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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

LIKELY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about FOLIC ACID)

POSSIBLY INEFFECTIVE

• Depression. Although it is unclear if oral L-tryptophan is beneficial in patients with depression, there is a lack of supporting evidence and a rare risk of adverse effects such as serotonin syndrome. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that L-tryptophan is not currently recommended for adjunctive or monotherapy use for major depressive disorder. The available small and low-quality studies have not supported L-tryptophan for this use (110318). Some older research suggests that taking L-tryptophan with clomipramine might improve the effectiveness of clomipramine (10856). However, it is not clear whether L-tryptophan is beneficial when taken along with newer classes of antidepressants. Also, the CANMAT Taskforce cautions the co-use of L-tryptophan with serotonergic antidepressants due to the rare risk of serotonin syndrome (110318).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there is interest in using oral L-tryptophan for anxiety, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Athletic performance. It is unclear if oral L-tryptophan is beneficial for improving athletic performance. Details: Some clinical research shows that taking L-tryptophan 300 mg orally along with a sugar and electrolyte drink twice daily for 3 days prior to exercise and on the day of exercise improves power output during the last 20 minutes of exercise when compared with taking a sugar and electrolyte drink without L-tryptophan. The improvement in power output increases distance covered by about 5% without increasing perceived exhaustion (91462). However, other clinical research shows that taking L-tryptophan 12 mg/kg after 5 minutes of warm-up and then 6 mg/kg orally every 15 minutes during exercise does not improve time to exhaustion in endurance-trained male athletes (1135). Reasons for the discrepancy are not clear. It is possible that L-tryptophan benefits some measures of athletic performance, but not others.
• Bruxism. It is unclear if oral L-tryptophan is beneficial for bruxism. Details: A very small clinical trial in adults with nocturnal bruxism shows that taking L-tryptophan 50 mg/kg daily orally for 8 days does not improve levels of teeth grinding when compared with placebo (1139).
• Cognitive impairment. It is unclear if oral L-tryptophan is beneficial in patients with cognitive impairment. Details: Clinical research in elderly individuals with mild cognitive impairment shows that taking L-tryptophan 95 mg orally with docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and melatonin 5 mg (IBSA Farmaceutici Italia) nightly for 12 weeks improves cognitive function and sensitivity to smells by a small amount when compared with placebo. Patients treated with the combination showed a 1-point improvement in cognitive function based on the mini-mental state examination (MMSE) scale, while patients in the placebo group showed a 2-point decline (62847). However, these results might not be clinically significant. Also, it is not known if any potential benefit is due to L-tryptophan, other ingredients, or the combination.
• Fibromyalgia. It is unclear if oral L-tryptophan is beneficial in patients with fibromyalgia. Details: Preliminary clinical research in females with fibromyalgia shows that eating a standardized Mediterranean diet supplemented with walnuts, to supply L-tryptophan 60 mg daily and magnesium 60 mg daily for 16 weeks, modestly reduces anxiety, mood disturbance, eating disorders, and dissatisfaction with body image, but does not affect sleep, when compared with the Mediterranean diet alone. It is unclear if these effects are due to L-tryptophan, magnesium, other components of the added foods, or the combination (103172).
• Gout. Oral L-tryptophan has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild hyperuricemia shows that taking a powder containing L-tryptophan 0.2 grams and glycine 3 grams nightly for 6 weeks decreases serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, the effect of this combination for gout-related pain is unknown. Also, it is not clear if this effect is due to L-tryptophan, glycine, or the combination.
• Helicobacter pylori. A small clinical study suggests that adding L-tryptophan to treatment with omeprazole increases ulcer healing. Details: Clinical research shows that taking L-tryptophan (Ardeydorm, Ardeypharm GmbH) 250 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Insomnia. Small clinical studies suggest that oral or intravenous L-tryptophan may modestly improve symptoms, particularly sleep latency, in patients with insomnia. Details: Clinical research shows that taking L-tryptophan 500 mg twice daily for 2 weeks improves insomnia in patients undergoing detoxification from methamphetamine or ketamine when compared with placebo. However, it does not seem to improve psychological symptoms in these patients (97242). One small clinical study shows that taking L-tryptophan orally, 1 gram 20 minutes before bed, might decrease sleep latency and improve mood when compared with placebo in healthy people with insomnia. Smaller doses of 250 mg and 500 mg did not demonstrate benefit (1146). Other clinical research shows that a single 5 gram intravenous infusion of L-tryptophan decreases sleep latency and increases total sleep time when compared with baseline in patients with insomnia (14896).
• Migraine headache. The incidence of migraine headaches may decrease with increased dietary L-tryptophan intake. Details: Preliminary clinical research shows that a dietary L-tryptophan intake of 0.84-1.06 grams per day reduces the odds of experiencing a migraine of any type by 54% to 60% when compared with an intake of 0.56 grams per day or less (103171).
• Myofascial pain syndrome. It is unclear if oral L-tryptophan is beneficial in patients with myofascial pain syndrome. Details: Some clinical research in adults with chronic maxillofacial pain shows that taking L-tryptophan orally 3 grams daily for 4 weeks is associated with a greater reduction in pain score and an increase in pain tolerance when compared with placebo (1145). However, other clinical research shows that L-tryptophan does not reduce pain when compared with placebo (1140).
• Obesity. Although there is interest in using oral L-tryptophan for obesity, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Premenstrual dysphoric disorder (PMDD). Limited clinical research suggests that L-tryptophan may reduce symptoms of PMDD. Details: A small clinical study in adults with PMDD shows that taking L-tryptophan orally 6 grams daily for approximately 17 days, from the time of ovulation to the third day of menstruation, for three consecutive cycles reduces mood swings, tension, and irritability when compared with placebo (6246).
• Premenstrual syndrome (PMS). Although there is interest in using oral L-tryptophan for premenstrual syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral L-tryptophan is beneficial in patients with SAD. Details: One very small clinical crossover study shows that taking L-tryptophan 4-6 grams orally daily in divided doses for 4 weeks improves seasonal affective disorder to a similar degree as receiving light therapy for 2 weeks (6247). However, this study was not powered to detect a difference between groups.
• Sleep apnea. Although there is interest in using oral L-tryptophan for sleep apnea, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Smoking cessation. It is unclear if oral L-tryptophan is beneficial for smoking cessation. Details: A small clinical study in adults attempting to quit smoking shows that taking L-tryptophan 50 mg/kg daily orally for 2 weeks in conjunction with standard smoking cessation treatments results in fewer daily cigarettes smoked when compared with placebo. Reported anxiety and other withdrawal symptoms were also lower in the L-tryptophan group (1138). However, the study was not powered to detect a statistically significant difference in these outcomes between groups.
• Tourette syndrome. Although there is interest in using oral L-tryptophan for Tourette syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition. More evidence is needed to rate L-tryptophan for these uses.

(Read more about L-TRYPTOPHAN)

LIKELY EFFECTIVE

• Delayed sleep phase syndrome (DSPS). Oral melatonin shortens the time needed to fall asleep in children and adults with DSPS. Details: Most clinical research shows that taking melatonin orally reduces the length of time needed to fall asleep and advances sleep onset time in young adults and children with DSPS (8244,12226,15005,62714,62792,63055,88288,88290,89509). In adults, 0.3-5 mg daily for up to 9 months has been used (8244,62714,62792,63055,88290,89509). In children, 1-6 mg before bedtime for up to one month has been used (62714,62792,89509). In addition to improving sleep, melatonin also improves measures of quality of life such as mental health, vitality, and bodily pain in young adults with DSPS (8244,12226,15005). However, relapse to pre-treatment sleeping patterns seems to occur within one year after stopping supplementation (63048).
• Non-24-hour sleep wake disorder. Oral melatonin improves non-24-hour sleep wake disorder in blind children and adults. Details: Taking oral melatonin 0.5-4 mg daily in children and 0.5-10 mg daily in adults for up to 6 years helps improve circadian rhythm sleep disorders in blind children and adults (1082,1744,1749,6585,62346,62350).

POSSIBLY EFFECTIVE

• Beta blocker-induced insomnia. Oral melatonin seems to improve sleep in patients with insomnia related to the use of beta-blockers. Details: Beta-blockers such as atenolol and propranolol seem to decrease endogenous melatonin levels (1780). This might result in insomnia as a side effect. Clinical and preclinical research shows that taking a melatonin supplement might decrease the insomnia caused by beta-blockers (1062,89502). Taking melatonin 5 mg at night after taking atenolol 100 mg appears to attenuate the changes in sleep onset latency, total wake time, and wakefulness after sleep onset when compared with taking atenolol 100 mg alone (1062). Also, in patients taking atenolol or metoprolol, taking melatonin 2.5 mg one hour before bedtime for 20-28 days increases total sleep time by 13-37 minutes and decreases sleep latency by 8-14 minutes when compared with placebo (89502).
• Cancer. In patients with various types of cancer, most research shows that oral or combined intramuscular/oral melatonin in combination with chemotherapy or other treatments seems to improve tumor regression and survival rates. Details: There is some evidence that taking combined high-dose melatonin with conventional chemotherapy or with interleukin-2 (IL-2) might improve tumor regression rate in patients with breast, lung, kidney, liver, pancreatic, stomach, or colon cancer (1692,5854,5855,5857,7040,7043,8268,62407,62844). Melatonin plus chemotherapy in patients with metastatic solid tumors seems to increase the regression rate and one-year survival rate by about 40% to 50% when compared with chemotherapy alone (7040,62407,62844,89504). The addition of melatonin also seems to help reduce chemotherapy toxicities, including hematologic complications, cachexia, asthenia, and neuropathy (8268,62844,89504). There is also some preliminary evidence that melatonin alone, orally or intramuscularly, might improve stabilization rate and possibly one-year survival rate in patients with resistant or untreatable neoplasms of the lung, liver, pancreas, colon, breast, or brain (1080,1688,1693,2566). Also, when used in combination with radiotherapy, high-dose melatonin seems to increase the survival time and percent survival in patients with brain glioblastomas when compared with radiotherapy alone (62991). However, high-dose melatonin treatment does not seem to improve the survival of patients with brain metastases who receive radiation therapy (62455). Melatonin 10-40 mg daily has been used in most clinical trials (1080,1692,1693,2566,5854,5855,5857,7040,7043,8268)(62455,62844,62991,89504). In one study, melatonin 20 mg intramuscularly daily for 2 months, followed by oral melatonin 10 mg daily as maintenance, was used (1688). The effect of melatonin on quality of life and sleep quality in patients with cancer has also been investigated. A meta-analysis of six clinical trials shows that taking melatonin 20 mg daily does not improve sleep quality or quality of life when compared with a control, usually placebo. The duration of studies varied widely; from a period of 7 days or until death. However, there was a modest effect of melatonin on symptoms of depression in patients taking it for at least 14 days or those who underwent surgery (109697).
• Emergence delirium. Oral melatonin seems to be beneficial for reducing sevoflurane-induced agitation in children. It is unclear if oral melatonin is beneficial for adults undergoing surgery. Details: A meta-analysis of clinical research in perioperative adults shows that taking melatonin 3-5 mg or ramelteon 8 mg orally daily for 1-7 days reduces the risk of emergence delirium by 59% when compared with placebo or no treatment. However, the validity of these results is limited by high heterogeneity (112053). In children, clinical research shows that taking melatonin reduces the incidence of sevoflurane-associated emergence delirium (97440,106292,113216). Meta-analyses of 3-4 small clinical studies in children aged 2-9 years show that taking melatonin 0.05-0.5 mg/kg 40-45 minutes prior to sevoflurane reduces the incidence of agitation by 60% when compared with placebo (97440,113216). The most recent analysis also shows that taking melatonin reduces the incidence of agitation by 52% when compared with midazolam (113216). Most research shows that doses of melatonin 0.2 mg/kg or greater may be most effective (97440,106292). However, clinical research shows that taking melatonin is less effective than dexmedetomidine (109701,113216). One study shows that taking melatonin 0.5 mg/kg before surgery is 55% less effective than intranasal dexmedetomidine 2 mg/kg for reducing the incidence of sevoflurane-associated emergence delirium (109701).
• Hypertension. Oral controlled-release melatonin seems to reduce blood pressure by a small amount in patients with hypertension. Immediate-release melatonin may not have the same effect. Details: Controlled-release melatonin 2-24 mg, taken before bedtime for up to 4 weeks, seems to lower systolic blood pressure (SBP) by 4-6 mmHg and diastolic blood pressure (DBP) by about 4 mmHg in individuals with essential hypertension or high blood pressure at nighttime (62359,62416,62441,62826,108947). Some evidence shows that immediate-release melatonin does not have this effect (62826). Some evidence also suggests that melatonin seems to slightly reduce blood pressure in patients without hypertension, but to a lesser degree (103689). However, a very small clinical study in healthy young adults consuming a high sodium diet (6900 mg daily) shows that taking melatonin 10 mg before bedtime for 10 days decreases nighttime SBP but does not improve nighttime DBP, daytime SBP or DBP, 24-hour SBP or DBP, or nocturnal dipping of SBP or DBP when compared with placebo (112442).
• Insomnia. In patents with insomnia, oral melatonin seems to shorten the time it takes to fall asleep by about 7-12 minutes, although the effect on the amount of time asleep is inconclusive. Melatonin is more likely to be beneficial in older adults or people with certain comorbidities. Details: Short-term melatonin treatment appears to modestly reduce the time it takes to fall asleep (sleep latency) in otherwise healthy adults with insomnia. This reduction in sleep latency appears to amount to only about 7-12 minutes and might not be considered clinically relevant. Melatonin does not appear to improve sleep efficiency and may only increase total sleep time by about 8 minutes (15005,88290). Despite lack of substantial improvements in objective measures, some patients report minor improvement in subjective feelings of sleep quality (1070,1083,12226,88290). In children aged 6-12 years with insomnia due to delayed onset of sleep, melatonin 5 mg or 0.05-0.15 mg/kg at bedtime for up to 4 weeks seems to shorten the time that it takes to fall asleep and increases the duration of sleep (9708,62345,62770). More evidence is needed on the long-term effects of melatonin for insomnia. Some evidence shows that taking oral melatonin might be most beneficial for insomnia in elderly patients who could be melatonin deficient (1072,1729,1738,1754,7081,15005,62357,62465,62472,62613)(62776,62789). Taking sustained-release melatonin preparations 2 mg daily seems to improve sleep maintenance and sleep quality in elderly individuals (1738,1754,62465,62472,62613,62776), while immediate-release preparations seem to decrease sleep latency (1738,63041). In these clinical trials, controlled-release, fast-release, or slow-release melatonin 2-3 mg before bedtime for up to 29 weeks has been used (1072,1738,1754,7081,62357,62465,62472,62613,62776,62789). However, using a melatonin patch placed on the gums does not improve sleep parameters in elderly patients with insomnia (63062). Some research shows that taking melatonin when taken either alone or in combination with other sleep aids such as bright-light treatment seems to be beneficial for insomnia in patients with certain comorbid conditions. Taking melatonin 2-12 mg for up to 4 weeks has been used to improve insomnia in patients with depression (1053,1729), schizophrenia (8245,62452), bipolar disorder (62140), asthma (62375), cystic fibrosis (62708), hospitalization (9709,106295), and insomnia termed "ICU syndrome", which refers to sleep disturbances while in the intensive care unit (8240). Insomnia is also improved in children with epilepsy aged 3-12 years taking 6-9 mg of melatonin before bedtime for 4 weeks and children aged 3 months to 2 years taking 3 mg of melatonin before bedtime for 2 weeks (62394,99342,113223), and quality of sleep is modestly improved in adults with epilepsy taking 3 mg before bedtime for 8 weeks (110299). There is also evidence that melatonin can improve total sleep time and sleep-onset latency in children with tuberous sclerosis (1747), autism spectrum disorders (1056,62811,88286,96318,106293,110290), developmental disabilities (9707), and neurodevelopmental disorders (21819,62143,88283). It also appears to decrease sleep latency and increase sleep time in adults and children with intellectual disabilities, with or without epilepsy (62373,62561). While some evidence shows that fast-release melatonin is more effective for improving the time to fall asleep in children with sleep-wake cycle disturbances and neurodevelopmental disabilities, it is unclear if controlled-release melatonin provides any additional benefits in this population (62143,95746). However, there is conflicting evidence regarding the effects of melatonin in patients with insomnia and comorbid conditions such as Alzheimer disease or dementia. Some clinical research shows that taking melatonin 3-5 mg before bedtime for up to 10 weeks, either alone or in combination with bright-light treatment, improves impaired sleep related to Alzheimer disease or dementia (1729,62474,63059). But not all research agrees. Meta-analyses of several clinical studies show that taking melatonin 3-10 mg daily improves subjective sleep quality, but not objective outcomes such as number of awakenings at night and sleep efficiency in these patients. Also, immediate-release melatonin 2.5-10 mg or prolonged-release melatonin 1.5-2.5 mg for 10 days to 24 weeks shows inconsistent effects on total sleep time at night in patients with Alzheimer disease (96319,96320). There is also mixed evidence regarding the effects of melatonin in patients with Parkinson disease. Some subjective outcomes such as sleep quality seem to improve. However, the improvement might not be clinically significant, and objective outcomes such as sleep efficiency and total sleep time at night do not seem to improve (62403,62454,62829,96320). Melatonin has also been evaluated in postoperative patients and patients with traumatic brain injury (TBI). Taking melatonin before bed does not improve sleep quality soon after tracheostomy, laparoscopic cholecystectomy, or total knee arthroplasty (62439,62552,99343,100255) or 2-6 weeks after total joint arthroplasty (106305). In adults with TBI, one clinical study shows that taking prolonged-release melatonin (Circadin, Sigma Pharmaceuticals) 2 mg two hours prior to bedtime for 4 weeks improves sleep quality, efficiency, and fatigue when compared with placebo. However, melatonin did not improve sleep onset latency or daytime sleepiness. There appears to be no association between TBI severity and the effect of treatment (96317). There is mixed evidence regarding the effect of melatonin in patients undergoing hemodialysis. Some evidence shows that taking melatonin (Pharma Nord) 3 mg before bed for 6 weeks reduces time needed to fall asleep, improves sleep efficiency, and increases actual sleep time when compared with placebo (62521). Other clinical research in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves various sleep measures when compared with placebo. After treatment, 63.0% of those taking melatonin had no insomnia compared with 7.7% of those taking placebo (110291). However, other evidence shows that taking immediate-release melatonin (Pharma Nord) 3 mg nightly for 12 months does not improve quality of life or sleep efficiency in these patients, indicating that melatonin may not improve sleep long-term (89501). Finally, limited evidence shows that melatonin does not improve insomnia in patients with substance use disorders (97441).
• Jet lag. Taking oral melatonin 2-3 mg daily while travelling seems to improve alertness and reduce daytime sleepiness in people with jet lag. It is unclear if it improves sleep efficiency in this population. Higher doses might have a hypnotic effect. Details: Most research shows that melatonin can modestly improve certain symptoms of jet lag such as alertness and psychomotor performance. Melatonin also seems to improve, to a lesser extent, other jet lag symptoms such as daytime sleepiness and fatigue (12226). Melatonin might not be effective for decreasing the time to fall asleep (sleep latency) or sleep efficiency in patients with jet lag (6496,14283), although some research shows a beneficial effect of melatonin on these outcomes (62364). Doses between 0.5-5 mg appear to be equally effective. Although doses of up to 8 mg have been used, doses greater than 5 mg do not seem to be more effective and seem to produce a greater hypnotic effect. Travelers traveling eastward through five or more time zones may find 2-3 mg of melatonin, either slow-release or fast-release, to be useful when taken at local bedtime on the day of arrival and for 2-5 nights thereafter. Taking melatonin in advance of travel does not help prevent jet lag. The usefulness of melatonin for westward travel or over fewer time zones is less clear, although some evidence suggests that slow-release formulations are less effective than fast-release preparations (1049,1077,1079,1085,1722,8273,9181,9750,62706).
• Migraine headache. Oral melatonin 3-4 mg seems to prevent migraines when used prophylactically. It is unclear if oral melatonin is beneficial for treating migraine. Details: Melatonin production might be altered in people with migraine headache (6712,96316). Meta-analyses and individual clinical studies in adults have shown that taking melatonin modestly reduces migraine severity, duration, and frequency, and increases the likelihood of a 50% reduction in the baseline frequency of migraine, when compared with placebo or baseline. Immediate- or prolonged-release melatonin (occasionally as Circadin, Sigma Pharmaceuticals) in doses of 3-4 mg each evening for up to 6 months have been used in these studies (12149,96316,97438,103486,110286). Meta-analyses have included two or three individual clinical trials (103486,110286). One meta-analysis shows that taking melatonin reduces the frequency of migraine days by about 1.7 (103486). An additional meta-analysis in adults with migraines shows that taking melatonin modestly reduces the use of analgesic medications from baseline, when compared with placebo (110286). In contrast, other clinical research shows that taking extended-release melatonin (Circadin, Neurim Pharmaceuticals Ltd.) 2 mg nightly for 8 weeks does not reduce migraine attack frequency when compared with placebo (62784). Some clinical research also shows that melatonin is as effective as standard treatment for migraine prevention. Some research shows that taking melatonin 3 mg daily for 12 weeks is as effective as amitriptyline 25 mg in reducing migraine frequency, intensity, and duration, as well as reducing analgesic use (96316). A meta-analysis of two clinical trials shows that taking melatonin 3 mg each evening for 8-12 weeks is as effective as standard treatment; however, only one study each compared melatonin with amitriptyline (96316) and valproate (110286). More research comparing melatonin with standard treatments is needed. Melatonin has also been investigated in children. Preliminary clinical research in children 5-15 years of age with migraine headache shows that taking melatonin 0.3 mg/kg daily for 90 days reduces migraine frequency, severity, and duration, and decreases analgesic use when compared to baseline (97446). Some research also suggests that melatonin might help to TREAT migraine headache in children and adolescents aged 9-17 years. Preliminary clinical research shows that taking melatonin 1-8 mg reduces pain by a small amount 2-4 hours later. The higher doses of 2 mg for children weighing less than 40 kg and 8 mg for children weighing at least 40 kg seemed to have the greatest benefit (103487). This study is limited by the lack of a comparator group and a very high drop-out rate.
• Pre-procedural anxiety. Most research shows that oral or sublingual melatonin reduces preoperative anxiety in adults. The benefit in children is unclear. Details: A meta-analysis of 18 clinical studies in adults shows that taking oral or sublingual melatonin 3-10 mg or 0.05-0.4 mg/kg 20-120 minutes prior to surgery reduces preoperative anxiety by an average of 12 points on a 100-point visual analogue scale when compared with placebo. It also reduces postoperative anxiety by about 5 points when compared with placebo. Furthermore, a meta-analysis of 7 small clinical trials suggests that melatonin is comparable to benzodiazepines such as midazolam, oxazepam, or alprazolam for reducing preoperative anxiety (105005). In some cases, melatonin might also be preferable to benzodiazepines because it does not cause anterograde amnesia, respiratory depression, or impairment of cognitive and psychomotor skills (88299,99337). However, research in children is conflicting. Two small clinical studies in children aged 2-10 years preparing to undergo outpatient elective surgery show that taking melatonin 0.05-0.5 mg/kg 30-45 minutes before anesthesia is less effective than midazolam 0.5 mg/kg for reducing preoperative anxiety, including during separation from parents and when putting on the anesthesia mask (62601). In contrast, another small clinical study in children aged 2-5 years undergoing minor elective surgery shows that taking oral melatonin 0.25-0.5 mg/kg 1 hour before anesthesia is similar to midazolam 0.25-0.5 mg/kg for reducing anxiety when separating from parents and when putting on the anesthesia mask (62399). A third study in children aged 3-8 years found no differences between melatonin 0.3 mg/kg, midazolam 0.3 mg/kg, and placebo for reducing preoperative anxiety (106292).
• Pre-procedural sedation. Oral melatonin might reduce the sedative dose required to achieve adequate sedation in children. It is unclear if oral melatonin is beneficial for this purpose in adults. Details: A clinical study in children aged 5-14 years undergoing surgery shows that oral melatonin 0.5 mg/kg reduces the propofol dose required for adequate sedation by 0.77 mg/kg when compared with midazolam 0.5 mg/kg (97444). However, taking melatonin 0.5 mg/kg 45 minutes before surgery is less effective than intranasal dexmedetomidine 2 mg/kg for successful mask acceptance and parental separation (109701). A meta-analysis of clinical and observational studies in children undergoing non-operative procedures, such as electroencephalogram (EEG) and magnetic resonance imaging (MRI), suggests that enteral or parenteral melatonin is no better for adequate sedation than sleep deprivation or chloral hydrate (105884). This finding is limited by imprecision, inconsistency, and a high risk of bias. A small clinical study in adults undergoing total abdominal hysterectomy shows that taking extended-release melatonin 5 mg, 90 minutes before surgery, decreases the use of midazolam for sedation during surgery when compared with placebo (108945). However, the validity of this finding is unclear, as 0% of patients in the melatonin group required midazolam, compared with 100% of patients in the placebo group. In adults undergoing lower extremity orthopedic surgery with spinal anesthesia, a small study shows that giving melatonin 10 mg orally the night before surgery, followed by 10 mg 2 hours prior to surgery, increases the sedation score when compared with placebo (108951).
• Sunburn. Most research shows that topical melatonin seems to protect against erythema from ultraviolet (UV) light exposure. Details: When applied prior to UV light exposure, a gel containing melatonin 0.05% to 2.5% seems to significantly decrease erythema (1066,1768,1769). In one study, topically applied melatonin in combination with vitamin E 2% and/or vitamin C 5%, was modestly photoprotective when used prior to UV exposure, but had no effect when used during or after UV exposure (4713,4714). Other preliminary clinical research shows that applying a cream containing melatonin 12.5% prior to sun exposure reduces erythema in adults with high sun reactivity, but not in those with mild to moderate sun reactivity. Creams containing melatonin 0.5% or 2.5% did not reduce erythema in any skin types when compared with placebo (97443). The differences in these findings may be related to the different topical formulations used.
• Temporomandibular disorders (TMD). Oral melatonin seems to moderately reduce pain in females with TMD. Details: Clinical research shows that taking melatonin 5 mg at bedtime for 4 weeks reduces pain by 44% and increases the ability to withstand pain by 39% when compared with placebo in females with TMD. This results in reduced analgesic use and improved sleep quality (89508).
• Thrombocytopenia. Oral melatonin seems to improve and prevent thrombocytopenia associated with cancer, cancer treatment, and other disorders. Details: Clinical research shows that taking melatonin can improve thrombocytopenia associated with cancer, cancer treatment, and other disorders. Melatonin 20-40 mg daily beginning up to 7 days before chemotherapy and continuing for up to four chemotherapy cycles or until disease progression has been used (1694,1695,1696,1697,2564,8268).

POSSIBLY INEFFECTIVE

• Athletic performance. Most research suggests that oral melatonin does not improve athletic performance or physical strength. Details: Taking melatonin 6 mg one hour prior to heavy resistance exercise does not seem to improve maximal strength or maximal jumping ability (62424). Also, taking melatonin 5 mg at night does not appear to improve exercise performance the following morning in healthy athletes (62179). Furthermore, taking melatonin 5 mg 15 minutes prior to exercise does not appear to impact endurance during a cycling trial when compared with placebo (99338). However, some research disagrees. One small clinical trial in professional soccer players shows that taking melatonin 5 mg daily during a six-day training schedule modestly attenuates deterioration in physical performance, such as jumping, agility, and sprints, when compared with placebo (109700).
• Cachexia. Oral melatonin does not seem to improve appetite or body composition in patients with cachexia and cancer. Details: Clinical research in cachectic patients with advanced lung or gastrointestinal cancers shows that taking melatonin 20 mg each evening for 28 days does not improve appetite, body weight, or body composition when compared with placebo (88287).
• Cancer-related fatigue. Oral melatonin does not seem to improve fatigue in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce fatigue in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 7 days to one year (99344,109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year. However, some research disagrees. Preliminary clinical research in adults with breast cancer shows that taking melatonin 18 mg orally daily for 2 years moderately improves fatigue scores when compared with placebo (112054).
• Cancer-related pain. Oral melatonin does not seem to improve pain in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce pain in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 10 days to one year (109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year.
• Critical illness (trauma). Oral melatonin does not seem to be beneficial for reducing hospital stay in critically ill patients. Details: A meta-analysis of clinical research in critically ill patients shows that taking melatonin does not reduce the length of stay in the ICU or the hospital, or affect mortality or sleep quality, when compared with placebo (109696). One additional small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997).
• Dementia. Oral melatonin does not seem to improve behavior or cognition in patients with dementia. However, it might reduce evening confusion (sundowning). Details: Most clinical research shows that taking melatonin does not improve cognition or behavioral or affective symptoms in patients with probable Alzheimer disease or other forms of dementia (62421,62530,96319). However, some research shows that taking melatonin 2.5-3 mg before bedtime for up to 10 weeks reduces sundowning, which is the confusion and restlessness experienced by some dementia patients in the evening (62788).
• Infertility. Oral melatonin does not seem to increase fertility in females undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Details: Some clinical research shows that taking melatonin does not improve fertility rate or clinical pregnancy rate in adults undergoing IVF, although oocyte and embryo quality might be improved (62775,62818,62819,88297,89512). Also, results from meta-analyses of clinical research show that melatonin does not improve clinical pregnancy rate, total number of oocytes retrieved, or the rate of miscarriage, although it seems to increase the number of mature oocytes (89505,106304). Most studies have used single doses of 3 mg daily which may not be adequate (106304). Melatonin has also been evaluated in adults undergoing ICSI. Although one study shows that taking melatonin improves the fertilization rate, the clinical pregnancy rate was not evaluated (88297). Other research in females taking melatonin and undergoing ICSI does not show an increase in clinical pregnancy rate (97445).
• Shift work disorder. Oral melatonin does not seem to improve sleep in individuals doing shift work. Details: Taking melatonin orally doesn't seem to significantly improve the time it takes to fall asleep (sleep latency), sleep efficiency, or adjustment to rotating shift work. However, slight increases in total sleep time during the day or overall sleep quality may occur (1052,1054,1721,14283,62200,62401,62462,62942).

LIKELY INEFFECTIVE

• Benzodiazepine withdrawal. Oral melatonin does not facilitate benzodiazepine discontinuation in patients with insomnia. Details: Although some small studies show benefit (349,1751), results from larger clinical studies and a meta-analysis of clinical research show that taking melatonin 2-5 mg before bedtime for up to 6 weeks does not help facilitate benzodiazepine discontinuation in patients with insomnia (62464,62467,63075,88295,96321,96323).
• Depression. Most research shows that oral melatonin does not reduce symptoms of depression or prevent depression. In some patients, taking melatonin might make symptoms worse. Details: Most research shows that taking melatonin 5-10 mg daily before bedtime for 4-12 weeks, alone or with fluoxetine, does not improve depression symptoms in patients with rapid cycling bipolar disorder (1766) or major depressive disorder (MDD) (1053,62746,96326). However, some research shows that taking slow-release melatonin 3 mg in combination with immediate-release buspirone 15 mg daily for 6 weeks is more effective at improving depression severity and depression symptoms than placebo or buspirone alone in patients with MDD (88289). However, buspirone is not commonly used for the management of depression. Also, there is some concern that oral melatonin may worsen symptoms in some patients with unipolar or bipolar depression (1764). Evidence regarding the effects of melatonin for preventing depression is unclear. One clinical study shows that taking melatonin 6 mg daily for 12 weeks reduces the percentage of breast cancer patients who develop depression following a lumpectomy or mastectomy by about 75% when compared with placebo when an intention to treat analysis is used. However, when only patients who took all of the doses are considered, melatonin does not appear to have an effect (89511). Also, a meta-analysis of clinical research including two studies in patients with irritable bowel syndrome (IBS) who were at risk for depression shows that melatonin does not prevent depression when compared with placebo (96326).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral melatonin is beneficial for acute kidney injury. Details: A meta-analysis of randomized clinical trials in adults with drug-induced acute kidney injury shows that taking melatonin 3-30 mg daily for up to 6 days modestly improves glomerular filtration rate, but not serum creatinine or incidence of acute kidney injury, when compared with placebo (111463). Another meta-analysis of 5 clinical trials shows that taking melatonin inhibits the occurrence of acute kidney injury in at risk patients by 44% when compared with placebo. However, changes in serum creatinine and urea nitrogen were not statistically significant. Doses of melatonin varied from single doses of up to 5 mg and 6 mg to 30 mg daily for 5 to 14 days (113225).
• Age-related macular degeneration (AMD). It is unclear if oral melatonin prevents vision loss in patients with AMD. Details: Preliminary clinical research shows that taking melatonin 3 mg daily for 3-6 months may delay the loss of clear vision in individuals with AMD when compared with baseline (62419). The validity of this finding is limited by the lack of a comparator group.
• Atopic dermatitis (eczema). Oral melatonin might improve some symptoms of atopic dermatitis. However, it is unclear if it improves sleep in this population. Details: Preliminary clinical research in children ages 1-18 years with atopic dermatitis and sleep disturbance shows that taking melatonin 3 mg daily for 4 weeks modestly reduces the overall atopic dermatitis symptom score by 19% when compared with placebo (97439). In another clinical study in children with atopic dermatitis, taking melatonin 6 mg daily 1 hour before bedtime for 6 weeks seems to improve disease severity and sleep quality when compared with placebo (99347). It is unclear whether melatonin improves sleep latency in this population, as conflicting results exist (97439,99347).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral melatonin is beneficial for ADHD. Details: Some small clinical studies in children with ADHD who are taking stimulants show that melatonin 3-5 mg daily for up to 3 months might reduce insomnia when compared with placebo (9980,15034). However, improved sleep related to melatonin treatment does not seem to result in fewer symptoms of ADHD (15034).
• Autism spectrum disorder. It is unclear if oral melatonin is beneficial for this condition. Details: One clinical trial in children aged 6-15 years with autism spectrum disorder shows that taking melatonin (Nobelpharma Co., Ltd) 1 mg or 4 mg before bedtime does not affect behavior when compared with placebo. However, this study was designed to evaluate sleep outcomes, not behavior, as a primary endpoint (106293). Also, a secondary analysis of results from a clinical trial in children with autism spectrum disorder shows that taking prolonged-release melatonin mini-tablets (PedPRM) 2-5 mg nightly for 13 weeks improves externalizing behavior in 26% more patients when compared with those taking placebo. There was no difference between groups in behaviors such as hyperactivity, inattention, emotional behavior, and relationships with peers (101256). The validity of these findings is limited by the secondary nature of the analysis, which was not designed to evaluate these outcomes.
• Benign prostatic hyperplasia (BPH). It is unclear if oral melatonin is beneficial for BPH. Details: One very small clinical study shows that taking controlled-release melatonin 2 mg nightly for 4 weeks reduces excessive urination at night in some men with BPH when compared with placebo. However, it is unclear if this improvement is clinically significant (62360).
• Bipolar disorder. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3 mg at bedtime for 30 days increases sleep duration and reduces mania severity when compared to baseline in patients with bipolar disorder and treatment-resistant insomnia (62140). However, other research shows that melatonin is not beneficial in patients with bipolar disorder when compared with placebo. Taking melatonin 3-10 mg daily before bedtime for 3-12 weeks does not seem to improve mania or other symptoms when compared with placebo (1766,103694). Also, taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks may attenuate the increase in blood pressure and fat mass that is associated with use of second-generation antipsychotics, but it does not appear to improve mania or depression in patients with bipolar disorder (88300). There is also some concern that oral melatonin may worsen symptoms in some patients with bipolar depression (1764).
• Bronchopulmonary dysplasia. It is unclear if oral melatonin reduces the risk of bronchopulmonary dysplasia (BPD) in premature infants. Details: A small clinical study in premature infants with respiratory distress syndrome who received surfactant shows that giving melatonin 3 mg daily for 7 days reduces the incidence of BPD to 45%, compared with 60% in those not receiving melatonin. Melatonin also reduced the duration of hospital stay, need for mechanical ventilation, and mortality (108948).
• Chronic fatigue syndrome (CFS). It is unclear if oral melatonin is beneficial for patients with CFS. Details: Many patients with CFS have circadian rhythm disturbances. Some very small clinical studies have evaluated the use of melatonin for addressing these disturbances. One study shows that taking melatonin 5 mg in the evening for 12 weeks might improve some measures of fatigue, concentration, motivation, and activity when compared with baseline (14437). However, other preliminary clinical research shows that taking the same dose of melatonin does not improve CFS symptoms when compared with placebo (9705). Melatonin has also been studied in combination with zinc. In patients with CFS, taking melatonin 1 mg plus zinc 10 mg before bedtime for 16 weeks modestly reduces self-reported levels of physical fatigue, but not self-reported cognitive or psychological symptoms, mood, sleep quality, or quality of life (QOL) measures, when compared with placebo. However, some measures of sleep quality and QOL worsened within 4 weeks of melatonin discontinuation, suggesting that there may have been a modest benefit (106241). It is unclear whether any benefit is related to melatonin, zinc, or the combination. Also, all patients in this study were White females, limiting the generalizability of the results.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral melatonin is beneficial for COPD. Details: Some clinical research shows that taking melatonin 3 mg daily for 3 months improves shortness of breath in patients with COPD when compared with placebo, although melatonin does not seem to improve lung function or exercise capacity (62854). Another small clinical trial shows that taking melatonin 3 mg daily in combination with rehabilitative exercise training improves exercise capacity, health status, and quality of life when compared with placebo. The distance walked in 6 minutes was increased by 46 meters (113221).
• Cluster headache. It is unclear if oral melatonin prevents cluster headaches. Details: A very small clinical study in adults with cluster headaches shows that taking melatonin orally 10 mg every evening for 14 days might reduce the frequency of episodic cluster headaches when compared with placebo (1127). However, 2 mg at bedtime does not seem to be effective (9702).
• Cognitive impairment. Oral melatonin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults 70 years and older with mild cognitive impairment shows that taking two capsules containing melatonin 5 mg, docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and L-tryptophan 95 mg (IBSA Farmaceutici) before bedtime for 12 weeks modestly improves cognitive function and sensitivity to smells when compared with placebo. The observed improvement on the mini-mental state examination (MMSE) scale falls below the score generally considered to be indicative of true changes in cognitive function, and may not be clinically significant. Also, it is not known if any potential benefit is due to melatonin, other ingredients, or the combination (62847).
• Colorectal cancer. It is unclear if oral melatonin is beneficial for colorectal cancer prevention. Details: Population research suggests that any history of melatonin use is associated with an approximate 20% reduction in the incidence of colorectal cancer, especially rectal cancer, in individuals aged 60 years and older (106291).
• Contraception. Although there has been interest in using oral melatonin for contraception, there is insufficient reliable information about the clinical effects of melatonin for this use.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral melatonin is beneficial for recovery from CABG surgery. Details: Clinical research shows that taking melatonin perioperatively during CABG surgery reduces the length of stay in the ICU by about 0.5 days and modestly reduces levels of creatine kinase-MB when compared with placebo. However, there was no effect on the length of hospital stay or levels of cardiac troponin-I, C-reactive protein, or erythrocyte sedimentation rate. Oral melatonin 3 mg was provided the night before and morning of surgery, as well as at bedtime for 3 days after surgery (109699).
• Coronavirus disease 2019 (COVID-19). Preliminary clinical studies suggest that oral melatonin may reduce disease severity in patients with COVID-19, although some conflicting findings exist. Details: A meta-analysis of mainly small and preliminary randomized clinical trials in patients with COVID-19 shows that taking melatonin improves clinical outcomes when compared with placebo. However, the clinical outcomes differed between individual trials, and included specific symptoms, hospital discharge, removal from quarantine, and survival. Dosing also varied, with doses of 2-24 mg daily in 1-4 divided doses for 6-14 days. There was no effect of melatonin on C-reactive protein levels or oxygen saturation (109695). Individual clinical trials have been conducted in hospitalized and/or non-hospitalized patients with mild to severe COVID-19. One clinical trial in outpatients with mild to moderate COVID-19 shows that taking melatonin 10 mg daily modestly reduces time to symptom resolution and quality of life improvement when compared with placebo (109462). However, it is unclear if any beneficial effects are clinically meaningful. In patients hospitalized and receiving standard care for mild to moderate COVID-19, a small clinical trial shows that taking melatonin 3 mg three times daily for 14 days reduces the mean time to hospital discharge by approximately 3.5 days when compared with placebo. Also, persistent symptoms of cough, dyspnea, and fatigue after 14 days occurred in only 0% to 8% of patients taking melatonin, compared with 15% to 30% of those taking placebo. However, there was no difference in the number of patients with other symptoms, including fever, myalgia, chill, and headache (106300). The validity of this study is limited by its high attrition rate. Another small clinical trial in patients hospitalized with COVID-19 shows that taking melatonin (Norm Life Vanatonin Melatonin) 3 mg nightly for 7 days does not reduce symptoms or prevent ICU admission or death when compared with standard care alone (106295). The low dose and short duration of use in this study might have played a role in the lack of benefit. Melatonin has also been evaluated in patients hospitalized for severe COVID-19. One large single-center preliminary clinical trial shows that taking melatonin 10 mg daily reduces the incidence of thrombosis at day 17 and the incidence of sepsis at day 11 when compared with standard care alone. Death occurred in approximately 17% of patients taking placebo, compared with 1% of those taking melatonin (106289). Another preliminary clinical trial in patients in the ICU for severe COVID-19 shows that taking melatonin (Danna Pharmaceutical Company, Iran) 5 mg twice daily for 7 days results in mortality and invasive mechanical ventilation rates of 67% and 51.4%, respectively, compared with 94% and 70.9% in patients given standard care only. There were also modest improvements in the time to improvement of clinical status and lengths of stay in the hospital and ICU (110297). The validity of these studies is limited by a lack of blinding.
• Delirium. It is unclear if oral melatonin is beneficial for preventing delirium in hospitalized patients; the available research is conflicting. Details: Research is conflicting on whether melatonin reduces the incidence of delirium. One meta-analysis of 10 clinical trials shows that melatonin reduces the incidence of delirium in critically ill patients in the intensive care unit (ICU) by 21% when compared with a control, usually placebo (109696). However, other meta-analyses of 14 small clinical and observational studies of hospitalized patients show that taking melatonin does not reduce the incidence of delirium when compared with control (105003,112440). Melatonin might be less beneficial in non-acute medical patients when compared with postoperative patients or those in the ICU (105003). There is also a lack of consensus within the available research on whether melatonin reduces the duration of delirium in hospitalized patients. One meta-analysis of 10 clinical trials shows that melatonin does not reduce the duration of delirium (109696). However, a meta-analysis of 2 small, randomized controlled trials shows that taking melatonin 3-5 mg daily for 5 or more days reduces the duration of delirium by approximately 2 days when compared with placebo (112051). This analysis is limited by substantial heterogeneity and a lack of dose-response evaluation. Most studies in these analyses have used doses of 0.5-10 mg daily for up to 14 days, although one study used a very high single dose of 50 mg/kg (105003,105891,107809,108949,109696,112051). Some research suggests that melatonin may be beneficial for patients undergoing cardiac procedures. A subgroup analysis of one meta-analysis including 3 small studies suggests that melatonin reduces the incidence of delirium in patients in cardiovascular care units, but not in the general ICU population (112440). Two large clinical studies in the meta-analysis suggest that, in older patients admitted to the ICU after acute heart failure or percutaneous coronary intervention (PCI), taking melatonin 3 mg once daily for up to 7 days is associated with a 27% incidence of delirium, compared with a 37% to 40% incidence with placebo (107809,108949). Additionally, a small clinical study in patients undergoing coronary artery bypass graft (CABG) surgery suggests that taking prolonged-release melatonin (Webber Naturals) 3 mg twice before surgery and twice after surgery reduces the occurrence of delirium over the next 48 hours when compared with placebo (105891). The validity of this study is limited by a high risk of bias due to insufficient blinding and incomplete outcome data. Additionally, a small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not reduce delirium or improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997).
• Diabetes. Most research shows that oral melatonin is beneficial for improving glycemic control. However, it is unclear if oral melatonin is beneficial in patients with type 2 diabetes. Details: Most research on the use of melatonin for glycemic control has been conducted in mixed populations, such as those with schizophrenia, metabolic syndrome, nonalcoholic steatohepatitis (NASH), or perimenopause (103490,106294,106298). Two recent meta-analyses of clinical research in these populations show that taking melatonin modestly reduces fasting glucose and insulin, insulin resistance, and glycated hemoglobin (HbA1c), and improves insulin sensitivity (106294,106298). The most common doses of melatonin used were 3 -10 mg for 8-24 weeks; however, 10 mg may be more effective (106294,106298). This contrasts with an earlier meta-analysis showing only modest beneficial effects of melatonin on fasting glucose levels and insulin sensitivity (103490). Research on the use of melatonin in patients with type 2 diabetes is limited. One small clinical trial in patients with type 2 diabetes show that taking melatonin (NatureMade) 6 mg daily for 8 weeks does not improve glycemic control (104368). However, this trial may have been underpowered to detect a difference. Another very small study in adults with type 2 diabetes shows that taking melatonin 3 mg daily before bed for 7 days increases absolute glucose level at breakfast on day 7 and the glycemic difference between post-dinner on day 6 and pre-breakfast on day 7 but does not change most measures of glycemic variability including mean glucose levels, pre-prandial glucose levels, and post-prandial glucose levels compared with placebo (112441).
• Diabetic neuropathy. It is unclear if oral melatonin is beneficial for improving pain in patients with diabetic neuropathy. Details: A clinical study in patients with painful diabetic neuropathy living in Iran shows that taking melatonin 3 mg nightly for 1 week and then 6 mg nightly for 7 weeks, in conjunction with pregabalin 150 mg daily seems to reduce pain and sleep interference to a greater degree than placebo and pregabalin (105895).
• Dry mouth. It is unclear if oral melatonin is beneficial for dry mouth caused by radiation treatment. Details: A small clinical study in patients with head and neck cancer undergoing chemoradiation shows that taking melatonin 20 mg orally at bedtime and using 10 mL of melatonin 0.2% oral gargle 15 minutes before each radiation session does not delay the onset or reduce the incidence of grade 2 dry mouth when compared with placebo. However, the incidence of grade 3 dry mouth is delayed by approximately 16 days (96314).
• Dysmenorrhea. It is unclear if oral melatonin is beneficial for dysmenorrhea. Details: A small clinical trial shows that taking melatonin 10 mg nightly before bed during the week of menstruation has a statistically significant effect on pain severity when compared with placebo. However, the pain reduction was not considered clinically significant (106301).
• Dyspepsia. It is unclear if oral melatonin is beneficial for dyspepsia in adults. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly for 12 weeks improves dyspeptic symptoms in individuals with functional dyspepsia. However, the benefit seems to be decreased in patients with prior Helicobacter pylori infection (62456).
• Endotracheal intubation-associated adverse effects. It is unclear if oral melatonin is beneficial for endotracheal intubation-related hemodynamic effects. Details: Clinical research shows that taking immediate-release melatonin (Healthy Hey Nutrition) 6 mg, 2 hours prior to the induction of anesthesia, is as effective as clonidine 0.2 mg for attenuating the hemodynamic response to laryngoscopy and tracheal intubation (103483). It is not known if melatonin prevents other adverse effects associated with endotracheal intubation.
• Endometriosis. It is unclear if oral melatonin reduces endometriosis-related pain. Details: Preliminary clinical research shows that taking melatonin 10 mg daily for 8 weeks reduces pain by about 39% and analgesic use by about 46%, as well as pain during menstruation, intercourse, and evacuation, when compared with placebo in adults with endometriosis (89503). Other clinical research in adults with endometriosis shows that taking melatonin 20 mg orally daily does not improve pain scores or reduce pain during intercourse, urination, or defecation when compared with placebo (111464). However, the study may have been inadequately powered to detect a difference between groups.
• Epilepsy. It is unclear if oral melatonin is beneficial for epilepsy in children or adults. Details: There is some low-quality evidence that taking melatonin 3 mg at bedtime for 3 months might reduce the frequency and duration of both nocturnal and daytime seizures in children aged 2-15 years with epilepsy (9699,9745,9746,62785). Also, taking melatonin 1.5 mg before bed for 3 months might reduce the seizure severity in children with epilepsy that is not successfully controlled with other treatment (62754). Furthermore, taking fast-release melatonin 10 mg daily for 3 weeks seems to reduce diurnal seizure frequency in both adults and children aged 9 years and up with intractable epilepsy (88291). However, taking melatonin might not be beneficial for seizure reduction in younger children. In infants and children aged 3 months to 2 years with infantile epileptic spasms syndrome receiving adrenocorticotrophic hormone (ACTH) and magnesium sulfate, adding on melatonin 3 mg daily for 2 weeks before bedtime does not reduce spasm frequency or improve response rate when compared with placebo (113223). Limited research has also assessed melatonin as an adjunct therapy in adults with seizure disorders. A small clinical study in adults with epilepsy involving generalized onset motor seizures that recurred within the last three days shows that adding melatonin 3 mg before bed to therapy with valproate 20 mg/kg in two divided doses daily for 8 weeks results in 82% of patients having at least a 50% reduction in seizure frequency, compared with only 53% of patients in the group taking valproate and placebo. Adding melatonin may also improve seizure severity (105006). However, other clinical research in adults under valproic acid treatment for idiopathic generalized tonic-clonic seizures alone shows that taking melatonin 3 mg before bed for 8 weeks modestly reduces seizure severity, but not frequency (110299).
• Fibromyalgia. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3-5 mg daily for up to 60 days may decrease the severity of pain and stiffness, as well as the number of painful joints, in people with fibromyalgia when compared with placebo (9701,62797).
• Gastroesophageal reflux disease (GERD). It is unclear if oral melatonin is beneficial for GERD. Details: Clinical research shows that taking melatonin 3 mg daily at bedtime for 8 weeks may improve symptoms of GERD, including heartburn and epigastric pain. However, taking omeprazole 20 mg twice daily seems to be more effective (62723).
• Helicobacter pylori. It is unclear if oral melatonin is beneficial for Helicobacter pylori eradication. Details: One very small clinical study shows that taking melatonin 5 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Heart failure. It is unclear if oral melatonin is beneficial for heart failure. Details: A small clinical study in adults with stable NYHA class II or III heart failure with reduced ejection fraction (HFrEF) and a left ventricular ejection fraction (LVEF) below 40%, shows that taking melatonin 10 mg orally every evening for 24 weeks improves a composite score reflecting all-cause mortality, hospitalization for exacerbation, and quality of life when compared with placebo. Melatonin also attenuates an increase in serum B-type natriuretic peptide levels, but does not affect LVEF or left ventricular end-diastolic or end-systolic diameter (108950).
• Irritable bowel syndrome (IBS). It is unclear if oral melatonin is beneficial for IBS. Details: In patients with IBS who also have poor sleep, taking melatonin 3 mg at bedtime for 2 weeks seems to decrease symptoms of IBS-related abdominal pain and increase the rectal pain threshold when compared with placebo. However, taking melatonin does not seem to influence stool frequency or consistency, bloating, mood, sleep, or overall quality of life (13112). In other small clinical studies, taking melatonin 3 mg at bedtime for 8 weeks decreased severity and frequency of pain, reduced bloating, improved bowel habits, decreased extracolonic symptoms such as headache, heartburn and nausea, and improved overall quality of life when compared with placebo (15216,62410). However, other clinical research shows that melatonin does not significantly affect the amount of time needed for food to travel through the colon in patients with IBS (62500). Also, one small clinical study shows that taking melatonin 3 mg in the morning and 5 mg in the evening for 6 months improves abdominal pain, bloating, and bowel habits in 50% to 70% of postmenopausal patients with constipation-predominant IBS when compared with placebo. However, beneficial effects were reduced in patients with diarrhea-predominant IBS (89510). Other clinical research in patients with IBS shows that taking melatonin 6 mg orally daily for 8 weeks improves IBS symptom severity scores, abdominal pain scores, and bloating scores, when compared with placebo. These results were not different between those with or without sleep disorders at baseline (112055). The large number of endpoints, many with inconsistent results, in these studies makes it difficult to draw conclusions.
• Ischemia-reperfusion injury. It is unclear if intravenous or intracoronary melatonin is beneficial for ischemia-reperfusion injury. Details: A meta-analysis of 9 low-quality clinical trials in patients with myocardial ischemia-reperfusion injury shows that giving melatonin in doses of 2-50 mg by intravenous or intracoronary injection within 2.5-3.5 hours of ischemia onset improves left ventricular ejection fraction and reduces the infarct size, but does not improve left ventricular end-diastolic or end-systolic volumes, when compared with control. Also, giving melatonin orally for up to 12 weeks does not improve cardiac function. The patients in this study experienced injury as a result of an ST-elevation myocardial infarction, ischemic heart disease, acute coronary syndrome, or coronary heart disease (108946).
• Kidney failure. It is unclear if oral melatonin is beneficial for improving mood and quality of life in patients on hemodialysis. Details: A small clinical trial in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves depression, anxiety, and quality of life when compared with placebo. After treatment, 73.1% and 57.7% of those taking placebo had severe depression and anxiety, respectively, when compared with 22.2% and 14.8% of those taking melatonin (110291).
• Kidney transplant. It is unclear if oral melatonin is beneficial for improving post-transplant kidney function. Details: A small clinical study in patients that have received kidney transplants shows that taking melatonin 3 mg daily for an average of 25 days does not affect urine volume or kidney function, as measured by the blood urea nitrogen over creatinine (BUN/Cr) ratio, when compared with placebo (103693).
• Lung cancer. It is unclear if melatonin is beneficial in patients with early stage non-small cell lung cancer (NSCLC). Details: A clinical study in patients who have undergone complete surgical resection of early stage NSCLC shows that taking melatonin 20 mg daily for 1 year does not improve 2-5 year disease-free survival, pain, anxiety, fatigue, or quality of life when compared with placebo (105894). The validity of these findings is limited by a high study withdrawal rate.
• Melasma. Although there has been interest in using oral melatonin for melasma and other causes of hyperpigmentation, there is insufficient reliable information about the clinical effects of melatonin for these conditions.
• Menopausal symptoms. It is unclear if oral melatonin is beneficial for improving symptoms of menopause; evidence is conflicting. Details: A meta-analysis of 3-5 clinical studies in patients with menopausal symptoms shows that taking melatonin does not seem to improve vasomotor or psychological symptoms, but may modestly improve physical symptoms, when compared with placebo (105897). This analysis is limited due to inconsistent evidence and some risk of bias within the included studies. Studies included in the meta-analysis used melatonin 3 mg daily for 3-12 months alone or in combination with soy isoflavones 80 mg or fluoxetine 20 mg (11806,62840,105897). In contrast, a small study in adults with menopausal symptoms shows that taking melatonin 3 mg daily for 12 weeks improves climacteric symptoms, anxiety, depressive symptoms, sleep quality, and menopausal quality of life and decreases luteinizing hormone and follicle stimulating hormone levels but does not change uterine volume, endometrial thickness, or estradiol levels when compared with placebo (112443).
• Metabolic syndrome. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking melatonin 5 mg nightly for 2 months reduces systolic and diastolic blood pressure, as well as low-density lipoprotein (LDL) cholesterol levels, when compared to baseline (62795). The validity of these findings is limited by the lack of a comparator group.
• Multiple sclerosis (MS). It is unclear if oral melatonin is beneficial for MS. Details: A small clinical study in patients with relapsing-remitting MS (RRMS) receiving interferon-beta once weekly shows that taking melatonin 3 mg daily for 12 months does not affect relapse rate, disability, brain lesions, fatigue, or depression when compared with placebo (99345). This small study may not have been adequately powered to detect a difference between groups.
• Myocardial infarction (MI). The benefits of administering oral or intravenous melatonin immediately after an MI are unclear. Details: A meta-analysis of 5 small clinical studies in patients after MI shows that oral or intravenous melatonin, used in conjunction with medical reperfusion, is associated with modestly lower troponin levels and modestly higher left ventricular ejection fraction when compared with control (105889). One clinical study included in this analysis that evaluated patients with ST-segment elevation myocardial infarction (STEMI) shows that intravenous administration of melatonin 51.7 mcmol over 60 minutes immediately prior to percutaneous coronary intervention, combined with a bolus intracoronary dose of melatonin 8.6 mcmol administered within 60 seconds after restoration of blood flow to the infarcted artery, does not reduce myocardial infarct size when compared with placebo. However, subgroup analyses suggest that the timing of melatonin administration after symptom onset may alter its effects (96324).
• Neonatal encephalopathy. It is unclear if oral or intravenous melatonin is beneficial for neonates with encephalopathy. Details: A meta-analysis of two small clinical studies in term or late preterm infants with neonatal encephalopathy who are receiving therapeutic hypothermia shows that receiving melatonin 5 mg/kg intravenously daily for 3 days, or 10 mg/kg orally daily for 5 days, does not reduce mortality when compared with hypothermia alone, although a nonsignificant trend towards a reduction was noted (104994). One of those small studies in term infants with neonatal encephalopathy also shows that receiving adjunct oral melatonin treatment results in fewer seizures and less white matter abnormalities when compared with hypothermia alone (99333).
• Nocturnal enuresis. It is unclear if oral melatonin is beneficial for reducing nighttime wettings. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly before bedtime for 3 months does not reduce the number of wet beds when compared with placebo in children with nighttime wettings (nocturnal enuresis) (62824).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral melatonin is beneficial for NAFLD. Details: A meta-analysis of clinical research, as well as individual clinical trials, show that taking melatonin 6-18 mg daily for 4-56 weeks improves some liver indices, but not others (62853,88285,103484,103485). Overall, taking melatonin seems to modestly reduce levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). However, there is no effect on alanine aminotransferase (ALT) and levels of aspartate aminotransferase (AST) slightly increased (103485). One small clinical study shows that taking melatonin (Nature Made, USA) 6 mg daily for 12 weeks has a small benefit on systolic and diastolic blood pressure, body mass index (BMI), abdominal circumference, and liver enzymes, but not plasma lipid levels, when compared with placebo (103484). Larger studies are needed to determine the effect of melatonin in this population.
• Obesity. It is unclear if melatonin is beneficial for improving weight loss. Details: A meta-analysis of clinical research shows that taking melatonin up to 10 mg daily, usually for 4-24 weeks, modestly reduces body weight when compared with placebo. However, there was no effect on body mass index (BMI) or waist circumference. Also, the studies included in the analysis were not limited to overweight or obese individuals. Populations included those with metabolic syndrome, nonalcoholic steatohepatitis (NASH), schizophrenia, polycystic ovary syndrome (PCOS), and others, as well as postmenopausal adults (106288). A small clinical trial in overweight or obese individuals shows that although taking melatonin 3 mg daily for 12 weeks modestly reduces waist circumference and body fat mass when compared with placebo, there is no effect on body weight or BMI (106290).
• Oral mucositis. Most research shows that melatonin does not prevent or reduce the severity of oral mucositis in patients with head and neck cancer receiving radiation and chemotherapy. It is unclear if oral or topical melatonin is beneficial in patients with other types of cancer. Details: A meta-analysis of seven clinical trials including patients undergoing chemotherapy or radiotherapy shows that melatonin does not reduce the rate of oral mucositis when compared with a control, usually placebo (109697). Although a small clinical study in patients with head and neck cancer undergoing radiation and chemotherapy with cisplatin shows that melatonin delays the onset of severe mucositis by 16 days when compared with placebo (96314), a meta-analysis shows that melatonin does not reduce the rate of oral mucositis in patients with head and neck cancer (109697). A sub-analysis in one meta-analysis suggests that taking melatonin, usually 20 mg daily, reduces the rate of oral mucositis by 53% in patients with cancer types other than head and neck (109697). Most studies investigating the effect of melatonin have used oral melatonin 20 mg at bedtime. However, in one study, 10 mL of melatonin 0.2% oral gargle was also used 15 minutes before radiation (96314). In another, swishing with 10 mL of a melatonin 3% gel mouthwash for 2 minutes and then swallowing, starting 2-3 days before radiotherapy and continuing until 1-4 weeks after the end of radiotherapy, was used (105893). Melatonin has also been investigated for oral mucositis severity. Although some individual research disagrees (96314), a meta-analysis of three clinical trials shows that melatonin does not reduce the severity of oral mucositis when compared with placebo. However, the form of melatonin provided in these studies was heterogeneous, including oral, gargle, and gel formulations (96314,105893,109697).
• Osteopenia. It is unclear if oral melatonin is beneficial for improving bone mineral density. Details: A small clinical study in postmenopausal adults with osteopenia shows that taking melatonin 3 mg nightly for 1 year increases tibia thickness by 2.2% and volumetric bone mineral density (BMD) in the spine by 3.6% when compared with placebo. However, the BMD of other skeletal sites was not impacted. Additionally, a 1 mg melatonin dose was not beneficial (99334).
• Osteoporosis. Although there has been interest in using oral melatonin for osteoporosis, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Pain (acute). It is unclear if oral melatonin is beneficial for acute pain. Details: Clinical research in patients undergoing laparoscopic cholecystectomy shows that taking melatonin 6 mg two hours before induction with propofol reduces the number of patients requiring intraoperative fentanyl to 10%, compared with 35% of those taking placebo (106299). Also, preliminary clinical research in preterm infants also given standard treatments shows that oral melatonin (Syrup Trunap, Brio Bliss Life Science Pvt. Ltd) 20 minutes prior to retinopathy of prematurity screening, is not inferior to 24% sucrose for reducing pain (110295). However, the effect of sucrose itself is inconclusive and this study is limited by a lack of blinding. Also, it is unclear if melatonin is beneficial for other causes of acute pain.
• Pain (chronic). It is unclear if melatonin is beneficial for most causes of chronic pain. Details: A meta-analysis of 5 clinical studies shows that taking melatonin 3-12 mg daily for up to 12 weeks modestly reduces chronic pain when compared with placebo (103692). However, it is difficult to draw clinical conclusions from this analysis, as it pools the effects observed in various types of chronic pain, including migraine, burning mouth syndrome, endometriosis, and irritable bowel syndrome (IBS).
• Periodontitis. Small clinical studies suggest that oral melatonin may improve some measures of periodontitis severity. Details: A meta-analysis of 7 small clinical trials in patients with periodontitis treated with subgingival instrumentation to remove calculus and bacterial biofilms shows that adding oral melatonin in doses of 3-10 mg daily improves probing depth, clinical attachment loss, and gingival index when compared with instrumentation alone (108953).
• Polycystic ovary syndrome (PCOS). It is unclear if melatonin is beneficial for PCOS. Details: A prospective cohort study in patients with PCOS has found that taking melatonin (Armonia Fast, Nathura) 2 mg before bedtime for 6 months increases follicle-stimulating hormone and the total number of menstrual cycles from approximately 2.5 to 4 when compared to baseline (96313). The validity of this study is limited by its observational nature and the lack of a comparator group. Additionally, a small clinical study in patients with PCOS shows that taking melatonin 6 mg daily for 8 weeks does not affect insulin levels, fasting blood glucose, lipid levels, or weight, but might modestly reduce testosterone levels, when compared with placebo (105887). This study may have not been adequately powered to detect differences between groups.
• Postoperative nausea and vomiting (PONV). It is unclear if melatonin is beneficial for reducing PONV. Details: A small clinical trial shows that taking melatonin (Nature Made, USA) 3 mg, 5 mg, or 10 mg, one hour prior to lumbar discectomy surgery does not reduce postoperative nausea when compared with placebo (110294).
• Postoperative pain. It is unclear if melatonin is beneficial for reducing pain postoperatively. Details: Three meta-analyses, as well as most individual clinical studies, show that taking melatonin in addition to standard therapy modestly alleviates pain and reduces analgesic use after surgery when compared with placebo (62471,62512,62551,62743,88293,88294,103488,103691,103692,105892)(110294,111462). However, any benefit is likely to be small and may not be clinically relevant (103488,109701,111462). Melatonin has been used in doses of 1-10 mg daily for a duration of 1-21 days, usually starting the night before surgery (62471,62512,62743,103488,103691,105892,110294,111462). This research is limited by poor methodology, as well as the heterogeneity of the included studies. The studies evaluated melatonin across a wide variety of surgeries, including abdominal hysterectomy, cataract surgery, cesarean section, prostatectomy, lumbar laminectomy, lumbar discectomy, laparoscopic cholecystectomy, wisdom teeth extraction, and corrective jaw surgery.
• Postoperative recovery. It is unclear if oral melatonin improves the rate of recovery after surgery. Details: In females undergoing total abdominal hysterectomy, taking extended-release melatonin 5 mg, 90 minutes before surgery, shortens hospital stay to a mean of 2.7 days, compared with 3.4 days for placebo (108945).
• Postoperative sleep disturbance. It is unclear if melatonin is beneficial for improving postoperative sleep disturbance. Details: A meta-analysis of randomized trials in adults undergoing anesthesia for surgery shows that taking melatonin 5-12 mg orally or sublingually or ramelteon 8 mg orally daily for 1-6 days does not improve sleep scores or sleep time when compared with placebo or no intervention (112052). In addition, a small clinical trial shows that taking melatonin (Nature Made) 5 mg each night before bed for 4 weeks, starting 2 weeks after surgery for orthopedic trauma, does not reduce postoperative sleep disturbance when compared with placebo. All patients were also given education related to sleep hygiene (110293).
• Postural tachycardia syndrome (POTS). It is unclear if melatonin is beneficial for POTS. Details: Preliminary clinical research in patients with POTS shows that taking a single dose of melatonin 3 mg reduces sitting and standing heart rate, after 2 and 4 hours, when compared with placebo. However, melatonin does not appear to affect blood pressure or orthostatic symptoms (88292). It is unclear if melatonin is beneficial when taken as more than a single dose.
• Pre-eclampsia. It is unclear if oral melatonin reduces the severity of pre-eclampsia. Details: A small clinical trial in patients with pre-eclampsia shows that taking sustained-release melatonin 10 mg with vitamin B6 10 mg three times daily, starting during recruitment and continuing until delivery, attenuates the need to increase the dose of antihypertensive medication on certain days, but does not affect overall pre-eclampsia severity, when compared with control (99341).
• Prostate cancer. Oral melatonin has only been evaluated in combination with medication; its effect when used alone is unclear. Details: One small clinical study in patients with metastatic prostate cancer that is refractory or resistant to treatment with the luteinizing hormone-releasing hormone (LHRH) analogue triptorelin shows that taking melatonin 20 mg daily in combination with intramuscular triptorelin injected every 28 days can decrease levels of prostate-specific antigen (PSA) and growth factors for prostate cancer when compared to baseline (7255). The validity of these findings is limited by the small study size and lack of a comparator group.
• Pruritus. Small clinical trials suggest that oral melatonin might be beneficial for some types of pruritus. Details: One small clinical trial in patients with pruritus due to various types of chronic liver disease shows that taking melatonin 10 mg nightly for 2 weeks modestly reduces the severity, frequency, and extent of pruritus when compared with placebo (106297). Another small clinical study in patients undergoing hemodialysis shows that taking melatonin 10 mg daily for 2 weeks reduces the severity of pruritus and reduces the affected body area when compared with placebo (104996).
• Radiation dermatitis. It is unclear if topical melatonin is beneficial for radiation-related dermatitis. Details: In females with breast cancer, a small clinical study shows that applying a specific melatonin emulsion cream (Praevoskin, PraevoMed GmbH) twice daily during radiation treatment and continuing for another 2 weeks results in fewer cases of grade 1 or 2 acute radiation dermatitis when compared with placebo (99336). In contrast, another clinical trial in patients with breast cancer shows that applying a cream providing melatonin 25 mg and dimethylsulfoxide 150 mg twice daily during and for 3 weeks after radiation treatment does not improve quality of life or breast symptoms at the end of treatment when compared with placebo. However, there was a modest reduction in breast symptoms over time (110298). Other preliminary clinical research in adults receiving radiation for breast cancer shows that applying melatonin cream 25 mg/gram twice daily throughout radiation therapy does not improve radiation dermatitis scores or reduce the need for adjunctive treatment when compared with placebo (112056).
• Rapid eye movement sleep behavior disorder (RBD). It is unclear if oral melatonin is beneficial for RBD. Details: One very small clinical study shows that taking melatonin 3 mg before bed for 4 weeks increases the likelihood of muscle atonia during rapid eye movement (REM) sleep in patients with RBD when compared with placebo (62762). The validity of this finding is limited by the small study size.
• Restless legs syndrome (RLS). It is unclear if oral melatonin is beneficial for RLS. Details: One very small clinical study shows that taking melatonin 3 mg before bedtime does not improve symptoms of RLS and may actually worsen motor symptoms in individuals with RLS when compared with baseline (62753). The validity of this finding is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). It is unclear if oral melatonin is beneficial for RA. Details: A small clinical study in patients with RA shows that taking melatonin 6 mg daily for 12 weeks does not affect disease activity or erythrocyte sedimentation rate (ESR) when compared with placebo (105890).
• Sarcoidosis. It is unclear if oral melatonin is beneficial for this condition. Details: One very small clinical study shows that taking melatonin 20 mg daily for one year, followed by 10 mg daily for another year, improves lung function and skin lesions in patients with chronic sarcoidosis when compared with baseline (62435). The validity of this finding is limited by the small study size and lack of a comparator group.
• Schizophrenia. It is unclear if oral melatonin is beneficial for schizophrenia or for attenuating the adverse effects associated with antipsychotic medications. Details: Some clinical research shows that taking melatonin orally 3 mg each evening for 8 weeks reduces the weight gain and increased waist circumference associated with olanzapine when compared with placebo. It also seems to improve some symptoms of schizophrenia (88296). Other clinical research shows that taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks reduces adverse effects from second generation antipsychotics, such as increased diastolic blood pressure and waist circumference, when compared with placebo. However, it does not seem to improve symptoms of schizophrenia (88300).
• Seasonal affective disorder (SAD). It is unclear if oral melatonin is beneficial for SAD. Details: Some preliminary clinical research shows that oral melatonin, 0.25-2 mg taken daily for 3 weeks, may decrease winter depression symptoms in patients with SAD (10670,62308). However, sublingual melatonin 0.5 mg daily for 6 days does not appear to improve this condition (62388). Reasons for these discrepancies may include the duration of treatment, route of administration, or the severity of SAD at baseline.
• Smoking cessation. It is unclear if oral melatonin is beneficial in patients trying to quit smoking. Details: One very small clinical study shows that taking melatonin 0.35 mg as a single oral dose 3.5 hours after initiation of nicotine withdrawal in smokers seems to reduce subjective symptoms of anxiety, restlessness, irritability, depression, and cigarette craving over the next 10 hours when compared with baseline (2424). The validity of these findings is limited by the small study size and lack of a comparator group.
• Sepsis. It is unclear if oral melatonin is beneficial for sepsis in neonates or adults. Details: There is conflicting research about the effect of melatonin on neonatal sepsis. While some preliminary research in Egypt shows that giving a single dose of melatonin 20 mg in addition to antibiotics reduces sepsis severity, another more recent study did not find a difference in outcomes between groups receiving antibiotics only or antibiotics with melatonin (99339,99340). In adults with early septic shock given standard care, a small clinical trial shows that taking melatonin 50 mg daily for 5 days increases the number of ventilator-free days by 6.9 and the number of vasopressor-free days by 2.6. ICU and hospital lengths of stay were reduced by 5.25 and 6.9 days, respectively. However, after 28 days there was no significant difference in the mortality rate, the number of patients requiring ventilation or renal replacement therapy, or the number of patients recovered from organ dysfunction (106296). Intravenous melatonin has also been investigated. A small clinical trial in patients with severe sepsis shows that a continuous infusion of melatonin, 60 mg over 24 hours, for 5 days following post-surgical sepsis diagnosis modestly reduces sepsis severity when compared with placebo. Hospital stay was reduced by approximately 5.2 days in patients given melatonin; however, it is unclear if this difference is statistically significant (110300).
• Stabbing headache. Although there has been interest in using oral melatonin for stabbing headaches, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Stress. It is unclear if oral melatonin is beneficial for stress reduction. Details: Preliminary clinical research shows that taking melatonin 3 mg one hour prior to stress modestly improves memory accuracy during a laboratory-induced stressful situation when compared with placebo (62509).
• Tardive dyskinesia. It is unclear if oral melatonin is beneficial for this condition. Details: One small clinical study shows that taking melatonin orally 10 mg daily for 6 weeks decreases symptoms by 24% to 30% in patients with tardive dyskinesia when compared with placebo (7082). However, other small clinical studies show that taking melatonin 2-20 mg daily for 4-12 weeks does not reduce abnormal, involuntary movement in patients with tardive dyskinesia when compared with placebo (62146,62825).
• Tension headache. It is unclear if oral melatonin is beneficial for reducing the frequency of tension headaches. Details: A small clinical study in patients with chronic tension headache shows that taking a specific melatonin supplement (Melaxen) 3 mg nightly for 30 days seems to reduce headache severity and reduce the median number of days with a headache by 6 when compared with baseline (104998). The validity of this finding is limited by the lack of a control group.
• Tinnitus. It is unclear if oral melatonin is beneficial for improving tinnitus intensity or severity. Details: Some clinical research shows that taking melatonin 3 mg nightly for one month reduces tinnitus intensity and improves the quality of sleep in individuals with chronic tinnitus when compared with placebo. The effect seems to be greatest in men, those who have not received prior treatment for tinnitus, and those with a history of noise exposure (62820). Other clinical research shows that taking melatonin 3 mg daily for 3 months is more effective for reducing tinnitus severity than sertraline 50 mg daily (97447). However, other clinical research shows that taking melatonin 3 mg nightly for 30-40 days does not significantly reduce tinnitus intensity when compared with placebo, although the effects might be significant when melatonin is combined with sulpiride or sulodexide (62469,62614).
• Traumatic brain injury (TBI). It is unclear if oral melatonin is beneficial for children who have experienced a concussion. Details: A small clinical study in children ages 8-18 years who have experienced a concussion shows that taking melatonin 3 mg or 10 mg one hour before bedtime for 28 days does not improve persistent post-concussive symptoms when compared with placebo (103690). One small observational study in children in the same age group who have experienced a concussion within 14 days has found that receiving a prescription for melatonin is not associated with improved symptoms and recovery at 15-35 days after concussion (105001). The validity of these findings is limited by small study size and short duration of follow-up.
• Ulcerative colitis. Oral melatonin may be modestly beneficial for reducing symptoms or sustaining remission in patients using the medication mesalazine. Details: A small clinical study shows that taking melatonin 5 mg daily in combination with mesalazine 1 gram twice daily for 12 months may help to sustain remission in patients with ulcerative colitis when compared with mesalazine alone (62821). Another small clinical trial in patients with mild to moderate ulcerative colitis shows that taking melatonin 3 mg daily for 3 months modestly improves overall symptoms, some measures of quality of life, and levels of fecal calprotectin when compared with placebo. However, there was no effect on other markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate (106303). More evidence is needed to rate melatonin for these uses.

(Read more about MELATONIN)

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).
• 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).
• 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 using oral contraceptives. Details: 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).
• 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.

(Read more about VITAMIN B6)

LIKELY SAFE ...when used orally or parenterally and appropriately. Folic acid has been safely used in amounts below the tolerable upper intake level (UL). The UL for folic acid is based only on supplemental folic acid and is expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for folic acid in adults is 1000 mcg (6241). In cases of megaloblastic anemia resulting from folate deficiency or malabsorption disorders such as sprue, oral doses of 1-5 mg per day can also be used safely until hematologic recovery is documented, as long as vitamin B12 levels are routinely measured (6241,7725,8739).

POSSIBLY SAFE ...when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks (104913,104914) and a dose of 113 mcg daily for 24 weeks (104920). A specific L-5-MTHF product (Metafolin, Eprova) has been used with apparent safety at a dose of 1.3 mg daily for 12 weeks (104912).

POSSIBLY UNSAFE ...when used orally in large doses, long-term. Clinical research shows that taking folic acid daily in doses of 800 mcg to 1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo (12150,13482,16822,17041). Doses above 1 mg per day should also be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency (6241,6242,6245). However, there is contradictory evidence suggesting that higher doses may not be harmful. There is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured (7725). Also, other clinical research suggests that folic acid supplementation at doses up to 5 mg, usually in combination with vitamin B12, does not increase the risk of cancer when taken for 2-7 years (91312). Very high doses of 15 mg per day can cause significant central nervous system (CNS) and gastrointestinal side effects (505).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Folic acid has been safely used in children in amounts below the tolerable upper intake level (UL). The ULs for folic acid are based only on supplemental folic acid and are expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for children is: 1-3 years of age, 300 mcg; 4-8 years of age, 400 mcg; 9-13 years of age, 600 mcg; 14-18 years of age, 800 mcg (6241).

CHILDREN: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately. One clinical study in infants aged 27 days and younger shows that consuming a formula containing L-5-MTHF (Metafolin, Merck & Cie) 10.4 mcg/100 mL daily has been used with apparent safety for up to 12 weeks (104918).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects (8739). Miscarriage rates and negative impacts on fetal growth have not been shown to increase with peri-conception supplemental folic acid intakes of 4 mg per day (91320,91322). However, other research shows that taking more than 5 mg per day during pregnancy may reduce development of cognitive, emotional, and motor skills in infants (91318). Also, the tolerable upper intake level (UL) of folic acid for pregnant or lactating women is 800 mcg daily for those 14-18 years of age and 1000 mcg daily for those 19 years and older (6241).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks during lactation. Compared to folic acid, this form seems to further increase the folate concentration of red blood cells, but not breast milk (104913,104914).

(Read more about FOLIC ACID)

LIKELY SAFE ...when used orally in the amounts commonly found in foods. L-tryptophan is an essential amino acid that must be obtained from the diet. A typical diet in the United States supplies 0.5-2 grams of L-tryptophan daily (1146).

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. L-tryptophan 5 grams daily for 21 days has been used with apparent safety (91460,97243). In 1989, L-tryptophan was linked to over 1500 reports of eosinophilia-myalgia syndrome (EMS) and several deaths (7067,8053,10085,11474,11478), leading to its removal from the U.S. market in 1990 (7067). The exact cause of EMS in patients taking L-tryptophan is unknown, but some evidence suggests that nearly all cases were due to contaminated L-tryptophan products from a single manufacturer (8050,8051,11477,11478). Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, L-tryptophan is currently available and marketed as a dietary supplement. There is insufficient reliable information available about the safety of L-tryptophan when used orally, long-term.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts because it may cause respiratory depression in utero (1142). Avoid using in amounts greater than those found in foods.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of larger medicinal amounts; avoid using.

(Read more about L-TRYPTOPHAN)

LIKELY SAFE ...when used orally and appropriately, short-term or as a single dose. Melatonin seems to be safe when used up to 8 mg daily for up to 6 months. Melatonin 10 mg daily has been used safely for up to 2 months (1049,1068,1077,1085,1738,1754,5854,5855,5857,12226), (14283,15005,62850,89502,89503,88285,88289,88293,88294,88295)(88296,88299,89508,89510,89511,96313,96314,96316,96317,96319)(96321,97438,99345,103484,106301,106303,107811,110286,110299). ...when used topically and appropriately (1066,1768,1769,4713,4714,96314).

POSSIBLY SAFE ...when doses of up to 8 mg daily are used orally and appropriately for longer than 6 months, doses of 10 mg daily are used for longer than 2 months, or doses of 50 mg daily are used for up to 5 days (7040,7043,62435,106296,107811). There is some evidence melatonin can be used safely in doses of up to 10 mg daily for up to 2 years in some patients (7040,7043,62435). ...when used intravenously under the supervision of a healthcare professional. A one-time dose of intravenous melatonin combined with a single bolus of intracoronary melatonin has been used with apparent safety in one clinical trial (96324).

CHILDREN: POSSIBLY SAFE
when used orally in low doses, short-term (9980,15034,62792,88282,88283,88286,88288,95748,96318,97434)(97439,97446,106293,110292,113216,113223,113224). Although melatonin has been safely used in clinical research in doses up to 12 mg daily (88283), it is often advised that daily doses of melatonin be limited to 3 mg daily for children and infants 6 months or older and 5 mg daily for adolescents (95746). There is some concern that taking melatonin might adversely affect gonadal development in children (1739,1740,1742,1743). While some evidence suggests that long-term use of melatonin in children may delay puberty, the available research includes only three small, observational studies with incomplete follow-up and poor measures of pubertal timing (95747). Although rare, pediatric overdose with melatonin has resulted in hospitalization, mechanical ventilation, and death (108145). Due to potential risks, melatonin should be used only in children with a medical reason for use; it should not be used to promote sleep in otherwise healthy children. There is insufficient reliable information available about the safety of melatonin when used long-term.

PREGNANCY: POSSIBLY UNSAFE
when used orally or parenterally in high doses or with frequent use. High doses of melatonin 75-300 mg daily seem to inhibit ovulation, causing a contraceptive effect (769,1740,6002,8271,95728). Advise pregnant patients and patients wishing to become pregnant to avoid using melatonin frequently or in high doses. There is insufficient reliable information available about the safety of melatonin in lower doses during pregnancy. Some research shows that taking melatonin 2 mg daily does not affect anterior pituitary hormone levels in females who are not pregnant; this suggests that low doses may not have a contraceptive effect (62898). Other research shows that taking melatonin 3 mg daily during the follicle stimulating stage of in vitro fertilization does not negatively impact pregnancy rates (62818,62819,88297,89512,88297). However, it is not known if melatonin is safe for use throughout pregnancy (95729). Until more is known about the safety of melatonin, avoid using during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about MELATONIN)

LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily for adults (15). ...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 (3094).

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 (3094).

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.

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 recommended dietary allowance (RDA) (3094). The RDA in lactating women is 2 mg daily. There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

(Read more about VITAMIN B6)

5-FLUOROURACIL Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.  Details Increases in gastrointestinal side effects of 5-fluorouracil, such as stomatitis and diarrhea, have been described in two clinical studies when leucovorin, a form of folic acid, was administered with 5-fluorouracil (16845).

CAPECITABINE (Xeloda) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Use of high-dose folic acid might contribute to capecitabine toxicity.  Details Clinical research suggests that higher serum folate levels are associated with an increased risk for moderate or severe toxicity during capecitabine-based treatment for colorectal cancer (105402). Additionally, in one case report, taking folic acid 15 mg daily might have contributed to increased toxicity, including severe diarrhea, vomiting, edema, hand-foot syndrome, and eventually death, in a patient prescribed capecitabine (16837).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Folic acid might reduce the efficacy of methotrexate as a cancer treatment when given concurrently.  Details Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells. There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce its efficacy in the treatment of other cancers (9420). Advise cancer patients to consult their oncologist before using folic acid supplements. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, folic acid supplements can reduce the incidence of side effects, without reducing efficacy (768,2162,4492,4493,4494,4546,9369).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Folic acid might have antagonistic effects on phenobarbital and increase the risk for seizures.  Details Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital and worsening seizure control (4427,9357,9358). Monitor closely for increased seizure activity.

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Folic acid might reduce serum levels of phenytoin in some patients.  Details Folic acid may be a cofactor in phenytoin metabolism (4471). Folic acid, in doses of 1 mg daily or more, can reduce serum levels of phenytoin in some patients (4471,4477,4531,4536). Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, monitor serum phenytoin levels closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin pharmacokinetics are avoided (4471,4472,4473,4531). Note that phenytoin also reduces serum folate levels.

PRIMIDONE (Mysoline) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Folic acid might have antagonistic effects on primidone and increase the risk for seizures.  Details Folic acid can have direct convulsant activity in some people, reversing the effects of primidone and worsening seizure control (4427,9357,9358). Monitor closely for increased seizure activity. Note that primidone also reduces serum folate levels.

PYRIMETHAMINE (Daraprim) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Folic acid might antagonize the effects of pyrimethamine.  Details Folic acid can antagonize the antiparasitic effects of pyrimethamine against toxoplasmosis and Pneumocystis carinii pneumonia. Folic acid doesn't antagonize the effects of pyrimethamine in the treatment of malaria, because malarial parasites cannot use exogenous folic acid. Use folinic acid as an alternative to folic acid when indicated (9380).

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CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of L-tryptophan with CNS depressants might cause additive sedative effects.  Details Clinical research shows that L-tryptophan can cause fatigue and drowsiness (1143).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining L-tryptophan with serotonergic drugs might cause additive serotonergic effects.  Details L-tryptophan is a precursor to serotonin (1141). Theoretically, combining serotonergic drugs with L-tryptophan might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin) (63067). The mechanism, if any, of this interaction is unknown (9181). Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men (62481).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking melatonin with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research shows that melatonin reduces levels of fasting blood glucose and improves glycemic control (19034,19035,103490). However, other research suggests that melatonin might impair glucose utilization and increase insulin resistance (9713), while other research has found no effect on glucose levels (19036,104368). Until more is known, use melatonin cautiously in combination with antidiabetes drugs.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking melatonin with antihypertensive drugs might increase the risk of hypotension or hypertension.  Details Some clinical research suggests that taking melatonin decreases blood pressure in healthy adults (1724,62165,62187,63042). Also, melatonin seems to lower systolic and diastolic blood pressure in individuals with high blood pressure at nighttime or untreated essential hypertension (62359,62416,62441,62826). However, melatonin seems to worsen blood pressure in patients who are taking antihypertensive medications. Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL) increases systolic blood pressure an average of 6.5 mmHg, diastolic blood pressure by an average of 4.9 mmHg, and heart rate by 3.9 bpm (6436). Also, results from animal research suggest that melatonin reduces the effectiveness of certain antihypertensive drugs, including methoxamine and clonidine (62432).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking caffeine with melatonin might increase levels of melatonin.  Details Some evidence suggests that caffeine consumption can decrease endogenous melatonin levels (8265,22303,37585), while other evidence suggests that caffeine increases endogenous melatonin levels (62328). When administered in combination with melatonin supplements, caffeine seems to increase melatonin effects and levels (62352,96315). The reason for this discrepancy is not completely clear. Part of the discrepancy may result from the fact that caffeine can inhibit melatonin synthesis as well as inhibit melatonin metabolism. By functioning as an adenosine receptor antagonist, caffeine may indirectly inhibit the synthesis of melatonin. Conversely, because melatonin and caffeine are both metabolized by cytochrome P450 1A2 (CYP1A2) enzyme, concomitant use of melatonin and caffeine may reduce the metabolism of melatonin, resulting in higher serum levels (22306,96315).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin might increase the sedative effects of CNS depressants.  Details Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation (96315).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking contraceptive drugs with melatonin might increase the effects and adverse effects of melatonin.  Details Contraceptive drugs can increase the levels of endogenous melatonin (8265). Theoretically, these drugs may increase the effects and adverse effects of oral melatonin.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405,96315). Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19. Also, other CYP2C19 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2C19 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP2C19 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.  Details Laboratory research suggests that certain lots of melatonin inhibit CYP2D6 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.  Details Laboratory research shows that certain lots of melatonin inhibit CYP3A4 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

FLUMAZENIL (Romazicon) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking flumazenil with melatonin might reduce the effects of melatonin.  Details Animal research shows that flumazenil may inhibit the effect of melatonin (9703).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fluvoxamine with melatonin might increase levels of melatonin.  Details Fluvoxamine can significantly increase melatonin levels. In some cases, fluvoxamine might increase bioavailability of exogenously administered melatonin by up to 20 times (5038,6499,8251). Some researchers think this might be a beneficial interaction and be potentially useful for cases of refractory insomnia (6499). However, this interaction might also cause unwanted excessive drowsiness and possibly other adverse effects. Fluvoxamine is known to increase endogenous melatonin secretion (6498,22313). It seems to increase serum levels of exogenously administered melatonin possibly by decreasing melatonin metabolism by inhibiting cytochrome P450 (CYP450) 1A2 and 2C19 or by inhibiting melatonin elimination. This effect has been found in healthy people taking fluvoxamine 50-75 mg and melatonin 5 mg (5038,6498,6499,8251).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin might interfere with immunosuppressive therapy.  Details Melatonin can stimulate immune function. Theoretically, melatonin might interfere with immunosuppressive therapy (7040).

METHAMPHETAMINE (Desoxyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with methamphetamine may increase the adverse effects of methamphetamine.  Details Animal research suggests that melatonin exacerbates the adverse effects of methamphetamine, resulting in greater depression of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activity, as well as a significant reduction in dopamine levels (22307). This has not been shown in humans.

NIFEDIPINE GITS (Procardia XL) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking melatonin with extended release nifedipine reduces the effects of nifedipine.  Details Melatonin can decrease the effectiveness of extended release nifedipine (GITS). Immediate-release melatonin 5 mg at night in combination with nifedipine GITS 30-60 mg daily increases systolic and blood pressure by an average of 6.5 mmHg and 4.9 mmHg, respectively. Concomitant use with melatonin also increases heart rate by 3.9 bpm (6436). The mechanism of this interaction is not known.

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.  Details Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities (8248,9744).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin may have antiplatelet effects and may increase the risk of bleeding with warfarin.  Details Three cases of increased prothrombin time have been reported for patients aged 48-72 years who took melatonin orally in combination with warfarin (9181). However, three cases of decreased prothrombin time have also been reported for patients aged 51-84 years who took melatonin orally in combination with warfarin (9181). Until more is known, use melatonin cautiously in patients taking warfarin.

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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, folic acid is generally well-tolerated in amounts found in fortified foods, as well as in supplemental doses of less than 1 mg daily.
Most Common Adverse Effects:
Orally: At doses of 5 mg daily - abdominal cramps, diarrhea, and rash. At doses of 15 mg daily - bitter taste, confusion, hyperactivity, impaired judgment, irritability, nausea, sleep disturbances.
Serious Adverse Effects (Rare):
Orally: Cancer (long-term use), cardiovascular complications, liver injury, seizures.
All ROAs: Allergic reactions such as bronchospasm and anaphylactic shock.

Cardiovascular ...There is some concern that high oral doses of folic acid might increase the risk of adverse cardiovascular outcomes. Clinical research shows that taking doses of 800 mcg to 1.2 mg/day might increase the risk of adverse cardiovascular events in patients with cardiovascular disease (12150,13482). High doses of folic acid might promote cell growth by providing large amounts of the biochemical precursors needed for cell replication. Overgrowth of cells in the vascular wall might increase the risk of occlusion (12150). Although some research suggests that use of folic acid might increase the need for coronary revascularization, analysis of multiple studies suggests that taking folic acid up to 5 mg/day for up to 24 months does not appear to affect coronary revascularization risk (90798).

Dermatologic ...Orally, folic acid 1-5 mg daily can cause rash (7225,90375,91319). Folic acid 15 mg daily can sometimes cause allergic skin reactions (15).

Gastrointestinal ...Orally, folic acid 5 mg daily can cause abdominal cramps and diarrhea (7225). Folic acid 15 mg daily can sometimes cause nausea, abdominal distention, flatulence, and bitter taste in the mouth (15). In children aged 6-30 months at risk of malnourishment, taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg daily, with or without vitamin B 12 0.9-1.8 mcg daily, for 6 months increases the likelihood of having persistent diarrhea (90391).

Hepatic ...Liver dysfunction, with jaundice and very high liver enzymes, occurred in a 30-year-old pregnant patient with severe nausea and vomiting taking a folic acid supplement (Folic acid, Nature Made) 400 mcg daily. Based on the timing of ingestion, the lack of other etiological factors, a positive drug-induced lymphocyte stimulation test, and liver function normalization once the folic acid had been stopped, the authors suggest the folic acid supplement was the cause. However, the authors did not determine which substance in the folic acid supplement was responsible and therefore it cannot be determined that folic acid itself was the cause (91309).

Neurologic/CNS ...Orally, folic acid 15 mg daily can sometimes cause altered sleep patterns, vivid dreaming, irritability, excitability, hyperactivity, confusion, and impaired judgment (15). Large doses of folic acid can also precipitate or exacerbate neuropathy in people deficient in vitamin B12 (6243). Use of folic acid for undiagnosed anemia has masked the symptoms of pernicious anemia, resulting in lack of treatment and eventual neurological damage (15). Patients should be warned not to self-treat suspected anemia. There is also some concern that consuming high amounts of folic acid from the diet and/or supplements might worsen cognitive decline in older people. A large-scale study suggests that people over 65 years of age, who consume large amounts of folic acid (median of 742 mcg/day), have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg/day). It's not known if this is directly attributable to folic acid. It is theorized that it could be due to folic acid masking a vitamin B12 deficiency. Vitamin B12 deficiency is associated with cognitive decline (13068). More evidence is needed to determine the significance of this finding. For now, suggest that most patients aim for the recommended folic acid intake of 400 mcg/day.

Oncologic ...There is some concern that high dose folic acid might increase the risk of cancer, although research is unclear and conflicting. A large-scale population study suggests that taking a multivitamin more than 7 times per week with a separate folic acid supplement significantly increased the risk of prostate cancer (15607). Clinical research also shows that taking folic acid 1 mg daily increase the absolute risk of prostate cancer by 6.4% over a 10-year period when compared with placebo. However, those with a higher baseline dietary intake of folic acid had a lower rate of prostate cancer, but this was not statistically significant. Also, folate and folic acid intake in patients with prostate cancer is not associated with the risk of prostate cancer recurrence after radical prostatectomy (91317). However, it is possible that discrepancies are due to dietary folate versus folic acid intake. Large analyses of population studies suggest that while dietary folate/folic acid is not associated with prostate cancer, high blood folate/folic acid increases the risk of prostate cancer (50411,91316).
Additional clinical research shows that taking folic acid 800 mcg daily, in combination with vitamin B12 400 mcg, significantly increases the risk of developing cancer, especially lung cancer, and all-cause mortality in patients with cardiovascular disease (17041). However, this may be due to vitamin B12, as other observational research found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). Meta-analyses of large supplementation trials of folic acid at levels between 0.5-2.5 mg daily also suggest an increased risk of cancer (50497,110318). Also, in elderly individuals, taking folic acid 400 mcg daily with vitamin B12 500 mcg daily increased the risk of cancer. The risk was highest in individuals over 80 years of age and in females and mainly involved gastrointestinal and colorectal cancers (90393).
Not all researchers suspect that high intake of folic acid supplements might be harmful. Some research suggests that increased dietary intake of folic acid, along with other nutrients, might be protective against cancer (16822). A meta-analysis of multiple clinical trials suggests that folic acid supplementation studies with folic acid levels between 500 mcg to 50 mg/day does not increase the risk of general or site-specific cancer for up to 7 years (91312,91321). Also, 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).

Psychiatric ...Orally, folic acid 15 mg daily can sometimes cause exacerbation of seizure frequency and psychotic behavior (15).

Pulmonary/Respiratory ...Folic acid use in late pregnancy has been associated with an increased risk of persistent and childhood asthma at 3. 5 years in population research (50380). When taken pre-pregnancy or early in pregnancy, population research has not found an association with increased risk of asthma or allergies in childhood (90799,103979). Folic acid use in pregnancy has been associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age in population research (50328).

(Read more about FOLIC ACID)

General ...Orally, L-tryptophan is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, diarrhea, drowsiness, dry mouth, flatulence, headache, heartburn, lightheadedness, nausea, stomach pain, visual blurring, and vomiting.
Serious Adverse Effects (Rare):
Orally: L-tryptophan has been associated with the neurological disorder eosinophilia-myalgia syndrome (EMS). However, almost all cases were traced to L-tryptophan produced by a single manufacturer in Japan and are likely related to contamination.

Cardiovascular ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include cardiovascular symptoms such as myocarditis, arrhythmias, and palpitations (8053,11477).

Dermatologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include dermatological symptoms such as sclerodermiform skin changes, alopecia, and rash (8053,11477).

Gastrointestinal ...Orally, L-tryptophan can cause gastrointestinal side effects such as heartburn, stomach pain, belching and flatulence, nausea, vomiting, diarrhea, dry mouth, and anorexia (10853,99884).

Hematologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hematologic symptoms such as eosinophilia (8053,11477).

Hepatic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hepatic symptoms such as hepatomegaly (8053,11477).

Musculoskeletal ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include musculoskeletal symptoms such as myalgia and inflammation of the joints and connective tissue (8053,11477).

Neurologic/CNS ...Orally, L-tryptophan can cause headache, lightheadedness, and ataxia (10853,99884).
In 1989, more than 1500 cases of the neurological disorder EMS were associated with oral L-tryptophan use in the US. About 95% of all EMS cases were traced to contaminated L-tryptophan produced by a single manufacturer in Japan (8054,10288,10289,11475,11476). In 1990, L-tryptophan was recalled in the U.S. and an FDA alert was put into force limiting the importation of all over-the-counter L-tryptophan products (7067,11477,11478). After the limitation of L-tryptophan products, the incidence of EMS dropped abruptly (11474). Symptoms of EMS associated with L-tryptophan use include intense eosinophilia; fatigue; myalgia; neuropathy; sclerodermiform skin changes; alopecia; rash; and inflammatory disorders affecting the joints, connective tissue, lungs, heart, and liver (8053,11477). Symptoms tend to improve over time, however some individuals may still experience symptoms up to 2 years after the onset of EMS and complete resolution of symptoms may not occur (8053,10287).
There is some evidence of an association between L-tryptophan-related EMS and the occurrence of chronic B-cell lymphocytic leukemia (8055).

Ocular/Otic ...Orally, L-tryptophan can cause side effects such as visual blurring (10853).

Pulmonary/Respiratory ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include respiratory symptoms such as dyspnea and cough (8053,11477).

(Read more about L-TRYPTOPHAN)

General ...Orally, melatonin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, headache, and nausea.
Serious Adverse Effects (Rare):
Orally: There is concern that melatonin may increase the risk for seizure.

Cardiovascular ...Melatonin might increase levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides (62176). Several rare or poorly described cases of abnormal heart rhythms, palpitations, fast heart rate, or chest pain have been reported. However, in these cases, the patients were taking other drugs that could account for the symptoms, and melatonin was not thought to be the cause (1079,9181,62776,62789,63067).

Dermatologic ...Papular skin rash and pruritus has been reported with melatonin use. However, the effect was generally mild and did not require cessation of melatonin treatment (62450,62754,109696), and had similar rates as placebo (96316). Cutaneous flushing has also been reported (62770,62914). Two cases of fixed drug eruption on the genitalia have been reported for patients who used oral melatonin (Nature's Bounty Natural melatonin) for preventing jet lag (88284).

Endocrine ...A case of gynecomastia (increased breast size) has been reported for a 56 year-old patient with amyotrophic lateral sclerosis (ALS) who used oral melatonin, long-term (89430). Also, reduced sperm concentration and sperm motility has been reported for two men who used oral melatonin 3 mg daily for 6 months. Improvement in sperm quality was observed for only one of the two men following melatonin cessation (62231).

Gastrointestinal ...Orally, melatonin may cause nausea (62384,62770), abdominal cramps, or mild abdominal pain (62450,62754,62914,96316), diarrhea (62804,62811,62914), constipation (96316), or decreased appetite (62345,62792). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). In some cases, rates of symptoms are similar between melatonin and placebo (96316). Less often, melatonin has been reported to cause abnormal feces (62450), odd taste in the mouth (1070), or reflux esophagitis (1745) when used orally. A case of exacerbated symptoms of Crohn disease, including increased diarrhea and abdominal cramps, has been reported for a patient who took oral melatonin 3 mg at bedtime for 4 days. Symptoms resolved within 24 hours of melatonin treatment cessation (62218).

Genitourinary ...Orally, melatonin may increase enuresis in adults and children (58685,62450,62710,62770,62804,62804,62811). In perimenopausal adults, melatonin has caused a resumption of spotting or menstrual flow (11806). Decreased libido has been noted for one patient treated with melatonin 3 mg daily for 8 weeks (15216).

Hematologic ...A case of nose bleed has been reported with oral melatonin (62450). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Hepatic ...A case of autoimmune hepatitis has been reported for a patient who took melatonin orally to treat insomnia (63037).

Musculoskeletal ...Preliminary clinical evidence shows that a single dose of melatonin 3 mg may increase fall risk due to increased postural swaying while standing on one or both feet in healthy adults ages 60-71 years (97442). A single case of ataxia has been reported for an 81-year-old female who used melatonin for 4 days (9181). Weakened muscle power has been reported for two patients treated with melatonin 5 mg in the evening (62456). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Neurologic/CNS ...Orally, melatonin may cause migraine-like headache (1070,1077,15034,62384,62450,62710,62754,62804,62792,62914,88288,88293,88294,96318)(106297) or dizziness (62345,62384,62450,62456,62770,62784,62792,62804,62811,89510)(110297). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). Melatonin may also cause drowsiness or fatigue when taken orally (1077,8273,15216,62384,62456,62784,62804,62811,88288,89510,96314,96316,96318,97446)(106293,106297). These symptoms appear to be more common if melatonin is taken in the morning or at very high doses (greater than 50 mg) (8269,62874). A case of excessive drowsiness has been reported when melatonin was combined with citalopram, nortriptyline, and oxycodone. Sedation improved with discontinuation of melatonin (96315). Indiscriminate use of melatonin may cause irregular sleep-wake cycles to occur (62998). Less commonly, melatonin may also cause behavior worsening (62811), confusion or disorientation (63014,63067), nighttime awakening (62710,62811), mood swings or agitation (96318), stereotypy (96318), excitement before bedtime (62811), nightmares or more intense dreams (62401,62462,62780,62784,88283), feelings of a "rocking" sensation (62155), or reduced alertness when taken orally.
A case of generalized epilepsy has reportedly occurred after treatment with melatonin for 4 months (9708). Also, some case reports raise concerns about increased risk of seizure with melatonin treatment, but conflicting evidence suggests that melatonin may decrease the risk of seizures (1699,8248,9695,9697,9744,9746,62123,62256,62384,62754)(63070,63071,89431). One patient experienced hyponatremia with confusion and seizures after taking prolonged-release melatonin 2 mg. However, malnutrition and cannabis abuse were also thought to contribute to this reaction (96321).
Although there is concern that melatonin might affect cognitive function in healthy adults, research in humans suggests that oral or topical melatonin do not impact most measures of cognitive function (97442,97448).

Psychiatric ...Orally, melatonin may cause mood changes, including dysphoria (sadness) (1764), dips in mood (62345,62450,62792), nervousness (62784), or transient depression (1077). Delusions and hallucinations have also been reported in clinical research (62347). An isolated incident of aggressiveness was also noted in a child diagnosed with attention deficit-hyperactivity disorder (ADHD) who took melatonin in combination with methylphenidate (9980). Severe irritability has been reported in two children with autism spectrum disorder who had abruptly discontinued melatonin due to the completion of a clinical trial (106293).

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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). Tell patients daily doses of 100 mg or less are unlikely to cause 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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