One-Daily Multi-Vitamin With Iron [Discontinued] by Geri-Care

EFFECTIVE

• Anemia of chronic disease. Oral and intravenous (IV) iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that IV iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, IV iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of IV or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous (IV) iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidance from the American Gastroenterological Association and the British Society of Gastroenterology recommends treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. Ferrous sulfate, fumarate, or gluconate daily are recommended. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels have normalized(110193,115890). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, IV or intramuscular iron were also used (104684). Intravenous iron has also been evaluated for the prevention of postoperative anemia. A meta-analysis of several, moderate-quality clinical studies in adults undergoing cardiac surgery, including patients with or without anemia, shows that various types of IV iron (e.g. ferric carboxymaltose, iron sucrose) reduce the risk of red blood cell transfusions by approximately 23%, and improve hemoglobin and iron levels by postoperative day 4, when compared with placebo and oral iron therapy (115898). The validity of these results is limited by heterogeneous methods across clinical studies including patient population, iron formulation, and use of erythropoietin.
• Pregnancy-related iron deficiency. Oral and intravenous (IV) iron are effective for managing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 15-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 50% to 100% (20122,20123,20124,110180,110188,115895). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements, with or without folic acid, on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Another meta-analysis shows that daily supplementation of iron with folic acid increases hemoglobin levels by 0.24 g/dL when compared with intermittent supplementation, given as 1, 2, or 3 doses weekly. However, clinical significance of this slight increase is unlikely, and no difference in rates of anemia are noted between dosing strategies (115896). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188,115895). However, in patients with anemia during pregnancy, meta-analyses of several, moderate-quality clinical studies show that IV iron (e.g. iron sucrose) is more effective than oral iron (e.g. ferrous sulfate) for improving hemoglobin levels and reducing the risk for anemia (110185,115897).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600). Most studies included in the analyses evaluated daily iron supplementation, with a few studies assessing iron taken 4-6 times weekly (110181,112600). In contrast, a large clinical trial in schoolchildren in Ethiopia shows that taking iron supplements, providing 42 mg of elemental iron, once weekly for 11 months does not improve working memory, nonverbal intelligence, planning, or problem-solving, and may even worsen one measure of attention and concentration when compared with placebo (113904). These discrepant findings may be related to differences in frequency of dosing (daily vs. weekly) and baseline demographics; only 20% and 4% of children in this study had iron deficiency and iron deficiency anemia, respectively.
• Heart failure. Intravenous (IV) iron seems to be effective for improving certain outcomes in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). A number of large clinical trials and meta-analyses of clinical research in patients with heart failure show that administering IV iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599,113900,113901). Based on these results, guidelines from the American Heart Association and European Society of Cardiology support the use of IV iron in patients with heart failure with reduced ejection fraction and iron deficiency to improve symptoms and quality of life. Additionally, IV iron supplementation in these patients is associated with a reduced risk of heart failure hospitalization (115935,115936). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous (IV) iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or IV ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of intravenous ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Intravenous iron sucrose has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of IV ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Iron sucrose, given IV, has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587). Additionally, IV and oral iron have been compared in the management of RLS. A clinical study in adults with RLS and iron deficiency anemia shows that administering IV ferumoxytol 1020 mg for 2 doses, 2-7 days apart, reduces self-reported symptom severity and frequency comparably to taking oral ferrous sulfate 650 mg daily for 6 weeks (115894). The validity of these results is limited by methodological concerns, including lack of a placebo control group and failure to obtain all follow-up data.

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: A meta-analysis of three small, lower quality clinical studies in children and adolescents with ADHD and iron deficiency shows that taking ferrous fumarate 200-400 mg, dependent upon body weight, or ferrous sulfate 80 mg daily for 3 months does not improve hyperactivity and inattention when compared with placebo. However, the results of individual clinical studies are inconsistent (115893). The validity of these results is limited by high heterogeneity across clinical studies, including patient baseline characteristics, use of investigator-, parent-, and teacher-rated ADHD scales, and concomitant use of ADHD medication therapy (e.g. stimulants).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626,115891).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous (IV) iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with IV iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that IV iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

(Read more about IRON)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about NIACIN)

EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about PANTOTHENIC ACID)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about RIBOFLAVIN)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

LIKELY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about VITAMIN A)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about VITAMIN B6)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

LIKELY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about VITAMIN D)

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

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

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

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

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

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

(Read more about IRON)

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

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

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

(Read more about NIACIN)

LIKELY SAFE ...when used orally and appropriately. The pantothenic acid derivative calcium pantothenate has a generally recognized as safe (GRAS) status for use in food products (111258). While a tolerable upper intake level (UL) has not been established, pantothenic has been used in doses of 10-20 grams daily with apparent safety (15,6243,111258) ...when applied topically and appropriately, short-term. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and its derivatives are safe for use in cosmetic products in concentrations up to 5.3% (111258). Gels or ointments containing a derivative of pantothenic acid, dexpanthenol, at concentrations of up to 5%, have been used safely for up to 30 days (67802,67806,67817).

POSSIBLY SAFE ...when applied intranasally and appropriately, short-term. A dexpanthenol nasal spray has been used with apparent safety up to four times daily for 4 weeks (67826). ...when applied in the eyes appropriately, short-term. Dexpanthenol 5% eyedrops have been used with apparent safety for up to 28 days (67783). ...when injected intramuscularly and appropriately, short-term. Intramuscular injections of dexpanthenol 500 mg daily for up to 5 days or 250 mg weekly for up to 6 weeks have been used with apparent safety (67822,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately (15,6243). Calcium pantothenate is generally recognized as safe (GRAS) when used as a food additive and in infant formula (111258). However, a tolerable upper intake level (UL) has not been established (15,6243). ...when applied topically and appropriately (67795,105190,111262). Infant products containing pantothenic acid and its derivatives have been used safely in concentrations of up to 5% for infant shampoos and 2.5% for infant lotions and oils. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and derivatives are safe for use in topical infant products. (111258).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during pregnancy is 6 mg (3094).

LACTATION: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during lactation is 7 mg (3094).

(Read more about PANTOTHENIC ACID)

LIKELY SAFE ...when used orally and appropriately. Riboflavin 400 mg daily has been taken for up to 3 months, and 10 mg daily has been taken safely for up to 6 months (4912,91752,105480). A tolerable upper intake level (UL) has not been established (3094,91752,94089).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089). ...when used orally in higher doses for up to 1 year. Doses of 100-200 mg daily have been used safely for 4-12 months in children ages 9-13 years (71483,105484).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089).

(Read more about RIBOFLAVIN)

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

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

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

(Read more about THIAMINE)

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

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

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

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

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

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

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

(Read more about VITAMIN A)

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

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

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

(Read more about VITAMIN B12)

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

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

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

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

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

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

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

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

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

(Read more about VITAMIN B6)

LIKELY SAFE ...when used orally, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15) and has been used with apparent safety in clinical trials up to 150 mg/kg daily for up to 4 days (114489) and up to 200 mg/kg daily for up to 2 days (114492).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).

CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.

(Read more about VITAMIN C)

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses (7555,16888,16891,17476,95913,98186,104619,105209,109040,109059)(115580,115590). When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults (17506,99773); however, much higher doses such as 50,000 IU (1250 mcg) weekly orally for 6-12 weeks are often needed for the short-term treatment of vitamin D deficiency (16891,17476,115590). Monthly oral doses of up to 60,000 IU (1500 mcg) have also been safely used for up to 5 years (105726). Toxicity usually does not occur until plasma levels exceed 150 ng/mL (17476).

POSSIBLY UNSAFE ...when used orally in excessive doses, long-term. Taking doses greater than the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults for long periods can increase the risk of hypercalcemia (17506); however, much higher doses are often needed for short-term treatment of vitamin D deficiency. Toxicity typically occurs when levels exceed 150 ng/mL (17476).

CHILDREN: LIKELY SAFE
when used orally and appropriately. When used long-term, doses should not exceed the tolerable upper intake level (UL) of 1000 IU (25 mcg) daily for those 0-6 months of age, 1500 IU (37.5 mcg) daily for those 6-12 months of age, 2500 IU (62.5 mcg) daily for those 1-3 years of age, 3000 IU (75 mcg) daily for those 4-8 years of age, and 4000 IU (100 mcg) daily for those 9 years and older (17506); however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU (350 mcg) weekly for a year in children aged 10-17 years is safe (16875). A meta-analysis of clinical studies shows that 1000 IU (25 mcg) daily in those up to a year of age and greater than 2000 IU (50 mcg) daily in those aged 1-6 years does not increase the risk of serious adverse events (108424).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses for longer than one year. Taking doses greater than the tolerable upper intake level (UL) long-term can increase the risk of hypercalcemia (17506).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506,95910).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily. Hypercalcemia during pregnancy due to excessive vitamin D intake can lead to several fetal adverse effects, including suppression of parathyroid hormone, hypocalcemia, tetany, seizures, aortic valve stenosis, retinopathy, and mental and/or physical developmental delay (17506).

LACTATION: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

LACTATION: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

(Read more about VITAMIN D)

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about IRON)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about NIACIN)

(Read more about PANTOTHENIC ACID)

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking riboflavin with tetracycline antibiotics may decrease the potency of these antibiotics.  Details In vitro research suggests that riboflavin may inhibit the potency of tetracycline antibiotics (23372). It is not clear if this effect is clinically significant, as this interaction has not been reported in humans.

(Read more about RIBOFLAVIN)

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

(Read more about THIAMINE)

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

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

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

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

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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).

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ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B High-dose vitamin C might slightly prolong the clearance of acetaminophen.  Details A small pharmacokinetic study in healthy volunteers shows that taking high-dose vitamin C (3 grams) 1.5 hours after taking acetaminophen 1 gram slightly increases the apparent half-life of acetaminophen from around 2.3 hours to 3.1 hours. Ascorbic acid competitively inhibits sulfate conjugation of acetaminophen. However, to compensate, elimination of acetaminophen glucuronide and unconjugated acetaminophen increases (6451). This effect is not likely to be clinically significant.

ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, antioxidant effects of vitamin C might reduce the effectiveness of alkylating agents.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin C have on chemotherapy.

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase the amount of aluminum absorbed from aluminum compounds.  Details Research in animals and humans shows that vitamin C increases aluminum absorption, theoretically by chelating aluminum and keeping it in solution where it is available for absorption (10549,10550,10551,21556). In people with normal renal function, urinary excretion of aluminum will likely increase, making aluminum retention and toxicity unlikely (10549). Patients with renal failure who take aluminum-containing compounds such as phosphate binders should avoid vitamin C supplements in doses above the recommended dietary allowances.

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the antioxidant effects of vitamin C might reduce the effectiveness of antitumor antibiotics.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as doxorubicin (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effects, if any, antioxidants such as vitamin C have on chemotherapy.

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase aspirin levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction is not clinically significant.

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase choline magnesium trisalicylate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046,4531). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C might increase blood levels of estrogens.  Details Increases in plasma estrogen levels of up to 55% occur under some circumstances when vitamin C is taken concurrently with oral contraceptives or hormone replacement therapy, including topical products (129,130,11161). It is suggested that vitamin C prevents oxidation of estrogen in the tissues, regenerates oxidized estrogen, and reduces sulfate conjugation of estrogen in the gut wall (129,11161). When tissue levels of vitamin C are high, these processes are already maximized and supplemental vitamin C does not have any effect on estrogen levels. Increases in plasma estrogen levels may occur when patients who are deficient in vitamin C take supplements (11161). Monitor these patients for estrogen-related side effects.

FLUPHENAZINE (Prolixin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitamin C might decrease levels of fluphenazine.  Details In one patient there was a clinically significant decrease in fluphenazine levels when vitamin C (500 mg twice daily) was started (11017). The mechanism is not known, and there is no further data to confirm this interaction.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can modestly reduce indinavir levels.  Details One pharmacokinetic study shows that taking vitamin C 1 gram orally once daily along with indinavir 800 mg orally three times daily reduces the area under the concentration-time curve of indinavir by 14%. The mechanism of this interaction is unknown, but it is unlikely to be clinically significant in most patients. The effect of higher doses of vitamin C on indinavir levels is unknown (11300,93578).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase levothyroxine absorption.  Details Two clinical studies in adults with poorly controlled hypothyroidism show that swallowing levothyroxine with a glass of water containing vitamin C 500-1000 mg in solution reduces thyroid stimulating hormone (TSH) levels and increases thyroxine (T4) levels when compared with taking levothyroxine alone. This suggests that vitamin C increases the oral absorption of levothyroxine, possibly due to a reduction in pH (102978).

NIACIN Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = A Vitamin C might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.  Details A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as vitamin C, or to the combination. It also is not known whether it will occur in other patient populations.

SALSALATE (Disalcid) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase salsalate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams/day vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D High-dose vitamin C might reduce the levels and effectiveness of warfarin.  Details Vitamin C in high doses may cause diarrhea and possibly reduce warfarin absorption (11566). There are reports of two people who took up to 16 grams daily of vitamin C and had a reduction in prothrombin time (9804,9806). Lower doses of 5-10 grams daily can also reduce warfarin absorption. In many cases, this does not seem to be clinically significant (9805,9806,11566,11567). However, a case of warfarin resistance has been reported for a patient who took vitamin C 500 mg twice daily. Cessation of vitamin C supplementation resulted in a rapid increase in international normalized ratio (INR) (90942). Tell patients taking warfarin to avoid taking vitamin C in excessively high doses (greater than 10 grams daily). Lower doses may be safe, but the anticoagulation activity of warfarin should be monitored. Patients who are stabilized on warfarin while taking vitamin C should avoid adjusting vitamin C dosage to prevent the possibility of warfarin resistance.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.  Details The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might reduce absorption of atorvastatin.  Details A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Taking calcipotriene with vitamin D increases the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.  Details There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.  Details Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.  Details Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.

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

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