5-HTP SeroTonic II powder by Life Enhancement Products, Inc.

POSSIBLY EFFECTIVE

• Depression. Oral 5-HTP seems to improve symptoms of depression. Details: A meta-analysis of preliminary clinical research shows that taking 5-HTP for up to 8 weeks might improve symptoms of depression in some patients. The pooled remission rate across 13 studies was 65%, and the pooled effect size across 7 studies assessing the change in depressive symptom scores from baseline was large (102854). In most studies, the dose of 5-HTP administered ranged from 150-800 mg daily, although doses as high as 3 grams daily have been used (903,30000,30125,30138,102854). Some research has compared 5-HTP to conventional antidepressants. In one clinical trial of adults experiencing a first episode of depression, taking 5-HTP orally, titrated up to a daily dose of 400 mg, decreased depression symptoms similarly to fluoxetine titrated up to 40 mg daily (30112). Limited research also suggests that taking 5-HTP 300-800 mg daily seems to work similarly to fluvoxamine 50 mg (2203) or imipramine 150 mg daily (30125). Adding 5-HTP 300 mg orally daily to clomipramine 50 mg daily for 28 days has also been shown to reduce depressive symptoms when compared with clomipramine alone (6245).

POSSIBLY INEFFECTIVE

• Down syndrome. Oral 5-HTP does not seem to improve muscle tone or cognitive skills in patients with this condition. Details: Although early reports suggested that 5-HTP might improve muscle tone and activity levels in infants with Down syndrome (88172), other research has shown no benefit. One small clinical study suggests that taking 5-HTP 0.5-5 mg/kg daily orally from early infancy until 3-4 years of age does not improve muscle tone or developmental ability scores in children with Down syndrome when compared with a control group (88173). Also, a prospective, double-blind study shows that taking 5-HTP 1-2 mg/kg daily orally, alone or with pyridoxine 5-10 mg/kg daily orally, beginning at birth and continuing until 3 years of age, does not improve muscle tone or development of cognitive, social, or language skills when compared with placebo (30153).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a food supplement containing 5-HTP 5 mg, phenylalanine 300 mg, and glutamine 150 mg daily for 40 days during alcohol detoxification therapy reduces withdrawal symptoms when compared with alcohol detoxification therapy alone (30100). However, taking a combination of 5-HTP 25-100 mg with carbidopa 25 mg four times daily for one year does not seem to improve alcohol abstinence rates when compared with placebo (30007). The effect of 5-HTP alone is unclear.
• Alzheimer disease. Although there has been interest in using oral 5-HTP for Alzheimer disease, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Anxiety. It is unclear if oral 5-HTP is beneficial in patients with anxiety disorders. Details: A small clinical study in people with anxiety disorders shows that taking 5-HTP 25-150 mg daily with carbidopa 150 mg daily for 8 weeks reduces anxiety when compared with baseline, but not when compared with clomipramine 25-150 mg daily (30124).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral 5-HTP for ADHD, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Cerebellar ataxia. It is unclear if oral 5-HTP reduces cerebellar ataxia symptoms. Details: One small clinical trial in people with cerebellar ataxia of various etiologies shows taking 5-HTP orally 10 mg/kg daily for 4 months improve quantitative ataxia scores when compared with placebo. Further improvement was noted in subjects continuing treatment for another 8 months (916). However, in a subsequent trial in this population, taking 5-HTP orally 1 gram daily for 10 months did not improve symptom scores when compared with placebo (30164). Also, a small clinical study in people with Friedreich's ataxia shows that taking 5-HTP 200-300 mg daily for 1 month, then 600-900 mg daily for 5 months (depending on body weight), does not improve symptoms when compared with placebo (30165).
• Fibromyalgia. Small clinical studies suggest that oral 5-HTP may improve symptoms of primary fibromyalgia syndrome. Details: Small clinical studies in people with primary fibromyalgia syndrome suggest that taking 5-HTP 100 mg orally three times daily for 30-90 days might improve pain, tenderness, sleep, anxiety, fatigue, and morning stiffness when compared with baseline or placebo (913,10286).
• Inflammatory bowel disease (IBD). It is unclear if oral 5-HTP is beneficial for IBD. Details: Preliminary clinical research in adults with stable IBD and fatigue shows that taking a specific 5-HTP (Levotonine, Panpharma) 100 mg orally twice daily for 8 weeks does not improve fatigue scores when compared with placebo. However, the validity of this study is limited by high patient drop-out (111311).
• Menopausal symptoms. It is unclear if oral 5-HTP is beneficial for symptoms of menopause. Details: A small clinical study in postmenopausal patients shows that taking 5-HTP orally 50 mg three times daily for 4 weeks does not reduce hot flash frequency when compared with placebo (30061).
• Migraine headache. It is unclear if oral 5-HTP reduces frequency of migraines. Details: Preliminary clinical research shows that taking 5-HTP 600 mg daily decreases migraine attack frequency similarly to methysergide 3 mg daily (30129). However, other small clinical studies show that taking 5-HTP 400 mg daily does not reduce the frequency or severity of migraine attacks when compared with placebo (30130,30184). Also, in children 6-12 years of age, one very small clinical study shows that taking 5-HTP 5 mg/kg daily in 3 divided doses for 12 weeks does not reduce the frequency or severity of migraine attacks when compared with placebo (30128).
• Obesity. It is unclear if oral 5-HTP is beneficial in for weight loss. Details: Some very small clinical studies show that taking 5-HTP orally, 300 mg three times daily 30 minutes before meals for 2-12 weeks, improves early satiety and decreases daily caloric intake in females with obesity when compared with placebo (914,30018). 5-HTP was also associated with a mean weight loss of 1.7 kg over 6 weeks when caloric intake was not restricted, and a mean weight loss of 3.3 kg over 6 weeks when caloric intake was restricted to about 1200 calories daily (914,30114). In moderately overweight adults with type 2 diabetes, taking 5-HTP 250 mg three times daily 30 minutes before meals for 2 weeks reduces caloric intake by about 22% and decreases body weight by about 2 kg when compared to baseline (30175).
• Obsessive-compulsive disorder (OCD). It is unclear if oral 5-HTP is beneficial in patients with OCD. Details: A small clinical study in patients with moderate to severe OCD shows that adding 5-HTP 200 mg orally daily to fluoxetine, titrated up to 60 mg daily, for 12 weeks reduces symptom severity when compared with placebo and fluoxetine. A complete response, defined as greater than or equal to 35% improvement in overall Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, was seen in 54% of those taking 5-HTP at week 12, compared with only 12% of those taking placebo (104250). These results were not observed until week 12, which indicates that a longer treatment period may be needed to see the full effects of the intervention.
• Opioid withdrawal. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese males undergoing detoxification for heroin addiction shows that taking 5-HTP 200 mg orally daily for 6 days, in combination with tyrosine, phosphatidylcholine, and L-glutamine, might reduce insomnia and withdrawal symptoms and improve mood when compared with a control group (88178).
• Panic disorder. It is unclear if intravenous 5-HTP is beneficial for reducing anxiety in panic disorder. Details: A small clinical trial in females with panic disorders shows that receiving an intravenous (IV) infusion of 5-HTP, 60 mg over 30 minutes after premedication with carbidopa 100 mg orally, does not appear to reduce anxiety when compared with control (30093).
• Parkinson disease. It is unclear if oral 5-HTP is beneficial for improving Parkinson disease symptoms. Details: Two preliminary clinical trials show that taking 5-HTP 50 mg daily for 1 month seems to improve levodopa-induced dyskinesia and symptoms of depression, but not motor functioning or apathy, when compared with placebo in patients with Parkinson disease (102853,104251). Both studies used a crossover design to correct for the small sample size, but may still have been inadequately powered to detect small changes in these outcomes. However, in another study, taking larger doses of 5-HTP, 275-1500 mg orally daily along with carbidopa 150-1000 mg daily for up to 38 days, worsened rigidity, bradykinesia, and functional disability (30140). Other research has evaluated 5-HTP in patients with Parkinson disease and REM sleep behavior disorder (RBD). A small crossover study in these patients shows taking oral 5-HTP 50 mg daily for 4 weeks does not improve the percentage of REM sleep without atonia or the frequency of RBD events when compared with baseline or placebo. Patients taking 5-HTP report modest improvements in part II (motor function; e.g. swallowing, walking, and dressing) of the Unified Parkinson Disease Rating Scale (UPDRS), but not other parts of the UPDRS, when compared with placebo (107793). This study may have been inadequately powered to detect a difference between groups.
• Premenstrual syndrome (PMS). Although there is interest in using oral 5-HTP for PMS, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Seizures. Although there is interest in using oral 5-HTP for seizures, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Tension headache. It is unclear if oral 5-HTP reduces tension headache severity. Details: A small clinical study in adults with a history of chronic tension headaches suggests that taking 5-HTP 100 mg three times daily for 8 weeks does not reduce pain intensity or the number of days with headache when compared with placebo (2204).
• Tinnitus. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Research has evaluated a specific capsule formulation (Tinnitan Duo; Laboratorios Salvat) containing 5-HTP, ginkgo extract, magnesium, melatonin, pantothenic acid, vitamin B6, and zinc at undeclared doses. A small clinical trial in patients with subjective tinnitus shows taking this product as one capsule twice daily for 3 months improves Tinnitus Handicap Inventory (THI) total score and THI emotional subscale score at 3 months when compared with baseline. Patients also report improvement in tinnitus-related distress (107792). The validity of this study is limited by the lack of randomization and placebo-control; additionally, it is unclear if any effects are due to 5-HTP, other ingredients, or the combination. More evidence is needed to rate 5-HTP for these uses.

(Read more about 5-HTP)

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)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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LIKELY EFFECTIVE

• Dyslipidemia. Niacin prescription products, in doses of 500 mg or greater, are FDA-approved for primary hyperlipidemia and mixed dyslipidemia. Niacin dietary supplements are generally available in lower doses and have not been shown to improve lipid levels. Details: Prescription niacin is not routinely recommended as second-line therapy for patients who primarily need to decrease low-density lipoprotein (LDL) cholesterol. This is due to results from clinical trials showing no effect on cardiovascular related events or mortality (93346,93354,96208,96211,97308,97477,97336). However, niacin might be considered for patients with mixed hyperlipidemia or patients who need to increase high-density lipoprotein (HDL) cholesterol and lower triglycerides. Niacin might also be effective for isolated hypoalphalipoproteinemia (4817). The most pronounced increases in HDL and decreases in triglycerides occur at 1-1.5 grams daily, and the greatest LDL reduction occurs at 2-3 grams daily. Niacin reduces LDL cholesterol by up to 25%, compared with up to a 55% reduction with statins. High-dose niacin can also decrease triglycerides by 20% to 50%, increase HDL by 13% to 35%, decrease apolipoprotein B levels by 2% to 20%, and decrease lipoprotein(a) levels by 23% (4818,4886,4887,4888,4889,4890,12033,25567,93347,96213). The effects of higher dose extended-release niacin on LDL cholesterol and triglycerides appear to be greater in females than males (25565). Experts recommend maximizing statins first because they have the best evidence for improving cardiovascular outcomes (97477,97336,97337). However, if patients cannot reach their LDL goal with a statin alone or if they cannot tolerate a statin, niacin might be combined with other cholesterol-lowering drugs when diet and single-drug therapy are not adequately effective (8545,25566,93351,94191,97337). Adding low-dose niacin, 50 mg daily, to statin therapy has no additional benefit on lipid levels (8546). Population research in adults without dyslipidemia has also found that higher dietary intake of niacin for 3-10 years is associated with a 29% lower risk of developing dyslipidemia when compared with low dietary niacin intake (110493).
• Pellagra. Oral niacin is FDA-approved for the prevention and treatment of pellagra. Details: Population research has found that low consumption of niacin is associated with an increased risk of developing pellagra (25903). Taking niacin 500-1000 mg daily can resolve symptoms of pellagra within a week of treatment initiation (25904). However, niacinamide is sometimes preferred for this indication because it lacks the vasodilating effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• HIV/AIDS-related dyslipidemia. Oral niacin seems to improve lipid levels in patients with dyslipidemia due to HIV/AIDs. Details: Small clinical trials in HIV patients with dyslipidemia associated with antiretroviral therapy shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated up to 2 grams daily for 14-48 weeks improves total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels when compared to baseline (25570,25902). Other preliminary clinical research in this population shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated to 2 grams daily for up to 2 years improves HDL cholesterol levels, but not total cholesterol or triglyceride levels, when compared with no treatment (25569).
• Metabolic syndrome. Oral niacin seems to improve lipid levels in patients with metabolic syndrome. Details: Clinical research shows that taking niacin (Niaspan, Abbott Laboratories) 2 grams daily orally for 16 weeks reduces triglyceride levels by 39 mg/dL and increases high-density lipoprotein (HDL) cholesterol by 5 mg/dL when compared to baseline in patients with metabolic syndrome. These improvements are significant when compared with placebo and are further increased when niacin is taken along with prescription omega-3 ethyl esters (Lovaza, GlaxoSmithKline Pharmaceuticals) 4 grams daily orally (93353). However, niacin does not seem to improve postprandial glucose levels in patients with metabolic syndrome (97333).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral niacin does not seem to reduce cardiovascular-related events in patients with or without CVD. Details: Overall, niacin is not recommended for primary or secondary prevention of CVD. Most clinical trials and meta-analyses conducted prior to 2011 showed a reduction in cardiovascular-related events, cardiovascular-related mortality, and all-cause mortality in patients taking niacin alone or in combination with a statin or clofibrate for primary or secondary prevention of CVD (4847,7388,25095,25911,25912,93349). However, recent meta-analyses of these studies and additional moderate-to-high quality research conducted in over 39,000 patients show no effect of niacin on cardiovascular-related events, cardiovascular-related mortality, or overall mortality (93346,93354,96208,96211,97308). Additionally, one meta-analysis shows that patients taking niacin are twice as likely to report side effects when compared with placebo (96211). Furthermore, an analysis of blood from adults at high cardiovascular risk suggests that higher levels of circulating niacin terminal metabolites are associated with greater risk of major adverse cardiovascular events independent of traditional risk factors (113554).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral niacin is beneficial for reducing Alzheimer disease risk. Details: Observational research has found that consuming higher amounts of niacin (17-45 mg daily) from food and supplements is associated with a slower cognitive decline and a lower risk of developing Alzheimer disease when compared with people who consume less niacin (14 mg daily) (12077). It is not known if the risk of Alzheimer disease is reduced by taking a stand-alone niacin supplement.
• Atherosclerosis. It is unclear if oral niacin prevents atherosclerosis progression. Details: Preliminary clinical studies show that taking niacin orally, in combination with colestipol for up to 2 years, might modestly reduce progression of atherosclerosis as measured by coronary lesions and carotid arterial intima-media thickness in high-risk males with existing coronary atherosclerosis (25906,25909,25910). However, niacin does not seem to be better than statins. One clinical study in adults with atherosclerosis and peripheral arterial disease shows that taking extended-release niacin 1500 mg, simvastatin 40 mg, and ezetimibe 10 mg daily for 2 years does not reduce atherosclerosis of the superficial femoral artery when compared with simvastatin alone (96208). Niacin has also not been shown to prevent cardiovascular events or mortality (93346,93354,96208,96211,97308).
• Athletic performance. It is unclear if oral niacin improves athletic performance. Details: Preliminary clinical research in untrained adult males shows that taking niacin 1000 mg orally once before a cycling test does not improve power, respiratory exchange ratio, or time to exhaustion when compared with placebo. In addition, these measures were significantly worse when compared with taking caffeine 5 mg/kg orally as a single dose (107942). Clinical research in untrained males also shows that taking a supplement containing niacin 40 mg, caffeine 400 mg, capsicum extract 66.7 mg, and black pepper extract 10 mg prior to exercising does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral niacin for ADHD, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Cancer. It is unclear if dietary niacin is beneficial for cancer. Details: Population research in adults with cancer has found that high dietary niacin intake is associated with 49% and 27% lower risk of cancer-related mortality and all-cause mortality when compared with low dietary niacin intake. The same study also found that taking niacin supplements is associated with a lower risk of cancer-related mortality, but not all-cause mortality when compared with not taking niacin supplements (110496).
• Cataracts. It is unclear if oral niacin is beneficial for preventing cataracts. Details: Population research has found that high dietary intake of niacin is associated with a reduced risk of nuclear cataracts (6378). However, there is no reliable evidence that niacin supplements reduce the risk of cataracts.
• Cholera. It is unclear if oral niacin is beneficial for cholera. Details: One small clinical study in adults with severe cholera shows that taking 1-2 grams niacin orally reduces fluid loss in the stool by 31% to 47% in the first 16 hours when compared with control. The 2 gram dose seemed to result in a greater reduction in fluid loss than the 1 gram dose (4868).
• Erectile dysfunction (ED). It is unclear if oral niacin is beneficial in patients with ED and dyslipidemia. Details: Clinical research in patients with erectile dysfunction and dyslipidemia shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated to 1.5 grams nightly for a total of 12 weeks significantly improves penetration frequency and the maintenance of an erection after penetration when compared to baseline (25913). The validity of this finding is limited by the lack of a comparator group.
• Glaucoma. It is unclear if oral niacin is beneficial for preventing or treating glaucoma. Details: Population research has found that higher dietary intake of niacin is associated with a lower odds of having glaucoma. However, this association was not consistently present when adjusting for confounders. The effects of niacin supplementation on glaucoma have not been evaluated (107942).
• Hyperphosphatemia. It is unclear if oral niacin is beneficial for preventing high levels of phosphorus in the blood. Details: Preliminary clinical research in patients on maintenance dialysis who are no longer using phosphate binders shows that taking niacin 375-750 mg daily for 8 weeks reduces serum phosphorus levels by 2.1 mg/dL, increases calcium levels by 0.4 mg/dL, and decreases serum alkaline phosphatase when compared with baseline (25914). However, clinical research in hemodialysis patients with inadequate phosphate control despite using standard phosphate-binding therapy shows that taking niacin at the maximum tolerated dose, up to 1000 mg daily, for 12 weeks, does not decrease serum phosphate levels when compared with placebo (93341). It is possible that this latter study was too small to observe between-group differences in changes in serum phosphate levels.
• Hypertension. It is unclear if dietary niacin is beneficial for preventing hypertension. Details: Observational research in Chinese adults found a J-shaped association between dietary niacin intake and development of hypertension, with the lowest risk occurring in those with a daily dietary niacin intake of 14.3-16.7 mg (104934).
• Meniere disease. Although there is interest in using oral niacin for Meniere disease, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Migraine headache. It is unclear if dietary niacin is beneficial for preventing migraine headaches. Details: Population research in adults has found that high dietary intake of niacin is associated with a 28% lower likelihood of having migraine headaches when compared with low dietary intake of niacin (110495). However, the effect of niacin supplementation on migraines has not been studied.
• Motion sickness. Although there is interest in using oral niacin for motion sickness, there is insufficient reliable information about the clinical effects of niacin for this purpose.
• Parkinson disease. It is unclear if oral niacin is beneficial for improving Parkinson disease symptoms. Details: Low-quality clinical research in adults with Parkinson disease shows that taking slow-release niacin 250 mg orally daily for 12 months improves Parkinson disease motor scores and fatigue scores by 17% and 26%, respectively, when compared with baseline (107944). However, higher quality clinical research shows that taking niacin 250 mg orally daily for 6 months does not improve Parkinson disease motor scores when compared with placebo (107943).
• Retinal vein occlusion. It is unclear if oral niacin is beneficial for improving retinal vein occlusion symptoms. Details: A small case series in patients with chronic retinal vein occlusion shows that taking niacin titrated to 500 mg three times daily for 1 year is associated with reduced central macular thickness and improved visual acuity in over 50% of patients when compared with a control group. The addition of prednisolone eye drops does not alter the outcomes of those taking niacin (96212). The validity of this finding is limited due to the retrospective nature of this study.
• Sickle cell disease. It is unclear if oral niacin is beneficial for improving lipid levels in patients with sickle cell disease. Details: A small clinical study in patients with sickle cell disease shows that taking extended-release niacin titrated to 1.5 grams daily for 12 weeks does not improve vascular function or increase high-density lipoprotein (HDL) or apolipoprotein A-I cholesterol levels when compared with placebo (96209).
• Schizophrenia. Although there is interest in using oral niacin for schizophrenia, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Vertigo. Although there is interest in using oral niacin for vertigo, there is insufficient reliable information about the clinical effects of niacin for this condition. More evidence is needed to rate niacin for these uses.

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LIKELY EFFECTIVE

• Depression. Specific formulations of oral St. John's wort are effective for mild or moderate major depressive disorder. St. John's wort may also cause fewer side effects than certain conventional antidepressants. Details: Moderate quality meta-analyses and individual clinical trials show that St. John's wort extracts are more effective than placebo (76057,76140,76143,76271,89669,104036), and likely as effective as low-dose tricyclic antidepressants (6434,76143), tetracyclic antidepressants (76174), and selective serotonin reuptake inhibitors (SSRIs) (76143,76144,96551), including fluoxetine (Prozac) (3550,4897), sertraline (Zoloft) (6400), and paroxetine (Paxil) (13021) for treating depression. However, some of these studies have been critiqued for using lower doses of SSRIs than typical dosing in comparative studies (104037). St. John's wort also seems to have better tolerability and less gastrointestinal, neurologic, and sexual adverse effects than certain conventional antidepressants (104036). Taking St. John's wort extract improves mood and decreases anxiety, somatic symptoms, and insomnia related to mild to severe major depression (3550,4897,6400,13021,13157,76143,104036). Short-term response rates to St. John's wort appear to be between 65% and 100%; however, long-term, the response rates appear to range from 60% to 69% (13156). Most studies have evaluated St. John's wort in adults; however, there is also some evidence that taking St. John's wort 300-1800 mg daily might be effective for depression in children less than 17 years old (4538,10844,76110). There is some concern that St. John's wort may not be effective for severe major depressive disorder necessitating psychiatric care. Two studies in psychiatric care settings showed no benefit of using St. John's wort (5096,10843). Clinical guidelines from the American College of Physicians state that St. John's wort may be as effective and better tolerated than conventional antidepressants for mild to moderate depression (104037). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that St. John's wort is recommended as monotherapy for mild to moderate forms of major depressive disorder (110318). There is no guarantee that people living in the United States can obtain St. John's wort preparations of similar potency and effectiveness as those used in clinical research (104037). The CANMAT Taskforce recommendation is for specific formulations of 3:1 to 7:1 extracts, standardized to approximately 0.2-0.3% hypericin and/or 5-6% hyperforin, in single or divided doses of 600 mg to 1800 mg daily (110318). Most studies have used St. John's wort extracts standardized to hypericin content, usually 0.3%, but extracts standardized to 1% to 4% hyperforin also seem to be effective. Extracts containing hypericin 0.2% to 0.3%, including LI 160 (Lichtwer Pharma) and Remotiv (Zeller) have most often been studied in doses of 300 mg three times daily for up to 6 weeks, or 250 mg twice daily for up to 6 weeks. Extracts containing 3% to 6% hyperforin, including Movana (Pharmaton) and WS 5570 (Schwabe Pharmaceuticals) have most often been studied in doses of 300-600 mg three times daily for 6-26 weeks (761,4538,4630,104036).

POSSIBLY EFFECTIVE

• Menopausal symptoms. Oral St. John's wort seems to be beneficial for patients with menopausal symptoms. Details: Most clinical research shows that taking St. John's wort as a single supplement can reduce menopausal symptoms. A meta-analysis of small clinical trials in menopausal adults shows that taking St. John's wort up to 900 mg daily for up to 16 weeks, alone or in combination with other herbs, reduces frequency and severity of hot flashes when compared with placebo (95510). Some research also suggests that St. John's wort might improve quality of life and psychological symptoms when compared with placebo (76043,76146,89666,95510). St. John's wort has also shown benefit when used in combination with black cohosh (Remifemin Plus, Schaper & Brummer GmbH & Co. KG; Gynoplus, Jin-Yang Pharm; Feramin Q, Dongkook Pharm) (15037,15893,35853,95510), and with Vitex agnus-castus (41482).
• Somatic symptom disorder. Oral St. John's wort seems to be beneficial for patients with somatoform disorder. Details: Two clinical trials in patients with somatoform disorders shows that taking a specific standardized St. John's wort extract (LI 160, Lichtwer Pharma) 600 mg daily seems to reduce symptoms of somatization disorder by 45% after 6 weeks of treatment when compared with placebo (9476,76089).

POSSIBLY INEFFECTIVE

• Burning mouth syndrome. Oral St. John's wort does not appear to reduce pain from burning mouth syndrome. Details: A small clinical study in patients with burning mouth syndrome shows that taking St. John's wort 300 mg (standardized to hypericin 0.3% and hyperforin 3.0%) three times daily for 12 weeks does not alleviate pain when compared to placebo (76133).
• Hepatitis C. St. John's wort contains hypericin. Synthetic hypericin has been studied and shown to be ineffective as an oral drug for hepatitis C. Details: A small clinical study in patients with chronic hepatitis C virus (HCV) infection shows that giving synthetic hypericin 0.05-0.1 mg/kg orally daily does not seem to be effective for reducing viral load and may be unsafe due to the risk for phototoxic reactions (4631).
• HIV/AIDS. St. John's wort contains hypericin. Synthetic hypericin has been studied and shown to be ineffective as an oral and intravenous drug for HIV. Details: A small clinical study in adults infected with HIV shows that giving synthetic hypericin 0.25-0.5 mg/kg, either intravenously 2-3 times weekly or orally every day, as an antiretroviral agent does not seem to be effective and may be unsafe due to the risk for phototoxic reactions, which occurred in about 50% of patients (206).
• Irritable bowel syndrome (IBS). Oral St. John's wort does not seem to improve symptoms in patients with IBS. Details: A small clinical study shows that taking a specific St. John's wort extract (St. John's Wort Extract Extra Strength, Enzymatic Therapy) 450 mg twice daily is no more effective than placebo for reducing symptoms of IBS after 12 weeks of treatment. In fact, patients taking placebo had improved symptoms compared to St. John's wort (16893).
• Peripheral neuropathy. Oral St. John's wort does not seem to relieve pain in patients with peripheral neuropathy. Details: A small clinical study in diabetic and non-diabetic patients with polyneuropathy shows that taking St. John's wort containing 0.9 mg hypericin orally daily for 5 weeks does not seem to relieve most measures of pain when compared with placebo (7047).
• Social anxiety disorder. Oral St. John's wort does not seem to be beneficial for patients with social anxiety disorder. Details: A small clinical study shows that taking St. John's wort 600-1800 mg daily for 12 weeks does not improve social phobia or social anxiety disorder when compared with placebo (76101).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical St. John's wort is beneficial for acne. Details: A small clinical trial in patients with mild to moderate acne treated with photodynamic therapy shows that topical application with 1.5 mL of a St. John's wort 0.5% extract (DR-Light complex; Genicos Co., Ltd, Cheongju, Korea) for 10 minutes for four weekly sessions reduces acne lesion count as effectively as treatment with indole-3-acetic acid (110327).
• Anxiety. Although there is interest in using oral St. John's wort for anxiety, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral St. John's wort is beneficial for improving symptoms in children with ADHD. Details: A small clinical study in children ages 6-17 years with ADHD shows that taking a specific St. John's wort extract standardized to 0.3% hypericin, 300 mg three times daily for 8 weeks, does not improve symptoms such as inattentiveness when compared with placebo (17986).
• Brain tumor. St. John's wort contains hypericin. Synthetic hypericin has been studied as an oral drug for malignant brain tumors, with unclear benefit. Details: A small clinical study in patients with malignant gliomas shows that taking synthetic hypericin 0.05-0.5 mg/kg daily orally for up to 3 months was associated with stable disease in 7 of 42 patients and partial response in 2 of 42 patients (76160). However, it is unclear how these outcomes would compare with historical controls or a prospectively enrolled control group.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral St. John's wort for CFS, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Crigler-Najjar syndrome type 2. It is unclear if oral St. John's wort is beneficial for patients with this condition. Details: Crigler-Najjar syndrome type 2 is a rare genetic disorder characterized by the accumulation of bilirubin in the body. One case report of a 24 year-old female with this condition shows that taking St. John's wort (Jarsin LI160, Vifor SA) 300 mg three times daily by mouth for two 8-week periods 18 months apart decreases bilirubin levels by 34%, reduces jaundice, and improves fatigue (95509).
• Fibromyalgia. Although there is interest in using oral St. John's wort for fibromyalgia, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Genital herpes. Topical St. John's wort has only been evaluated in combination with copper sulfate; its effect when used alone is unclear. Details: A clinical study in patients with herpes simplex virus 1 (HSV-1) or 2 (HSV-2) shows that applying a single dose of a specific topical product (Dynamiclear, Global Herbal Supplies Pty Ltd), which contains St. John's wort 0.1% and copper sulfate pentahydrate 5%, helps reduce symptoms such as stinging, burning, erythema, and pain. In fact, the combination product appears to reduce erythema, itching, and pain more than applying acyclovir 5% (Zovirax, Glaxo Smith Kline) five times daily for 7 days (76164).
• Herpes labialis (cold sores). Topical St. John's wort has only been evaluated in combination with copper sulfate; its effect when used alone is unclear. Details: A clinical study in patients with herpes simplex virus 1 (HSV-1) or 2 (HSV-2) shows that applying a single dose of a specific topical product (Dynamiclear, Global Herbal Supplies Pty Ltd), which contains St. John's wort 0.1% and copper sulfate pentahydrate 5%, helps reduce symptoms such as stinging, burning, erythema, and pain. In fact, the combination product appears to reduce erythema, itching, and pain more than applying acyclovir 5% (Zovirax, Glaxo Smith Kline) five times daily for 7 days (76164).
• Mastitis. It is unclear if topical St. John's wort is beneficial for granulomatous mastitis. Details: In patients with idiopathic granulomatous mastitis, persistent or intractable skin lesions may remain after treatment with oral steroids and antibiotics. Preliminary clinical research shows that topical application with St. John's wort oil for two minutes twice daily for 6 weeks reduces the severity of skin lesions in patients with persistent lesions following treatment. After treatment, the success rate, based on clearance or remaining mild symptoms, was 94.1% (110326).
• Memory. It is unclear if oral St. John's wort is beneficial for improving memory in healthy people. Details: A small clinical study in healthy adults shows that taking a specific supplement (Remotiv, Zeller) containing St. John's wort 250 mg, standardized to 0.5 mg of hypericin, by mouth as a single dose, seems to improve short-term memory when compared with baseline. In contrast, the same product containing a higher dose of St. John's wort, 500 mg, seems to worsen memory when compared with baseline (100245). The validity of this finding is limited by the lack of a control group.
• Migraine headache. It is unclear if oral St. John's wort is beneficial for reducing migraine headache. Details: A small low quality clinical study in patients with migraines suggests that adding a specific St. John's wort product (Perforan, Godaru) 160 mg three times daily to sodium valproate 400 mg daily might modestly improve migraine intensity, but not migraine frequency, when compared with sodium valproate alone (89667).
• Obsessive-compulsive disorder (OCD). It is unclear if oral St. John's wort is beneficial for reducing OCD symptoms. Details: There is conflicting evidence about the effectiveness of St. John's wort for OCD. A small open-label study suggests that taking a specific St. John's wort extract standardized to 0.3% hypericin (Alterra, Upsher-Smith Laboratories) 450 mg twice daily for 12 weeks might improve symptoms of OCD when compared to baseline (5075). The validity of this finding is limited by the lack of a control group. A small, higher quality clinical study using a different St. John's wort extract (LI 160, Lichtwer Pharma AG) 600-1800 mg daily for 12 weeks shows that it does not improve symptoms of OCD when compared with placebo (14417). However, this study excluded patients with concomitant depression, so it's unclear if St. John's wort might improve OCD symptoms in patients with depression.
• Osteoarthritis. It is unclear if topical St. John's wort is beneficial for osteoarthritis. Oral St. John's wort is not studied for this use. Details: A moderate-sized clinical study in adults with knee osteoarthritis shows that applying St. John's wort oil (concentration unknown) to the knees three times a day for 21 days improves patient-reported pain, stiffness, and function scores when compared with placebo (olive oil) (113093). However, participants were aware of which treatment they received and were allowed to continue use of analgesics as needed, which limits the validity of this study.
• Polycystic ovary syndrome (PCOS). Oral St. John's wort has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking three tablets containing St. John's wort, licorice root, Ceylon cinnamon, levant berry, peony, and Tribulus daily for 3 months, in addition to lifestyle changes, improves oligomenorrhea by 33% and quality of life by 30% when compared with lifestyle changes alone in adults with PCOS (97216). It is unclear if these effects are due to St. John's wort, other ingredients, or the combination.
• Premenstrual syndrome (PMS). It is unclear if oral St. John's wort is beneficial for patients with PMS. Details: There is conflicting evidence on the effects of St. John's wort for treating PMS, although most evidence suggests benefit. A small clinical study shows that taking a specific St. John's wort extract standardized to contain 0.18% hypericin and 3.38% hyperforin (LI 160, Lichtwer Pharma AG) 450 mg twice daily for two menstrual cycles reduces physical and behavioral PMS symptoms, but not mood or pain, when compared with placebo (76150). Another clinical study shows that taking St. John's wort extract containing hypericin 1.36 mg daily for two menstrual cycles can reduce symptoms of PMS, including anxiety, depression, forgetfulness, crying, headache, and fatigue, when compared with placebo (76159). However, one clinical study shows that taking St. John's wort 600 mg (standardized to contain 1.8 mg of hypericin) does not reduce anxiety or other PMS symptoms when compared with placebo (76104). The conflicting results may be due to differences in St. John's wort formulations and dosages.
• Psoriasis. It is unclear if topical St. John's wort improves symptoms in patients with plaque psoriasis. Details: A small clinical study in patients with mild or moderate plaque psoriasis shows that applying an ointment containing St. John's wort extract 5% twice daily to one side of the body for 4 weeks modestly decreases the severity, thickness, and degree of erythema of psoriasis plaques when compared with applying placebo ointment to the other side of the body (95940).
• Seasonal affective disorder (SAD). It is unclear if oral St. John's wort is beneficial for patients with SAD. Details: Preliminary clinical research shows that St. John's wort extract improves symptoms associated with SAD, including anxiety, decreased libido, and sleep disturbances, when compared with baseline. It may be beneficial when used alone or in combination with light therapy (9686,76175). However, the validity of these findings is limited by the lack of a comparator group.
• Scleroderma. Topical St. John's wort has only been evaluated in combination with neem oil; its effect when used alone is unclear. Details: A small observational study in patients with systemic sclerosis has found that topical application of a specific cream (Holoil, RI.MOS. SRL) containing St. John's wort and neem oil is associated with improved healing, decreased pain, and reduced need for surgical interventions and antibiotics when compared with a control group (102867). It is unknown if these effects are due to St. John's wort, neem, or the combination. Additionally, the validity of these results is limited by a lack of randomization, blinding, and placebo-control.
• Smoking cessation. It is unclear if oral St. John's wort is beneficial for patients trying to quit smoking. Details: A small clinical study in cigarette smokers shows that taking a specific St. John's wort extract (LI-160, Lichtwer Pharma US) 300 mg once or twice daily, starting 1 week before and continuing for 3 months after quitting smoking, is associated with a continuous abstinence rate of 18% at 3 months and 0% at 12 months, suggesting a lack of benefit (14481).
• Wound healing. Topical St. John's wort seems to improve wound healing and wound-related pain for certain types of surgery. Details: A clinical study in patients who have had a Cesarean section shows that applying ointment containing St. John's wort extract 20% three times a day for 16 days improves wound healing and reduces scar formation when compared with placebo ointment (17225). Preliminary clinical research in patients who have had impacted third molars removed shows that using a mouthwash, prepared by macerating the above ground parts of St. John's wort in virgin olive oil, for 60 days is as effective as chlorhexidine gluconate plus benzydamine hydrochloride mouthwash for improving periodontal healing, and reducing swelling, pain, and infectious complications. However, it was also as effective as plain virgin olive oil, suggesting that St. John's wort did not provide additional benefit. 15 mL of each mouthwash was swished for 30 seconds 3 times daily for 7 days (104957). St. John's wort has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with dehisced post-surgical wounds shows that applying a specific aerosol product (1PWD, Kerecis AG) containing St. John's wort and neem oil to wounds during dressing changes does not improve wound healing scores at day 28 but may reduce pain scores when compared with silver-based dressings (alginates or polyurethane foam) (111592). However, this study may have been inadequately powered to detect a difference between groups. It is also unclear if these effects are due to St. John's wort, neem oil, or the combination.
• Tinnitus. St. John's wort has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in adults with tinnitus shows that taking St. John's wort 600 mg and ginkgo biloba daily for 12 weeks does not suppress tinnitus or improve tinnitus-related handicap when compared with ginkgo biloba monotherapy (111513). More evidence is needed to rate St. John's wort for these uses.

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EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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POSSIBLY SAFE ...when used orally and appropriately. 5-HTP has been used safely in doses up to 400 mg daily for up to one year (913,30007,30130). Doses up to 1.2 grams daily have been used with apparent safety for up to 10 months (914,30018,30125,30164,30165). Doses of 3 grams daily have been used safely for 3 weeks (30138). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

POSSIBLY UNSAFE ...when used orally in large doses. Doses of 6-10 grams daily have been associated with severe gastrointestinal effects and hyperkinesis (30139,30183). The risk may be reduced if the dose is increased gradually.

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

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Doses of 5-HTP up to 5 mg/kg daily have been used safely for up to 3 years in infants and children up to 12 years old (30128,30153,88173). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

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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).

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LIKELY SAFE ...when used orally and appropriately. Oral magnesium is safe when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555). ...when used parenterally and appropriately. Parenteral magnesium sulfate is an FDA-approved prescription product (96484).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 350 mg daily frequently cause loose stools and diarrhea (7555).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Magnesium is safe when used in doses below the tolerable upper intake level (UL) of 65 mg daily for children 1 to 3 years, 110 mg daily for children 4 to 8 years, and 350 mg daily for children older than 8 years (7555,89396). ...when used parenterally and appropriately (96483).

CHILDREN: LIKELY UNSAFE
when used orally in excessive doses. Tell patients not to use doses above the tolerable upper intake level (UL). Higher doses can cause diarrhea and symptomatic hypermagnesemia including hypotension, nausea, vomiting, and bradycardia (7555,8095).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Magnesium is safe for those pregnant and breast-feeding when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for up to 5 days (12592,89397,99354,99355). However, due to potential adverse effects associated with intravenous and intramuscular magnesium, use during pregnancy is limited to patients with specific conditions such as severe pre-eclampsia or eclampsia. There is some evidence that intravenous magnesium can increase fetal mortality and adversely affect neurological and skeletal development (12590,12593,60818,99354,99355). However, a more recent analysis of clinical research shows that increased risk of fetal mortality seems to occur only in the studies where antenatal magnesium is used for tocolysis and not for fetal neuroprotection or pre-eclampsia/eclampsia (102457). Furthermore, antenatal magnesium does not seem to be associated with increased risk of necrotizing enterocolitis in preterm infants (104396). There is also concern that magnesium increases the risk of maternal adverse events. A meta-analysis of clinical research shows that magnesium sulfate might increase the risk of maternal adverse events, especially in Hispanic mothers compared to other racial and ethnic groups (60971,99319).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients to avoid exceeding the tolerable upper intake level (UL) of 350 mg daily. Taking magnesium orally in higher doses can cause diarrhea (7555). ...when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for longer than 5 days (12592,89397,99354,99355). Maternal exposure to magnesium for longer than 5-7 days is associated with an increase in neonatal bone abnormalities such as osteopenia and fractures. The U.S. Food and Drug Administration (FDA) recommends that magnesium injection not be given for longer than 5-7 days (12590,12593,60818,99354,99355).

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LIKELY SAFE ...when niacin is taken in food or as a supplement in amounts below the tolerable upper intake level (UL) of 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243). ...when prescription products are used orally and appropriately in doses of up to 2 grams daily (12033). CHILDREN:

LIKELY SAFE ...when used orally in amounts that do not exceed the tolerable upper intake level (UL). The ULs of niacin for children are: 1-3 years of age, 10 mg daily; 4-8 years of age, 15 mg daily; 9-13 years of age, 20 mg daily; 14-18 years of age, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL). The UL of niacin during pregnancy and lactation is 30 mg daily for 14-18 years of age and 35 mg daily for 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacin during pregnancy or lactation; avoid using.

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LIKELY SAFE ...when used orally and appropriately. St. John's wort extracts in doses up to 900 mg daily seem to be safe when used for up to 12 weeks (3547,3550,4835,5096,6400,6434,7047,13021,13156,13157)(14417,76143,76144,89666,89669,95510). Some evidence also shows that St. John's wort can be safely used for over one year (13156,13157,76140), and may have better tolerability than selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) (4897,76153,76143,104036).

POSSIBLY SAFE ...when used topically and appropriately. St. John's wort 0.5% extract seems to be safe when used once weekly for 4 weeks (110327). St. John's wort oil has been used with apparent safely twice daily for 6 weeks (110326). However, topical use of St. John's wort can cause photodermatitis with sun exposure (110318).

POSSIBLY UNSAFE ...when used orally in large doses. St. John's wort extract can be unsafe due to the risk of severe phototoxic skin reactions. Taking 2-4 grams of St. John's wort extract (containing hypericin 5-10 mg) daily appears to increase the risk of photosensitivity (758,4631,7808).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Preliminary population research has found that taking St. John's wort while pregnant is associated with offspring that develop neural tube, urinary, and cardiovascular malformations. Subgroup analyses suggest that these risks may be higher when taking St. John's wort during the first trimester when compared with the second or third trimester. However, more research is needed to confirm these findings (106052). Animal-model research also shows that constituents of St. John's wort might have teratogenic effects (9687,15122). Until more is known, St. John's wort should not be taken during pregnancy.

LACTATION: POSSIBLY UNSAFE
when used orally. Nursing infants of mothers who take St. John's wort have a greater chance of experiencing colic, drowsiness, and lethargy (1377,15122,22418); avoid using.

CHILDREN: POSSIBLY SAFE
when used orally, and appropriately, short-term. St. John's wort extracts in doses up to 300 mg three times daily seem to be safe when used for up to 8 weeks in children aged 6-17 years (4538,17986,76110).

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LIKELY SAFE ...when used orally and appropriately. A tolerable upper intake level (UL) has not been established for thiamine, and doses up to 50 mg daily have been used without adverse effects (15,6243). ...when used intravenously or intramuscularly and appropriately. Injectable thiamine is an FDA-approved prescription product (15,105445).

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).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 1. 4 mg daily. A tolerable upper intake level (UL) has not been established for healthy individuals (3094,6243).

(Read more about THIAMINE)

LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).

POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).

POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).

LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older. The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

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CARBIDOPA (Lodosyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Combining 5-HTP and carbidopa can increase the risk of serotonergic side effects.  Details Carbidopa is sometimes used with 5-HTP to minimize peripheral 5-HTP metabolism and boost the amount that reaches the brain. However, this combination might also increase the risk of some side effects including hypomania, restlessness, rapid speech, anxiety, insomnia, and aggressiveness (30076,30132,30158). Combining carbidopa and 5-HTP might also increase the risk of scleroderma-like skin changes due to elevated serotonin levels (1403).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of 5-HTP with medications that cause sedation might have additive effects.  Details In clinical trials, 5-HTP has been associated with drowsiness and somnolence (914,30093,30129,30130).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Combining serotonergic drugs with 5-HTP might cause additive serotonergic effects.  Details 5-HTP can increase serotonin levels and cause serotonergic effects (901). Theoretically, combining serotonergic drugs with 5-HTP might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056). However, serotonin syndrome with 5-HTP has not yet been reported in humans (104941). Monitor patients for signs of serotonin syndrome and other serotonergic side effects if using 5-HTP with serotonergic drugs.

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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.

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AMINOGLYCOSIDE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use of aminoglycoside antibiotics and magnesium can increase the risk for neuromuscular weakness.  Details Both aminoglycosides and magnesium reduce presynaptic acetylcholine release, which can lead to neuromuscular blockade and possible paralysis. This is most likely to occur with high doses of magnesium given intravenously (13362).

ANTACIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Use of acid reducers may reduce the laxative effect of magnesium oxide.  Details A retrospective analysis shows that, in the presence of H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs), a higher dose of magnesium oxide is needed for a laxative effect (90033). This may also occur with antacids. Under acidic conditions, magnesium oxide is converted to magnesium chloride and then to magnesium bicarbonate, which has an osmotic laxative effect. By reducing acidity, antacids may reduce the conversion of magnesium oxide to the active bicarbonate salt.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, magnesium may have antiplatelet effects, but the evidence is conflicting.  Details In vitro evidence shows that magnesium sulfate inhibits platelet aggregation, even at low concentrations (20304,20305). Some preliminary clinical evidence shows that infusion of magnesium sulfate increases bleeding time by 48% and reduces platelet activity (20306). However, other clinical research shows that magnesium does not affect platelet aggregation, although inhibition of platelet-dependent thrombosis can occur (60759).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Magnesium can decrease absorption of bisphosphonates.  Details Cations, including magnesium, can decrease bisphosphonate absorption. Advise patients to separate doses of magnesium and these drugs by at least 2 hours (13363).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium can have additive effects with calcium channel blockers, although evidence is conflicting.  Details Magnesium inhibits calcium entry into smooth muscle cells and may therefore have additive effects with calcium channel blockers. Severe hypotension and neuromuscular blockades may occur when nifedipine is used with intravenous magnesium (3046,20264,20265,20266), although some contradictory evidence suggests that concurrent use of magnesium with nifedipine does not increase the risk of neuromuscular weakness (60831). High doses of magnesium could theoretically have additive effects with other calcium channel blockers.

DIGOXIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Magnesium salts may reduce absorption of digoxin.  Details Clinical evidence suggests that treatment with oral magnesium hydroxide or magnesium trisilicate reduces absorption of digoxin from the intestines (198,20268,20270). This may reduce the blood levels of digoxin and decrease its therapeutic effects.

GABAPENTIN (Neurontin) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Gabapentin absorption can be decreased by magnesium.  Details Clinical research shows that giving magnesium oxide orally along with gabapentin decreases the maximum plasma concentration of gabapentin by 33%, time to maximum concentration by 36%, and area under the curve by 43% (90032). Advise patients to take gabapentin at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

KETAMINE (Ketalar) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium might precipitate ketamine toxicity.  Details In one case report, a 62-year-old hospice patient with terminal cancer who had been stabilized on sublingual ketamine 150 mg four times daily experienced severe ketamine toxicity lasting for 2 hours after taking a maintenance dose of ketamine following an infusion of magnesium sulfate 2 grams (105078). Since both magnesium and ketamine block the NMDA receptor, magnesium is thought to have potentiated the effects of ketamine.

LEVODOPA/CARBIDOPA (Sinemet) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Magnesium can reduce the bioavailability of levodopa/carbidopa.  Details Clinical research in healthy volunteers shows that taking magnesium oxide 1000 mg with levodopa 100 mg/carbidopa 10 mg reduces the area under the curve (AUC) of levodopa by 35% and of carbidopa by 81%. In vitro and animal research shows that magnesium produces an alkaline environment in the digestive tract, which might lead to degradation and reduced bioavailability of levodopa/carbidopa (100265).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Potassium-sparing diuretics decrease excretion of magnesium, possibly increasing magnesium levels.  Details Potassium-sparing diuretics also have magnesium-sparing properties, which can counteract the magnesium losses associated with loop and thiazide diuretics (9613,9614,9622). Theoretically, increased magnesium levels could result from concomitant use of potassium-sparing diuretics and magnesium supplements.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of quinolones.  Details Magnesium can form insoluble complexes with quinolones and decrease their absorption (3046). Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

SEVELAMER (Renagel, Renvela) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Sevelamer may increase serum magnesium levels.  Details In patients on hemodialysis, sevelamer use was associated with a 0.28 mg/dL increase in serum magnesium. The mechanism of this interaction remains unclear (96486).

SKELETAL MUSCLE RELAXANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Parenteral magnesium alters the pharmacokinetics of skeletal muscle relaxants, increasing their effects and accelerating the onset of effect.  Details Parenteral magnesium shortens the time to onset of skeletal muscle relaxants by about 1 minute and prolongs the duration of action by about 2 minutes. Magnesium potentiates the effects of skeletal muscle relaxants by decreasing calcium-mediated release of acetylcholine from presynaptic nerve terminals, reducing postsynaptic sensitivity to acetylcholine, and having a direct effect on the membrane potential of myocytes (3046,97492,107364). Magnesium also has vasodilatory actions and increases cardiac output, allowing a greater amount of muscle relaxant to reach the motor end plate (107364). A clinical study found that low-dose rocuronium (0.45 mg/kg), when given after administration of magnesium 30 mg/kg over 10 minutes, has an accelerated onset of effect, which matches the onset of effect seen with a full-dose rocuronium regimen (0.6 mg/kg) (96485). In another clinical study, onset times for rocuronium doses of 0.3, 0.6, and 1.2 mg/kg were 86, 76, and 50 seconds, respectively, when given alone, but were reduced to 66, 44, and 38 seconds, respectively, when the doses were given after a 15-minute infusion of magnesium sulfate 60 mg/kg (107364). Giving intraoperative intravenous magnesium sulfate, 50 mg/kg loading dose followed by 15 mg/kg/hour, reduces the onset time of rocuronium, enhances its clinical effects, reduces the dose of intraoperative opiates, and prolongs the spontaneous recovery time (112781,112782). It does not affect the activity of subsequently administered neostigmine (112782).

SULFONYLUREAS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Magnesium increases the systemic absorption of sulfonylureas, increasing their effects and side effects.  Details Clinical research shows that administration of magnesium hydroxide with glyburide increases glyburide absorption, increases maximal insulin response by 35-fold, and increases the risk of hypoglycemia, when compared with glyburide alone (20307). A similar interaction occurs between magnesium hydroxide and glipizide (20308). The mechanism of this effect appears to be related to the elevation of gastrointestinal pH by magnesium-based antacids, increasing solubility and enhancing absorption of sulfonylureas (22364).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of tetracyclines.  Details Magnesium can form insoluble complexes with tetracyclines in the gut and decrease their absorption and antibacterial activity (12586). Advise patients to take these drugs 1 hour before or 2 hours after magnesium supplements.

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ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Concomitant use of alcohol and niacin might increase the risk of flushing and hepatotoxicity.  Details Alcohol can exacerbate the flushing and pruritus associated with niacin (4458,11689). Large doses of niacin might also exacerbate liver dysfunction associated with chronic alcohol use. A case report describes delirium and lactic acidosis in a patient taking niacin 3 grams daily who ingested 1 liter of wine (14510). Advise patients to avoid large amounts of alcohol while taking niacin.

ALLOPURINOL (Zyloprim) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as allopurinol.  Details Large doses of niacin can reduce urinary excretion of uric acid, potentially resulting in hyperuricemia (4860,4863,12033). Doses of uricosurics such as allopurinol might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, niacin may have additive effects when used with anticoagulant or antiplatelet drugs.  Details Several cases of clotting factor synthesis deficiency and coagulopathy have been reported in patients taking sustained-release niacin (25915). Also, thrombocytopenia has been reported in patients treated with niacin or niacin plus lovastatin (25916).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Niacin can increase blood glucose levels and may diminish the effects of antidiabetes drugs.  Details Niacin impairs glucose tolerance in a dose-dependent manner, probably by causing or aggravating insulin resistance and increasing hepatic production of glucose (4860,4863,11692,11693). In diabetes patients, niacin 4.5 grams daily for 5 weeks can increase plasma glucose by an average of 16% and glycated hemoglobin (HbA1c) by 21% (4860). However, lower doses of 1.5 grams daily or less appear to have minimal effects on blood glucose (12033). In some patients, glucose levels increase when niacin is started, but then return to baseline when a stable dose is reached (12033,93344). Up to 35% of patients with diabetes may need adjustments in hypoglycemic therapy when niacin is added (4458,4860,4863,11689,12033).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, niacin may increase the risk of hypotension when used with antihypertensive drugs.  Details The vasodilating effects of niacin can cause hypotension (4863,12033,93341). Furthermore, some clinical evidence suggests that a one-hour infusion of niacin can reduce systolic, diastolic, and mean blood pressure in hypertensive patients. This effect is not observed in normotensive patients (25917).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Likely •  Level of Evidence = B Large doses of aspirin might alter the clearance of niacin.  Details Aspirin is often used with niacin to reduce niacin-induced flushing (4458,11689). Doses of 80-975 mg aspirin have been used, but 325 mg appears to be optimal (4458,4852,4853,11689). Aspirin also seems to reduce the clearance of niacin by competing for glycine conjugation. Taking aspirin 1 gram seems to reduce niacin clearance by 45% (14524). This is probably a dose-related effect and not clinically significant with the more common aspirin dose of 325 mg (11689,14524).

BILE ACID SEQUESTRANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Bile acid sequestrants can bind niacin and decrease absorption. Separate administration by 4-6 hours to avoid an interaction.  Details In vitro studies show that colestipol (Colestid) binds about 98% of available niacin and cholestyramine (Questran) binds 10% to 30% (14511).

GEMFIBROZIL (Lopid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and gemfibrozil might increase the risk of myopathy in some patients.  Details A case of myopathy from concomitant use of niacin and gemfibrozil has been reported (25920). Niacin alone has also been associated with cases of myopathy (26100,26111). Using gemfibrozil with niacin might further increase the risk of developing myopathy.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and hepatotoxic drugs might increase the risk of hepatotoxicity.  Details Niacin has been associated with cases of liver toxicity, especially when used in pharmacologic doses (4863,11689,11691,25929,25930,25931,113553). Sustained-release niacin preparations appear to be associated with a higher risk of hepatotoxicity than immediate-release niacin (11691,25930,25931,93342,113553).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and statins might increase the risk of myopathy and rhabdomyolysis in some patients.  Details Some case reports have raised concerns that niacin might increase the risk of myopathy and rhabdomyolysis when combined with statins (14508,25918). However, a significantly increased risk of myopathy has not been demonstrated in clinical trials, including those using an FDA-approved combination of lovastatin and niacin (Advicor) (7388,11689,12033,14509).

PROBENECID (Benemid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as probenecid.  Details Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as probenecid might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

SULFINPYRAZONE (Anturane) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as sulfinpyrazone.  Details Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as sulfinpyrazone might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, niacin might antagonize the therapeutic effects of thyroid hormones.  Details Clinical research and case reports suggests that taking niacin can reduce serum levels of thyroxine-binding globulin by up to 25% and moderately reduce levels of thyroxine (T4) (25916,25925,25926,25928). Patients taking thyroid hormone for hypothyroidism might need dose adjustments when using niacin.

TRANSDERMAL NICOTINE (Nicoderm) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and transdermal nicotine might increase the risk of flushing and dizziness.  Details Niacin and nicotine can both cause flushing and dizziness (496,96211).

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ALPRAZOLAM (Xanax) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort increases the clearance of alprazolam and decreases its effects.  Details Alprazolam, which is used as a probe for cytochrome P450 3A4 (CYP3A4) activity, has a two-fold increase in clearance when given with St. John's wort. St. John's wort reduces the half-life of alprazolam from 12.4 hours to 6 hours (10830).

AMBRISENTAN (Letairis) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the clearance of ambristentan and decrease its effects.  Details Clinical research in healthy volunteers shows that taking St. John's wort 900 mg daily decreases the area under the concentration-time curve of ambrisentan 5 mg by 17% to 26%. Ambrisentan clearance was increased by 20% to 35% depending on CYP2C19 genotype. However, these small changes are unlikely to be clinically significant (99511).

AMINOLEVULINIC ACID Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might have additive phototoxic effects with aminolevulinic acid.  Details Concomitant use with St. John's wort extract may cause synergistic phototoxicity. Delta-aminolevulinic acid can cause a burning erythematous rash and severe swelling of the face, neck, and hands when taken with St. John's wort (9474).

BOCEPREVIR (Victrelis) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of boceprevir.  Details Boceprevir increases the maximum concentration and concentration at 8 hours of the St. John's wort constituent, hypericin, by approximately 30%. However, St. John's wort does not significantly change the area under the concentration-time curve or maximum plasma concentration of boceprevir 800 mg three times daily in healthy adults (95507,96552).

BUPROPION (Wellbutrin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might reduce the levels and effects of bupropion.  Details Clinical research shows that taking St. John's wort 325 mg three times daily for 14 days along with bupropion reduces the area under the concentration-time curve by approximately 14% and increases the clearance of bupropion by approximately 20%. This effect is attributed to the induction of cytochrome P450 2B6 (CYP2B6) by St. John's wort (89662).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B St. John's wort might increase the levels and effects of clopidogrel.  Details Taking St. John's wort with clopidogrel seems to increase the activity of clopidogrel. In clopidogrel non-responders, taking St. John's wort seems to induce metabolism of clopidogrel to its active metabolite by cytochrome P450 enzymes 3A4 and 2C19. This leads to increased antiplatelet activity (13038,89671,96552). Theoretically, this might lead to an increased risk of bleeding in clopidogrel responders.

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D St. John's wort might decrease the levels and clinical effects of clozapine.  Details A case report describes a female with schizophrenia controlled on clozapine who had a return of symptoms when she started taking St. John's wort. The plasma concentration of clozapine was reduced, likely because its clearance was increased due to induction of the cytochrome P450 enzymes 3A4, 1A2, 2C9, and 2C19 by St. John's wort (96552).

CONTRACEPTIVE DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort increases the clearance of contraceptive drugs and reduces their clinical effects.  Details Females taking St. John's wort and oral contraceptives concurrently should use an additional or alternative form of birth control. St. John's wort can decrease norethindrone and ethinyl estradiol levels by 13% to 15%, resulting in breakthrough bleeding, irregular menstrual bleeding, or unplanned pregnancy (11886,11887,13099). Bleeding irregularities usually occur within a week of starting St. John's wort and regular cycles usually return when St. John's wort is discontinued. Unplanned pregnancy has occurred with concurrent use of oral contraceptives and St. John's wort extract (9880). St. John's wort is thought to induce the cytochrome P450 1A2 (CYP1A2), 2C9 (CYP2C9), and 3A4 (CYP3A4) enzymes, which are responsible for metabolism of progestins and estrogens in contraceptives (1292,7809,9204).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of cyclosporine.  Details Concomitant use can decrease plasma cyclosporine levels by 30% to 70% (1234,4826,4831,4834,7808,9596,10628,96552). Using St. John's wort with cyclosporine in patients with heart, kidney, or liver transplants can cause subtherapeutic cyclosporine levels and acute transplant rejection (1234,1293,1301,6112,6435,7808,9596). This interaction has occurred with a St. John's wort extract standardized to 0.3% hypericin and dosed at 300-600 mg per day (6435,10628). Withdrawal of St. John's wort can result in a 64% increase in cyclosporine levels (1234,4513,4826,4831,4834). St. John's wort induces cytochrome P450 3A4 (CYP3A4) and the multi-drug transporter, P-glycoprotein/MDR-1, which increases cyclosporine clearance (1293,1340,9204,9596).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP1A2 substrates.  Details Clinical and in vitro research shows that St. John's wort induces CYP1A2, but to a lesser extent than CYP3A4 (9204,10848,76163,111404).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2B6 substrates.  Details Clinical research shows that taking St. John's wort 325 mg three times daily for 14 days along with bupropion, a CYP2B6 substrate, reduces the area under the concentration-time curve by approximately 14% and increases the clearance of bupropion by approximately 20% (89662).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2C19 substrates.  Details Preliminary clinical research in healthy males shows that taking St. John's wort for 14 days induces CYP2C19 and increases metabolism of mephenytoin (Mesantoin). In patients with wild-type 2C19 (2C19*1/*1) metabolism was almost 4-fold greater in subjects who received St. John's wort compared to placebo. In contrast, patients with 2C19*2/*2 and *2/*3 genotypes did not demonstrate a similar increase in metabolism (17405). Theoretically, St. John's wort might increase metabolism of other CYP2C19 substrates.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2C9 substrates.  Details There is contradictory research about the effect of St. John's wort on CYP2C9. Some in vitro research shows that St. John's wort induces CYP2C9, but to a lesser extent than CYP3A4 (9204,10848,11889). St. John's wort also induces metabolism of the S-warfarin isomer, which is a CYP2C9 substrate (11890). Other research shows that St. John's wort 300 mg three times daily for 21 days does not significantly affect the pharmacokinetics of a single 400 mg dose of ibuprofen, which is also a CYP2C9 substrate (15546). Until more is known, use St. John's wort cautiously in patients who are taking CYP2C9 substrates.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort increases the metabolism and reduces the levels of CYP3A4 substrates.  Details St. John's wort induces CYP3A4 enzymes and increases metabolism of CYP3A4 substrates (9204,10830,10847,10848,11889,22423,22424,22425,22427,48603,111404,111644,113094). Clinically significant interactions have been reported with St. John's wort products containing hyperforin 1 mg or more (97171).

DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of digoxin.  Details St. John's wort can reduce the bioavailability, serum levels, and therapeutic effects of digoxin. Taking an extract of St. John's wort 900 mg, containing hyperforin 7.5 mg or more, daily for 10-14 days, can reduce serum digoxin levels by 25% in healthy people. St. John's wort is thought to affect the multidrug transporter, P-glycoprotein, which mediates the absorption and elimination of digoxin and other drugs (382,6473,7808,7810,9204,96552,97171). St. John's wort products providing less than 7.5 mg of hyperforin daily do not appear to affect digoxin levels (97171).

DOCETAXEL (Taxotere) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of docetaxel.  Details Clinical research shows that taking a specific St. John's wort product (Hyperiplant, VSM) 300 mg three times daily for 14 days increases docetaxel clearance by about 14%, resulting in decreased plasma concentrations of docetaxel in cancer patients. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (89661).

FENTANYL Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, St. John's wort may reduce the levels and clinical effects of fentanyl.  Details Given that St. John's wort induces cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, it is possible that concomitant use of St. John's wort with fentanyl will reduce plasma levels and analgesic activity of fentanyl (96552). However, some clinical research in healthy adults shows that taking St. John's wort (LI-160, Lichtwer Pharma) 300 mg daily for 21 days does not alter the pharmacokinetics or clinical effects of intravenous fentanyl (102868). It is unclear if these findings can be generalized to oral, intranasal, or transdermal fentanyl.

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the levels and clinical effects of fexofenadine.  Details A single dose of St. John's wort decreases the clearance of fexofenadine and increases its plasma levels. However, the effect of St. John's wort on plasma levels of fexofenadine seems to be lost if dosing is continued for more than 2 weeks (9685). Patients taking fexofenadine and St. John's wort concurrently should be monitored for possible fexofenadine toxicity.

FINASTERIDE (Proscar, Propecia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D St. John's wort may reduce the levels and clinical effects of finasteride.  Details St. John's wort reduces plasma levels of finasteride in healthy male volunteers due to induction of finasteride metabolism via cytochrome P450 3A4 (CYP3A4). The clinical significance of this interaction is not known (96552).

GLICLAZIDE (Diamicron, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort may reduce the levels and clinical effects of gliclazide.  Details Taking St. John's wort decreases the half-life and increases clearance of gliclazide in healthy people (22431).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the effectiveness of atorvastatin, lovastatin, and rosuvastatin. However, it does not seem to affect pravastatin, pitavastatin, or fluvastatin.  Details Concomitant use of St. John's wort can reduce plasma concentrations of the active simvastatin metabolite, simvastatin hydroxy acid, by 28%. St. John's wort induces intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug transporter. This increases simvastatin clearance. It also increases the clearance of atorvastatin (Lipitor), lovastatin (Mevacor), and rosuvastatin (Crestor). St. John's wort does not seem to affect the plasma concentrations of pravastatin (Pravachol), pitavastatin (Livalo) or fluvastatin (Lescol), which are not substrates of CYP3A4 or P-glycoprotein (10627,96552,97171).

IMATINIB (Gleevec) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A St. John's wort reduces the levels and clinical effects of imatinib.  Details Taking St. John's wort 900 mg daily for 2 weeks reduces the bioavailability and half-life of a single dose of imatinib and decreases its serum levels by 30% in healthy volunteers. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort, which increases clearance of imatinib (11888,96552).

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort may reduce the levels and clinical effects of indinavir.  Details In healthy volunteers, taking St. John's wort concurrently with indinavir reduces plasma concentrations of indinavir by inducing metabolism via cytochrome P450 3A4 (CYP3A4) (96552). Theoretically, this could result in treatment failure and viral resistance.

IRINOTECAN (Camptosar) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A St. John's wort reduces the levels and clinical effects of irinotecan.  Details St. John's wort 900 mg daily for 18 days decreases serum levels of irinotecan by at least 50%. Clearance of the active metabolite of irinotecan, SN-38, is also increased, resulting in a 42% decrease in the area under the concentration-time curve (9206,97171). This is thought to be due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (7092,96552).

IVABRADINE (Corlanor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might reduce the levels and clinical effects of ivabradine.  Details Taking St. John's wort 900 mg containing 7.5 mg of hyperforin daily for 14 days with a single dose of ivabradine causes a 62% reduction in plasma levels of ivabradine. This interaction is thought to be due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort, increasing the metabolism of ivabradine (96552,97171).

KETAMINE (Ketalar) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of ketamine.  Details Taking St. John's wort 300 mg three times daily for 14 days can decrease maximum serum levels of ketamine by around 66% and area under the concentration-time curve of ketamine by 58%. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (89663).

MEPHENYTOIN (Mesantoin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of mephenytoin.  Details Preliminary clinical research in healthy males shows that taking St. John's wort for 14 days induces cytochrome P450 2C19 (CYP2C19) and significantly increases metabolism of mephenytoin (Mesantoin). In people with wild-type 2C19, metabolism was almost 4-fold greater in subjects who received St. John's wort compared to placebo. In contrast, patients with 2C19*2/*2 and *2/*3 genotypes did not demonstrate a similar increase in metabolism (17405).

METHADONE (Dolophine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might reduce the levels and clinical effects of methadone.  Details St. John's wort might decrease the effectiveness of methadone by reducing its blood concentrations. In one report, two out of four patients on methadone maintenance therapy for addiction experienced methadone withdrawal symptoms after taking St. John's wort 900 mg daily for a median of 31 days. There was a median decrease in blood methadone concentration of 47% (range: 19% to 60%) when compared to baseline (22419).

METHYLPHENIDATE (Concerta, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D St. John's wort might reduce the levels and clinical effects of methylphenidate.  Details St. John's wort might decrease the effectiveness of methylphenidate. In one report, an adult male, stabilized on methylphenidate for attention deficit-hyperactivity disorder (ADHD), experienced increased attention problems and ADHD symptoms after taking St. John's wort 600 mg daily for 4 months. ADHD symptoms improved when St. John's wort was discontinued (15544). The mechanism of this interaction is unknown.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of NNRTIs.  Details St. John's wort increases the oral clearance of nevirapine (Viramune) by 35%. Subtherapeutic concentrations are associated with therapeutic failure, development of viral resistance, and development of drug class resistance. St. John's wort induces intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug transporter (1290,1340,4837,96552).

OMEPRAZOLE (Prilosec) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of omeprazole.  Details Taking St. John's wort, 300 mg orally three times daily for 14 days, reduces serum concentrations of omeprazole by inducing its metabolism via cytochrome P450 (CYP) 2C19 and 3A4. The reduction of omeprazole serum levels is dependent on CYP2C19 genotype, with reductions up to 50% in extensive metabolizers and 38% in poor metabolizers (22440,96552).

OXYCODONE (Oxycontin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of oxycodone.  Details St. John's wort can increase oxycodone metabolism by inducing cytochrome P450 3A4 (CYP3A4), reducing plasma levels and analgesic activity (96552).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of P-glycoprotein substrates.  Details St. John's wort induces P-glycoprotein. P-glycoprotein is a carrier mechanism responsible for transporting drugs and other substances across cell membranes. When P-glycoprotein is induced in the gastrointestinal (GI) tract, it can prevent the absorption of some medications. In addition, induction of p-glycoprotein can decrease entry of drugs into the central nervous system (CNS) and decrease access to other sites of action (382,1340,7810,11722).

PHENOBARBITAL (Luminal) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenobarbital.  Details St. John's wort may increase the metabolism of phenobarbital. Plasma concentrations of phenobarbital should be monitored carefully. The dose of phenobarbital may need to be increased when St. John's wort is started and decreased when it is stopped (9204).

PHENPROCOUMON (Marcoumar, others) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenprocoumon.  Details St. John's wort appears to increase the metabolism of phenprocoumon (an anticoagulant that is not available in the US) by increasing the activity of the cytochrome P450 2C9 (CYP2C9) enzyme. This may result in decreases in the anticoagulant effect and international normalized ratio (INR) (9204).

PHENYTOIN (Dilantin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenytoin.  Details St. John's wort may increase the metabolism of phenytoin. Plasma concentrations of phenytoin should be monitored closely. The dose of phenytoin may need to be increased when St. John's wort is started and decreased when it is stopped (9204).

PHOTOSENSITIZING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might increase the likelihood for photosensitivity reactions when used in combination with photosensitizing drugs.  Details St. John's wort might increase photosensitivity reactions due to its hypericin content (166,111644). However, some clinical research shows that very high doses of St. John's wort are needed to produce phototoxicity in humans (3900,4542,76266).

PROCAINAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might decrease the levels and clinical effects of procainamide.  Details Animal research shows that taking St. John's wort extract increases the bioavailability of procainamide, but does not increase its metabolism (14865). Whether this interaction is clinically significant in humans is not known.

PROTEASE INHIBITORS (PIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of PIs.  Details In healthy volunteers, St. John's wort can reduce the plasma concentrations of indinavir (Crixivan) by inducing cytochrome P450 3A4 (CYP3A4). This might result in treatment failure and viral resistance (1290,7808,96552). St. John's wort also induces P-glycoprotein, which can result in decreased intracellular protease inhibitor concentrations and increased elimination (9204).

RESERPINE (Raudixin, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might decrease the effectiveness of reserpine.  Details Animal research shows that St. John's wort can antagonize the effects of reserpine (758).

RIVAROXABAN (Xarelto) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of rivaroxaban.  Details A small pharmacokinetic study in healthy volunteers shows that taking a single dose of rivaroxaban 20 mg after using a specific St. John's wort extract (Jarsin, Vifor SA) 450 mg orally twice daily for 14 days reduces the bioavailability of rivaroxaban by 24% and reduces rivaroxaban's therapeutic inhibition of factor Xa by 20% (104038).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might inhibit reuptake and increase levels of serotonin, resulting in additive effects with serotonergic drugs.  Details Concomitant use of serotonergic drugs with St. John's wort can lead to increased adverse effects and increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstriction disorders (166,542,3569,8056,110318).

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of tacrolimus.  Details Taking a St. John's wort extract (Jarsin) 600 mg daily significantly decreases tacrolimus serum levels. Dose increases of 60% may be required to maintain therapeutic tacrolimus levels in patients taking St. John's wort. St. John's wort is thought to lower tacrolimus levels by inducing cytochrome P450 3A4 (CYP3A4) enzymes (7095,10329). A small clinical study in healthy adults also shows that taking St. John's wort 300 mg three times daily for 10 days decreases the total systemic exposure to tacrolimus by 27% and 33% after taking a single 5 mg dose of immediate-release or prolonged-release tacrolimus, respectively (113094).

THEOPHYLLINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D St. John's wort might decrease the levels of theophylline, although this effect might not be clinically relevant.  Details St. John's wort does not seem to significantly affect theophylline pharmacokinetics (11802). There is a single case report of a possible interaction with theophylline. A patient who smoked and was taking 11 other drugs experienced an increase in theophylline levels after discontinuation of St. John's wort. This increase has been attributed to a rebounding of theophylline serum levels after St. John's wort was no longer present to induce metabolism via cytochrome P450 1A2 (CYP1A2) (3556,7808,9204). However, studies in healthy volunteers show that St. John's wort is unlikely to affect theophylline to any clinically significant degree (11802).

TRAMADOL (Ultram) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might decrease the levels and clinical effects of tramadol.  Details St. John's wort can increase tramadol metabolism via induction of cytochrome P450 3A4 (CYP3A4), reducing plasma levels and analgesic activity (96552). Theoretically, concurrent use of St. John's wort with tramadol might also cause additive serotonergic effects (763,6427,8056,8936).

VORICONAZOLE (Vfend) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of voriconazole.  Details Clinical research shows that taking St. John's wort with voriconazole reduces voriconazole exposure and increases voriconazole metabolism by approximately 107%. Voriconazole is primarily metabolized by cytochrome P450 (CYP) 2C19, with CYP3A4 and CYP2C9 also involved (89660). St. John's wort induces CYP2C19, CYP3A4, and CYP2C9 (9204,10830,10847,10848,11889,11890,17405,22423,22424,22425)(22427,48603).

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of warfarin.  Details Taking St. John's wort significantly increases clearance of warfarin, including both its R- and S-isomers (11890,15176). This is likely due to induction of cytochrome P450 (CYP) 1A2 and CYP3A4 (11890). St. John's wort can also significantly decrease International Normalized Ratio (INR) in people taking warfarin (1292). In addition, taking warfarin at the same time as St. John's wort might reduce warfarin bioavailability. When a dried extract is mixed with warfarin in an aqueous medium, up to 30% of warfarin is bound to particles, reducing its absorption (10448).

ZOLPIDEM (Ambien) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of zolpidem.  Details In clinical research, concomitant use of zolpidem with St. John's wort decreased zolpidem plasma levels due to induction of its metabolism by cytochrome P450 3A4 (22441,96552). Whether this interaction is clinically significant is not known.

(Read more about ST. JOHN'S WORT)

TRIMETHOPRIM (Proloprim) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Trimethoprim might increase blood levels of thiamine.  Details In vitro, animal, and clinical research suggest that trimethoprim inhibits intestinal thiamine transporter ThTR-2, hepatic transporter OCT1, and renal transporters OCT2, MATE1, and MATE2, resulting in paradoxically increased thiamine plasma concentrations (111678).

(Read more about THIAMINE)

AMIODARONE (Cordarone) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.  Details Despite initial case reports suggesting that pyridoxine may have a protective effect against amiodarone-induced photosensitivity, preliminary clinical research suggests that pyridoxine may actually exacerbate this adverse effect (8892,8893).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.  Details Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).

LEVODOPA Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.  Details Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenobarbital, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenobarbital to avoid high doses of vitamin B6 (3046,10801).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenytoin, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenytoin to avoid high doses of vitamin B6 (3046,10801).

(Read more about VITAMIN B6)

General ...Orally, 5-HTP is generally well tolerated, short-term.
Most Common Adverse Effects:
Orally: Abdominal pain, anorexia, dizziness, diarrhea, drowsiness, fatigue, headache, insomnia, nausea, and vomiting. Severity appears to be dose-dependent.
Serious Adverse Effects (Rare):
Orally: Aggression, hallucinations, mania, severe gastrointestinal complaints.

Cardiovascular ...Orally, palpitations have been reported with 5-HTP (30076,30130,30167). Conversely, bradycardia has been reported in patients taking 5-HTP 0.4-2 grams daily in combination with carbidopa 100-300 mg daily (30132). In patients with schizophrenia, a combination of 5-HTP in doses up to 6 grams daily and carbidopa 150 mg daily was associated with diaphoresis and mild diastolic hypotension, especially when doses were increased at a rate faster than 200 mg per day (30183).

Dermatologic ...Orally, 5-HTP has been reported to cause urticaria, other allergic-type skin reactions, and flushing (2204,30000,30140). A scleroderma-like illness was reported in a 70-year-old man who had been taking 5-HTP 1400 mg daily and carbidopa 150 mg daily for 20 months. Elevated serotonin levels may be linked to this condition (1403).

Gastrointestinal ...Orally, 5-HTP has been reported to cause gastrointestinal side effects such as nausea, vomiting, abdominal or epigastric pain, heartburn, constipation, diarrhea, flatulence, anorexia, and taste alteration at any dose (2203,2204,30000,30112,30114,30125,30132,30139,30140)(30165,30183,104250). Severity may be dose-dependent and also related to how quickly doses are increased (30183). Some data suggests that these effects may diminish or disappear with continued use of 5-HTP (30132).

Hematologic ...Symptoms suggestive of eosinophilia myalgia syndrome (EMS) have been reported in some patients using 5-HTP (902,10084,30178,88174,90927). In one case, a woman was exposed to 5-HTP, tetrahydrobiopterin, carbidopa, and levodopa while administering them to her children for 2 years (90927). Her diagnosis was not confirmed, and the validity of the tests performed on the 5-HTP product has been questioned (88174). Other cases of eosinophilia or EMS in patients taking 5-HTP have been attributed to impurities that resemble previously identified contaminants found in L-tryptophan products (902,919,7067,10084). The L-tryptophan contaminants associated with EMS were linked to a specific manufacturer's production method that is not used in the preparation of 5-HTP (88174). Although 5-HTP supplements have been associated with EMS, it seems that this adverse effect is likely due to the presence of contaminants in the 5-HTP products, not 5-HTP itself.

Musculoskeletal ...Orally, rhabdomyolysis was noted in one patient with progressive myoclonus epilepsy who was treated with 5-HTP 300 mg daily for 21 days (30162).

Neurologic/CNS ...Orally, 5-HTP has been reported to cause drowsiness, dizziness, insomnia, fatigue, and headache (30076,30112,30132).

Psychiatric ...Orally, 5-HTP has been associated with euphoria, hypomania and mania, anxiety, insomnia, and aggressiveness (30076,30132,30158,88179). In patients with schizophrenia, a combination of high-dose 5-HTP, up to 6 grams daily, and carbidopa 150 mg daily was associated with transient increases in hallucinations, delusions, marked confusion, looseness of associations, flight of ideas, and a hyperkinetic syndrome consisting of restlessness, hand wringing, pacing, and an inability to sit quietly in a chair (30183).

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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).

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General ...Magnesium is generally well tolerated. Some clinical research shows no differences in adverse effects between placebo and magnesium groups.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal irritation, nausea, and vomiting.
Intravenously: Bradycardia, dizziness, flushing sensation, hypotension, and localized pain and irritation. In pregnancy, may cause blurry vision, dizziness, lethargy, nausea, nystagmus, and perception of warmth.
Serious Adverse Effects (Rare):
All ROAs: With toxic doses, loss of reflexes and respiratory depression can occur. High doses in pregnancy can increase risk of neonatal mortality and neurological defects.

Cardiovascular ...Intravenously, magnesium can cause bradycardia, tachycardia, and hypotension (13356,60795,60838,60872,60960,60973,60982,61001,61031,114681). Inhaled magnesium administered by nebulizer may also cause hypotension (113466). Magnesium sulfate may cause rapid heartbeat when administered antenatally (60915,114681).
In one case report, a 99-year-old male who took oral magnesium oxide 3000 mg daily for chronic constipation was hospitalized with hypermagnesemia, hypotension, bradycardia, heart failure, cardiomegaly, second-degree sinoatrial block, and complete bundle branch block. The patient recovered after discontinuing the magnesium oxide (108966).

Dermatologic ...Intravenously, magnesium may cause flushing, sweating, and problems at the injection site (including burning pain) (60960,60982,111696,114681). In a case study, two patients who received intravenous magnesium sulfate for suppression of preterm labor developed a rapid and sudden onset of an urticarial eruption (a skin eruption of itching welts). The eruption cleared when magnesium sulfate was discontinued (61045). Orally, magnesium oxide may cause allergic skin rash, but this is rare. In one case report, a patient developed a rash after taking 600 mg magnesium oxide (Maglax) (98291).

Gastrointestinal ...Orally, magnesium can cause gastrointestinal irritation, nausea, vomiting, and diarrhea (1194,4891,10661,10663,18111,60951,61016,98290). In rare cases, taking magnesium orally might cause a bezoar, an indigestible mass of material which gets lodged in the gastrointestinal tract. In a case report, a 75-year-old female with advanced rectal cancer taking magnesium 1500 mg daily presented with nausea and anorexia from magnesium oxide bezoars in her stomach (99314). Magnesium can cause nausea, vomiting, or dry mouth when administered intravenously or by nebulization (60818,60960,60982,104400,113466,114681). Antenatal magnesium sulfate may also cause nausea and vomiting (60915,114681). Two case reports suggest that giving magnesium 50 grams orally for bowel preparation for colonoscopy in patients with colorectal cancer may lead to intestinal perforation and possibly death (90006).
Delayed meconium passage and obstruction have been reported rarely in neonates after intravenous magnesium sulfate was given to the mother during pregnancy (60818). In a retrospective study of 200 neonates born prematurely before 32 weeks of gestation, administration of prenatal IV magnesium sulfate, as a 4-gram loading dose and then 1-2 grams hourly, was not associated with the rate of meconium bowel obstruction when compared with neonates whose mothers had not received magnesium sulfate (108728).

Genitourinary ...Intravenously, magnesium sulfate may cause renal toxicity or acute urinary retention, although these events are rare (60818,61012). A case of slowed cervical dilation at delivery has been reported for a patient administered intravenous magnesium sulfate for eclampsia (12592). Intravenous magnesium might also cause solute diuresis. In a case report, a pregnant patient experienced polyuria and diuresis after having received intravenous magnesium sulfate in Ringer's lactate solution for preterm uterine contractions (98284).

Hematologic ...Intravenously, magnesium may cause increased blood loss at delivery when administered for eclampsia or pre-eclampsia (12592). However, research on the effect of intravenous magnesium on postpartum hemorrhage is mixed. Some research shows that it does not affect risk of postpartum hemorrhage (60982), while other research shows that intrapartum magnesium administration is associated with increased odds of postpartum hemorrhage, increased odds of uterine atony (a condition that increases the risk for postpartum hemorrhage) and increased need for red blood cell transfusions (97489).

Musculoskeletal ...Intravenously, magnesium may cause decreased skeletal muscle tone, muscle weakness, or hypocalcemic tetany (60818,60960,60973).
Although magnesium is important for normal bone structure and maintenance (272), there is concern that very high doses of magnesium may be detrimental. In a case series of 9 patients receiving long-term tocolysis for 11-97 days, resulting in cumulative magnesium sulfate doses of 168-3756 grams, a lower bone mass was noted in 4 cases receiving doses above 1000 grams. There was one case of pregnancy- and lactation-associated osteoporosis and one fracture (108731). The validity and clinical significance of this data is unclear.

Neurologic/CNS ...Intravenously, magnesium may cause slurred speech, dizziness, drowsiness, confusion, or headaches (60818,60960,114681). With toxic doses, loss of reflexes, neurological defects, drowsiness, confusion, and coma can occur (8095,12589,12590).
A case report describes cerebral cortical and subcortical edema consistent with posterior reversible encephalopathy syndrome (PRES), eclampsia, somnolence, seizures, absent deep tendon reflexes, hard to control hypertension, acute renal failure and hypermagnesemia (serum level 11.5 mg/dL), after treatment with intravenous magnesium sulfate for preeclampsia in a 24-year-old primigravida at 39 weeks gestation with a previously uncomplicated pregnancy. The symptoms resolved after 4 days of symptomatic treatment in an intensive care unit, and emergency cesarian delivery of a healthy infant (112785).

Ocular/Otic ...Intravenously, magnesium may cause blurred vision (114681). Additionally, cases of visual impairment or nystagmus have been reported following magnesium supplementation, but these events are rare (18111,60818).

Psychiatric ...A case of delirium due to hypermagnesemia has been reported for a patient receiving intravenous magnesium sulfate for pre-eclampsia (60780).

Pulmonary/Respiratory ...Intravenously, magnesium may cause respiratory depression and tachypnea when used in toxic doses (12589,61028,61180).

Other ...Hypothermia from magnesium used as a tocolytic has been reported (60818).

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General ...Orally, niacin is well tolerated in the amounts found in foods. It is also generally well tolerated in prescription doses when monitored by a healthcare provider.
Most Common Adverse Effects:
Orally: Flushing, gastrointestinal complaints (abdominal pain, constipation, diarrhea, heartburn, nausea, vomiting), and elevated liver enzymes.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity, myopathy, thrombocytopenia, and vision changes.

Cardiovascular ...Orally, flushing is a common dose-related adverse reaction to niacin. A large meta-analysis of clinical studies shows that up to 70% of patients may experience flushing (96211). Although flushing can occur with doses of niacin as low as 30 mg daily, it is more common with the larger doses used for treatment of dyslipidemia. The flushing reaction is due to prostaglandin-induced blood vessel dilation and can also include symptoms of burning, tingling, urticaria, erythema, pain, and itching of the face, arms, and chest. There may also be increased intracranial blood flow and headache (4889,26089,93341,104933). Onset is highly variable and ranges from within 30 minutes to as long as 6 weeks after the initial dose (6243). Flushing can be minimized via various strategies, including taking doses with meals, slow dose titration, using extended release formulations, pretreating with non-steroidal anti-inflammatory drugs, taking regular-release niacin with meals, or taking the sustained-release product at bedtime (4852,4853,4854,4857,4858,25922,26073,26084). Flushing often diminishes with continued use but can recur when niacin is restarted after missed doses (4863,6243,26081). The vasodilating effects of niacin can also cause hypotension, dizziness, tachycardia, arrhythmias, syncope, and vasovagal attacks, especially in patients who are already taking antihypertensive drugs (4863,12033,93341,110494).
High doses of niacin can raise homocysteine levels. A 17% increase has been reported with 1 gram daily and a 55% increased has been reported with 3 grams daily. Elevated homocysteine levels are an independent risk factor for cardiovascular disease (490); however, the clinical significance of this effect is unknown. A large-scale study (AIM-HIGH) found that patients receiving extended-release niacin (Niaspan) 1500-2000 mg daily with a statin had an over two-fold increased risk of ischemic stroke (1.6%) when compared with those receiving only simvastatin (0.7%). However, when the risk was adjusted for confounding factors, niacin was not found to be associated with increased stroke risk (17627,93354). A meta-analysis of three clinical trials conducted in approximately 29,000 patients showed a higher risk of mortality in patients taking niacin in addition to a statin when compared with a statin alone. However, with a p-value of 0.05 and confidence interval including 1, the validity of this finding remains unclear (97308).

Endocrine ...Orally, niacin can impair glucose tolerance in a dose-dependent manner. Dosages of 3-4 grams daily appear to increase blood glucose in patients with or without diabetes, while dosages of 1.5 grams daily or less have minimal effects (12033). Niacin is thought to impair glucose tolerance by increasing insulin resistance or increasing hepatic output of glucose (4863,11692,11693). In patients with diabetes, niacin 4.5 grams daily for 5 weeks has been associated with an average 16% increase in plasma glucose and 21% increase in glycated hemoglobin (HbA1C) (4860). Up to 35% of patients with diabetes may need to increase the dose or number of hypoglycemic agents when niacin is started (4458,4860,4863,11689,12033). Occasionally, severe hyperglycemia requiring hospitalization can occur (11693). In patients with impaired fasting glucose levels, niacin may also increase fasting blood glucose, and adding colesevelam might attenuate this effect (93343).
Although patients without diabetes seem to only experience small and clinically insignificant increases in glucose (4458), niacin might increase their risk of developing diabetes. A meta-analysis of clinical research involving over 26,000 patients shows that using niacin over 5 years is associated with increased prevalence of new onset type 2 diabetes at a rate of 1 additional case of diabetes for every 43 patients treated with niacin (96207). This finding is limited because the individual trials were not designed to assess diabetes risk and the analysis could not be adjusted for confounding factors like obesity. One small clinical study shows that taking extended-release niacin with ezetimibe/simvastatin does not increase the risk of a new diagnosis of diabetes or need for antidiabetic medication when compared with ezetimibe/simvastatin alone after 16 months (93344). This may indicate that the increased risk of developing diabetes is associated with niacin use for more than 16 months.
Niacin therapy has also been linked with hypothyroidism and its associated alterations in thyroid hormone and binding globulin tests (such as decreased total serum thyroxine, increased triiodothyronine, decreased thyroxine-binding globulin levels, and increased triiodothyronine uptake) (25916,25925,25926,25928).

Gastrointestinal ...Orally, large doses of niacin can cause gastrointestinal disturbances including nausea, vomiting, bloating, heartburn, abdominal pain, anorexia, diarrhea, constipation, and activation of peptic ulcers (4458,4863,12033,26083,93341,96211). These effects may be reduced by taking the drug with meals or antacid, and usually disappear within two weeks of continued therapy (4851,26094). Gastrointestinal effects may be more common with time-release preparations of niacin (11691).

Hematologic ...Orally, sustained-release niacin has been associated with cases of reversible coagulopathy, mild eosinophilia, and decreased platelet counts (4818,25915,26097,93340). Also, there have been reports of patients who developed leukopenia while taking niacin for the treatment of hypercholesterolemia (25916).

Hepatic ...Orally, niacin is associated with elevated liver function tests and jaundice, especially with doses of 3 grams/day or more, and when doses are rapidly increased (4458,4863,6243). The risk of hepatotoxicity appears to be higher with slow-release and extended-release products (4855,4856,4863,6243,11691,12026,12033,93342). Niacin should be discontinued if liver function tests rise to three times the upper limit of normal (4863). There are rare cases of severe hepatotoxicity with fulminant hepatitis and encephalopathy due to niacin (4863,6243,11691). In one case, a patient taking extended-release niacin 2500 mg daily for 15 years developed decompensating cirrhosis and was diagnosed with chronic, toxic, metabolic liver injury. Despite medical intervention, the patient died (113553). Also, there is at least one case of niacin-induced coagulopathy resulting from liver injury without liver enzyme changes (93340).

Musculoskeletal ...Orally, niacin has been associated with elevated creatine kinase levels (4818,4888). Also, several cases of niacin-induced myopathy have been reported (26100,26111). Concomitant administration of niacin and HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis (14508,25918,26111); patients should be monitored closely.

Neurologic/CNS ...Orally, high-dose niacin has been associated with cases of neuropsychiatric adverse events such as extreme pain and psychosis. Two 65-year-old males taking niacin orally for 5 months for the treatment of dyslipidemias developed severe dental and gingival pain. The pain was relieved by the discontinuation of niacin. The pain was thought to be due to inflammation and pain referral to the teeth (4862). In one case report, a 52-year-old male with no history of psychiatric illness who initially complained of hot flushes when taking niacin 500 mg daily, presented with an acute psychotic episode involving mania after niacin was increased to 1000 mg daily (93350).

Ocular/Otic ...Orally, chronic use of large amounts of niacin has been associated with dry eyes, toxic amblyopia, blurred vision, eyelid swelling, eyelid discoloration, loss of eyebrows and eyelashes, proptosis, keratitis, macular edema, and cystic maculopathy, which appear to be dose-dependent and reversible (4863,6243,26112).

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General ...Orally, St. John's wort is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dizziness, dry mouth, gastrointestinal discomfort (mild), fatigue, headache, insomnia, restlessness, and sedation.
Topically: Skin rash and photodermatitis.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of suicidal ideation and psychosis after taking St. John's wort.

Cardiovascular ...In clinical research, palpitations have been reported for patients taking St. John's wort orally, although the number of these events was higher for the patients taking sertraline (76070). In one case report, an adult female developed recurrent palpitations and supraventricular tachycardia (SVT) within 3 weeks of initiating St. John's wort 300 mg daily. SVT and related symptoms responded to Valsalva maneuvers and did not recur after discontinuing therapy (106051).
Edema has also been reported in clinical research for some patients treated with St. John's wort 900-1500 mg daily for 8 weeks (10843). Cardiovascular collapse following induction of anesthesia has been reported in an otherwise healthy patient who had been taking St. John's wort for 6 months (8931). A case of St. John's wort-induced hypertension has been reported for a 56-year-old patient who used St. John's wort extract 250 mg twice daily for 5 weeks. Blood pressure normalized after discontinuation of treatment (76073). A case of new-onset orthostatic hypotension and light-headedness has been reported for a 70 year-old homebound patient who was taking multiple prescription medications and herbal products, including St. John's wort (76128). When all herbal products were discontinued, these symptoms improved, and the patient experienced improvement in pain control.

Dermatologic ...Both topical and chronic oral use of St. John's wort can cause photodermatitis (206,620,758,4628,4631,6477,13156,17986,76072,76148)(95506,110318). The average threshold dose range for an increased risk of photosensitivity appears to be 1.8-4 grams St. John's wort extract or 5-10 mg hypericin, daily. Lower doses might not cause this effect (4542,7808). For example, a single dose of St. John's wort extract 1800 mg (5.4 mg hypericin) followed by 900 mg (2.7 mg hypericin) daily does not seem to produce skin hypericin concentrations thought to be high enough to cause phototoxicity (3900,4542,76266). Females appear to have a higher risk of dose-related photosensitivity. In a dose-ranging, small clinical trial, almost all of the female participants experienced mild to moderate photosensitivity with paresthesia in sun-exposed skin areas after administration of St. John's wort (Jarsin, Casella Med) 1800 mg daily for 3-6 days. Symptoms resolved about 12-16 days after discontinuation (95506). Male participants reported no adverse effects at this dose, and both genders reported no adverse effects at lower doses. Light or fair-skinned people should employ protective measures against direct sunlight when using St. John's wort either topically or orally (628).
Total body erythroderma without exposure to sunlight, accompanied by burning sensation of the skin, has also been reported (8930). Orally, St. John's wort may cause pruritus or skin rash, although these events seem to occur infrequently (76140,76148,76245). A case of persistent scalp and eyebrow hair loss has been reported for a 24-year-old schizophrenic female who was taking olanzapine plus St. John's wort 900 mg/day orally (7811). Also, a case of surgical site irritation has been reported for a patient who applied ointment containing St. John's wort (17225).

Endocrine ...A case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 67-year-old male with depression has been reported. During a 3-month period, the patient was taking St. John's wort 300 mg daily then increased to 600-900 mg daily with no adverse effects despite a low serum sodium level of 122mEq/L, elevated levels of urine sodium, and urine osmolality suggestive of SIADH. St. John's wort appeared to be the only contributing factor. The patient's sodium level normalized 3 weeks after discontinuation of St. John's wort (95508).

Gastrointestinal ...Orally, St. John's wort may cause dyspepsia, anorexia, diarrhea, nausea, vomiting, and constipation, although these events seems to occur infrequently (4897,13021,17986,76070,76071,76113,76146,76150,76271).

Genitourinary ...Orally, St. John's wort can cause intermenstrual or abnormal menstrual bleeding (1292,76056). However, this effect has occurred in patients who were also taking an oral contraceptive. Changes in menstrual bleeding might be the result of a drug interaction (1292,76056). Also, St. John's wort has been associated with anorgasmia and frequent urination when used orally (10843,76070).
Sexual dysfunction can occur with St. John's wort, but less frequently than with SSRIs (10843). A case of erectile dysfunction and orgasmic delay has been reported for a 49-year-old male after taking St. John's wort orally for one week. Co-administration of sildenafil 25-50 mg prior to sexual activity reversed the sexual dysfunction. Previously, the patient had experienced orgasmic delay, erectile dysfunction, and inhibited sexual desire when taking a selective serotonin reuptake inhibitor (sertraline) (4836).

Hepatic ...A case of acute hepatitis with prolonged cholestasis and features of vanishing bile duct syndrome has been reported for a patient who used tibolone and St. John's wort orally for 10 weeks (76135). A case of jaundice with transaminitis and hyperbilirubinemia has been reported for a 79 year-old female who used St. John's wort and copaiba (95505). Laboratory values normalized 7 weeks after discontinuation of both products.

Musculoskeletal ...Orally, St. John's wort may cause muscle or joint stiffness, tremor, muscle spasms, or pain, although these events appear to occur rarely (76070).

Neurologic/CNS ...St. John's wort may cause headache, dizziness, fatigue, lethargy, or insomnia (5096,13021,76070,76071,76113,76132,76133,76150,89666). Isolated cases of paresthesia have been reported for patients taking St. John's wort (5073). A case of subacute toxic neuropathy has been reported for a 35-year-old female who took St. John's wort 500 mg daily orally for 4 weeks (621).

Ocular/Otic ...There is concern that taking St. John's wort might increase the risk of cataracts. The hypericin constituent of St. John's wort is photoactive and, in the presence of light, may damage lens proteins, leading to cataracts (1296,17088). In population research, people with cataracts were significantly more likely to have used St. John's wort compared to people without cataracts (17088). Ear and labyrinth disorders have been possibly attributed to use of St. John's wort in clinical research, although these events rarely occur (76120).

Psychiatric ...St. John's wort can induce hypomania in depressed patients and mania in depressed patients with occult bipolar disorder (325,3524,3555,3568,10845,76047,76064,76137,110318). Cases of first-episode psychosis have been reported for females who used St. John's wort orally. In both cases, symptoms resolved following discontinuation of St. John's wort and treatment with antipsychotics for several weeks (13015,89664). Also, psychosis and delirium have been reported for a 76-year-old female patient who used St. John's wort for 3 weeks. The patient may have been predisposed to this effect due to undiagnosed dementia (76270). Restlessness, insomnia, panic, and anxiety have been noted for some patients taking St. John's wort orally (5073,13156,76070,76132,76268,76269,89665).
In isolated cases, St. John's wort has been associated with a syndrome consisting of extreme anxiety, confusion, nausea, hypertension, and tachycardia. These symptoms may occur within 2-3 weeks after it is started, in patients with no other predisposing factors. This syndrome has been diagnosed as the serotonin syndrome (6201,7811,110318). In one case, the symptoms began after consuming tyramine-containing foods, including aged cheese and red wine (7812). In an isolated case, a 51-year-old female reported having had suicidal and homicidal thoughts for 9 months while taking vitamin C and a St. John's wort extract. Symptoms disappeared within 3 weeks of discontinuing treatment (76111). A case of decreased libido has been reported for a 42-year-old male with mood and anxiety disorders who had taken St. John's wort orally for 9 months (7312).
St. John's wort has been associated with withdrawal effects similar to those found with conventional antidepressants. Headache, nausea, anorexia, dry mouth, thirst, cold chills, weight loss, dizziness, insomnia, paresthesia, confusion, and fatigue have been reported. Withdrawal effects are most likely to occur within two days after discontinuation but can occur one week or more after stopping treatment in some people. Occurrence of withdrawal symptoms may not be related to dose or duration of use (3569,11801).

Pulmonary/Respiratory ...Orally, St. John's wort may cause sore throat, swollen glands, laryngitis, sinus ache, sweating, and hot flashes, although the frequency of these events appears to be similar to placebo (76150).

Renal ...Orally, St. John's wort has been associated with a case report of acute kidney failure in a 46-year-old female after one dose of homemade St. John's wort tea. Three sessions of hemodialysis were required before there was full recovery (106741). However, causality is unclear since the patient had also been taking diclofenac intermittently for a month prior to developing kidney failure.

Other ...Sjogren's syndrome has been reported in a patient taking herbal supplements including St. John's wort, echinacea, and kava. Echinacea may have been the primary cause, because Sjogren's syndrome is an autoimmune disorder. The role of St. John's wort in causing this syndrome is unclear (10319).

(Read more about ST. JOHN'S WORT)

General ...Orally and parenterally, thiamine is generally well tolerated.
Serious Adverse Effects (Rare):
Parenterally: Hypersensitivity reactions including angioedema and anaphylaxis.

Immunologic ...Orally, thiamine might rarely cause dermatitis and other allergic reactions. Parenterally, thiamine can cause anaphylactoid and hypersensitivity reactions, but this is also rare (<0.1%). Reported symptoms and events include feelings of warmth, tingling, pruritus, urticaria, tightness of the throat, cyanosis, respiratory distress, gastrointestinal bleeding, pulmonary edema, angioedema, hypotension, and death (15,35585,105445).
In one case report, a 46-year-old female presented with systemic allergic dermatitis after applying a specific product (Inzitan, containing lidocaine, dexamethasone, cyanocobalamin and thiamine) topically by iontophoresis; the allergic reaction was attributed to thiamine (91170).

(Read more about THIAMINE)

General ...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).

Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).

Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).

Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.

Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).

Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Daily doses of 100 mg or less are unlikely to cause these problems (3094).

Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).

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