INTRODUCTION — Vitamins are chemically unrelated families of organic compounds that are essential in small amounts for normal metabolism. Because vitamins (with the exception of vitamin D) cannot be synthesized by humans, they need to be ingested in the diet to prevent disorders of metabolism. They should be distinguished from minerals (such as calcium and iron), some of which are also essential micronutrients.

The prevalence of vitamin deficiency among those consuming a typical Western diet is higher than generally presumed, particularly in older adults. Pregnancy and alcohol consumption may increase requirements for certain vitamins. In observational studies, subtle deficiencies in several vitamins (although above the low levels causing classic vitamin deficiency syndromes including scurvy or pellagra) have been associated with chronic diseases such as atherosclerosis, cancer, and osteoporosis.

However, the role of vitamin supplementation in prevention or reversal of many chronic diseases is less well established. Studies evaluating the effects of vitamin supplementation have been variable; randomized trials often fail to demonstrate the associations seen in observational studies. Additionally, methodological flaws, including lack of standardization of baseline vitamin status and dose, may contribute to inconsistent study results [1].

Genetic factors may also affect how vitamins are metabolized and the consequences of supplementation in various clinical situations. Not enough is yet known about how to use genetic information to guide clinical decisions about vitamin deficiencies and supplementation dosing, but that information is likely to become available in the future.

The evidence for using vitamin supplementation to prevent chronic disease is reviewed here. The potential benefits of vitamin supplementation in specific disease conditions are discussed on topics about those conditions. Overviews of individual vitamins, dietary minerals, and dietary supplements are also discussed separately. (See "Overview of water-soluble vitamins" and "Overview of vitamin A" and "Overview of vitamin D" and "Overview of vitamin E" and "Overview of dietary trace elements" and "Overview of herbal medicine and dietary supplements".)

VITAMIN DEFICIENCY — The concept of vitamin deficiency has evolved since vitamins were first discovered, from obvious vitamin deficiency syndromes to the subtle effects of suboptimal vitamin intake on chronic diseases.

Gross vitamin deficiency may be recognized by obvious clinical syndromes (table 1). These syndromes are still seen in areas of the world with very poor diets. In Western societies, they occur in several special populations, including older adults; vegans; new immigrants; the very poor; patients with alcohol use disorder, malabsorption, little sun exposure, history of gastric bypass surgery, or inborn errors of metabolism; and those undergoing hemodialysis or receiving parenteral nutrition (table 2).

Dietary reference intakes (DRIs) represent four concepts: the Recommended Dietary Allowance (RDA); Adequate Intake (AI); Estimated Average Requirement (EAR); and Tolerable Upper Intake Level (UL). DRIs are established in the United States by the National Academy of Sciences, National Research Council, and the Institute of Medicine (IOM) (table 3). For clinical purposes, we still refer to the RDA, which is the average daily intake that is sufficient to meet the dietary requirement of nearly all healthy people. The AI is used when the RDA cannot be determined (as is still the case for vitamin supplementation in infants <12 months and for vitamin K) (table 3). However, these intake levels may not be adequate for preventing chronic disease in some people.

Testing — Measurement of serum levels of several vitamins is widely available. Fueled by popular belief in the importance of vitamins and by commercial interests, testing is being promoted to screen for unrecognized deficiency and to tailor supplements to individual needs. This practice is unwarranted in most patients for two main reasons:

●There is insufficient information about the optimum serum levels of vitamins, making it difficult to interpret subtle deficiency states.

●There is a lack of evidence that vitamin supplementation can prevent disease in most healthy adults with low blood levels of vitamins (apart from those individuals with specific diets or medical conditions).

Testing for specific deficiencies remains appropriate in clinical situations where deficiencies are suspected or are an important part of the evaluation (eg, measuring levels of vitamin D in older adult patients with osteoporosis or vitamin B12 in patients with cognitive decline of unknown etiology).

When evaluating for gross vitamin deficiency, test results are useful if clearly high or low. However, the meaning of a "normal" value is uncertain; normal is defined by the range of usual values in the general population. However, many of these people may have suboptimal intake, and a "normal" value may actually represent a deficient level in a given individual.

Inadequate intake or low serum levels of some vitamins can be associated with biochemical abnormalities. As examples, the serum concentration of homocysteine rises with diets low in folic acid, methylmalonic acid rises with low intake of vitamin B12, and parathyroid hormone rises with low intake of vitamin D. These biochemical abnormalities generally improve with increasing intake and reach a plateau beyond which more intake causes no further improvement, suggesting a correctable metabolic disorder.

Additional information about genetic polymorphisms, which increase requirements for specific vitamins, is likely to become available. This appears to be the case for certain genes, such as those controlling the metabolism of folate and vitamin D. However, there is not enough understanding of individual risk to warrant routine testing for vitamin levels or testing for polymorphisms. (See "Pathogenesis of osteoporosis", section on 'Genetics'.)

The remainder of this topic review will address the effectiveness of individual vitamin supplements in preventing specific diseases.

FOLIC ACID — Folate is the natural form of the vitamin found in food and is present in green, leafy vegetables, fruits, cereals, grains, nuts, and meats. Folic acid is the synthetic form of the vitamin that is included in supplements and food fortification, and has many of the same biologic effects as folate, but is more bioavailable and therefore more effective dose for dose [2]. Some evidence suggests that the metabolism of folic acid differs from folate and may have toxicities under certain circumstances [3]. Gross deficiency of folate leads to megaloblastic anemia. (See "Treatment of vitamin B12 and folate deficiencies".)

Folic acid has been studied for prevention of many disease states. Overall, the only well-established benefit of folic acid supplementation is the prevention of neural tube defects. (See "Folic acid supplementation in pregnancy".)

Neural tube defects — Folic acid supplementation reduces the risk of neural tube defects, probably because folate is required for normal cell division. This has been shown in multiple observational studies and confirmed by randomized trials [4-8]. This is discussed in detail elsewhere. (See "Folic acid supplementation in pregnancy", section on 'Folic acid supplementation for prevention of neural tube defects'.)

Cancer — Folate deficiency may contribute to aberrant DNA synthesis and carcinogenesis by decreasing methionine availability and interfering with normal DNA methylation. Biologic and observational evidence suggest that sufficient folate intake might prevent cancers in certain populations at risk [9-12], but randomized trials have not confirmed any benefits of folic acid supplementation and have raised the possibility of harm [13-16]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

In a 2013 meta-analysis of randomized trials of folic acid in patients with colorectal adenoma (3 trials; n = 2652) or for prevention of cardiovascular disease (10 trials; n = 46,969), during an average of 5.2 years of treatment, there was no significant difference in overall cancer incidence for patients assigned to folic acid or placebo (7.7 versus 7.3 percent; relative risk [RR] 1.06, 95% CI 0.99-1.13) [17]. There was also no statistical difference in the incidence of specific cancers, including cancers of the large intestine, prostate, lung, or breast. The doses of folic acid in the included trials ranged from 0.5 to 5 mg daily, which is greater than the amount of folic acid in fortified cereal products and flour. One limitation of the included trials is that the average duration of intervention (five years) is short and may not be sufficient to characterize long-term benefits or harm of folic acid supplementation. In addition, the trials do not address underlying nutrition status and other preventive measures. Since the evidence is inconclusive, we recommend not taking folic acid supplementation for the sole purpose of reducing cancer risk.

Cardiovascular disease — High levels of homocysteine are associated with an increased risk of cardiovascular disease. Supplementation with folic acid, vitamin B6, and vitamin B12 can lower homocysteine levels. However, meta-analyses of randomized trials of supplementation for secondary prevention do not support the hypothesis that these vitamins prevent cardiovascular disease [18-22].

The potential benefits of folic acid supplementation in patients at risk for cardiovascular disease are discussed separately.

Other

●High folate intake may reduce the risk of hypertension. In multivariate analyses from the large prospective Nurses' Health Study, compared with females who consumed diets with less than 200 mcg folate per day, the risk of hypertension was reduced in those age 27 to 44 years consuming diets with more than 1000 mcg per day (RR 0.54, 95% CI 0.45-0.66) and to a lesser extent in older individuals age 43 to 70 years (RR 0.82, 0.69-0.97) [23]. There is insufficient evidence to recommend folic acid supplementation to reduce the risk of hypertension.

●It is unclear whether folate intake is associated with hearing loss. There is conflicting observational evidence about whether increased serum folate levels are associated with a decreased risk of age-related hearing loss [24,25].

In one randomized trial of folic acid supplementation (800 mcg daily for three years) versus placebo in adults age 50 to 70 years with elevated homocysteine, those randomly assigned to folic acid had a slightly slower decline in low-frequency hearing than those receiving placebo [24]. No such difference was seen for decline in hearing in the high frequencies. The trial was performed in the Netherlands at a time when food was not supplemented with folic acid.

Additional studies are needed before folate supplementation can be recommended for the purpose of preventing hearing loss.

●Elevated homocysteine levels have been associated with osteoporosis and dementia. It is not known whether these associations are causal and whether lowering homocysteine levels with folic acid supplementation would affect risk. (See "Prevention of dementia" and "Overview of homocysteine" and "Overview of the management of osteoporosis in postmenopausal women", section on 'Therapies not recommended'.)

●Excess folate intake (approximately twice the recommended dose) has been associated with peripheral neuropathy, despite normal serum levels of vitamin B12, in older individuals who have a common polymorphism in the transcobalamin vitamin B-12 transporter gene [26].

VITAMIN D — Because dietary vitamin D intake is often low in older adults, we suggest supplementation with 1000 units of vitamin D3 (cholecalciferol) daily, with downward adjustment in this dose for those with a higher dietary intake [27]. The supplement can be taken daily, or the adjusted dose taken as a once weekly or monthly preparation. Other experts, including other authors for UpToDate, suggest somewhat lower daily doses of vitamin D supplements. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Subclinical vitamin D deficiency or insufficiency is extremely common and may contribute to the development of osteoporosis, falls, and fractures in older adults. We do not routinely measure serum 25-hydroxyvitamin D levels in most individuals [28]. However, serum 25-hydroxyvitamin D should be measured in patients who are at risk for inadequate serum vitamin D concentrations, including institutionalized individuals, patients being evaluated for osteoporosis, and patients with malabsorption (eg, Crohn disease and celiac disease). The evaluation and supplementation of vitamin D in patients with vitamin D deficient states and in patients with osteoporosis are discussed elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin D insufficiency and deficiency in children and adolescents".)

The intake at which the dose of vitamin D becomes toxic is not clear. The Institute of Medicine (IOM) has defined the upper limit for vitamin D as 4000 units daily for healthy adults [27]. This is also the upper limit for pregnant and lactating individuals. It is important to ask patients about additional dietary supplements (some of which contain vitamin D) before prescribing supplemental vitamin D [29]. (See "Overview of vitamin D".)

Osteoporosis — Physiologic doses of vitamin D attenuate bone loss and may decrease fracture rate. Evidence regarding the efficacy and necessary dose of vitamin D to prevent osteoporosis and reduce fracture risk, as well as the possible need for concurrent calcium therapy, is discussed in detail separately. (See "Calcium and vitamin D supplementation in osteoporosis".)

As is the case with other vitamins, there is evidence that host factors such as genetic polymorphisms strongly influence fracture risk and may determine the host response to vitamin D. (See "Pathogenesis of osteoporosis", section on 'Genetics'.)

Falls — There are several meta-analyses of randomized trials showing a reduction in risk of falls (relative risk reduction as high as 20 percent) following vitamin D supplementation, particularly when the baseline vitamin D status is poor [30-34]. (See "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation' and "Vitamin D and extraskeletal health", section on 'Falls'.)

Cancer — While there are biologic reasons why vitamin D may protect against cancer, evidence for this effect in humans is mixed, and expert groups have not recommended vitamin D supplements for the specific purpose of cancer prevention [35-37]. The VITAL trial, a large randomized controlled trial of vitamin D3 supplementation, did not show a reduction in cancer diagnoses after a median follow-up of five years. (See "Vitamin D and extraskeletal health", section on 'Cancer'.)

Mortality — Studies evaluating the relationship between vitamin D levels and mortality have conflicting results. The evidence regarding vitamin D and mortality is discussed separately. (See "Vitamin D and extraskeletal health", section on 'Mortality'.)

Other — In addition to its role in calcium and bone homeostasis, vitamin D potentially regulates many cellular functions. Vitamin D deficiency has been implicated as a risk factor for many diseases. However, a causal relationship between poor vitamin D status and major diseases, including infections, autoimmune disorders, cardiovascular, and metabolic diseases, has not been established [38]. This is reviewed in detail separately. (See "Vitamin D and extraskeletal health".)

ANTIOXIDANT VITAMINS — The antioxidant vitamins include vitamin A (consisting of preformed vitamin A, or retinol, and the carotenoids such as beta-carotene) as well as vitamins C and E. Many other compounds found in food, especially vegetables and fruits, also have antioxidant properties. A number of studies have examined the hypothesis that antioxidants can prevent cancer and cardiovascular disease by augmenting the body's ability to dispose of toxic free radicals, thereby retarding oxidative damage [39].

In observational studies, diets high in vegetables and fruits that are rich in antioxidants are associated with a reduced risk of cancer and cardiovascular disease [40,41]. However, the association may be due to non-vitamin antioxidants, other compounds such as flavonoids, the substitution of dietary meat and fat with vegetables and fruits, or the other components of healthy lifestyles seen in people who have high dietary intake of fruits and vegetables.

Randomized trials evaluating antioxidant supplements have not found a reduction the risk of cancer or cardiovascular disease [42-45]. As an example, in a meta-analysis of randomized trials of antioxidant supplements for the prevention of gastrointestinal cancers, there was no decreased risk of these cancers with antioxidant supplementation [42].

While antioxidants are often grouped together, specific antioxidant vitamins (including different forms of some vitamins) might be expected to have distinct effects. In addition, individual responses may vary based upon genetic predisposition, vitamin dose, and other exposures, including smoking. Antioxidant vitamins are discussed separately in this section, since findings suggest that specific types of antioxidant vitamins affect cancer and cardiovascular disease differently. Overall, however, there is a lack of evidence that antioxidant vitamins are beneficial in disease prevention [46,47].

Vitamin A and the carotenoids — Total vitamin A consists of preformed vitamin A (retinol) and the carotenoids such as beta-carotene. Retinol is only found in animal products and supplements, while carotenoids that can be converted into vitamin A (provitamin A carotenoids) are found in fruits and vegetables. In addition to antioxidant properties, retinol may also decrease cancer risk via other mechanisms such as inducing cellular differentiation.

Most diets in high-income and other resource-abundant countries contain adequate amounts of retinol and carotenoids. Vegetarians, including vegans, do not need to take vitamin A supplements if they eat an adequate variety of vegetables containing carotenoids. While vitamin A supplementation in resource-limited countries is recommended by the World Health Organization to prevent blindness, dietary intake of vitamin A in other countries is generally adequate. Thus, in these countries, we do not recommend vitamin A or beta-carotene supplementation given lack of proven efficacy and the possibility of harm. (See "Overview of vitamin A".)

Cancer — Trials evaluating vitamin A or carotenoid supplementation have reported no benefit or an increased risk of cancer [48-58]:

●Two large, randomized trials assessed the effect of beta-carotene supplementation on the risk of lung cancer among men at increased risk because of smoking or asbestos exposure [48,49]. In both trials, there was an increased lung cancer risk among men who received the supplements; the excess risk resolved over time once supplements were stopped [50]. (See "Chemoprevention of lung cancer", section on 'Investigative strategies'.)

●In the Physicians Health Study, 12 years of beta-carotene, 50 mg every other day, produced neither benefit nor harm with respect to the incidence of malignant neoplasms [51]. Overall, however, the cohort was at low risk for lung cancer since few smoked. Similar results were seen in the Women's Health Study [52].

●In the ATBC Cancer Prevention Study, there was an increase in both prostate cancer incidence and mortality (23 and 15 percent, respectively) among subjects randomly assigned to receive beta-carotene [43]. The excess risk resolved over time once supplements were stopped [45].

●In a randomized trial of almost 8000 females in the Women's Antioxidant Cardiovascular Study, beta-carotene 50 mg every other day had no effect on the incidence of cancer at nine years (relative risk [RR] 1.00, 95% CI 0.85-1.17) [53].

●In the Polyp Prevention Study Group, a four-year randomized trial evaluating antioxidants to prevent colorectal adenoma, there was no reduction in adenoma risk with antioxidant supplementation [58].

●Observational studies of vitamin A (or carotenoid) intake and breast cancer have yielded varying results. In the Iowa Women's Health Study, no association between dietary vitamin A and breast cancer was observed [54]. By contrast, evidence from the Nurses' Health Study suggested that high intake of carotenoids may decrease the risk of breast cancer [55,56]. This association may be strongest in premenopausal females with a positive family history who appear to have significant reductions in breast cancer risk with increasing dietary alpha- and beta-carotene, lutein/zeaxanthin, and total vitamin A [56]. Similarly, another report from the Nurses' Health Study found a decreased risk of breast cancer in females with higher plasma levels of carotenoids [57]. There are no clinical trials of vitamin A intake and breast cancer.

The discordant results between observational studies and randomized trials with regard to vitamin A and carotenoids and cancer risk may be explained by the inability of observational studies to control for confounding by other healthy behaviors, differences in forms or dose of vitamins, and other exposures such as tobacco [59]. The increase in risk of lung cancer in two randomized trials of beta-carotene has dampened enthusiasm for further clinical trials of antioxidants to prevent cancer [48,49]. In addition, there are no high-quality data supporting the use of vitamin A and carotenoid supplements to reduce the risk of cancer.

Cardiovascular disease — Randomized trials of vitamin A and beta-carotene have shown no benefit for primary or secondary prevention of coronary heart disease (CHD) and one trial suggested potential harm with regard to cardiovascular mortality [43].

Immunity — Vitamin A improves immunity in children living in resource-limited countries where dietary intake is inadequate and life-threatening infectious diseases are common. A meta-analysis of 12 randomized trials of vitamin A showed a 30 percent reduction in overall mortality, with a 61 percent reduction in mortality among hospitalized patients with measles [60]. One United States study of children with measles showed more severe illness in children with more depressed serum retinol levels [61]. The World Health Organization (WHO) recommends community-based Vitamin A supplementation in resource-limited countries even in the absence of signs and symptoms of deficiency [60]. There is no reason to expect an improvement in immunity with vitamin A supplementation in people who already have adequate dietary intake.

Fractures — There is consistent evidence from observational studies that higher vitamin A intake (specifically retinol), within the range taken by many people in Western societies, is a risk factor for osteopenia and fractures [62-64]. As an example, 72,337 postmenopausal females age 34 to 77 years were followed for 18 years in the Nurses’ Health Study [63]. Females in the highest quintile of total vitamin A intake had a relative risk for hip fracture of 1.48 compared with those in the lowest quintile. This increased risk was attributed primarily to retinol. An earlier Finnish cohort study had similar findings [62]. Thus, patients should be cautioned against diets high in retinol (preformed vitamin A), especially if they have other risk factors for osteopenia, and should avoid vitamin A supplements, including multivitamins containing preformed vitamin A, if their dietary intake is high. Common food sources of preformed vitamin A include liver, milk, egg yolk, and butter. (See "Drugs that affect bone metabolism", section on 'Vitamin A and synthetic retinoids'.)

Congenital anomalies — Supplements with preformed vitamin A in doses >10,000 international units taken in the first trimester of pregnancy have been shown to increase the risk of congenital anomalies [65]. (See "Overview of vitamin A", section on 'Teratogenic effects'.)

Cataracts and macular degeneration — In randomized trials, there was no benefit of vitamin A or carotenoid supplementation in the primary prevention of cataracts or macular degeneration. These trials are discussed in detail separately. (See "Cataract in adults", section on 'Prevention' and "Age-related macular degeneration: Treatment and prevention", section on 'Nutritional and vitamin supplements'.)

Vitamin C — Vitamin C is commonly found in citric fruits and many types of vegetables. Vitamin C may have a minor role in preventing the common cold, specifically for persons involved in high-intensity physical activity in extreme cold climates [66].

Evidence does not support the use of vitamin C supplementation for chronic disease prevention. In particular, vitamin C supplementation does not appear to be beneficial for the primary or secondary prevention of cancer or coronary heart disease.

Cancer — Large randomized trials have found no reduction in cancer in patients given vitamin C supplementation [67]:

●The Physicians' Health Study II randomly assigned 14,641 male physicians ages 50 and older to vitamin C 500 mg daily or placebo [68]. After an average follow-up of 8.0 years, vitamin C had no effect on the incidence of cancer (hazard ratio [HR] 1.01, 95% CI 0.92-1.10). During an additional three years of post-trial follow-up, there was no difference in risk of total cancer or incident prostate cancer among the two groups [69].

●An analysis of 7627 females who were free of cancer at random assignment in the Women's Antioxidant Cardiovascular Study found that after a mean follow-up of 9.4 years, vitamin C 500 mg daily had no effect on the incidence of cancer (relative risk [RR] 1.11, 95% CI 0.95-1.30) [53].

Cardiovascular disease — Randomized trials have shown no benefit of vitamin C for primary or secondary prevention of coronary heart disease.

The Health Professionals Follow-up Study, an observational study including 43,738 men, showed no association between supplemental vitamin C (700 mg or more daily) and stroke risk [45].

Kidney stones — Vitamin C increases urinary oxalate excretion and may increase the risk of kidney stones. In the highest-quality study examining this, a cohort study of 23,355 males who had not already had kidney stones and were followed up for 12 years, those taking vitamin C but not other supplements were twice as likely to develop stones as those taking no vitamin supplements [70]. (See "Kidney stones in adults: Epidemiology and risk factors".)

Cataracts and macular degeneration — In randomized trials, there was no benefit of vitamin C supplementation in the primary prevention of cataracts or macular degeneration. These trials are reviewed separately. (See "Cataract in adults", section on 'Prevention' and "Age-related macular degeneration: Treatment and prevention", section on 'Nutritional and vitamin supplements'.)

Vitamin E — Vitamin E is a family of related chemicals. There are a number of biologically active vitamin E compounds in nature, including alpha-, beta-, gamma-, and delta- tocopherol. Vitamin E compounds are commonly found in sunflowers, wheat germ oil, corn, and nuts.

Evidence does not support a role for vitamin E supplementation in the prevention or treatment of cancers, cardiovascular disease, dementia, and infection. Since the best available evidence, while not conclusive, suggests that high-dose vitamin E (≥400 units/day) might increase all-cause mortality [71], patients without special indications should not take vitamin E supplements for disease prevention. In addition, individuals taking anticoagulants should be particularly advised against high doses of vitamin E because of the synergistic action of vitamin E with these drugs. Vitamin E supplementation is discussed in detail elsewhere. (See "Overview of vitamin E".)

Cancer — Observational studies have found variable effects of vitamin E on certain cancers, particularly within subgroups such as smokers [54-56,72-74], but most randomized trials do not support a protective effect [53,58,68,75-77].

As an example, the Women's Health Study was a randomized trial that followed 39,876 apparently healthy females ages 45 and older for a mean of 10.1 years [75]. Compared with placebo, supplementation with 600 units of natural-source vitamin E on alternate days had no effect on the incidence of all cancer (RR 1.01, 95% CI 0.94-1.08) or on breast cancer (RR 1.00), lung cancer (RR 1.09), colon cancer (RR 1.00), or cancer death (RR 1.12).

Randomized trials of vitamin E for prevention of prostate cancer have found conflicting results. The ATBC Cancer Prevention Study observed a 32 percent decrease in prostate cancer incidence and 41 percent decrease in prostate cancer mortality among male smokers randomly assigned to 50 mg (75 units) of alpha-tocopherol (vitamin E) for five to eight years compared with placebo [78]. However, subsequent large randomized trials found no reduction, and possible harm, with vitamin E supplementation in prostate cancer incidence (see "Chemoprevention strategies in prostate cancer", section on 'Vitamin E'):

●The SELECT trial followed 35,533 men (ages 50 and older for African-American men and ages 55 and older for other men) for a median of seven years [79]. Compared with placebo, vitamin E supplementation (400 units daily) was associated with an increased risk of prostate cancer (HR 1.17, 99% CI 1.004-1.36).

●The Physicians' Health Study II followed 14,641 male physicians ages 50 and older for an average of 8.0 years [68]. Compared with placebo, vitamin E supplementation (400 units every other day) had no effect on the incidence of prostate cancer (HR 0.97, 95% CI 0.85-1.09) or total cancer (HR 1.04, 95% CI 0.95-1.13). During an additional three years of post-trial follow-up, there was still no difference in risk of incident prostate cancer or total cancer among the two groups [69].

Cardiovascular disease — Nearly all randomized trials of vitamin E have shown no benefit for primary or secondary prevention of coronary heart disease [43]. Additionally, vitamin E supplementation may increase the risk of heart failure [76].

Randomized trials have not found convincing benefit of vitamin E supplementation for stroke prevention. In a meta-analysis of nine randomized trials of vitamin E supplementation versus placebo, vitamin E had no significant effect on risk of total stroke (RR 0.98, 95% CI 0.91-1.05) [44]. Findings were similar for patients with and without previous cardiovascular disease. Vitamin E supplementation was associated with an increased risk of hemorrhagic stroke (RR 1.22, 95% CI 1.00-1.48); however, it was also associated with a decreased risk of ischemic stroke (RR 0.90, 95% CI 0.82-0.99).

Dementia — Although observational studies suggested that increased dietary intake of vitamin E or vitamin E supplementation might protect against the development of Alzheimer disease and vascular dementia [80-82], randomized trials have found no benefit of vitamin E supplementation for the prevention of dementia [83,84]. (See "Prevention of dementia", section on 'Antioxidant vitamins' and "Treatment of Alzheimer disease", section on 'Antioxidants'.)

Infection — Several studies have reported that supplementation with vitamin E improves the immune response [85,86]. Such an effect is of particular interest in older adults, in whom an age-related decline in immune response may increase the risk of infections and their complications. However, randomized trials that have examined the use of vitamin E to prevent infections in older adults have not found clinical benefits [87-89]. Large trials found no reduction in the incidence of respiratory infections when either institutionalized [87,88] or noninstitutionalized [89] older adult patients received daily vitamin E supplements. Furthermore, in the study of noninstitutionalized older adults, among patients experiencing a respiratory infection, those who received vitamin E (200 units per day) had a significantly longer total illness duration (19 versus 14 days), more symptoms, and a higher frequency of fever and activity restriction [89].

Venous thromboembolism — High doses of vitamin E may interfere with vitamin K and affect coagulation.

A secondary analysis from the Women's Health Study found that females randomly assigned to receive 600 units vitamin E every other day had a lower risk of venous thromboembolism than those receiving placebo (HR 0.79, 95% CI 0.66-0.94) [90].

This effect needs to be confirmed in other randomized trials before vitamin E can be recommended for prevention of venous thromboembolism.

Cataracts and macular degeneration — Randomized trials have found no benefit to vitamin E supplementation for the prevention of cataracts or macular degeneration. These trials are reviewed separately. (See "Age-related macular degeneration: Treatment and prevention", section on 'Nutritional and vitamin supplements'.)

All-cause mortality — A meta-analysis of randomized trials of vitamin E supplementation (many of which are discussed individually above) examined the effects of supplementation on all-cause mortality [71]. There was no significant effect on mortality across all trials; however, mortality was increased in patients who received high-dose vitamin E supplementation (≥400 units/day) (increase in mortality of 39 per 10,000 persons, 95% CI 3-74 per 10,000 persons). There appeared to be a dose-response relationship. As a whole, patients treated with low-dose supplementation had a decrease in mortality; however, trials of these doses were often performed in malnourished populations or used other supplements in combination with vitamin E. A number of the trials of high-dose supplementation were performed in patients with chronic diseases, and it is unclear whether the observed harm from such supplementation would carry over to a healthier population.

Similar to the overall results of the above analysis, a meta-analysis that did not stratify trials by dose of vitamin E found no significant effect of supplementation on all-cause mortality [43].

VITAMIN B2 (RIBOFLAVIN) — Vitamin B2 is found in many commonly consumed foods, including milk, meat, eggs, cereal, and green leafy vegetables. This may explain why overt riboflavin deficiency is rare. (See "Preventive treatment of episodic migraine in adults".)

There is no strong evidence that supplemental vitamin B2 is helpful in healthy people eating a balanced diet.

VITAMIN B6 (PYRIDOXINE) — Vitamin B6 is found in bananas, nuts, and many common vegetables such as potatoes, green beans, cauliflower, and carrots. Vitamin B6 is thought to reduce the risk of cardiovascular disease and cancer. However, it has been difficult to separate out the effects of vitamin B6 from that of other vitamins and of other substances in fruits and vegetables [91]. Furthermore, the optimal dose is not well-characterized.

High levels of homocysteine are associated with an increased risk of cardiovascular disease. Supplementation with folic acid, vitamin B6, and vitamin B12 can lower homocysteine levels. However, randomized trials of supplementation for secondary prevention do not support the hypothesis that these vitamins prevent cardiovascular disease [18-22]. (See "Overview of homocysteine".)

Higher levels of vitamin B6 and their metabolites are associated with a lower risk of cancer. However, randomized trials of B6 supplementation have not demonstrated a benefit in cancer risk reduction [92].

VITAMIN B12 (COBALAMIN) — Suboptimal vitamin B12 level is most commonly caused by poor absorption and inadequate intake of vitamin B12-containing food sources (eg, liver, milk, fish, meat). Malabsorption of cobalamin is primarily the result of inability to release cobalamin from dietary proteins, especially in the presence of autoimmune antibodies against intrinsic factor or reduced gastric acid secretion. In older adults, gastric atrophy and hypochlorhydria result in reduced gastric acid and inefficient vitamin B12 absorption. Vitamin B12 deficiency can also be seen among people following a vegan diet. (See "Treatment of vitamin B12 and folate deficiencies" and 'Special diets' below.)

In a population-based cross-sectional analysis of 3511 older adults from the United Kingdom, the age-specific prevalence of cobalamin deficiency was approximately 5 and 10 percent in those ages 65 to 74 years and those ≥75 years, respectively [93].

Vitamin B12 deficiency is associated with several disease states:

●Severe vitamin B12 deficiency causes neurologic disease and megaloblastic anemia. Subtle B12 deficiency, even without anemia, is associated with dementia and low cognitive function [94]. However, there is no solid evidence that taking vitamin B12 supplements prevents dementia. In addition, B12 deficiency may lead to deteriorating balance in some older adults, but this has not been well-studied. (See "Treatment of vitamin B12 and folate deficiencies" and "Prevention of dementia", section on 'Vitamins B6, B12, and folate'.)

●Vitamin B12 deficiency may also be an important cause of hyperhomocysteinemia, particularly in older adults [95]. High levels of homocysteine are associated with an increased risk of cardiovascular disease. Supplementation with folic acid, vitamin B6, and vitamin B12 can lower homocysteine levels, but randomized trial data do not support the hypothesis that these vitamins prevent cardiovascular disease [18-22]. (See "Overview of homocysteine".)

●Hyperhomocysteinemia is also associated with osteoporosis. It is not known whether this association is causal or whether lowering homocysteine levels would affect risk. Similarly, it is unknown whether supplementation with folate and vitamin B12 in high risk groups would reduce the risk of fractures. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Therapies not recommended'.)

Measuring vitamin B12 levels may be indicated in individuals at increased risk for poor vitamin B12 intake, including vegans, those with alcohol use disorder, and people with little dietary variation or poor-quality diets (such as some older adults and people living in poverty). Vitamin B12 supplementation in healthy adults and in those with vitamin B12 deficiency is well-tolerated without significant adverse effects [96,97]. The diagnostic approach and treatment of B12 deficiency is discussed elsewhere. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

There is no high-quality evidence that supplemental vitamin B12 is beneficial in healthy people eating a balanced diet.

MULTIVITAMINS — Most generic and brand-name multivitamins contain 50 to 150 percent of the Recommended Dietary Allowance (RDA) for all vitamins, including folic acid and vitamins A, C, D, E, B2, B6, and B12. However, there are several variations of multivitamins, such as B vitamins alone, multivitamins with minerals, and multivitamins for specific groups (eg, females, males, younger and older populations). The proposed rationale for taking a daily multivitamin for adults includes known or potential effectiveness for some of the component vitamins, relative safety in low doses, low cost (one multivitamin per day can cost as little as $15 to $35 per year in the United States, but can also be much more expensive), and efficiency of taking one pill rather than multiple vitamin pills.

Many multivitamins contain minerals as well, but the doses of minerals in these supplements (such as calcium and iron) are well below one daily value (DV). DVs are reference values that provide recommended dietary nutrient intakes that appear on package labels. Toxicities of individual minerals are discussed elsewhere. (See "Overview of dietary trace elements".)

Multivitamin supplementation should be considered for patients at risk for vitamin deficiency, such as those with alcohol use disorder, poor-quality diets with low fruit and vegetable intake, malabsorption, a vegan diet, a history of gastric bypass surgery, or some inborn errors of metabolism, as well as those being treated with hemodialysis or parenteral nutrition. In addition, in patients with a specific vitamin deficiency, a multivitamin may be a reasonable choice over supplementation with individual vitamins if a multivitamin is less costly and the formulation contains an appropriate dose. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Management' and "Bariatric surgery: Postoperative nutritional management", section on 'Micronutrient management' and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease", section on 'Our approach to ESA resistance'.)

Unless there is a specific indication, however, we do not suggest multivitamin supplementation for primary prevention of chronic diseases in people with adequate dietary intake because of insufficient evidence of effectiveness. However, many patients wish to take multivitamins based on their own belief systems; we advise that clinicians not struggle against that practice as long as there is no absolute contraindication for an individual patient. Other experts disagree and would recommend more strongly against such supplements [98].

Efficacy — The health effects of multivitamins could be greater than the sum of their component vitamins if the component vitamins interacted. An example is the combined effects of folic acid, vitamin B6, and vitamin B12 on homocysteine metabolism.

Randomized trials and systematic reviews have evaluated the effect of individual and various combinations of vitamins on a variety of disease outcomes, including cancer, cardiovascular disease, eye disease [99], as well as on total mortality.

A 2013 systematic review of randomized trials (for efficacy) and both trials and observational studies (for safety) performed for the US Preventive Services Task Force (USPSTF) found limited evidence to support any benefit of vitamin and mineral supplements for preventing cancer or cardiovascular disease [100]. The review included two large trials of multivitamin supplements, and meta-analysis of these trials showed a borderline significant reduction in the risk of cancer (relative risk [RR] 0.94, 95% CI 0.89-1.00) and no effect on cardiovascular disease (RR 1.02, CI 0.94-1.10). Multivitamin supplementation also did not appear to reduce the risk of mortality (RR 0.95, CI 0.89-1.01).

A randomized trial that examined long-term multivitamin supplementation in males found no benefit on cognitive function [101].

A subsequent randomized trial that looked at many outcomes and various vitamin supplements found a small reduction in the risk of cataracts with multivitamin supplementation [102]. However, the overall evidence is mixed, and there is not a clear recommendation to use vitamin supplements for the prevention of cataracts. (See "Cataract in adults", section on 'Prevention'.)

It has not been established that multivitamin and mineral supplements provide added benefit to a balanced, healthful diet for most individuals [99].

Safety — In the United States, the federal government does not regulate food supplements (vitamins, minerals, and herbs) to assure safety and efficacy. Multivitamins are sold in a variety of combinations and doses. However, manufacturers are required to list contents in a standard way, making it easier for consumers to compare brands.

Individual vitamin doses in multivitamins are apparently safe for most adults. The dose of vitamin E is well below the levels reported to cause an increase in overall mortality, and the dose of beta-carotene, usually a part of the total vitamin A activity, is well below levels associated with lung cancer. The dose of folic acid is also lower than that found to potentially increase cancer risk. Some formulations of vitamins sold over-the-counter may contain several times the RDA of vitamin B12, which is harmless even at much higher doses.

Some individuals may be harmed by even ordinary doses of vitamin A. Vitamin A has been shown in observational studies to be a risk factor for osteopenia and fractures in the range ingested by a substantial proportion of the adult population in the United States. People at increased risk of osteopenia, or with relatively high dietary intake of vitamin A, should not take additional supplements containing vitamin A until further research clarifies whether the association between vitamin A and osteopenia is causal. Additionally, vitamin A is teratogenic starting at doses of only 10,000 units/day of supplementation. Manufacturers have been reducing the amount of vitamin A in multivitamins, but supplementation, even at less than 100 percent of the RDA, does not seem prudent in people who are otherwise at increased risk. (See 'Fractures' above and 'Toxicity at high doses' below.)

TOXICITY AT HIGH DOSES — Potentially toxic levels of individual vitamins can be achieved easily in people who take very high-potency vitamins, which can be obtained in specialty stores, over the internet, and even in pharmacies. High doses can also be achieved by taking a large number of pills even if the dose per pill is not high. The Institute of Medicine (IOM) and the Office of Dietary Supplements has suggested Tolerable Upper Intake Levels for specific vitamins, which is the highest daily dose that is unlikely to cause adverse health effects in the general population (table 4).

Water soluble vitamins (folate, vitamin C, B vitamins) can generally be tolerated at high doses, with toxicity occurring only at doses thousands of times the Recommended Dietary Allowance (RDA). A possible exception is the risk of kidney stones, which may be increased after doses of vitamin C that are 10 to 25 times the RDA.

Fat soluble vitamins (vitamins A, D, E, K) are generally more toxic than water soluble vitamins. Vitamin D may cause hypercalcemia at doses as low as 4000 units/day (recommended upper limit) in some people. Vitamin A in pregnancy is teratogenic at doses as low as several times the RDA (with an apparent threshold at 10,000 units/day of supplemental vitamin A) [65]. Beta-carotene appears to increase the risk of lung cancer in adults who are otherwise at high risk because of smoking or exposure to asbestos. As discussed above, there are concerns that vitamin E supplementation above 400 units per day may be associated with increased all-cause mortality. (See 'Cancer' above and 'All-cause mortality' above.)

SPECIAL DIETS — A balanced diet with fruits and vegetables promotes health not only by providing known vitamins, but also because it contains fiber and thousands of other less well-defined micronutrients and replaces meat and animal fat. However, people on restricted or special diets may have additional needs for vitamin supplementation. As an example, adequate vitamin B12 levels are strongly affected by dietary intake in addition to absorption. In younger adults, low consumption of animal-source food is the main cause of low vitamin B12 levels; in older adults, malabsorption of vitamin B12 from food is the most common cause [103]. The lowest intakes of vitamin B12 are seen in those who eat no animal products, and vitamin B12 intake increases with increasing intake of animal source foods [104]. (See "Treatment of vitamin B12 and folate deficiencies".)

Some special diets include (see "Vegetarian diets for children"):

●Semi-vegetarian – Meat occasionally is included in the diet. Some people who follow such a diet may not eat red meat but may eat fish and perhaps chicken.

●Lacto-ovo vegetarian – Eggs, milk, and milk products (lacto = dairy; ovo = eggs) are included, but no meat is consumed.

●Lacto-vegetarian – Milk and milk products are included in the diet, but no eggs or meat are consumed.

●Macrobiotic – Whole grains, especially brown rice, are emphasized and vegetables, fruits, legumes, and seaweeds are included in the diet. Locally grown fruits are encouraged. Animal foods limited to white meat or fish may be included in the diet once or twice a week.

●Vegan – All animal products, including eggs, milk, and milk products, are excluded from the diet. Some vegans do not use honey and may refrain from using animal products such as leather or wool. They also may avoid foods that are processed or not organically grown.

People who consume a vegan diet should be supplemented with vitamin B12 (at the RDA of 2.4 micrograms/day) if they do not consume other fortified food products (such as cereals). They are also at risk for inadequate vitamin D status and should consider a supplement, particularly during winter months [105].

Lactoovovegetarians and lactovegetarians should also consider supplementation with vitamin B12.

There are many other specialized diets that have not been adequately researched for their nutritional effects. Because most of the vitamins are available in a variety of foods, diets excluding one specific food generally would not be expected to result in deficiency or need for supplementation. By contrast, people who restrict entire categories of foods or consume only a few types of specific foods or groups may be at risk for deficiency of specific vitamins. Reasonable options in such patients are to recommend a daily multivitamin or consider specific testing (eg, 25-hydroxyvitamin D levels) based on the expected nutrient deficiencies in the diet.

RECOMMENDATIONS OF OTHERS — The US Preventive Services Task Force (USPSTF) clinical practice guideline provides several recommendations for vitamin supplementation. They recommend a folic acid supplement of 400 to 800 micrograms/day for all individuals planning or capable of pregnancy [106]. The USPSTF found insufficient evidence to recommend for or against the use of multivitamins or single or paired vitamin or mineral supplements, with the exception of beta-carotene and vitamin E, for the prevention of cancer or cardiovascular disease [107]. In addition, the USPSTF recommends against the use of beta-carotene or vitamin E supplements for the prevention of cancer or cardiovascular disease.

The US National Institutes of Health (NIH) consensus statement reports that there is insufficient evidence to recommend either for or against the use of multivitamins for chronic disease prevention [108].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies" and "Society guideline links: Healthy diet in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Vitamin D deficiency (The Basics)" and "Patient education: Vitamin B12 deficiency and folate (folic acid) deficiency (The Basics)" and "Patient education: Vitamin supplements (The Basics)")

●Beyond the Basics topic (see "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — In general, vitamin supplementation is not necessary for most adults who eat a balanced and varied diet and get regular sun exposure or drink vitamin D-fortified dairy products. However, many people take multivitamins, and common formulations, generally containing 0.5 to 1.5 times the daily reference intakes of individual vitamins, are likely safe in nearly all people. Because some vitamins in larger doses can be harmful in some people, high-dose vitamin recommendations should be tailored to individual patients.

●A balanced diet with fruits and vegetables promotes health not only by providing known vitamins, but also because it contains fiber and other less well-defined nutrients and replaces meat and animal fat. People on restricted or special diets, or those living in regions of the world with widespread malnutrition, may have additional needs for vitamin supplementation. (See 'Special diets' above.)

●For adults with a balanced diet, there is no convincing evidence that taking multivitamins in the usual doses of 50 to 200 percent of the Recommended Dietary Allowance (RDA) is either helpful or harmful. If the multivitamin includes vitamins E and/or A, these should be in low doses (eg, no more than 30 units of vitamin E; no more than 2500 international units of vitamin A).

Clinicians should strongly recommend vitamin supplements in the doses and clinical situations in which they are known to be beneficial (see below) and against vitamin supplements in doses or clinical situations in which they are harmful (see below).

For people in resource-abundant countries eating balanced diets (ie, those eating a variety of fruits, vegetables, grains, and proteins), we suggest not taking multivitamin supplements (Grade 2B). Clinicians can advise patients that such supplements are unnecessary but should understand that many patients wish to take multivitamins based on their own belief systems; clinicians should not struggle against that practice as long as there is no absolute contraindication for an individual patient. (See 'Multivitamins' above.)

●Patients are at increased risk of vitamin deficiency in some clinical situations (table 2). Classical vitamin deficiency syndromes such as scurvy, beriberi, and pellagra do exist in special clinical populations and more generally in resource-limited regions of the world. (See 'Vitamin deficiency' above.)

●Testing for vitamin blood levels is not indicated in healthy adults and should be undertaken only if there is clinical suspicion of vitamin deficiency, such as measurement of B12 and/or methylmalonic acid levels in patients with macrocytic anemia and vitamin D levels in the evaluation of established osteoporosis. (See 'Testing' above.)

●Vitamin supplementation is known to be effective in some specific clinical situations:

•In females who could become pregnant, we recommend supplementation with folic acid (Grade 1A). (See "Folic acid supplementation in pregnancy".)

•In most older adults, particularly those at increased risk of falls, we suggest supplementation with vitamin D (Grade 2B). We advise supplementation with 1000 units of vitamin D daily, with downward adjustment depending on dietary intake. Other experts, including other authors for UpToDate, use somewhat lower daily doses of vitamin D. (See 'Falls' above and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

In children in resource-limited countries, vitamin A supplementation reduces mortality, presumably by strengthening the immune system against common infections.

●High doses of vitamins, especially fat soluble vitamins, are toxic and some may be risky even at doses short of toxicity.

Vitamin A supplementation is known to have harms, particularly in certain populations:

•In the first trimester of pregnancy, vitamin A at doses >10,000 international units increases the risk of congenital anomalies. (See 'Congenital anomalies' above.)

•In unselected adults, vitamin A supplementation may increase the risk of osteoporosis, especially in females at increased risk or in people with a high dietary intake of vitamin A. (See 'Fractures' above.)

•High-dose vitamin A may increase cardiovascular mortality. (See 'Cardiovascular disease' above.)

•Beta-carotene apparently increases the risk of lung cancer in adults at increased risk because of smoking or asbestos exposure. (See 'Cancer' above.)

High-dose vitamin C increases the risk of kidney stones. (See 'Kidney stones' above.)

●A large and growing research literature suggests many other harms and benefits of vitamins, but so far without high enough quality evidence to change clinical decision-making, except as noted above. Specifically, the possibility raised by observational studies that folic acid, vitamin B12, and vitamin B6 supplementation might prevent cardiovascular disease by lowering homocysteine has not been consistently supported by results of randomized trials. Similarly, the hypothesis that antioxidants prevent cardiovascular disease and cancer has also not been borne out by results of randomized trials. Also, in adults in resource-abundant countries, vitamin D supplementation appears to have little or no effect on bone mineral density in the short term. (See 'Antioxidant vitamins' above and 'Osteoporosis' above.)

●Genetic factors may affect how vitamins are metabolized and the consequences of supplementation in various clinical situations and doses. Not enough is yet known to use genetic information to guide clinical decisions about vitamin dose and deficiencies, but that information is likely to become available. (See 'Introduction' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Robert H Fletcher, MD, MSc, who contributed to an earlier version of this topic review.