Optimal Iron Plus Cofactors [Discontinued] by Seeking Health

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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LIKELY EFFECTIVE

• Biotin deficiency. Oral and injectable biotin prevents and treats biotin deficiency. Details: Biotin up to 10 mg daily has been used to treat and prevent biotin deficiency. Injections of biotin 150 mcg daily for 3-5 days have been used in adults. Biotin deficiency might occur due to different etiologies such as inherited biotinidase deficiency, malnutrition, chronic use of anticonvulsants, pregnancy, and excessive and chronic raw egg consumption (6243,19347). A very small study in newborns aged 1-6 months shows that adding biotin to infant formula safely improves biotin status in formula-fed infants (111365). The validity of these findings is limited by a lack of blinding, no randomization, and the small sample size.

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). In spite of contrary reports, high-dose biotin (300 mg daily) does not reduce disability in patients with progressive MS. It also does not seem to be linked to an increased risk for relapse. Details: Although most earlier research suggested benefit, the highest quality evidence shows that high-dose biotin does not improve outcomes in progressive MS (95662,102963,102966,104011). A large multi-centered randomized clinical trial (SPI2) in patients with progressive MS and high disability shows that taking biotin 100 mg three times daily for 15 months does not improve disability, as measured on the expanded disability status scale (EDSS), or 25-foot walking time, when compared with placebo. The SPI2 clinical trial also did not find that biotin increases the rate of relapse (104011), a concern raised in one observational study of high-dose biotin (104000). Also, a large observational study of adults with progressive MS failed to identity an increase in annualized relapse rates in patients that reported taking biotin when compared with controls (105716). Other observational research has also found no effect on the relapse risk (102963,102964). There is some speculation that any increased rate of relapse identified in some high-dose biotin cohorts might be due to detection bias or reduced compliance with disease-modifying therapies.
• Seborrheic dermatitis. Oral biotin doesn't seem to improve seborrheic dermatitis of infancy. Details: A clinical trial in infants with seborrheic dermatitis shows that biotin given by mouth does not improve symptoms when compared with placebo (8469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if oral biotin is beneficial for alopecia areata. Details: A small clinical study in healthy adults with alopecia areata shows that weekly injections of intramuscular biotin 5 mg/1 mL and dexpanthenol 250 mg/2 mL for 6 weeks reduces hair fall count and transiently increases hair density compared with baseline (111366). The validity of these findings is limited by a lack of a placebo control group, small sample size, and short duration of treatment. It is unclear if the effects are due to biotin, dexpanthenol, or the combination. Another small clinical study in 9-year-old children with alopecia areata shows that taking biotin 20 mg with zinc aspartate 100 mg orally along with topical application of clobetasol propionate 0.025% daily for one year promotes hair regrowth in 33% of children, compared with 0% in the group receiving the steroid deflazacort (6932). It is unclear if these effects are due to biotin, zinc, topical clobetasol, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral biotin for ALS, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Biotin-thiamine-responsive basal ganglia disease. Adding oral biotin to oral thiamine does not seem to improve most symptoms associated with this condition, although it may slightly speed recovery from acute crisis in children. Details: A small case series in children ages 1-12 years with biotin-thiamine-responsive basal ganglia disease has found that adding biotin 5 mg/kg daily to thiamine 40 mg/kg daily for 30 months is not associated with additional symptomatic improvement in encephalopathy, seizures, dystonia, or other neurologic sequelae when compared with taking only thiamine. However, taking biotin with thiamine is associated with a 1-day reduction in recovery from acute crisis when compared with thiamine alone (95661).
• Brittle nails. Low quality clinical studies suggest that oral biotin might improve nail thickness and prevent the splitting of brittle nails. Details: Some small, low quality clinical studies in people with brittle nails shows that taking biotin 2.5 mg orally daily for 1.5 to 15 months increases nail thickness and decreases the splitting of fingernails and toenails in some people when compared with baseline (171,35593). The validity of these findings is limited by the small study sizes and the lack of a comparator group.
• Depression. Although there is interest in using oral biotin for mild depression, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Diabetes. It is unclear if oral biotin is beneficial for type 2 diabetes. Details: A meta-analysis of randomized controlled trials shows that taking biotin 1.5-15 mg orally daily for 1-3 months does not improve fasting blood glucose or serum insulin levels when compared with placebo. However, the validity of these results is limited by inclusion of subjects with and without diabetes (110044). A very small study in adults with type 2 diabetes also shows that taking biotin 5 mg three times daily for 28 days does not affect glucose or insulin levels when compared to baseline (11579). Biotin has also been studied in combination with other ingredients. Preliminary clinical research shows that a taking a specific supplement containing a combination of biotin 2 mg and chromium picolinate 600 mcg (Diachrome, Nutrition 21) can lower blood glucose and glycated hemoglobin levels in patients with type 2 diabetes who are poorly controlled on oral hypoglycemic drugs (12385,12390,15169). It is unclear if these effects are due to biotin, chromium, or the combination.
• Diabetic neuropathy. Although there is interest in using oral and intramuscular biotin for diabetic neuropathy, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Muscle cramps. It is unclear if biotin is beneficial for improving muscle cramps in patients undergoing hemodialysis. Details: Patients undergoing hemodialysis are prone to muscle cramps. A small clinical study in patients with hemodialysis-related muscle cramps shows that taking biotin 1 mg in the morning daily for at least one week prevents and reduces severity of muscle cramps when compared to baseline. Cessation of biotin led to recurrence of cramps, and restarting oral biotin led to resolution of cramps during hemodialysis (89475). The validity of these findings is limited by the lack of comparator group. More evidence is needed to rate biotin for these uses.

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LIKELY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about IRON)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

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

• 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 oral vitamin A seems to reduce mortality from measles in children under 2 years of age and may also reduce the incidence of measles in children up to 5 years of age. Details: 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 (82373,82502,95055,109755). However, in children with measles who are less than 2 years of age, taking vitamin A 200,000 IU orally for at least two doses seems to reduce mortality by up to 83% when compared with placebo (82373,82502). Also, taking vitamin A seems to reduce the incidence of measles in children ages 6 months to 5 years (95055,109755).
• 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). In 2010, a meta-analysis of 17 trials involving over 194,000 patients, showed that vitamin A supplementation reduces all-cause mortality by about 24% in children 6 months to 5 years of age (82559). However, some research published after this meta-analysis shows conflicting results (90773,90777). In fact, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which was published after the analysis and involved one million preschool children, 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). Furthermore, in 2017, a meta-analysis including the DEVTA trial along with 46 additional studies involving over 1.2 million preschool children, shows that vitamin A supplementation does reduce all-cause mortality by 12% when compared with control (95055). This meta-analysis was updated in 2022 with no additional studies or changes in conclusions (109755). 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).
• 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

• 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 wrist or distal radius fracture or after orthopedic surgery seems to reduce the risk of developing complex regional pain. 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 orthopedic surgery has also shown benefit with the use of vitamin C for the prevention of complex regional pain syndrome (90422,108076,108087). One meta-analysis of clinical research in patients undergoing wrist, foot, or ankle 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. Another meta-analysis of clinical research in patients undergoing orthopedic surgery (i.e. wrist, knee, ankle, foot, lumbar, rotator cuff) suggests that oral and intravenous vitamin C may have similar effectiveness; however, this evidence is low quality (108087).
• 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). 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. However, vitamin C does not reduce postoperative pain scores or analgesic requirements when compared with placebo (111645). For dental surgery, 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). Further research is needed to determine the effects of vitamin C for acute postoperative pain. 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. 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).
• 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. 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).
• 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 topical application of 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).
• 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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POSSIBLY SAFE ...when taken orally as a single dose of up to 1500 mg (93328,93329). There is insufficient reliable information available about the safety of betaine hydrochloride when used in multiple doses.

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

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LIKELY SAFE ...when used orally and appropriately. Biotin has been safely used in doses up to 300 mg daily for up to 6 months. A tolerable upper intake level (UL) has not been established (1900,6243,95662,102965). ...when applied topically as cosmetic products at concentrations of 0.0001% to 0.6% biotin (19344).

POSSIBLY SAFE ...when used intramuscularly and appropriately (8468,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at adequate intake doses of 5-25 mcg daily for up to 6 months (173,6243,19347,19348,111365). A tolerable upper intake level (UL) has not been established.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at the adequate intake (AI) dose of 30 mcg daily during pregnancy and 35 mcg daily during lactation. It has also been used in supplemental doses of up to 300 mcg daily (6243,7878). A tolerable upper intake level (UL) has not been established.

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LIKELY SAFE ...when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 10 mg daily (7135).

POSSIBLY SAFE ...when copper oxide is used topically. A wound dressing impregnated with copper oxide in concentrations of 3% by weight has been used with apparent safety in one clinical trial (105363).

POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 10 mg daily. Higher intake can cause liver damage (7135,45865). Kidney failure and death can occur with ingestion of as little as 1 gram of copper sulfate (17).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 1 mg daily for 1-3 years of age, 3 mg daily for 4-8 years of age, 5 mg daily for 9-13 years of age, and 8 mg daily for 14-18 years of age (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the UL (7135). Higher intake can cause liver damage (7135).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

PREGNANCY: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

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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). Despite these findings, there are rare reports of hypophosphatemia and/or osteomalacia (112603,112608,112609,112610).

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. Higher doses frequently cause gastrointestinal side effects such as constipation and nausea (7135,20097). Iron is the most common cause of pediatric poisoning deaths. Doses as low as 60 mg/kg can be fatal (15).

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

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

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There is insufficient reliable information available about the safety of lipase.

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

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

(Read more about LIPASE)

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).

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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).

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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)

ANTACIDS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Betaine hydrochloride increases stomach acidity and could decrease the effects of antacids.  Details In human research, betaine hydrochloride increases stomach acidity (93328,93329). Antacids are taken to decrease stomach acidity. Theoretically, taking betaine hydrochloride along with antacids might decrease the effects of the antacids.

H2-BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Betaine hydrochloride increases stomach acidity and could decrease the effects of H2-blockers.  Details In human research, betaine hydrochloride increases stomach acidity (93328,93329). H2-blockers are used to decrease stomach acidity. Theoretically, taking betaine hydrochloride along with H2-blockers might decrease the effects of H2-blockers.

PROTON PUMP INHIBITORS (PPIs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Betaine hydrochloride increases stomach acidity and could decrease the effects of PPIs.  Details In human research, betaine hydrochloride increases stomach acidity (93328,93329). PPIs are used to decrease stomach acidity. Theoretically, taking betaine hydrochloride along with PPIs might decrease the effects of PPIs

(Read more about BETAINE HYDROCHLORIDE)

(Read more about BIOTIN)

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking copper with contraceptive drugs might increase the levels and toxic effects of copper.  Details A meta-analysis of clinical studies suggests that chronic use of oral contraceptives increases serum copper levels by a mean of 57 mcg/dL. In most people, this resulted in levels above the normal reference range for copper (92395).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking copper with penicillamine might decrease the absorption of penicillamine; separate dosing by at least 2 hours.  Details Copper chelates penicillamine, which decreases its absorption and may reduce its clinical effects (4412,4453,4531,4535,9630).

(Read more about COPPER)

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.

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

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

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

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

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

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

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

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

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

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(Read more about LIPASE)

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)

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.

(Read more about VITAMIN A)

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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General ...Orally, betaine hydrochloride is generally well tolerated when taken as a single dose.

Gastrointestinal ...Theoretically, the hydrochloric acid produced from betaine hydrochloride might irritate gastric or duodenal ulcers or impede ulcer healing. It might also cause heartburn.

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General ...Orally and topically, biotin is generally well tolerated.
Most Common Adverse Effects: None.

Gastrointestinal ...Orally, high-dose biotin has been rarely associated with mild diarrhea. Transient mild diarrhea was reported by 2 patients taking biotin 300 mg daily (95662).

Pulmonary/Respiratory ...In one case report in France, a 76-year-old female frequent traveler developed eosinophilic pleuropericarditis after taking biotin 10 mg and pantothenic acid 300 mg daily for 2 months. She had also been taking trimetazidine for 6 years (3914). Whether eosinophilia in this case was related to biotin, pantothenic acid, other substances, or patient-specific conditions is unknown. There have been no other similar reports.

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General ...Orally, copper is generally well tolerated when consumed in doses below the tolerable upper intake level (UL).

Dermatologic ...Contact dermatitis caused by copper has been reported rarely. A case report describes a 5-year-old male who developed recurrent fingertip dermatitis and a positive skin test to copper after playing with toy cars made with a copper-containing alloy (95538). Also, in a small clinical trial in children 1-3 months of age with umbilical granuloma, 3 of 33 children receiving a single topical application of copper sulfate developed superficial burns, whereas no superficial burns occurred in those receiving topical sodium chloride (109403).
In one case report, a 68-year-old male with type 2 diabetes and peripheral neuropathy developed second- and third-degree burns after wearing a copper-containing compression sock on the right leg for 3 hours while sitting in the sun. The patient received treatment with topical silver sulfadiazine and oral clindamycin. After 6 weeks, the patient was found to have multiple persistent wounds containing necrotic tissue which required debridement, daily dressing changes, and tubular compression. It is thought that the heat conductance of copper magnified the effects of sun exposure in this case (109402).

Endocrine ...There is evidence from observational studies that people with diabetes (type 1 or type 2) have higher copper levels in their blood than people without diabetes, although not all studies have shown this (95537). It is not known if elevated copper levels contribute to development or worsening of diabetes.

Hematologic ...A case report of copper overdose in a 28-year-old male resulted in hemolysis exacerbated by glucose-6-phosphate dehydrogenase deficiency. The patient was hospitalized, received D-penicillamine chelation, blood transfusion, and ultimately, 4 cycles of plasmapheresis which led to clinical recovery (112378).

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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).

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

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

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

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

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

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

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

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General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.

Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).

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General ...Orally, riboflavin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dose-related nausea and urine discoloration.

Gastrointestinal ...Orally, riboflavin has been associated with rare diarrhea and dose-related nausea (1398,71483). In one clinical study, one subject out of 28 reported having diarrhea two weeks after starting riboflavin 400 mg daily (1398).

Genitourinary ...Orally, high doses of riboflavin can cause bright yellow urine. Furthermore, in one clinical study, one subject out of 28 reported polyuria two weeks after starting riboflavin 400 mg daily (1398,3094).

(Read more about RIBOFLAVIN)

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

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

Gastrointestinal ...There is some evidence that oral vitamin A supplementation might increase the risk of diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with diarrhea in well-nourished children (319). Diarrhea (82326,82389), nausea (7135,100329), abdominal pain (95051), abdominal fullness (100329), and vomiting (7135,82559,95051,95055,109755) have been reported following use of large doses of oral vitamin A. Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause vomiting and diarrhea (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including anorexia, abdominal discomfort, and nausea and vomiting (7135).

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

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

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

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

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

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

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

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

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

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

(Read more about VITAMIN A)

General ...Orally, intravenously, and topically, vitamin C is well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, esophagitis, heartburn, headache, osmotic diarrhea, nausea, vomiting. Kidney stones have been reported in those prone to kidney stones. Adverse effects are more likely to occur at doses above the tolerable upper intake level of 2 grams daily.
Topically: Irritation and tingling.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of carotid inner wall thickening after large doses of vitamin C.
Intravenously: There have been case reports of hyperoxalosis and oxalate nephropathy following high-dose infusions of vitamin C.

Cardiovascular ...Evidence from population research has found that high doses of supplemental vitamin C might not be safe for some people. In postmenopausal adults with diabetes, supplemental vitamin C intake in doses greater than 300 mg per day is associated with increased risk of cardiovascular mortality. However, dietary intake of vitamin C is not associated with this risk. Also, vitamin C intake is not associated with an increased risk of cardiovascular mortality in patients without diabetes (12498).
Oral supplementation with vitamin C has also been associated with an increased rate of carotid inner wall thickening in men. There is preliminary evidence that supplemental intake of vitamin C 500 mg daily for 18 months can cause a 2.5-fold increased rate of carotid inner wall thickening in non-smoking men and a 5-fold increased rate in men who smoked. The men in this study were 40-60 years old (1355). This effect was not associated with vitamin C from dietary sources (1355).
There is also some concern that vitamin C may increase the risk of hypertension in some patients. A meta-analysis of clinical research suggests that, in pregnant patients at risk of pre-eclampsia, oral intake of vitamin C along with vitamin E increases the risk of gestational hypertension (83450). Other clinical research shows that oral intake of vitamin C along with grape seed polyphenols can increase both systolic and diastolic blood pressure in hypertensive patients (13162). Three cases of transient hypotension and tachycardia during intravenous administration of vitamin C have also been reported (114490).

Dental ...Orally, vitamin C, particularly chewable tablets, has been associated with dental erosion (83484).

Dermatologic ...Topically, vitamin C might cause tingling or irritation at the site of application (6166). A liquid containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to vitamin C, the other ingredients, or the combination.

Gastrointestinal ...Orally, the adverse effects of vitamin C are dose-related and include nausea, vomiting, esophagitis, heartburn, abdominal cramps, gastrointestinal obstruction, and diarrhea. Doses greater than the tolerable upper intake level (UL) of 2000 mg per day can increase the risk of adverse effects such as osmotic diarrhea and severe gastrointestinal upset (3042,4844,96707,104450,114493,114490). Mineral forms of vitamin C, such as calcium ascorbate (Ester-C), seem to cause fewer gastrointestinal adverse effects than regular vitamin C (83358). In a case report, high dose intravenous vitamin C was associated with increased thirst (96709).

Genitourinary ...Orally, vitamin C may cause precipitation of urate, oxalate, or cysteine stones or drugs in the urinary tract (10356). Hyperoxaluria, hyperuricosuria, hematuria, and crystalluria have occurred in people taking 1 gram or more per day (3042,90943). Supplemental vitamin C over 250 mg daily has been associated with higher risk for kidney stones in males. There was no clear association found in females, but the analysis might not have been adequately powered to evaluate this outcome (104029). In people with a history of oxalate kidney stones, supplemental vitamin C 1 gram per day appears to increase kidney stone risk by 40% (12653). A case of hematuria, high urine oxalate excretion, and the presence of a ureteral stone has been reported for a 9-year-old male who had taken about 3 grams of vitamin C daily since 3 years of age. The condition resolved with cessation of vitamin C intake (90936).

Hematologic ...Prolonged use of large amounts of vitamin C can result in increased metabolism of vitamin C; subsequent reduction in vitamin C intake may precipitate the development of scurvy (15). In one case, a patient with septic shock and a large intraperitoneal hematoma developed moderate hemolysis and increased methemoglobin 12 hours after a high-dose vitamin C infusion. The patient received a blood transfusion and the hemolysis resolved spontaneously over 48 hours (112479).

Neurologic/CNS ...Orally, the adverse effects of vitamin C are dose-related and include fatigue, headache, insomnia, and sleepiness (3042,4844,83475,83476).

Renal ...Hyperoxalosis and oxalate nephropathy have been reported following high-dose infusions of vitamin C. Hyperoxalosis and acute kidney failure contributed to the death of a 76-year-old patient with metastatic adenocarcinoma of the lung who received 10 courses of intravenous infusions containing vitamins, including vitamin C and other supplements over a period of 1 month. Dosages of vitamin C were not specified but were presumed to be high-dose (106618). In another case, a 34-year-old patient with a history of kidney transplant and cerebral palsy was found unresponsive during outpatient treatment for a respiratory tract infection. The patient was intubated for acute hypoxemic respiratory failure, initiated on vasopressors, hydrocortisone, and antibacterial therapy, and received 16 doses of vitamin C 1.5 grams. Serum creatinine level peaked at greater than 3 times baseline and the patient required hemodialysis for oliguria and uncontrolled acidosis. Kidney biopsy revealed oxalate nephropathy with concomitant drug-induced interstitial nephritis (106625). In another case, a 41-year-old patient with a history of kidney transplant presented with fever, nausea, and decreased urine output 4 days after receiving intravenous vitamin C 7 grams for urothelial carcinoma. Serum creatinine levels increased from 1.7 mg/dL to 7.3 mg/dL over those 4 days, and hemodialysis was initiated 3 days after admission due to anuria. Renal biopsy confirmed the diagnosis of acute oxalate nephropathy (109962).

Other ...Intravenously, hypernatremia and falsely elevated ketone levels is reported in a patient with septic shock and chronic kidney disease after a high-dose vitamin C infusion. The hypernatremia resolved over 24 hours after cessation of the infusion (112479).

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