU daily for another year, does not reduce the risk of second primary tumors or tumor recurrence when compared with placebo. Also, vitamin A does not seem to improve survival or event-free survival (1710).
• HIV transmission. Oral vitamin A does not reduce vertical HIV transmission risk. There is some concern that vitamin A might increase HIV transmission through breast milk. Details: Observational and intervention research shows that taking vitamin A orally does not decrease the risk of HIV transmission to the fetus during pregnancy, to newborns during delivery, or to infants during early breast-feeding (6376,82470,95059). Preliminary clinical research also shows that vitamin A supplementation of pregnant adults with HIV infection might increase the risk of HIV transmission to their babies through breast milk (9801).
• Lower respiratory tract infections. Oral vitamin A does not reduce the risk for lower respiratory tract infections in children. It is unclear if supplementation of oral vitamin A while breast-feeding reduces the risk of lower respiratory tract infections in nursing infants. Details: Taking vitamin A by mouth does not prevent or reduce symptoms of lower respiratory tract infections, such as cough and fever, in children (82288,82443). Furthermore, some research shows that vitamin A is associated with a slight increase in the risk of respiratory tract infections when administered to children with adequate nutritional status (82288). Additionally, one small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of febrile illness or respiratory tract infections in the nursing infants when compared with placebo (107293).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although prescription vitamin A analogs are approved to treat acne, it is unclear if non-prescription topical vitamin A products help with acne symptoms. Details: The high-dose vitamin A analogs adapalene (Differin) and tazarotene (Tazorac) are prescription drugs approved by the US Food and Drug Administration for the treatment of acne (103712,103713). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol, which have not been extensively evaluated in clinical research. A small preliminary clinical trial in adolescents and young adults with mild to moderate acne shows that applying topical benzoyl peroxide 2.5% each morning and a topical retinol plus salicylic acid product each evening for 12 weeks modestly improves acne severity and other measures of complexion when compared with baseline. All patients also used the same cleanser twice daily (109748). The validity of this finding is limited by the lack of a comparator group.
• Alcohol-related liver disease. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute alcoholic hepatitis shows that taking vitamin A in combination with coenzyme Q10 and other vitamins and minerals daily for 6 months does not improve survival when compared with placebo (61392).
• Asthma. It is unclear if oral vitamin A is beneficial for preventing asthma in children. Details: An observational study in children has found that higher dietary intake of vitamin A is associated with a lower risk of asthma. Children in the highest quartile of vitamin A intake (median of 2267 IU daily) at 7 years of age had improved lung function and 32% lower odds of asthma at 11-14 years of age when compared with children in the lowest quartile of vitamin A intake (median of 870 IU daily) (107291).
• Atopic dermatitis (eczema). It is unclear if supplementation of oral vitamin A while breast-feeding is beneficial for preventing eczema in nursing infants. Details: One small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of eczema in the nursing infants when compared with placebo (107293).
• Autism spectrum disorder. It is unclear if oral vitamin A is beneficial for improving symptoms of autism. Details: Children with autism spectrum disorder are at increased risk for vitamin A deficiency, and vitamin A levels have been inversely associated with autism symptoms. Preliminary clinical research shows that taking a single dose of vitamin A 200,000 IU slightly improves emotional response, communication, and other symptoms when compared to baseline (97168). The lack of a control group limits the validity of these findings. Another preliminary clinical study in children with autism and vitamin A deficiency shows that taking vitamin A 50,000 IU weekly for 6 months, but not as a single dose of 200,000 IU, seems to improve social impairment scores when compared with control. Controls were children with autism without vitamin A deficiency that did not take a supplement (104459).
• Breast cancer. Although vitamin A intake has been associated with a reduced risk for breast cancer, it is unclear if vitamin A supplements are beneficial. Details: Epidemiological evidence has found an association between high intake of vitamin A and a reduced risk of breast cancer. A meta-analysis of epidemiological research has found that the adults with the highest intake of vitamin A, either from diet alone or also from supplements, reduces the odds of developing breast cancer by 16% when compared with the lowest intake (1444,34610,109752). However, the effects of supplemental vitamin A, specifically, are unclear.
• Cataracts. It is unclear if oral vitamin A is beneficial for cataract prevention. Details: Observational research has found that higher dietary intake of vitamin A is associated with a modestly reduced risk of cataracts (6378,112095). Also, other population research has found that the highest dietary intake of vitamin A is associated with a 17% lower risk of cataracts when compared with the lowest intakes (90786). However, there is conflicting evidence regarding the association between blood levels of vitamin A and the risk of cataracts (90786,90944). It is not known if supplemental vitamin A is beneficial for this purpose.
• Cervical cancer. It is unclear if oral vitamin A is beneficial for cervical cancer prevention. Details: A meta-analysis of clinical research shows that increased vitamin A levels in the blood or higher vitamin A intakes are associated with a reduced risk of cervical cancer. However, this effect is observed when both forms of vitamin A, either retinol or carotenoids, are considered. When only the retinol form is considered, vitamin A supplementation does not seem to reduce the risk of cervical cancer (34613,109752). Also, a meta-analysis of epidemiological research has found that vitamin A intake, either from diet alone or supplements, does not affect the risk of cervical cancer (109752).
• Chemotherapy-induced diarrhea. It is unclear if oral vitamin A helps to prevent diarrhea caused by chemotherapy. Details: A very small clinical study in children receiving chemotherapy shows that taking vitamin A orally does not seem to prevent GI adverse effects, including diarrhea and mouth pain, when compared with control (9802).
• Child development. Oral vitamin A might improve growth and development in children with vitamin A deficiency, but not in those with good nutritional status. Details: Supplementing with vitamin A 60 mg for up to 9 years does not promote or improve child growth in children with appropriate nutritional status (20132). However, in children with vitamin A deficiency, supplementation with vitamin A may improve growth (82246).
• Chronic obstructive pulmonary disease (COPD). There is limited evidence on the oral use of vitamin A in patients with emphysema. Details: Observational research has found that consuming recommended amounts of vitamin A in the diet is associated with 33% lower odds of developing emphysema (103678).
• Cognitive function. It is unclear if oral vitamin A is beneficial for cognitive function. Details: A large clinical trial in schoolchildren in Ethiopia, most without vitamin A deficiency, shows that taking vitamin A 200,000 IU at baseline and after 5 months improves working memory, but not other measures of cognitive development, when compared with placebo (113904). However, results are unlikely to be clinically significant.
• Colorectal adenoma. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination supplement containing selenium, zinc, vitamin A, vitamin C, and vitamin E orally daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by about 40% when compared with placebo in patients with large-bowel adenomas (92903). It is not clear if this benefit is due to vitamin A or other constituents.
• Colorectal cancer. It is unclear if oral vitamin A is beneficial for colorectal cancer prevention. Details: Taking vitamin A alone or in combination with beta-carotene does not seem to reduce the risk of colorectal cancer (12185).
• Corneal abrasion. It is unclear if topical vitamin A is beneficial for preventing corneal abrasion during surgery. Details: A clinical study in patients undergoing general anesthesia for non-ophthalmic surgery shows that applying a specific vitamin A containing gel (Ziyang® Vitamin A Palmitate Eye Gel, Shenyang Xingqi Pharmaceutical Co., Ltd) to the ocular surface prior to eye taping decreases evidence of corneal abrasion and increases tear production 30 minutes after surgery when compared with taping without vitamin A gel. However, by 24 hours there was no difference between the two eyes (114501).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin A improves recovery after CABG surgery. Details: Preliminary clinical research shows that taking vitamin A 5000 IU daily (as retinol palmitate) for 21 days starting on the day of CABG surgery reduces time in intensive care after surgery by 46% to 69% compared to a control group not given vitamin A (90783). Supplementation with vitamin A also improves total hospitalization time for those patients with adequate zinc status (90783).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin A is beneficial for the treatment of mild to moderate COVID-19. Details: Clinical research in COVID-19 outpatients treated with hydroxychloroquine shows that taking vitamin A 25,000 IU daily for 10 days modestly reduces the number of patients with symptoms of fever, body ache, and fatigue when compared with placebo. However, there was no effect on the number of patients with cough, shortness of breath, lack of appetite, chest pain, diarrhea, loss of smell, or headache (109745).
• Depression. It is unclear if oral vitamin A is beneficial for depression. Details: A meta-analysis of observational research has found that dietary intake of vitamin A is inversely associated with depression. The highest intake of vitamin A was associated with a 17% reduced risk of depression when compared with the lowest intake. Also, vitamin A intake was lower in individuals with depression (109743). The effect of vitamin A supplementation is unclear.
• Esophageal cancer. It is unclear if oral vitamin A is beneficial for esophageal cancer prevention. Details: Observational research has found that higher beta-carotene and vitamin A intake is associated with a reduced risk of esophageal cancer (34551,103675). However, evidence from higher-quality clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of esophageal cancer (12185).
• Gastric cancer. It is unclear if oral vitamin A is beneficial for gastric cancer prevention. Details: Taking vitamin A alone and in combination with beta-carotene does not seem to reduce the risk of gastric cancer (12185).
• Glaucoma. It is unclear if oral vitamin A is beneficial for glaucoma prevention. Details: Meta-analyses of observational research suggests that a high dietary intake of vitamin A is associated with a 37% reduced risk or 42% lower odds of glaucoma when compared with a low intakes (109742,112095).
• Graft-versus-host disease (GVHD). It is unclear if taking vitamin A prior to hematopoietic stem cell transplant (HSCT) decreases the incidence of acute or chronic GVHD. Details: A clinical study in patients 1-28 years of age with serum vitamin A levels below the 75th percentile shows that taking a single oral dose of vitamin A 4000 IU/kg (maximum dose: 250,000 IU) approximately 1 week before allogenic HSCT decreases the incidence of chronic GVHD at 1 year to 5%, compared with 12.5% in those taking placebo. However, patients who took vitamin A did not have a lower rate of acute GVHD or acute gastrointestinal GVHD at 100 or 180 days when compared with placebo. All patients in this study with low vitamin D levels also received vitamin D supplementation per an institutional protocol (114498).
• HIV/AIDS. It is unclear if oral vitamin A is beneficial for improving HIV/AIDs outcomes. Details: A meta-analysis of clinical trials and population research shows that maternal vitamin A supplementation of mothers with poor vitamin A status at baseline does not influence child or maternal mortality, hospitalization rate, or HIV/AIDS progression. However, pediatric vitamin A supplementation seems to decrease mortality rates in children with HIV/AIDS when compared with placebo (34529,95059).
• HIV/AIDS-related diarrhea. It is unclear if oral vitamin A is beneficial for preventing diarrhea associated with HIV. Details: A large clinical trial shows that taking vitamin A can decrease the rate of diarrhea-specific mortality by up to 92% in vitamin A-deficient children with or without HIV/AIDS (1465). However, a meta-analysis of clinical research shows that taking vitamin A does not significantly reduce diarrhea-specific mortality when only children with HIV/AIDS are considered (82511). But vitamin A does appear to reduce overall mortality in these children by 50% to 63% (1465,82511).
• Human papillomavirus (HPV). It is unclear if topical or oral vitamin A is beneficial for the resolution of genital warts caused by HPV. Details: A meta-analysis of small clinical trials in patients with genital warts suggests that the oral prescription drugs isotretinoin and etretinate might promote resolution of warts when compared with baseline. However, the topical prescription drug tretinoin 0.05% cream does not seem to help (104460). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Infant development. It is unclear if intramuscular vitamin A improves the development of low birth weight infants. Details: A meta-analysis of clinical research shows that giving intramuscular vitamin A to very low birth weight infants reduces the risk of chronic lung disease at 36 weeks postmenstrual age by about 13% compared to control (95053). Preliminary clinical research also shows that giving intramuscular vitamin A along with inhaled nitric oxide gas for 3 weeks to low birth weight infants on mechanical ventilation might improve mental development at one year in some of these patients when compared with inhaled nitric oxide gas alone (90778). However, a meta-analysis of clinical research shows that intramuscular vitamin A does not improve neurodevelopment in very low birth weight infants (95053).
• Iron deficiency anemia. It is unclear if oral vitamin A is beneficial for the prevention or treatment of anemia due to iron deficiency. Details: Some research in children and pregnant adults without anemia shows that taking vitamin A increases plasma levels of hemoglobin and ferritin, and may reduce the risk of developing anemia (9518,34627). However, another study in pregnant patients, half of whom had anemia at baseline and half of whom did not have anemia, shows that taking 3000 mcg retinol orally in combination with iron and folate does not improve hemoglobin or erythropoietin concentrations when compared with taking iron and folate (9188). In preterm infants with existing anemia, taking vitamin A 5000 IU and vitamin B complex 40 mg daily improves serum ferritin, hemoglobin, and reticulocyte levels and reduces the need for blood transfusions when compared with taking either vitamin alone. Taking vitamin A alone, however, does not improve these outcomes (100330).
• Leukemia. It is unclear if oral vitamin A is beneficial for leukemia prevention. Details: Preliminary clinical research in adults with chronic myelogenous leukemia shows that taking a specific vitamin A product (Aquasol, Armour Pharmaceuticals) 50,000 IU orally daily in combination with busulfan therapy does not significantly increase progression-free survival or overall survival when compared with busulfan alone. Furthermore, supplementation with vitamin A plus busulfan seems to increase the percentage of patients who experience grade 2 toxicity by about 5-fold when compared with busulfan alone (82652).
• Liver cancer. It is unclear if oral vitamin A is beneficial for liver cancer prevention. Details: Population research has found that vitamin A supplementation or serum levels of vitamin A are not associated with the risk of liver cancer (97169).
• Lung cancer. It is unclear if oral vitamin A is beneficial for lung cancer treatment or prevention. Details: A large clinical trial in patients with existing lung cancer shows that vitamin A 300,000 IU daily for one year followed by 150,000 IU daily for a second year does not increase survival (1710). However, some clinical research shows that high-dose vitamin A 300,000 IU daily following curative lung cancer resection reduces the risk of new primary tumors in patients heavily exposed to tobacco (7875). Observational research on the relationship between vitamin A and lung cancer risk is conflicting. One large observational study suggests that higher dietary intake of vitamin A is associated with a lower risk of lung cancer. Specifically, each quartile increase in dietary vitamin A intake was associated with a 15%, 25%, and 37% lower relative risk of lung cancer when compared with the lowest intake. However, taking vitamin A in supplement form was not associated with lung cancer risk (112096). Other observational research has found that increased dietary intake of vitamin A is not associated with a reduced risk of lung cancer (35628). Furthermore, supplementation with vitamin A and beta-carotene seems to increase the risk of lung cancer in smokers or those exposed to asbestos (2642,34675).
• Malaria. It is unclear if oral vitamin A is beneficial for reducing symptoms of malaria in young children. Details: Taking vitamin A orally seems to help decrease symptoms of malaria in children less than 3 years of age living in endemic areas (1464). However, other clinical research shows that single doses of vitamin A 100,000 to 200,000 IU do not improve coma resolution, convulsions, fever, parasite clearance, or mortality in infants and children less than 5 years of age with cerebral malaria (90785).
• Multiple sclerosis-related fatigue. It is unclear if oral vitamin A is beneficial for reducing fatigue in patients with multiple sclerosis. Details: Preliminary clinical research in patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a shows that taking vitamin A 25,000 IU (as retinyl palmitate) (Zahravi Pharmaceutical) daily for 6 months followed by 10,000 IU daily for 6 months, improves physical, cognitive, and psychosocial fatigue when compared with placebo (95052).
• Necrotizing enterocolitis (NEC). A meta-analysis of several small clinical trials suggests that intramuscular vitamin A does not seem to prevent NEC. Details: A meta-analysis of 3 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 1500-5000 IU every other day or three times weekly for 28 days does not reduce the risk of NEC when compared with a control (107297).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin A is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that intake of vitamin A at levels above 2330 mcg daily is associated with a 17% lower risk of non-Hodgkin lymphoma when compared with those whose daily intake of vitamin A is less than 642 mcg per day (90945).
• Nonmelanoma skin cancer. It is unclear if oral vitamin A is beneficial for nonmelanoma skin cancer prevention. Details: Observational research over 26 years found that higher dietary vitamin A intake is associated with a 12% reduced risk for cutaneous squamous cell carcinoma in healthy patients when compared with lower vitamin A intake (101673).
• Oral clefts. It is unclear if oral vitamin A is beneficial for oral cleft prevention. Details: A meta-analysis of observational research has found that periconceptional use of vitamin A, from diet and/or supplements, is associated with a 13% reduced incidence of cleft lip alone or with a cleft palate, but is not associated with the risk of cleft palate alone, in the child (109751).
• Osteoarthritis. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with osteoarthritis shows that taking a specific product containing vitamin A in combination with selenium, vitamin C, and vitamin E (Selenium ACE, Carls-Berghs Farmaceutiska AB) does not appear to alleviate symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral vitamin A is beneficial for ovarian cancer prevention. Details: Most observational research has found that increased dietary intake of vitamin A is associated with a reduced risk of developing ovarian cancer (9193,103679,109752). The most recent meta-analysis of epidemiological research has found that adults with the highest intake of vitamin A, either from diet alone or supplements, reduces the odds of developing ovarian cancer by 19% when compared with the lowest intake (109752).
• Pancreatic cancer. It is unclear if oral vitamin A is beneficial for pancreatic cancer prevention. Details: A meta-analysis of observational research has found that higher intake of vitamin A is associated with a reduced risk of pancreatic cancer; however, this benefit appears to be limited to only hospital-based cases and studies conducted in Europe (95060). In contrast, a meta-analysis of clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of pancreatic cancer (12185).
• Parkinson disease. It is unclear if oral vitamin A prevents Parkinson disease development. Details: Population research has found that blood levels or dietary intake of vitamin A are not associated with the risk of Parkinson disease (91164).
• Photoreactive keratectomy. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking a specific product (Evitex capsules, Alcon) containing vitamin A along with vitamin E seems to improve healing after photoreactive keratectomy. High dose (50,000 to 75,000 IU) vitamin A in the form of retinol palmitate taken daily with vitamin E (alpha-tocopheryl nicotinate) 460-590 mg daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity in patients undergoing laser surgery for myopia (348).
• Pneumonia. Oral vitamin A does not seem to prevent mortality related to pneumonia in children. However, it is unclear if vitamin A reduces symptom severity and hospitalization in children. Details: Clinical research in children living in developing countries shows that taking vitamin A orally does not prevent mortality related to pneumonia (1466,82362,82504,82717,109749). However, the evidence related to symptom duration and severity is mixed. A large study and early meta-analyses show that vitamin A does not prevent pneumonia or decrease the severity or length of hospitalization in children with pneumonia (1466,82362,82504,82717). A more recent meta-analysis also shows that giving vitamin A to children at or below 5 years of age does not affect the duration of hospitalization (109755). The best evidence to date comes from a recent meta-analysis of randomized clinical trials. This meta-analysis shows that, when given in combination with conventional therapy to children up to 10 years of age, vitamin A reduces the duration of symptoms including fever, cough, lung rale, and shortness of breath, as well as the duration of hospitalization and time to a negative X-ray, when compared with conventional therapy alone (109749). However, the number of trials evaluating each endpoint is small and more research is needed to confirm these findings.
• Prematurity. It is unclear if vitamin A reduces the duration of hospitalization for premature infants. Details: A meta-analysis of four randomized controlled trials in preterm infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the duration of hospitalization when compared with placebo (109750).
• Prostate cancer. It is unclear if oral vitamin A is beneficial for prostate cancer prevention. Details: Observational studies suggest that dietary intake of vitamin A is not associated with a reduced risk of prostate cancer (14134).
• Psoriasis. It is unclear if topical vitamin A is beneficial for psoriasis symptoms. Details: The vitamin A analog tazarotene (Tazorac) is a prescription drug that is approved by the U.S. Food and Drug Administration to treat stable plaque psoriasis covering up to 20% body surface area (103713). This drug is not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Radiation proctopathy. It is unclear if oral vitamin A is beneficial for reducing chronic radiation proctopathy symptoms. Details: A small clinical study in patients experiencing chronic radiation proctopathy caused by pelvic radiotherapy shows that taking retinol palmitate 10,000 IU daily for 90 days might reduce rectal symptoms when compared with placebo (82350).
• Retinopathy of prematurity. Most small studies show that oral or intramuscular vitamin A does not reduce the risk of retinopathy of prematurity (ROP). Details: A meta-analysis of 4 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 2000-10,000 IU every other day or three times weekly, or oral vitamin A 2000 IU daily, for 28 days does not reduce the risk of ROP when compared with a control (107297). Another meta-analysis of clinical research shows that providing supplemental enteral vitamin A 1500 IU or an average of 5000 IU daily, starting within four days of birth, does not reduce the incidence of severe ROP (109750,109753). However, a very small clinical study in preterm infants, which was not included in the meta-analysis, shows that receiving retinol palmitate drops 3000 IU/kg daily for 28 days reduces the risk of ROP by 88% when compared with no treatment (103672).
• Upper respiratory tract infection (URTI). It is unclear if vitamin A is beneficial for the prevention or treatment of URTIs in young children. Details: A meta-analysis of 3 low-quality clinical studies in children under 7 years of age living in low- to middle-income countries found that there is no association between vitamin A supplementation and rate of acute URTI, although this finding was considered to be of low certainty. There was insufficient data to determine whether vitamin A may reduce the severity of URTI symptoms (114499). The interpretation of findings is limited by high heterogeneity of the study populations and dosing regimens, as well as variability in selected outcomes.
• Urinary tract infections (UTIs). It is unclear if adding oral vitamin A to antibiotic therapy is beneficial for symptoms of acute pyelonephritis in young females. Details: A small clinical study in females 2-12 years of age with a first occurrence of acute pyelonephritis shows that taking vitamin A 1500 units/kg daily for 10 days in conjunction with antibiotics decreases the duration of fever by about 1.3 days and reduces urinary frequency by about 1.5 episodes per day when compared to taking placebo with antibiotics. Taking vitamin A might also reduce the occurrence of moderate or severe renal scarring after 6 months when compared with placebo (100327). The validity of these findings is limited by small study size and a high dropout rate.
• Warts. It is unclear if topical or oral vitamin A improves the resolution of viral warts. Details: A meta-analysis of observational and clinical research in patients with viral warts suggests that receiving prescription oral retinoids (isotretinoin, acitretin, etretinate) seems to produce a 61% rate of wart resolution. Prescription topical retinoids seems to produce a 64% rate of wart resolution (104461). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol. More evidence is needed to rate vitamin A for these uses.

(Read more about VITAMIN A)

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

• Hemorrhagic disease. Oral or intramuscular vitamin K1 is effective for preventing hemorrhagic disease in newborns. Details: Vitamin K1 (phytonadione) administered orally or intramuscularly can prevent classic hemorrhagic disease of newborns (15,85367,85484). A single intramuscular administration of vitamin K1 1 mg is considered to be the most effective method, while oral administration of three doses of vitamin K1 1-2 mg over 8 weeks is considered to be an acceptable alternative (85506). The effects of vitamin K on late hemorrhagic disease of newborns is less clear (85367,85484). In the Netherlands, an oral dose of 25 mcg daily for 3 months was used until 2011, when it was increased to 150 mcg daily. A reduction of late intracranial vitamin K deficiency bleeding in the general pediatric population, from 1.6 per 100,000 to 1.3 per 100,000, was associated with this dose increase (102351). The effect of various doses of intramuscular birth vitamin K prophylaxis has also been investigated in premature infants. A small clinical study in premature infants born at or before 32 weeks gestation or who weigh 1500 grams or less shows that administering intramuscular vitamin K1 at doses of 0.3, 0.5, or 1.0 mg (Kenadione, Samarth Life Sciences PVT Ltd) within 1 hour of admission to the neonatal intensive care unit improves subclinical vitamin K deficiency. While infants in all 3 dosing groups had sufficient vitamin K levels at 5 days old, by day 28 those who were initially administered vitamin K 0.3 mg had higher rates of subclinical vitamin K deficiency and lower rates of vitamin K sufficiency. Rates of intraventricular or periventricular hemorrhage, pulmonary hemorrhage, necrotizing enterocolitis, and mortality did not differ across dosing groups (112100).
• Hypoprothrombinemia. Oral or parenteral vitamin K1 is effective for treating and preventing hypoprothrombinemia. Details: Vitamin K1 (phytonadione) 2.5-25 mg, used orally or parenterally, can prevent and treat hypoprothrombinemia caused by vitamin K deficiency or induced by salicylates, sulfonamides, quinine, quinidine, or broad-spectrum antibiotic therapy (15).
• Vitamin K-dependent clotting factors deficiency (VKCFD). Oral and intravenous vitamin K1 is the primary treatment for VKCFD. Details: Oral supplementation with vitamin K 10 mg two to three times weekly seems to prevent major hemorrhages and reduce mucocutaneous bleeding in individuals with VKCFD. Also, intravenous vitamin K may improve the prothrombin time-international normalized ratio (PT-INR) values in these patients. While vitamin K supplementation is the primary treatment method for VKCFD, the response to treatment varies significantly (85481).
• Warfarin anticoagulation. Oral and intravenous vitamin K1 reverse warfarin-related excessive anticoagulation. Evidence for the use of oral vitamin K1 in patients with an unstable INR is conflicting. Details: Taking vitamin K1 (phytonadione) orally or parenterally, but not subcutaneously, can counteract excessive warfarin anticoagulation and restore therapeutic international normalized ratio (INR) levels. Usually a single dose of 1-5 mg is used (85406,85425,85429). Vitamin K might also be effective for stabilizing warfarin anticoagulation in patients with low intake of vitamin K. Patients with a low dietary vitamin K intake are significantly more likely to have an unstable INR than those who ingest higher amounts of vitamin K (16803). It is thought that vitamin K-depleted patients become more sensitive when vitamin K is ingested, even in small quantities, resulting in erratic or unstable INR (16804). One small clinical study and one small retrospective chart review show that taking oral vitamin K1 (phytonadione) 100-150 mcg daily improves INR stability in patients taking warfarin who previously had an unstable INR (16805,16806). However, a larger clinical study found no significant differences in INR stability in patients taking vitamin K 100 mcg daily when compared with placebo (16807). Also, some research suggests that, although taking vitamin K 1250 mcg daily may reduce INR in patients with excessive warfarin anticoagulation more significantly than placebo, there may not be a significant difference in the risk of bleeding complications (23380). It is important to keep in mind that, if a patient is stabilized on warfarin therapy plus vitamin K supplementation, discontinuing vitamin K can significantly increase the INR within 2-3 weeks after discontinuation (17714). The most recent guidelines by the American College of Chest Physicians do not recommend routine use of vitamin K supplementation for patients on warfarin therapy with unstable INR (94926). However, the previous guidelines recommended vitamin K 100-200 mcg daily for these patients. Therefore, some providers still use vitamin K for this purpose (16808).

POSSIBLY EFFECTIVE

• Osteoporosis. Oral vitamin K might reduce the risk of fractures and bone loss in patients with osteoporosis. However, it may not be beneficial in patients at risk for developing osteoporosis. Details: Although observational and clinical research on dietary and supplemental vitamin K for osteoporosis has been conflicting (14364,85392,85445,102354,112106), overall, vitamin K supplementation seems to slightly reduce fracture risk (102354). A meta-analysis combining data from 36 heterogeneous studies in osteoporotic or postmenopausal patients shows that taking different regimens of either vitamin K1 or vitamin K2 is associated with a small reduction in clinical fractures (from 3.1% to 2.2%), but not with changes in vertebral fractures or BMD when compared with control (102354). This analysis is limited by the high variability in study designs and a lack of subgroup analyses stratifying different patient populations and forms of vitamin K. In contrast, a meta-analysis of 16 studies in postmenopausal adults shows that taking various forms of vitamin K2 improves lumbar spine BMD based on 10 studies, especially when combined with other therapies such as vitamin D, calcium, or alendronate. However, vitamin K2 does not improve hip, femoral neck, or forearm BMD when compared with placebo. Furthermore, meta-analyses of 25 studies show that vitamin K2 does not reduce the incidence of fractures when compared with control (91451,112106). However, a sensitivity analysis that excluded the largest negative study of over 4000 postmenopausal Japanese females with mild osteoporosis (85456), shows that vitamin K2 45 mg daily reduces the risk of fractures by 53% and improves lumbar and vertebral BMD in patients with osteoporosis when compared with control (91451). This effect was not seen in patients without osteoporosis (91451). Vitamin K2 also does not seem to benefit patients with osteopenia. A recent clinical trial in postmenopausal patients with osteopenia shows that taking a larger dose of vitamin K2 (375 mcg, MK-7) with calcium 800 mg and vitamin D 1500 IU daily for 3 years does not seem to affect BMD, bone turnover, or bone microarchitecture when compared with placebo (105035). Vitamin K1 (phytonadione) has also been evaluated, with mixed findings. One clinical study in postmenopausal patients with osteopenia shows that taking vitamin K1 5 mg daily with calcium 1500 and vitamin D 800 IU for up to 4 years reduces clinical fractures, but does not reduce clinical fragility fractures or improve BMD, when compared with placebo and vitamin D with calcium (85453). In healthy, non-osteoporotic patients ages 60-80 years, one clinical study shows that taking vitamin K1 500 mcg daily with calcium 600 mg and vitamin D 400 IU for 3 years does not affect BMD, despite increased plasma vitamin K levels and reduced undercarboxylated osteocalcin concentrations, when compared with taking calcium and vitamin D alone (16404). The same null effect on BMD and a reduced undercarboxylated osteocalcin was shown in a small clinical study in patients with Crohn disease without osteoporosis, taking vitamin K1 1-2 mg in combination with vitamin D3 400 IU and calcium 500 mg daily for 12 months (91454). One small clinical trial compared vitamin K1 with vitamin K2 in postmenopausal adults with osteoporosis. This research shows that taking either vitamin K1 1 mg or vitamin K2 45 mg orally daily for 18 months in conjunction with a bisphosphonate does not improve femoral, spine, or hip BMD when compared with taking placebo and a bisphosphonate. All participants also took vitamin D supplements throughout the study (114778).

POSSIBLY INEFFECTIVE

• Intraventricular hemorrhage. Oral vitamin K does not reduce the risk of periventricular hemorrhage in preterm infants. Details: A meta-analysis of results from clinical research shows that administering vitamin K to pregnant patients at risk for very preterm birth does not reduce the overall risk of periventricular hemorrhage in preterm infants, perinatal mortality, or the associated neurological injury by the age of 7 years when compared to control. A subgroup analysis shows that vitamin K might reduce the risk of severe periventricular hemorrhage by 42% in preterm infants. However, when trials with inadequate blinding were excluded, this result was not statistically significant (85469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral vitamin K2 improves athletic performance. Details: A small clinical study shows that taking vitamin K2 (menaquinone) 320 mcg orally daily for 4 weeks followed by 160 mg daily for 4 weeks, increases maximal cardiac output by 12% when compared with placebo in trained athletes performing standardized cycle ergometer exercise tests (95937).
• Beta-thalassemia. Oral vitamin K2 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking the menaquinone-7 (MK-7) form of vitamin K2 50 mcg daily plus vitamin D3 (calcitriol) 5 mcg daily for 12 months modestly improves bone mineral density (BMD) at the lumbar spine when compared to baseline in children with beta-thalassemia aged 3-18 years (91456). It is not clear if this improvement can be attributed to vitamin K, vitamin D3, or the combination.
• Breast cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of breast cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of premenopausal or postmenopausal breast cancer (85474).
• Cancer. It is unclear if dietary intake of vitamin K reduces the risk of cancer or cancer-related mortality. Details: One large population study involving healthy German patients has found that consuming more than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 27% reduced risk of cancer mortality, but not cancer incidence, when compared with consuming less than 23-26 mcg daily. Dietary intake of vitamin K1 (phytonadione) was not associated with the risk of cancer or cancer mortality (85474). Another population study involving Mediterranean patients at high risk for cardiovascular disease has found that consuming about 630 mcg of vitamin K1 daily is associated with a 46% lower risk of cancer mortality when compared with consuming about 171 mcg of vitamin K1 daily. However, higher dietary intake of vitamin K2, 87 mcg daily, was not associated with a lower risk of cancer mortality when compared to those with lower dietary intake (79 mcg daily) (91452). Reasons for these discrepancies may relate to the definitions for high and low intake, the use of different databases to calculate vitamin K intake, and the different populations studied.
• Cardiovascular disease (CVD). It is unclear if dietary or supplemental vitamin K reduces the risk of CVD events; the available research is conflicting. Details: Most population research, including a meta-analysis of 21 observational cohort studies, has found that dietary intake of vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is not associated with reduced risk for most cardiovascular events, such as CVD mortality, nonfatal MI, or stroke, although there might be a slightly reduced risk for CHD (85414,85482,91452,102353,103922). However, some population studies have found benefit. Observational research in a Danish cohort aged 50-65 years with no history of atherosclerotic cardiovascular disease at baseline shows that those in the highest quintile of dietary vitamin K1 intake have a 21% lower risk of CVD-related hospitalization and complications, such as ischemic heart disease, ischemic stroke, or peripheral artery disease, over 17-22 years when compared with the lowest quintile of intake. This inverse association tapers off at intakes above 100 mcg daily. For vitamin K2 intake, the highest quintile has a 14% lower risk of hospitalization when compared with the lowest quintile, although the association is U-shaped, indicating an increased risk at high doses. The researchers theorize that this may be due to the fact that vitamin K2-rich foods include cheese, eggs, and butter (109910,109920). There is also interest in using vitamin K to slow aortic valve calcification (AVC) and coronary artery calcification (CAC), which are CVD risk factors. In healthy patients ages 60-80 years with pre-existing CAC, taking a multivitamin with vitamin K1 (phytonadione) 500 mcg orally daily for 3 years reduces CAC progression by 6% when compared with the multivitamin alone (85461). However, research in patients with AVC has found no benefit. One small clinical study in patients on hemodialysis shows that taking the menaquinone-7 form of vitamin K2, 200 mcg orally daily for 1 year, does not affect the rate of AVC progression when compared with placebo (102352). Also, clinical research in males with significant AVC shows that taking the menaquinone-7 form of vitamin K2 720 mcg and vitamin D 25 mcg orally daily for 2 years does not reduce the rate of AVC progression or the rate of cardiovascular events, heart valve surgery, or all-cause mortality when compared with placebo (109916).
• Cataracts. It is unclear if dietary vitamin K reduces the risk of cataracts in older adults. Details: A secondary analysis of results from clinical research has found that higher dietary vitamin K1 (phytonadione) intake over a mean 5.6 years' follow-up is associated with a lower risk of cataracts and a lower incidence of cataract surgery in older adults at high risk for cardiovascular disease. The hazard ratio for developing cataracts was 0.71 and the hazard ratio for cataract surgery was 0.75 for people in the highest tertile of dietary vitamin K1 intake when compared with the lowest tertile (95936).
• Cognitive impairment. It is unclear if dietary vitamin K alters the rate of decline in adults with cognitive impairment. Details: Clinical research in adults aged 55-75 years with overweight or obesity, metabolic syndrome, and cognitive impairment shows that the largest increases in dietary vitamin K intake over a 2-year period are linked to a slower rate of cognitive decline when compared with the lowest increases in intake. This is demonstrated by higher scores on the mini-mental state examination (MMSE) and verbal fluency tests, and a greater number of patients maintaining an MMSE score of at least 24 (109919).
• Colorectal cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of colorectal cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of colorectal cancer (85474).
• Cystic fibrosis. It is unclear if oral vitamin K improves coagulopathy in patients with cystic fibrosis. Details: Suboptimal vitamin K status is common in patients with cystic fibrosis, especially those with pancreatic insufficiency, due to problems with fat digestion (85359,85479). Preliminary clinical research in patients with cystic fibrosis shows that taking vitamin K 1-5 mg orally for one month might decrease osteocalcin levels when compared with baseline, which suggests a lower risk of bone fractures (103920). Also, a small clinical trial in adults and children with cystic fibrosis and pancreatic insufficiency shows that taking a supplement containing fat-soluble vitamins A, D, E, and K for an average of 8.6 months reduces the number of patients with abnormal levels of protein induced by vitamin K absence (PIVKA-II), a defective form of prothrombin (85374).
• Depression. It is unclear if dietary intake of vitamin K reduces depression. Details: Population research has found that a dietary intake of vitamin K greater than 232 mcg daily is associated with reduced odds of depressive symptoms when compared with intakes of less than 83 mcg daily in older adults who are not taking vitamin D supplements. For every 100 mcg increase in vitamin K intake per day, the study found an 18% reduction in odds of depressive symptoms. However, there was no association identified in individuals taking vitamin D (100181). The effect of vitamin K for the prevention or treatment of clinical depression has not been investigated.
• Diabetes. It is unclear if oral vitamin K improves glycemic control in adults with diabetes. Details: A small clinical study in patients with diabetes on oral antidiabetes medications shows that taking vitamin K2 (MK-7) 180 mcg twice daily for 12 weeks seems to reduce glycated hemoglobin (HbA1c) by 1.6%, compared with a slight increase in the placebo group (105034). This study is limited by the high dropout rate in the placebo group. A meta-analysis of clinical studies in patients with type 2 diabetes shows that taking vitamin K1 or K2 for 1 to 36 months modestly improves fasting blood glucose levels and markers of insulin resistance when compared with placebo (11475). The validity of this analysis is limited by high heterogeneity, including different forms and dosing regimens of vitamin K. One small clinical study in adults with type 2 diabetes shows that taking vitamin K4 1 mg orally daily for 6 months does not improve HbA1c or fasting blood glucose levels when compared with placebo. However, subjects taking vitamin K4 had a greater improvement in certain markers of insulin resistance and were more likely to be able to reduce the dose of their antidiabetes medications (114776). There is also interest in vitamin K for the prevention of diabetes. A meta-analysis of population research suggests that low dietary vitamin K intake is associated with an increased risk of developing type 2 diabetes when compared with higher intake (114775). The validity of this study is limited by the identification of publication bias.
• EGFR inhibitor-induced acneiform rash. It is unclear if topical vitamin K is beneficial for the treatment or prevention of acneiform rash caused by EGFR inhibitors. Details: Preliminary clinical research in adults receiving treatment with cetuximab, an EGFR inhibitor, shows that applying vitamin K1 (phytonadione) 0.1% cream (Vigorskin, Merck Serono SpA) twice daily to the face and trunk for 12 weeks may modestly reduce the percentage of patients who develop a moderate to severe acneiform rash (91455). The validity of this finding is limited by the lack of a control group. In patients with an existing rash after receiving the EGFR inhibitors cetuximab and panitumumab, a small clinical study shows that applying vitamin K1 (phytonadione) 1% ointment twice daily for 8 weeks to half of the affected area does not reduce the number of acneiform eruptions when compared with using placebo ointment on the other half of the affected area (103919). Patients in this study were allowed to use concomitant antibiotics and moisturizing agents, which may have confounded the results.
• Kidney failure. It is unclear if oral vitamin K2 reduces the incidence or severity of muscle cramps in adults with kidney failure. Details: Preliminary clinical research in patients on maintenance hemodialysis for at least 3 months with treatment-resistant muscle cramps shows that taking the menaquinone form of vitamin K2 360 mcg orally daily for 8 weeks reduces the frequency, severity, and duration of muscle cramps when compared with placebo (109917).
• Kidney transplant. It is unclear if vitamin K is beneficial for reducing cardiovascular risk in kidney transplant recipients. Details: Preliminary clinical research in adults with a stable kidney transplant for at least 1 year shows that taking vitamin K (menadiol diphosphate) 5 mg three times weekly for 1 year does not reduce aortic stiffness or coronary artery calcification, which are markers of cardiovascular disease, when compared with placebo (109913). The effects of long-term supplementation are unclear. Additionally, another very small study in adult kidney transplant recipients with vitamin K deficiency shows that taking supplemental vitamin K2 360 mcg daily for 12 weeks improves vitamin K status and prevents the progression of arterial stiffness but does not reduce serum calcification propensity when compared with placebo (112132).
• Liver cancer. Small clinical studies suggests that vitamin K2 reduces mortality and the risk for hepatocellular carcinoma recurrence. Details: Meta-analyses of 9-11 small clinical trials in patients with resectable hepatocellular carcinoma show that adding vitamin K2 45 mg daily for up to 3 years seems to reduce cancer recurrence by 9.5% and reduce the risk of mortality by 7% when compared with control. Meta-analyses of 3-4 small clinical trials in patients with non-resectable carcinoma show that taking vitamin K2 45 mg for up to 2 years seems to reduce cancer recurrence by 3% and reduce mortality by 16% when compared with control (105032). Most of the included studies were conducted in Japan, so it is unclear if these results are generalizable to other geographic locations.
• Liver disease. It is unclear if dietary intake of vitamin K reduces the risk of liver disease. Details: A small observational study in patients with chronic liver failure due to cholestatic liver disease has found that receiving intramuscular vitamin K1 10 mg daily for an average of 16 days is associated with a lower risk of death when compared with control (103926).
• Lung cancer. It is unclear if dietary intake of vitamin K reduces the risk of lung cancer. Details: Population research has found that consuming greater than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 62% lower risk of lung cancer occurrence and a 59% lower risk of lung cancer mortality when compared to those who consume less than 23-26 mcg of vitamin K2 daily. Dietary intake of vitamin K1 (phytonadione) is not associated with a reduced risk of lung cancer or lung cancer mortality (85474).
• Multiple sclerosis (MS). It is unclear if topical vitamin K reduces cutaneous adverse effects of MS treatment. Details: In patients with relapsing-remitting MS, burning and pain can accompany subcutaneous interferon treatment. Preliminary clinical research shows that topical application of vitamin K cream (dose not specified) for 8 weeks reduces burning by approximately 8% and pain by 9% when compared with no prophylactic treatment. Redness of the skin is also reduced with vitamin K (91453).
• Overall mortality. It is unclear if dietary intake of vitamin K reduces overall mortality. Details: Observational research in healthy older adults has found that serum vitamin K levels 0.5 nmol/L or less, which corresponds to consuming about 50% of the recommended vitamin K adequate intake, is associated with a 19% higher risk of overall mortality when compared with higher serum levels of vitamin K (103922). In a Danish cohort of adults with a median age of 56 years at baseline, the comparative risk for all-cause mortality between the highest and lowest quintiles of K1 intake over a period of 17-23 years was 0.76. The risk for cardiovascular mortality was 0.72, and the risk of cancer-related mortality in smokers or former smokers, specifically, was 0.8. However, the correlation tapered off above a daily intake of 100 mcg (109911).
• Pancreatic cancer. It is unclear if dietary intake of vitamin K reduces the risk of pancreatic cancer. Details: Observational research in over 100,000 Americans aged 55-74 years at baseline has found no association between dietary vitamin K2 intake and pancreatic cancer incidence over an average follow-up of 9 years. However, the hazard ratio for development of pancreatic cancer was 0.57 for the highest quintile of dietary vitamin K1 intake when compared with the lowest quintile (109912).
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin K improves PCOS symptoms. Details: Small clinical study in patients with PCOS show that taking vitamin K2 (menaquinone-7) 90 mcg daily for 8 weeks does not reduce fasting blood glucose, acne, hirsutism, or weight, although it improves depression and seems to reduce fasting insulin, when compared with placebo (105036,109918).
• Prostate cancer. It is unclear if dietary intake of vitamin K reduces the risk of prostate cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone), but not vitamin K1 (phytonadione), is associated with a reduced risk of prostate cancer, particularly advanced prostate cancer (85443,85474).
• Rheumatoid arthritis (RA). It is unclear if oral vitamin K improves RA symptoms. Details: One small clinical study in patients with RA shows that adding the MK-7 form of vitamin K2 (menaquinone) 100 mcg daily to treatment with conventional antirheumatic agents for 3 months improves disease activity and inflammatory markers when compared with antirheumatic agents alone. When compared to the control group, vitamin K2 reduced disease activity scores by 41% (91449). However, another small clinical study in patients with mild to moderate RA shows that taking vitamin K1 (phytonadione) 10 mg daily for 8 weeks with conventional antirheumatic agents does not improve disease activity or inflammatory markers when compared with placebo (100182). These contrasting outcomes may be related to the type of vitamin K used, the duration of treatment, and the severity of the illness.
• Rosacea. Although there is interest in using topical vitamin K1 for rosacea, there is insufficient reliable information about the clinical effects of vitamin K for this condition.
• Stroke. It is unclear if dietary intake of vitamin K1 reduces the risk of stroke. Details: Population research has found that higher dietary intake of vitamin K1 is not associated with a reduced risk of stroke (85482).
• Wound healing. Although there is interest in using topical vitamin K1 for wound healing, there is insufficient reliable information about the clinical effects of vitamin K for this condition. More evidence is needed to rate vitamin K for these uses.

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POSSIBLY EFFECTIVE

• Age-related macular degeneration (AMD). Oral zeaxanthin, when used in low levels as part of multi-ingredient products containing lutein, seems to improve some aspects of vision in patient with AMD. It is unclear if oral zeaxanthin alone or in amounts similar to lutein is beneficial for slowing AMD progression. Details: Epidemiological research has found that people who consume higher amounts of zeaxanthin plus lutein in the diet have a reduced risk of developing late AMD, but not early or intermediate AMD (60238,106353,106359). However, any association between intake of zeaxanthin itself and the development of AMD is not clear. Some clinical research has assessed whether zeaxanthin alone can reduce symptoms and progression of AMD. A small clinical trial shows that taking supplemental zeaxanthin 8 mg daily for 12 months modestly improves some aspects of vision, such as macular pigment optical density, the ability to see details of near objects (near vision acuity), and resolution of scotoma (blind spot), when compared with placebo in patients with AMD (60245). Other clinical research in a healthy population shows that taking zeaxanthin alone (Optisharp) as 10 mg daily for 6-12 months increases macular pigment optical density (60175). Most clinical research in patients with AMD has assessed zeaxanthin in combination with lutein. In general, this combination has been shown to increase macular pigment optical density, as well as the ability to see under low-contrast conditions (contrast sensitivity) and visual acuity. However, most research has used much higher doses of lutein compared with zeaxanthin (60281,91160,97225,106366,108615). Use of near equal amounts, such as zeaxanthin 8-10 mg daily plus lutein 9-10 mg daily for up to 2 years, seems to improve macular density in adults with or without AMD (60175,60268,60270,106358); however, effects on vision when used for up to 2 years in patients with AMD are conflicting (60245,60268,60270,106358). Zeaxanthin has also been evaluated in combination with other ingredients, with conflicting findings. A specific supplement (AZYR SIFI) containing zeaxanthin 1 mg, lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 22.5 mg, copper 1 mg, and astaxanthin 4 mg has been used daily for 1-2 years with moderate evidence of benefit (19196,60244). Taking zeaxanthin 2 mg plus lutein 10 mg in addition to the original Age-Related Eye Disease Study (AREDS) formulation (vitamins C and E, beta-carotene, and zinc) does not seem to prevent the progression to advanced AMD more than the AREDS formulation alone. However, this progression was modestly inhibited in individuals with low dietary intakes of lutein and zeaxanthin. While progression to late AMD was only modestly inhibited at 5 years when these doses of lutein and zeaxanthin were included in a revised formulation devoid of beta-carotene (60281), results of an additional 5 years of follow up showed that this revised formulation reduces the risk of progression to late AMD by 15% when compared with the formulation containing beta-carotene (108615). Clinical research shows that adding meso-zeaxanthin 10 mg to this revised AREDS formulation (AREDS2) does not further improve contrast sensitivity in patients with non-advanced AMD (106369). In first-generation offspring of parents with neovascular AMD, taking zeaxanthin 2 mg, lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 15 mg, and copper 1 mg daily for 6 months does not improve the macular pigment optical density (106347). Reasons for these discrepancies are not clear but may relate to the patient population, zeaxanthin dose, treatment duration, or other ingredients included in combination products.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral zeaxanthin is beneficial for attenuating cognitive decline in older adults. Details: Clinical research in adults 40-75 years old shows that taking zeaxanthin 2 mg with lutein 10 mg daily for 6 months improves some, but not all, measures of visual memory when compared with placebo. However, other measures of memory and cognitive function were not improved (109763). Also, preliminary clinical research in older adults shows that taking the same dose of zeaxanthin and lutein for one year modestly improves some measures of cognitive function, such as complex attention and cognitive flexibility, when compared with placebo (106367). Some observational research in patients 50 years and older has found that higher dietary lutein and zeaxanthin intake is associated with greater word recall when compared with lower intake (102891). However, clinical research in patients over 60 years old shows that taking zeaxanthin 2 mg with lutein 10 mg daily for 5 years in addition to vitamins C and E, beta-carotene, and zinc (AREDS) does not improve markers of cognitive function, such as memory and verbal fluency, when compared with AREDS alone (94702).
• Alzheimer disease. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking zeaxanthin 2 mg, lutein 10 mg, meso-zeaxanthin 10 mg, fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 mg), and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases in the number of patients experiencing either an improvement or attenuated decline in memory and mood (109764). The effect of zeaxanthin alone is unclear.
• Asthenopia (eye strain). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Results from one clinical trial show that taking a combination product (Cerebos Pacific Limited) containing zeaxanthin 1 mg, lutein 5 mg, and black currant extract 200 mg daily for 2 weeks modestly improves visual fatigue and eye stress when compared with placebo in patients completing a two-hour visual proof reading task (60214). The effect of zeaxanthin alone on eye strain is unclear.
• Asthma. It is unclear if oral zeaxanthin is beneficial for asthma prevention. Details: Population research has found that a higher dietary intake of zeaxanthin plus lutein is associated with up to 30% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of zeaxanthin intake alone or zeaxanthin supplementation are unclear.
• Breast cancer. It is unclear if oral zeaxanthin is beneficial for breast cancer prevention. Details: Epidemiological research has found that higher serum levels of lutein plus zeaxanthin are associated with a reduced risk of developing breast cancer (10132). The effects of supplemental zeaxanthin are unclear.
• Bronchopulmonary dysplasia. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing zeaxanthin 0.0006 mg and lutein 0.14 mg orally once daily, starting at birth and continuing until 36 weeks' corrected gestational age, does not decrease the incidence of bronchopulmonary dysplasia when compared with placebo (91163). The effect of zeaxanthin alone is unclear.
• Cardiovascular disease (CVD). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults 50-85 years old shows that taking lutein 10 mg plus zeaxanthin 2 mg daily for an average of 4.8 years does not decrease the risk of CVD-related mortality or cardiovascular events such as stroke, myocardial infarction, or angina when compared with no supplementation (94701). Individual cardiovascular outcomes were not separately evaluated in this study. The effect of zeaxanthin alone on CVD prevention is unknown.
• Cataracts. Increased levels of zeaxanthin in the blood seems to reduce the odds of developing cataracts. It is unclear if dietary or supplemental zeaxanthin is beneficial for cataract treatment or prevention. Details: Some population research has found that higher blood levels of zeaxanthin are associated with a 30% lower odds of developing age-related cataracts, and more specifically, a 37% decreased risk of developing nuclear cataracts (90944,91161). Population research has also found that higher dietary combined intake of lutein plus zeaxanthin is associated with lower odds of developing cataracts. However, any association between intake of zeaxanthin itself and the development of cataracts is unclear (91162). Clinical research shows that taking zeaxanthin 2 mg and lutein 10 mg daily orally, in addition to the Age-Related Eye Disease Study (AREDS) formulation containing vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, zinc 80 mg, and copper 2 mg, for an average of 4.7 years decreases the risk of needing cataract surgery by 32% when compared with the AREDS formulation alone in patients with low dietary intake of lutein and zeaxanthin, but not in those with higher dietary intake of lutein and zeaxanthin (94703).
• Child development. It is unclear if oral zeaxanthin is beneficial for child development. Details: Epidemiological research has found that a higher dietary intake of zeaxanthin in the first and second trimesters of pregnancy is associated with increased verbal intelligence and improved behavior in the child at 6-10 years of age. However, the ability to discriminate between a novel or familiar visual stimulus was reduced at about 6 months of age, and there were no effects on most cognitive outcomes in children aged 3-6 years (107106). Other epidemiological research has found that a higher dietary intake of zeaxanthin plus lutein in children aged 3-6 years may be associated with modestly improved executive function at 6-11 years. However, there were no effects on most cognitive outcomes in children aged 3-6 years or 6-11 years (109761).
• Cognitive function. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in younger adults shows that taking zeaxanthin 2 mg and lutein 10 mg for one year modestly improves some measures of cognitive function, such as spatial memory, when compared with placebo (106348). Observational research has found that intake of choline and lutein plus zeaxanthin is positively associated with cognitive flexibility task performance speed. However, this association is not present with the intake of lutein plus zeaxanthin in the absence of choline (106354). The effect of zeaxanthin alone is unclear.
• Colorectal cancer. It is unclear if oral zeaxanthin is beneficial for colorectal cancer prevention. Details: Although some individual epidemiological research disagrees (3962), most research has found that dietary intake of lutein plus zeaxanthin is not associated with a reduced risk of developing colorectal cancer (34481,106372). However, any association with intake of zeaxanthin alone, as supplements or in the diet, is unclear.
• Diabetes. Observational research suggests that oral zeaxanthin may not be beneficial for the prevention of diabetes or diabetic complications. Details: Some epidemiological research has found that low serum levels of carotenoids, including zeaxanthin and lutein, are associated with impaired glucose tolerance (60161). Other population research has found that increased dietary intake of zeaxanthin plus lutein does not decrease the risk of developing type 2 diabetes (14004,97227). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of zeaxanthin is not associated with reduced cardiovascular mortality over 14 years (109768).
• Esophageal cancer. It is unclear if oral zeaxanthin is beneficial for esophageal cancer prevention. Details: Population research has found that people who consume higher combined amounts of zeaxanthin and lutein in the diet have a 29% lower risk of developing esophageal squamous cell cancer when compared with lower intake (91159). The effects of supplemental zeaxanthin are unclear.
• Fractures. It is unclear if oral zeaxanthin is beneficial for fracture prevention. Details: A meta-analysis of observational research has found that increased dietary intake of zeaxanthin and/or lutein is not associated with a reduced risk of hip fractures (97228). The effects of supplemental zeaxanthin are unclear.
• Gastric cancer. It is unclear if oral zeaxanthin is beneficial for gastric cancer prevention. Details: A meta-analysis of observational research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of developing gastric cancer (97231). The effects of supplemental zeaxanthin are unclear.
• Glaucoma. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with open-angle glaucoma shows that taking oral zeaxanthin 2 mg, lutein 10 mg, and meso-zeaxanthin 10 mg daily for 18 months increases macular pigment density, but does not affect visual function, when compared with placebo (109756).
• Hyperlipidemia. Although there has been interest in using oral zeaxanthin for hyperlipidemia, there is insufficient reliable information about the clinical effects of zeaxanthin for this condition.
• Lung cancer. It is unclear if oral zeaxanthin is beneficial for lung cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including zeaxanthin, are associated with an increased risk of lung cancer (12874). However, other epidemiological research has found that higher serum levels of zeaxanthin are not associated with a reduced risk of dying from lung cancer (39690,60160).
• Macular telangiectasia type 2. It is unclear if oral zeaxanthin is beneficial for macular telangiectasia type 2. Details: In patients with macular telangiectasia type 2, observational research has found that taking a specific combination of lutein 10 mg, meso-zeaxanthin 10 mg, and zeaxanthin 2 mg (MacuShield; Alliance Pharmaceuticals) for at least 6 months, with an average duration of 15.7 months, was associated with a stabilization of visual acuity. Also, the number and size of cavitations in the macula were reduced (106355).
• Metabolic syndrome. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research in females shows that the highest dietary intake of zeaxanthin plus lutein is associated with 54% reduced odds of developing metabolic syndrome when compared with the lowest intake. However, when supplements containing zeaxanthin plus lutein were included in the total intake, there was no association with metabolic syndrome (109760).
• Necrotizing enterocolitis (NEC). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing zeaxanthin 0.0006 mg and lutein 0.14 mg orally once daily, starting at birth and continuing until 36 weeks' corrected gestational age, does not decrease the incidence of NEC when compared with placebo (91163).
• Non-Hodgkin lymphoma. It is unclear if oral zeaxanthin is beneficial for non-Hodgkin lymphoma prevention. Details: A meta-analysis of observational research has found that increased intake of zeaxanthin/lutein in the diet is associated with an 18% lower risk of developing non-Hodgkin lymphoma when compared with low dietary intake. However, no dose-response relationship was reported (97229). It is unknown if supplemental zeaxanthin has any effect on non-Hodgkin lymphoma risk.
• Pancreatic cancer. It is unclear if oral zeaxanthin is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research has found that increased dietary intake of zeaxanthin and/or lutein is not associated with a reduced risk of pancreatic cancer (97230). The effects of supplemental zeaxanthin are unclear.
• Parkinson disease. It is unclear if oral zeaxanthin is beneficial for Parkinson disease prevention. Details: Population research has found that people who consume higher amounts of zeaxanthin in the diet do not have a lower risk of developing Parkinson disease (91164). The effects of supplemental zeaxanthin are unclear.
• Pre-eclampsia. It is unclear if oral zeaxanthin is beneficial for the prevention of pre-eclampsia. Details: Some epidemiological research has found that the highest intake of lutein plus zeaxanthin during pregnancy is associated with 68% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). The effects of zeaxanthin supplements are unclear.
• Prostate cancer. It is unclear if oral zeaxanthin is beneficial for prostate cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including zeaxanthin, are not associated with an increased risk of prostate cancer (12874). The effects of supplemental zeaxanthin are unclear.
• Respiratory tract infections. It is unclear if oral zeaxanthin is beneficial for the treatment or prevention of respiratory tract infections. Details: Epidemiological research has found that high serum levels of zeaxanthin are not associated with decreased incidence or severity of respiratory tract infections in the elderly (60152). The effects of supplemental zeaxanthin are unclear.
• Retinopathy of prematurity. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in preterm and low birth weight infants shows that giving a specific product (LUTEINofta, SOOFT Italia SpA) providing lutein 0.14 mg or 0.5 mg/kg plus zeaxanthin 0.0006 mg or 0.02 mg/kg orally once daily, starting at birth and continuing until 36-40 weeks' corrected gestational age, does not decrease the incidence or severity of retinopathy of prematurity when compared with placebo (60240,60243,91163,102889).
• Ulcerative colitis. It is unclear if oral zeaxanthin is beneficial for ulcerative colitis. Details: In patients in the remission phase of ulcerative colitis, observational research has found that a higher dietary intake of lutein plus zeaxanthin is associated with a reduced incidence of constipation, but not flatulence or feelings of urgency (tenesmus) (106362). The effects of supplemental zeaxanthin are unclear.
• Visual development. It is unclear if taking oral zeaxanthin during pregnancy can improve the visual acuity of the child. Details: Some observational research has found that the highest maternal plasma zeaxanthin levels at delivery are associated with a 38% lower risk of poor visual acuity in children at 3 years of age when compared with the lowest maternal zeaxanthin levels (102888). However, other epidemiological research has found that dietary intake of zeaxanthin plus lutein during the first or third trimesters of pregnancy is not associated with contrast vision or visual acuity in the child at 11-12 years of age (109759). The effects of zeaxanthin supplements are unclear. More evidence is needed to rate zeaxanthin for these uses.

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POSSIBLY SAFE ...when non-contaminated species of spirulina blue-green algae are used orally and appropriately (91713). The blue-green algae species Arthrospira platensis has been used with apparent safety in doses up to 19 grams daily for 2 months, or 10 grams daily for 6 months (18296,18300,18306,75944,91705,99703,104567,109965). The blue-green algae species Arthrospira fusiformis has been used with apparent safety in doses up to 4 grams daily for 3 months, or 1 gram daily for 12 months (15782,91717). Another blue-green algae species, Arthrospira maxima, has been used with apparent safety in a dose of 4.5 grams daily for up to 12 weeks (18297,99654,99655,102688). ...when non-contaminated, non-toxin producing strains of blue-green algae from the Aphanizomenon flos-aquae species are used orally and appropriately. Doses up to 1.6 grams daily have been used with apparent safety for up to 6 months (14842,18310). Some blue-green algae species can produce toxins called microcystins. According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549).

POSSIBLY UNSAFE ...when contaminated blue-green algae are used orally. Blue-green algae can be contaminated with heavy metals (including mercury, cadmium, lead, or arsenic), neurotoxins, and toxic microcystin-producing cyanobacteria such as Microcystis aeruginosa (9171,75966,91704,91711,96550). Microcystins are most commonly reported in the blue-green algae species Aphanizomenon flos-aquae harvested from Upper Klamath Lake in Oregon. The Oregon Department of Health has set a limit of 1 mcg of microcystin-LR equivalents per gram dry weight of blue-green algae, assuming consumption of about 2 grams/day by adults (91704,91713). However, many samples of Aphanizomenon flos-aquae have been reported to contain higher levels than this (9171,91704). According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549). When consumed orally, microcystins accumulate in the liver, binding to and inhibiting protein phosphatases, causing hepatocyte damage and possible tumor promotion (9171). Aphanizomenon flos-aquae can also produce neurotoxic compounds that may be present in supplements containing this organism (91704).

CHILDREN: POSSIBLY UNSAFE
when blue-green algae products are used orally. Blue-green algae can accumulate heavy metals such as lead and mercury (91704,91711). They can also contain toxic microcystins produced by contaminating species of cyanobacteria such a Microcystis aeruginosa (91704). Children are more sensitive to poisoning by microcystins (3536). The Oregon Department of Health has set a limit for microcystins of 1 mcg per gram dry weight of blue-green algae, but some countries have set very low exposure limits of 0.2 mcg per day and 0.8 mcg per day for infants and children, respectively (91704).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Some blue-green algae products, specifically those of the species Aphanizomenon flos-aquae, have been found to contain low amounts of beta-methylamino-L-alanine (BMAA). BMAA is associated with neurodegenerative diseases, and breast milk has been shown to be a potential source of BMAA exposure in infants (96550).

(Read more about BLUE-GREEN ALGAE)

LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

(Read more about CALCIUM)

LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. There is insufficient reliable information available about the safety of chlorophyll when used orally in medicinal amounts or when used topically or as an injection.

PREGNANCY AND LACTATION:
Insufficient reliable information available.

(Read more about CHLOROPHYLL)

POSSIBLY SAFE ...when used orally and appropriately. GLA appears to be safe when taken in oral doses of up to 2.8 grams daily for up to a year (1983,7701,7702,8926,107927).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about GAMMA-LINOLENIC ACID (GLA))

LIKELY SAFE ...when used orally and appropriately. For people age 14 and older with adequate iron stores, iron supplements are safe when used in doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron. The UL is not meant to apply to those who receive iron under medical supervision (7135,96621). To treat iron deficiency, most people can safely take up to 300 mg elemental iron per day (15). ...when used intravenously and appropriately. Ferric carboxymaltose 200 mg and iron sucrose 200 mg have been given intravenously for up to 10 doses with no reported serious adverse effects (91179). A meta-analysis of clinical studies of hemodialysis patients shows that administering high-dose intravenous (IV) iron does not increase the risk of hospitalization, infection, cardiovascular events, or death when compared with low-dose IV iron, oral iron, or no iron treatment (102861). A more recent meta-analysis of clinical studies of all patient populations shows that administering IV iron does not increase the risk of hospital length of stay or mortality, although the risk of infection is increased by 16% when compared with oral iron or no iron (110186). Another meta-analysis of 3 large clinical trials in patients with heart failure shows that intravenous ferric carboxymaltose at a dose of around 1500 mg every 6 months for a year does not increase the incidence of adverse effects when compared with placebo (113901). Despite these findings, there are rare reports of hypophosphatemia and/or osteomalacia (112603,112608,112609,112610,113905).

LIKELY UNSAFE ...when used orally in excessive doses. Doses of 30 mg/kg are associated with acute toxicity. Long-term use of high doses of iron can cause hemosiderosis and multiple organ damage. The estimated lethal dose of iron is 180-300 mg/kg; however, doses as low as 60 mg/kg have also been lethal (15).

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135,91183,112601).

CHILDREN: LIKELY UNSAFE
when used orally in excessive amounts. Tell patients who are not iron-deficient not to use doses above the tolerable upper intake level (UL) of 40 mg per day of elemental iron for infants and children aged 0-13 years and 45 mg per day for children aged 14-18 years. Higher doses frequently cause gastrointestinal side effects such as constipation and nausea (7135,20097). Iron is the most common cause of pediatric poisoning deaths. Doses as low as 60 mg/kg can be fatal (15).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Iron is safe during pregnancy and breast-feeding in patients with adequate iron stores when used in doses below the tolerable upper intake level (UL) of 45 mg daily of elemental iron (7135,96625,110180).

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally in high doses. Tell patients who are not iron deficient to avoid exceeding the tolerable upper intake level (UL) of 45 mg daily of elemental iron. Higher doses frequently cause gastrointestinal side effects such as nausea and vomiting (7135) and might increase the risk of preterm labor (100969). High hemoglobin concentrations at the time of delivery are associated with adverse pregnancy outcomes (7135,20109).

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LIKELY SAFE ...when used orally in doses up to 100 mEq total potassium daily, not to exceed 200 mEq in a 24-hour period (95010,107989). Oral potassium chloride and potassium citrate are FDA-approved prescription products (95010,107989). Larger doses increase the risk of hyperkalemia (15). ...when administered intravenously (IV) at appropriate infusion rates (95011). Parenteral potassium is an FDA-approved prescription product (15,95011). A tolerable upper intake level (UL) for potassium has not been established; however, potassium levels should be monitored in individuals at increased risk for hyperkalemia, such as those with kidney disease, heart failure, and adrenal insufficiency (100310,107966).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established for healthy individuals (6243,100310).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 40-80 mEq daily (15). A tolerable upper intake level (UL) has not been established for healthy individuals (100310).

(Read more about POTASSIUM)

LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

(Read more about SODIUM)

POSSIBLY SAFE ...when used orally and appropriately. A gliadin-protected formulation of superoxide dismutase (Glisodin, Isocell Laboratory) has been used with apparent safety at doses up to 1 gram daily for up to 12 weeks or 500 mg daily for up to 24 weeks (106849). In combination with other ingredients, superoxide dismutase 140 IU and 10 mg have been used with apparent safety for up to 4 months and 12 months, respectively (20488,105502). ...when used parenterally, short term. Intravenous, intramuscular, and local injections of superoxide dismutase have been used with apparent safety, short-term (2230,2231,2232,2233,2241,2243). However, since some preparations are derived from animals, there is concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated preparations. Lecithinized recombinant superoxide dismutase 20-160 mg as a single intravenous dose has been used with apparent safety (105503). There is insufficient reliable information available about the safety of superoxide dismutase when used topically or in the eye.

CHILDREN: POSSIBLY SAFE
when administered via subcutaneous injection. Superoxide dismutase 0.25 mg/kg twice daily until ventilator support is no longer required has been used with apparent safety in pre-term infants (2242).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about SUPEROXIDE DISMUTASE (SOD))

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe in adults when taken in doses below the tolerable upper intake level (UL) of 10,000 IU (3000 mcg) daily (7135). Higher doses increase the risk of side effects. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake refer to pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount to determine safety.

POSSIBLY SAFE ...when used topically and appropriately, short-term. Retinol up to 0.5% has been used on the skin daily for up to 12 weeks with apparent safety. No serious adverse effects have been reported in clinical trials (103671,103680,114500).

POSSIBLY UNSAFE ...when used orally in high doses. Doses higher than the UL of 10,000 IU (3000 mcg) per day of pre-formed vitamin A (retinol or retinyl ester) might increase the risk of side effects (7135). While vitamin A 25,000 IU (as retinyl palmitate) daily for 6 months followed by 10,000 IU daily for 6 months has been used with apparent safety in one clinical trial (95052), prolonged use of excessive doses of vitamin A can cause hypervitaminosis A (7135). The risk for developing hypervitaminosis A is related to total cumulative dose of vitamin A rather than a specific daily dose (1467,1469). In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). There is insufficient reliable information available about the safety of using sublingual formulations of vitamin A.

CHILDREN: LIKELY SAFE
when used orally or intramuscularly and appropriately. The amount of pre-formed vitamin A (retinol or retinyl ester) that is safe depends on age. For children up to 3 years of age, doses less than 2000 IU (600 mcg) per day seem to be safe. For children ages 4 to 8, doses less than 3000 IU (900 mcg) per day seem to be safe. For children ages 9 to 13, doses less than 5667 IU (1700 mcg) per day seem to be safe. For children 14 to 18, doses less than 9333 IU (2800 mcg) per day seem to be safe (7135). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount for determining safety.

CHILDREN: POSSIBLY UNSAFE
when pre-formed vitamin A (retinol or retinyl ester) is used orally in excessive doses. For children up to 3 years of age, avoid doses greater than 2000 IU (600 mcg) per day. For children ages 4 to 8, avoid doses greater than 3000 IU (900 mcg) per day. For children ages 9 to 13, avoid doses greater than 5667 IU (1700 mcg) per day. For children ages 14 to 18, avoid doses greater than 9333 IU (2800 mcg) per day (7135). Higher doses of vitamin A supplementation have been associated with increased risk of side effects such as pneumonia, bone pain, and diarrhea (319,95051). Long-term supplementation with low to moderate doses on a regular basis can cause severe, but usually reversible, liver damage (11978).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe during pregnancy and lactation when used in doses less than 10,000 IU (3000 mcg) per day in adults 19 years of age and older and 2800 mcg daily in those 14-18 years of age (7135,16823,107293). Vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used as the reference amount to determine safety.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally or intramuscularly in excessive doses. Daily intake of greater than 10,000 IU (3000 mcg) can cause fetal malformations (3066,7135). Excessive dietary intake of vitamin A has also been associated with teratogenicity (11978). The first trimester of pregnancy seems to be the critical period for susceptibility to vitamin A-associated birth defects such as craniofacial abnormalities and abnormalities of the central nervous system (7135). Pregnant patients should monitor their intake of pre-formed vitamin A (retinol or retinyl ester). This form of vitamin A is found in several foods including animal products, particularly fish and animal liver, some fortified breakfast cereals, and dietary supplements (3066).

(Read more about VITAMIN A)

LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111334,111551).

PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.

(Read more about VITAMIN B12)

LIKELY SAFE ...when vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is used orally and appropriately. A tolerable upper intake level for vitamin K in adults has not been set, because no adverse effects have been noted at a wide range of studied doses. For example, Vitamin K1 up to 10 mg daily and vitamin K2 up to 45 mg daily have been safely used in clinical trials lasting up to 2 years. (54,55,58,6799,7135,14364). Notably, some of these studied doses are exponentially higher than various recommendations for daily adequate intake. See Dosing & Administration and Effectiveness sections for additional information...when vitamin K1 (phytonadione) is used parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is an FDA-approved drug (7135).

POSSIBLY SAFE ...when vitamin K1 (phytonadione) 0. 1% is used topically in a cream or ointment for up to 12 weeks (91455,103919).

CHILDREN: LIKELY SAFE
when vitamin K1 (phytonadione) is used orally or parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is FDA approved for use in children. A tolerable upper intake level for vitamin K in children has not been set (7135).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the daily adequate intake level (AI). A tolerable upper intake level for vitamin K in pregnancy and lactation has not been set (7135).

(Read more about VITAMIN K)

LIKELY SAFE ...when used orally and appropriately in doses of up to 2 mg daily. Zeaxanthin supplements have been safely used in clinical trials at doses of up to 2 mg daily for up to 10 years (94701,94702,94703,108615).

POSSIBLY SAFE ...when used orally and appropriately in amounts greater than 2 mg daily. Zeaxanthin supplements in doses of 8-10 mg daily for up to 12 months have been used with apparent safety in clinical trials (60175,60245).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. A specific product containing zeaxanthin (LUTEINofta, SOOFT Italia SpA) has been used with apparent safety in infants at a dose of 0.0006 mg daily for 36 weeks (91163). There is insufficient reliable information available about the safety of zeaxanthin at higher doses or in older children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in amounts found in foods. Zeaxanthin is found in breast milk and levels correlate with infant status (106365). There is insufficient reliable information available about the safety of supplemental zeaxanthin.

(Read more about ZEAXANTHIN)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, spirulina blue-green algae might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs. However, this is unlikely.  Details Spirulina blue-green algae have shown antiplatelet and anticoagulant effects in vitro (18311,18312,75892,92162,92163). However, one preliminary study in 24 patients receiving spirulina blue-green algae 2.3 grams daily for 2 weeks showed no effect on platelet activation or measures of clotting time (97202).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking blue-green algae with antidiabetes drugs might increase the risk of hypoglycemia.  Details Human research shows that spirulina blue-green algae can have hypoglycemic effects in patients with diabetes, at least some of whom were using antidiabetes drugs (18299). However, blue-green algae does not seem to improve glycated hemoglobin (HbA1c) levels in patients with diabetes (102689,109970). A meta-analysis of animal studies also suggests that spirulina blue-green algae have hypoglycemic effects (109970).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of blue-green algae might interfere with immunosuppressive therapy.  Details Blue-green algae have been shown to stimulate the immune system (2534,10267).

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

(Read more about CALCIUM)

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, chlorophyll may reduce the clearance of methotrexate.  Details In one case report, a 54-year-old male developed delayed clearance of intravenous high-dose methotrexate with concomitant use of chlorophyll. When chlorophyll was stopped 2 days prior to methotrexate treatment, methotrexate clearance was unaffected (93891).

PHOTOSENSITIZING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of chlorophyll with photosensitizing drugs may have additive effects.  Details Chlorophyll has been reported to cause photosensitization. In two case reports, pseudoporphyria developed after oral intake of chlorophyll (93892). Theoretically, concomitant use with other photosensitizing drugs may exacerbate this effect (1326).

(Read more about CHLOROPHYLL)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, GLA might increase the risk of bleeding when taken with anticoagulant or antiplatelet rugs.  Details Animal and human research suggests that GLA reduces platelet aggregation (1979).

(Read more about GAMMA-LINOLENIC ACID (GLA))

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron reduces the absorption of bisphosphonates.  Details Advise patients that doses of bisphosphonates should be separated by at least two hours from doses of all other medications, including supplements such as iron. Divalent cations, including iron, can decrease absorption of bisphosphonates by forming insoluble complexes in the gastrointestinal tract (15).

CHLORAMPHENICOL Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking chloramphenicol with iron might reduce the response to iron therapy in iron deficiency anemia.  Details Chloramphenicol interferes with erythrocyte maturation (15,3046). However, since chloramphenicol isn't usually taken for prolonged periods, this isn't likely to be clinically significant.

DENOSUMAB (Prolia, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Administration of intravenous iron within one month of denosumab administration might increase the risk of severe hypophosphatemia and hypocalcemia.  Details A case of severe hypocalcemia (albumin corrected calcium 6.88 mg/dL, ionized calcium 3.68 mg/dL) and hypophosphatemia (<0.5 mg/dL) with respiratory acidosis, QT interval prolongation, and nonsustained ventricular tachycardia was reported in a 76-year-old male who had received an iron polymaltose infusion within 2 weeks of a subcutaneous injection of denosumab. Serum parathyroid hormone was also elevated (348 pg/mL). Subsequent iron infusions with iron polymaltose and ferric carboxymaltose were followed by transient hypophosphatemia, but without hypocalcemia. Additionally, a literature review describes 6 additional cases of hypophosphatemia and hypocalcemia in patients 52-92 years of age who had been administered intravenous iron as either ferric carboxymaltose or iron polymaltose and subcutaneous denosumab within 1-4 weeks of each other (113905).

DOLUTEGRAVIR (Tivicay) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease dolutegravir levels by reducing its absorption.  Details Advise patients to take dolutegravir at least 2 hours before or 6 hours after taking iron. Pharmacokinetic research shows that iron can decrease the absorption of dolutegravir from the gastrointestinal tract through chelation (93578). When taken under fasting conditions, a single dose of ferrous fumarate 324 mg orally along with dolutegravir 50 mg reduces overall exposure to dolutegravir by 54% (94190).

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking iron along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Iron is a divalent cation. There is concern that iron may decrease the absorption of integrase inhibitors from the gastrointestinal tract through chelation (93578). One pharmacokinetic study shows that iron can decrease blood levels of the specific integrase inhibitor dolutegravir through chelation (94190). Also, other pharmacokinetic research shows that other divalent cations such as calcium can decrease the absorption and levels of some integrase inhibitors through chelation (93578,93579).

LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levodopa levels by reducing its absorption.  Details Advise patients to separate doses of levodopa and iron as much as possible. There is some evidence in healthy people that iron forms chelates with levodopa, reducing the amount of levodopa absorbed by around 50% (9567). The clinical significance of this hasn't been determined.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levothyroxine levels by reducing its absorption.  Details Advise patients to separate levothyroxine and iron doses by at least 2 hours. Iron can decrease the absorption and efficacy of levothyroxine by forming insoluble complexes in the gastrointestinal tract (9568).

METHYLDOPA (Aldomet) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease methyldopa levels by reducing its absorption.  Details Advise patients to separate methyldopa and iron doses by at least 2 hours. Iron can decrease the absorption of methyldopa from the gastrointestinal tract through chelation, resulting in increases in blood pressure (7900,20151).

MYCOPHENOLATE MOFETIL (CellCept) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, iron might decrease mycophenolate mofetil levels by reducing its absorption.  Details Advise patients to take iron 4-6 hours before, or 2 hours after, mycophenolate mofetil. It has been suggested that a decrease of absorption is possible, probably by forming nonabsorbable chelates. However, mycophenolate pharmacokinetics are not affected by iron supplementation in available clinical research (3046,20152,20153,20154,20155).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease penicillamine levels by reducing its absorption.  Details Advise patients to separate penicillamine and iron doses by at least 2 hours. Oral iron supplements can reduce absorption of penicillamine by 30% to 70%, probably due to chelate formation. In people with Wilson's disease, this interaction has led to reduced efficacy of penicillamine (3046,3072,20156).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of quinolone antibiotics by reducing their absorption.  Details Advise patients to separate quinolone antibiotics and iron doses by at least 2 hours. Iron decreases the absorption of quinolones due to formation of insoluble complexes in the gastrointestinal tract (15,3072).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of tetracycline antibiotics by reducing their absorption.  Details Advise patients to take iron at least 2 hours before or 4 hours after tetracycline antibiotics. Concomitant use can decrease absorption of tetracycline antibiotics from the gastrointestinal tract by 50% to 90% (15).

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ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ACEIs with high doses of potassium increases the risk of hyperkalemia.  Details ACEIs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ARBs with high doses of potassium increases the risk of hyperkalemia.  Details ARBs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Concomitant use increases the risk of hyperkalemia.  Details Using potassium-sparing diuretics with potassium supplements increases the risk of hyperkalemia (15).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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(Read more about SUPEROXIDE DISMUTASE (SOD))

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = C Theoretically, taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease.  Details The tolerable upper intake level (UL) is the highest level of intake that is likely to pose no risk of adverse effects. Doses of vitamin A above the UL can cause hepatotoxicity, ranging from elevated liver enzymes to liver failure (7135,82554).

RETINOIDS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Concomitant use of retinoids with vitamin A supplements might produce supratherapeutic vitamin A levels.  Details Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements (3046).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tetracycline antibiotics with high doses of vitamin A can increase the risk of pseudotumor cerebri.  Details Benign intracranial hypertension (pseudotumor cerebri) can occur with tetracyclines and with acute or chronic vitamin A toxicity. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition (10545,10546,10547). Avoid high doses of vitamin A in people taking tetracyclines chronically.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, high doses of vitamin A could increase the risk of bleeding with warfarin.  Details Vitamin A toxicity is associated with hemorrhage and hypoprothrombinemia, possibly due to vitamin K antagonism (505). Advise patients taking warfarin to avoid doses of vitamin A above the tolerable upper intake level of 10,000 IU/day for adults.

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WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = C Vitamin K can antagonize and reverse the therapeutic effects of warfarin.  Details Vitamin K antagonizes the effects of warfarin (15,23380,25507,25508,85425,85429). Excessive vitamin K intake, either from supplements or from changes in the diet, can reduce the anticoagulant effect of warfarin (15).

(Read more about VITAMIN K)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking zeaxanthin with antidiabetes drugs might increase the risk of hypoglycemia.  Details In an animal diabetic model, zeaxanthin has hypoglycemic effects (106363). However, population research has found that increasing intake of dietary zeaxanthin plus lutein does not decrease the risk of developing type 2 diabetes (14004,97227).

(Read more about ZEAXANTHIN)

General ...Orally, spirulina blue-green algae seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, bloating, diarrhea, dizziness, fatigue, flatulence, headache, nausea, and vomiting.

Dermatologic ...Orally, a severe rash has been reported in a 49-year-old woman after taking a spirulina blue-green algae supplement (species and dose unknown). After stopping the supplement, inflammatory myopathy with muscle weakness and elevated creatine kinase occurred. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). In another case report, an 82 year-old woman developed a blistering skin condition over a 2-year period while taking spirulina blue-green algae (A. platensis, dose unknown). She had partly hemorrhagic bullae, secreting erosions and macerations. These symptoms resolved when the supplement was stopped and the patient was treated with oral prednisone, topical silver sulfadiazine, and topical triamcinolone / neomycin (75921).

Gastrointestinal ...Orally, gastrointestinal complaints are amongst the most common adverse effects associated with spirulina blue-green algae, including nausea, vomiting, diarrhea, and abdominal cramps (19272,75924,91713,109969). Similarly, common adverse effects associated with the blue-green algae species Aphanizomenon flos-aquae are stomach upset, flatulence, diarrhea, and bloating (14842).

Hematologic ...Orally, three cases of mild gum bleeding and one case of mild bruising have been reported in patients taking spirulina blue-green algae (Cyactiv, Cerule LLC) 2. 3 grams daily (containing approximately 1 gram of phycocanin) for 2 weeks (97202).

Hepatic ...Orally, significant elevations of liver function tests within 2 weeks of starting a spirulina blue-green algae supplement (species and dose unknown) have been reported in a 52-year-old man stabilized on amlodipine, simvastatin, and acarbose. A biopsy showed feathery degeneration and ballooning of hepatic cells. Cholestasis was present, and an ex-vivo lymphocyte stimulation test for spirulina blue-green algae was positive. All drugs and the spirulina blue-green algae supplement were stopped, with return of the LFTs to normal (9172).

Immunologic ...Orally, urticarial rashes and pruritus have occurred as part of generalized allergic reactions to blue-green algae (91706,91711,91712).
In one case report, a 14-year-old male experienced anaphylaxis with urticaria, lip edema, and asthma 6 hours after taking five tablets of spirulina blue-green algae (A. platensis, strength unknown). He had a positive skin prick test. Oral challenge to an extract of the tablets, and IgE from his serum, reacted with the beta chain of C-phycocyanin from A. platensis (91712).
In another case report, a 17-year-old male with a history of multiple allergies developed rash, pruritus, angioedema, wheezing, and dyspnea within 10 minutes of taking spirulina blue-green algae (A. platensis) 300 mg. He had a positive skin test to A. platensis but no other ingredients of the tablets (91706).

Musculoskeletal ...Orally, after a 49-year-old woman stopped taking a spirulina blue-green algae supplement (species and dose unknown), the patient experienced inflammatory myopathy with muscle weakness and elevated creatine kinase. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). Another case report describes acute rhabdomyolysis that occurred after consumption of spirulina (Arthrospira platensis, Hawaiian spirulina, Solgar Inc., Leonia, NJ) 3 grams daily for 1 month. The 24-year old man presented with weakness, myalgias, elevated creatine kinase and liver function tests, and myoglobinuria (75922).

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). 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 CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or 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). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

(Read more about CALCIUM)

General ...Orally, topically, or intravenously, significant adverse effects have not been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Photosensitization.
Topically: Dermatitis, photosensitization.
Serious Adverse Effects (Rare):
Orally: Pseudoporphyria.

Dermatologic ...Topically, chlorophyll cream has been reported to cause dermatitis (41912). Orally, chlorophyll can cause photosensitization (1326). Certain carotenoids such as beta-carotene and canthaxanthin seem to prevent or lessen the photosensitivity that results from taking chlorophyll (1326). Oral consumption of chlorophyll has been associated with the development of pseudoporphyria in case reports. Two females developed easily traumatized blisters on their hands after consumption of a Swisse Chlorophyll drink (93892). In one case series, four males developed skin blisters and skin erosions after taking oral chlorophyll 100-1200 mg daily for 6.5 months up to 7 years. Resolution of symptoms was delayed for 2-8 months after chlorophyll discontinuation (97933).

(Read more about CHLOROPHYLL)

General ...Orally, GLA seems to be well tolerated.
Most Common Adverse Effects:
Orally: Mild gastrointestinal adverse effects, including belching, bloating, diarrhea, dyspepsia, flatulence, nausea, and vomiting.

Gastrointestinal ...Orally, GLA may cause mild gastrointestinal effects such as dyspepsia, nausea, bloating, vomiting, soft stools, diarrhea, flatulence, and belching (7701,7702,8926,107927).

Hematologic ...Orally, GLA might prolong bleeding time (1979).

(Read more about GAMMA-LINOLENIC ACID (GLA))

General ...Orally or intravenously, iron is generally well tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, gastrointestinal irritation, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about oral or gastric ulcerations.
Intravenously: Case reports have raised concerns about hypophosphatemia and osteomalacia.

Cardiovascular ...There is debate regarding the association between coronary heart disease (CHD) or myocardial infarction (MI) and high iron intake or high body iron stores. Some observational studies have reported that high body iron stores are associated with increased risk of MI and CHD (1492,9542,9544,9545,15175). Some observational studies reported that only high heme iron intake from dietary sources such as red meat are associated with increased risk of MI and CHD (1492,9546,15174,15205,15206,91180). However, the majority of research has found no association between serum iron levels and cardiovascular disease (1097,1099,9543,9547,9548,9549,9550,56469,56683).
There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).
There is also a case of a 56-year-old female, negative for HFE mutation homozygosity, diagnosed with acquired iron overload cardiomyopathy after starting ferrous sulfate 325 mg twice daily 3 years prior for iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy. The patient had no follow-up care over the 3 years and denied any blood transfusions over that time (113906).

Dermatologic ...Cutaneous hemosiderosis, or skin staining, has been reported following intravenous iron infusion in various case reports. Most of these cases are due to extravasation following iron infusion (112605,112611). In one case, extravasation has occurred following iron derisomaltose infusion in a 41-year-old female with chronic kidney disease (112605). Rarely, diffuse cutaneous hermosiderosis has occurred. In one case, a 31-year-old female with excessive sweating developed cutaneous hemosiderosis in the armpits following an intravenous iron polymaltose infusion (112611).

Endocrine ...Population research in females shows that higher ferritin levels are associated with an approximately 1. 5-fold higher odds of developing gestational diabetes. Increased dietary intake of heme-iron, but not non-heme iron, is also associated with an increased risk for gestational diabetes. The effects of iron supplementation could not be determined from the evaluated research (96618). However, in a sub-analysis of a large clinical trial in pregnant adults, daily supplementation with iron 100 mg from 14 weeks gestation until delivery did not affect the frequency or severity of glucose intolerance or gestational weight gain (96619).

Gastrointestinal ...Orally, iron can cause dry mouth, gastrointestinal irritation, heartburn, abdominal pain, constipation, diarrhea, nausea, or vomiting (96621,102864,104680,104684,110179,110185,110188,110189,110192). These adverse effects are uncommon at doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron in adults with normal iron stores (7135). Higher doses can be taken safely in adults with iron deficiency, but gastrointestinal side effects may occur (1095,20118,20119,56698,102864). Taking iron supplements with food seems to reduce gastrointestinal side effects (7135). However, food can also significantly reduce iron absorption. Iron should be taken on an empty stomach, unless it cannot be tolerated.
There are several formulations of iron products such as ferrous sulfate, ferrous gluconate, ferrous fumarate, and others. Manufacturers of some formulations, such as polysaccharide-iron complex products (Niferex-150, etc), claim to be better tolerated than other formulations; however, there is no reliable evidence to support this claim. Gastrointestinal tolerability relates mostly to the elemental iron dose rather than the formulation (17500).
Enteric-coated or controlled-release iron formulations might reduce nausea for some patients, however, these products also have lower absorption rates (17500).
Liquid oral preparations can blacken and stain teeth (20118).
Iron can also cause oral ulcerations and ulcerations of the gastric mucosa (56684,91182,96622,110179). In one case report, an 87-year-old female with Alzheimer disease experienced a mucosal ulceration, possibly due to holding a crushed ferrous sulfate 80 mg tablet in the mouth for too long prior to swallowing (91182). The ulceration was resolved after discontinuing iron supplementation. In another case report, a 76-year old male suffered gastric mucosal injury after taking a ferrous sulfate tablet daily for 4 years (56684). In a third case report, a 14-year-old female developed gastritis involving symptoms of upper digestive hemorrhage, nausea, melena, and stomach pain. The hemorrhage was attributed to supplementation with ferrous sulfate 2 hours after meals for the prior 2 weeks (96622). In one case report, a 43-year old female developed atrophic gastritis with non-bleeding ulcerations five days after starting oral ferrous sulfate 325 mg twice daily (110179).
Intravenously, iron can cause gastrointestinal symptoms sch as nausea (104684,110192).

Hematologic ...Orally, iron supplements have been associated with hemochromatosis. In one case report, a 56-year-old female, negative for HFE mutation homozygosity, was diagnosed with acquired hemochromatosis after starting ferrous sulfate 325 mg twice daily 3 years prior, without follow-up care, for a previous iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy (113906).

Immunologic ...Although there is some clinical research associating iron supplementation with an increased rate of malaria infection (56796,95432), the strongest evidence to date does not support this association, at least for areas where antimalarial treatment is available (95433,96623). In an analysis of 14 trials, iron supplementation was not associated with an increased risk of malaria (96623). In a sub-analysis of 7 preliminary clinical studies, the effect of iron supplementation was dependent upon the access to services for antimalarial treatment. In areas where anemia is common and services are available, iron supplementation is associated with a 9% reduced risk of clinical malaria. In an area where services are unavailable, iron supplementation was associated with a 16% increased risk in malaria incidence (96623). The difference in these findings is likely associated with the use of malaria prevention methods.
A meta-analysis of clinical studies of all patient populations shows that administering IV iron, usually iron sucrose and ferric carboxymaltose, increases the risk of infection by 16% when compared with oral iron or no iron. However, sub-analyses suggest this increased risk is limited to patients with inflammatory bowel disease (IBD) (110186).
Intravenously, iron has rarely resulted in allergic reactions, including anaphylactoid reactions (110185,110192,112606,112607). There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).

Musculoskeletal ...Intravenously, iron administration may trigger hypophosphatemia in some patients (113905). However, parenteral iron rarely results in osteomalacia related to hypophosphatemia (112609). At least 2 cases exist of hypophosphatemic osteomalacia. In one case, a 70-year-old male with a genetic hemorrhagic disorder infused with ferric carboxymaltose developed lower limb pain with hypophosphatemia and diffuse bone demineralization in the feet (112609). In a second case, a 61-year-old male developed femoral neck insufficiency fractures following repeated ferric carboxymaltose transfusions for anemia related to vascular malformation in the bowel (112603). Severe hypophosphatemia requiring intravenous phosphate in the absence of osteomalacia has also occurred following intravenous ferric carboxymaltose (112608,112610).

Oncologic ...There is a debate regarding the association between high levels of iron stores and cancer. Data are conflicting and inconclusive (1098,1099,1100,1102). Epidemiological studies suggest that increased body iron stores may increase the risk of cancer or general mortality (56703).
Occupational exposure to iron may be carcinogenic (56691). Oral exposure to iron may also be carcinogenic. Pooled analyses of population studies suggest that increasing the intake of heme iron increases the risk of colorectal cancer. For example, increasing heme iron intake by 1 mg/day is associated with an 11% increase in risk (56699,91185).

Pulmonary/Respiratory ...Orally, iron has been associated with rare reports of iron pill aspiration. This occurs when all or part of the pill is aspirated into the lungs. Once in the lungs, it can cause a chemical burn of the bronchial mucosa. Dozens of cases of iron pill aspiration have been reported in individuals ranging in age from 22 months to 92 years. Patients presented with cough, dyspnea, wheezing, and hemoptysis. The hemoptysis led to death in 2 patients due to hemorrhage. Long-term complication of fibrosis and bronchial stenosis was reported in a few of the cases. In one case, a 48-year-old female accidentally aspirated a ferrous sulfate tablet and presented to the emergency department with cough, blood-stained sputum, chest pain, dyspnea, and acute distress. Bronchoscopy was performed, parts of the pill were retrieved, and chemical burns and necrotic tissue were observed in the bronchus intermedius mucosa and throughout the middle and lower lobes. Debridement with bronchoalveolar lavage was performed. The patient was transferred to the intensive care unit, placed on mechanical ventilation for 2 days, treated with corticosteroids, and discharged on the fifth day of hospitalization. Four weeks post-discharge the patient had significantly improved but still had some reduction in lung capacity.

Other ...Intravenously, sodium ferric gluconate complex (SFGC) caused drug intolerance reactions in 0. 4% of hemodialysis patients including 2 patients with pruritus and one patient each with anaphylactoid reaction, hypotension, chills, back pain, dyspnea/chest pain, facial flushing, rash and cutaneous symptoms of porphyria (56527).

(Read more about IRON)

General ...Orally or intravenously, potassium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, belching, diarrhea, flatulence, nausea, and vomiting.
Serious Adverse Effects (Rare):
All ROAs: High potassium levels can cause arrhythmia, heart block, hypotension, and mental confusion.

Cardiovascular ...Orally or intravenously, high potassium levels can cause hypotension, cardiac arrhythmias, heart block, or cardiac arrest (15,16,3385,95011,95626,95630).

Gastrointestinal ...Orally or intravenously, high doses of potassium can cause, nausea, vomiting, abdominal pain, diarrhea, and flatulence (95010,95011). Bleeding duodenal ulcers have also been associated with ingestion of slow-release potassium tablets (69625,69672).

Neurologic/CNS ...Orally or intravenously, high potassium levels can cause paresthesia, generalized weakness, flaccid paralysis, listlessness, vertigo, or mental confusion (15,16,3385,95011).

(Read more about POTASSIUM)

General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

(Read more about SODIUM)

General ...Orally and parenterally, superoxide dismutase seems to be well tolerated.
Most Common Adverse Effects:
Parenterally: Pain and injection site reactions.
Serious Adverse Effects (Rare):
Parenterally: Anaphylaxis, possibly related to impurities in parenteral formulations.

Hematologic ...As an injection, superoxide dismutase may cause elevations in triglyceride and direct bilirubin levels. Cases of transient elevations in triglycerides and direct bilirubin have been reported after a single injection of lecithinized recombinant superoxide dismutase (105503).

Immunologic ...As an injection, superoxide dismutase can cause allergic reactions at the injection site in some patients (2235). It can also cause anaphylactic shock, which may be caused by product impurities (11008).

Musculoskeletal ...As an injection, superoxide dismutase can cause pain at the injection site in some patients (2235).

Neurologic/CNS ...Superoxide dismutase may be prepared from bovine liver. Products made from contaminated or diseased organs might present a human health hazard. There is also concern that spleen extracts produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be contaminated with diseased tissue (1825). Thus far, there have been no reports of BSE transfer to humans from contaminated SOD products.

(Read more about SUPEROXIDE DISMUTASE (SOD))

General ...Orally, vitamin A is generally well-tolerated at doses below the tolerable upper intake level (UL).
Serious Adverse Effects (Rare):
Orally: In very high doses, vitamin A can cause pseudotumor cerebri, pain, liver toxicity, coma, and even death.

Dermatologic ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity including dry skin and lips; cracking, scaling, and itchy skin; skin redness and rash; hyperpigmentation; shiny skin, and massive skin peeling (7135,95051). Hypervitaminosis A can cause brittle nails, cheilitis, gingivitis, and hair loss (15,95051). Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause skin redness and generalized peeling of the skin a few days later and may last for several weeks (15).

Gastrointestinal ...There is some evidence that oral vitamin A supplementation might increase the risk of diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with diarrhea in well-nourished children (319). Diarrhea (82326,82389), nausea (7135,100329), abdominal pain (95051), abdominal fullness (100329), and vomiting (7135,82559,95051,109755) have been reported following use of large doses of oral vitamin A. Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause vomiting and diarrhea (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including anorexia, abdominal discomfort, and nausea and vomiting (7135).

Genitourinary ...Hypervitaminosis A can cause reduced menstrual flow (15). Intravaginally, all-trans retinoic acid can cause vaginal discharge, itching, irritation, and burning (9199).

Hematologic ...Hypervitaminosis A can cause spider angiomas, anemia, leukopenia, leukocytosis, and thrombocytopenia (15,95051).

Hepatic ...Since the liver is the main storage site for vitamin A, hypervitaminosis A can cause hepatotoxicity, with elevated liver enzymes such as alanine aminotransferase (ALT, formerly SGPT) and aspartate aminotransferase (AST, formerly SGOT), as well as fibrosis, cirrhosis, hepatomegaly, portal hypertension, and death (6377,7135,95051).

Musculoskeletal ...Vitamin A can increase the risk for osteoporosis and fractures. Observational research has found that chronic, high intake of vitamin A 10,000 IU or more per day is associated with an increased risk of osteoporosis and hip fracture in postmenopausal adults, as well as overall risk of fracture in middle-aged males (7712,7713,9190). A meta-analysis of these and other large observational studies shows that high dietary intake of vitamin A or retinol is associated with a 23% to 29% greater risk of hip fracture when compared with low dietary intake (107294). High serum levels of vitamin A as retinol also increase the risk of fracture in males. Males with high serum retinol levels are seven times more likely to fracture a hip than those with lower serum retinol levels (9190). Vitamin A damage to bone can occur subclinically, without signs or symptoms of hypervitaminosis A. Some researchers are concerned that consumption of vitamin A fortified foods such as margarine and low-fat dairy products in addition to vitamin A or multivitamin supplements might cause excessive serum retinol levels. Older people have higher levels of vitamin A and might be at increased risk for vitamin A-induced osteoporosis.
Vitamin A's effects on bone resorption could lead to hypercalcemia (95051).
Hypervitaminosis can cause slow growth, premature epiphyseal closure, painful hyperostosis of the long bones, general joint pain, osteosclerosis, muscle pain, and calcium loss from the bones (15,95051). One child experienced severe bone pain after taking vitamin A 600,000 IU daily for more than 3 months (95051). Vitamin A was discontinued and symptoms lessened over a period of 2 weeks. The patient made a full recovery 2 months later.

Neurologic/CNS ...Orally, adverse effects from a single large dose of vitamin A are more common in young children than adults (15). Headache, increased cerebrospinal fluid pressure, vertigo, and blurred vision have been reported following an acute oral dose of vitamin A 500,000 IU (7135). In children, approximately 25,000 IU/kg can cause headache, irritability, drowsiness, dizziness, delirium, and coma (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including fatigue, malaise, lethargy, and irritability (7135).
There are reports of bulging of the anterior fontanelle associated with an acute high oral dose of vitamin A in infants (7135,90784,95053,95054). In children, approximately 25,000 IU/kg can cause increased intracranial pressure with bulging fontanelles in infants (15). Also, muscular incoordination has been reported following short-term high doses of vitamin A (7135).
A case of intracranial hypertension involving diffuse headaches and brief loss of vision has been reported secondary to topical use of vitamin A. The patient was using over-the-counter vitamin A preparations twice daily including Avotin 0.05% cream, Retin-A gel 0.01%, and Isotrexin gel containing isotretinoin 0.05% and erythromycin 2%, for treatment of facial acne. Upon exam, the patient was noted to have bilateral optic disc edema. The patient discontinued use of topical vitamin A products. Two months later, the patient reported decreased headaches and an improvement in bilateral optic disc edema was seen (95056).

Ocular/Otic ...In children, oral vitamin A approximately 25,000 IU/kg can cause swelling of the optic disk, bulging eyeballs, and visual disturbances (15). Adverse effects from a single ingestion of a large dose of vitamin A are more common in young children than adults (15).

Oncologic ...There is concern that high intake of vitamin A might increase some forms of cancer. Population research suggests high vitamin A intake might increase the risk of gastric carcinoma (9194).

Psychiatric ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity, which can include symptoms that mimic severe depression or schizophrenic disorder (7135).

Pulmonary/Respiratory ...There is some evidence that oral vitamin A supplementation might increase the risk of pneumonia and diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with pneumonia and diarrhea in well-nourished children (319). In preschool children, high-dose vitamin A also increases the risk of respiratory infection (82288).

Other ...Chronic use of large amounts of vitamin A (>25,000 IU daily for more than 6 years or 100,000 IU daily for more than 6 months) can cause symptoms of vitamin A toxicity including mild fever and excessive sweating (7135). High intakes of vitamin A may result in a failure to gain weight normally in children and weight loss in adults (15).

(Read more about VITAMIN A)

General ...Orally, intramuscularly, and topically, vitamin B12 is generally well-tolerated.
Most Common Adverse Effects:
Intramuscular: Injection site reactions.
Serious Adverse Effects (Rare):
Intramuscularly: Severe hypokalemia has been rarely linked with correction of megaloblastic anemia with vitamin B12.

Cardiovascular ...In human clinical research, an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by daily oral administration after coronary stenting, increased restenosis rates (12150). Hypertension following intravenous administration of hydroxocobalamin has been reported in human research (82870,82864).

Dermatologic ...Orally or intramuscularly, vitamin B12 can cause allergic reactions such as rash, pruritus, erythema, and urticaria. Theoretically, allergic reactions might be caused by the cobalt within the vitamin B12 molecule (82864,90373,90381,103974). In one case report, oral methylcobalamin resulted in contact dermatitis in a 59-year-old Japanese female with a cobalt allergy (103974). In another case report, a 69-year-old female developed a symmetrical erythematous-squamous rash for 5 years after oral vitamin B12 supplementation for 10 years. A patch test confirmed that the systemic allergic dermatitis was due to vitamin B12 supplementation, which resolved 3 months after discontinuation (114578).
Vitamin B12 (intramuscular or oral) has also been associated with at least 19 cases of acneiform eruptions which resolved upon discontinuation of vitamin B12 (90365,90369,90388). High-dose vitamin B12 (20 mcg daily) and vitamin B6 (80 mg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may last up to four months after the supplement is stopped and can be treated with systemic corticosteroids and topical therapy (10998,82870,82871).

Gastrointestinal ...Intravenously, vitamin B12 (hydroxocobalamin) 2. 5-10 grams can cause nausea and dysphagia (82864).

Genitourinary ...Intravenously, vitamin B12 (hydroxocobalamin) 5-15 grams has been associated with chromaturia in clinical research (82870,82871,112282,112264).

Hematologic ...According to case report data, the correction of megaloblastic anemia with vitamin B12 may result in fatal hypokalemia (82914).

Musculoskeletal ...According to case report data, correction of megaloblastic anemia with vitamin B12 has precipitated gout in susceptible individuals (82879).

Neurologic/CNS ...Treatment with vitamin B12 has been rarely associated with involuntary movements in infants with vitamin B12 deficiency (90370,90385,90397). In some cases these adverse reactions were misdiagnosed as seizures or infantile tremor syndrome (90370,90385). These adverse reactions presented 2-5 days after treatment with vitamin B12 and resolved once vitamin B12 was discontinued (90370,90385,90397).

Oncologic ...Although some epidemiological research disagrees (9454), most research has found that elevated plasma levels of vitamin B12 are associated with an increased risk of various types of cancer, including lung and prostate cancers and solid tumors (50411,102383,107743). One study found, when compared with blood levels of vitamin B12 less than 1000 ng/mL, plasma vitamin B12 levels of at least 1000 ng/mL was strongly associated with the occurrence of solid cancer (107743). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of cancer. It is possible that having cancer increases the risk of vitamin B12 elevation. However, one observational study has found that the highest quintile of dietary intake of vitamin B12 is associated with a 75% increased incidence of developing esophageal cancer when compared with the lowest quintile in never drinkers, but not drinkers (107147).

Renal ...There is a case report of oxalate nephropathy in a 54-year-old male which was determined to be related to the use of intravenous hydroxocobalamin as treatment for cyanide poisoning. Intermittent hemodialysis was started 5 days after admission, along with a low-oxalate diet, oral calcium acetate, and pyridoxine 5 mg/kg daily (107148). A review of the use of intravenous hydroxocobalamin for suspected cyanide poisoning in 21 intensive care units in France between 2011 and 2017 resulted in a 60% increased odds of acute kidney injury and a 77% increased odds of severe acute kidney injury in the first week. However, biopsies were not conducted and a direct link with use of hydroxocobalamin could not be made (107139).

Other ...Several studies have found that higher vitamin B12 levels may be associated with increased mortality or decreased survival rates in hospitalized elderly patients (82889,82812,82857,82895). Human research has also found a positive correlation between vitamin B12 status and all-cause mortality in Pima Indians with diabetes (82863).

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General ...Orally, vitamin K is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, nausea, and stomach upset.
Serious Adverse Effects (Rare):
Intravenously: There have been rare cases of anaphylaxis and hyperbilirubinemia (in infants).

Dermatologic ...Orally, intake of vitamin K2 (menaquinone) along with calcium and vitamin D3 can cause an increased incidence of skin and skin appendage lesions compared to taking calcium and vitamin D3 alone. However, the risk of this adverse event is low, with 0.5 incidences per 100 patient-years occurring for patients treated with vitamin K, calcium, and vitamin D3 and 0.1 incidences per 100 patient-years occurring for patients treated with calcium and vitamin D3 alone (85467).

Gastrointestinal ...Orally, vitamin K can cause mild to moderate gastrointestinal side effects (91450,91451). The most common effects include nausea, abdominal pain, and diarrhea (91450,91451).

Hepatic ...Orally, vitamin K3 (menadione) has been linked to hepatotoxicity. Vitamin K3 is no longer used therapeutically in North America because it has been linked to hepatic toxicity and jaundice in animal research (7135).

Other ...Intravenously, vitamin K can cause reactions that resemble hypersensitivity or anaphylaxis (85389). These reactions are rare. It is unclear whether the adverse effect is caused by the drug or a component of the solution. There have been very rare cases of hyperbilirubinemia, particularly in premature neonates, following large doses of vitamin K (15). One clinical study in premature infants shows that intramuscular administration of vitamin K 1.0 mg increases bilirubin levels and the duration of phototherapy when compared with vitamin K 0.3 mg and 0.5 mg. However, the clinical relevance of these findings is unclear, as no differences in bilirubin-induced neurologic dysfunction were reported (112100).

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General ...Orally, dietary and supplemental zeaxanthin are generally well tolerated. No adverse effects have been reported in clinical research.

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