Vitamin A

What is vitamin A and what does it do?

Vitamin A is a fat-soluble vitamin that is naturally present in many foods. Vitamin A is important for normal vision, the immune system, and reproduction. Vitamin A also helps the heart, lungs, kidneys, and other organs work properly.

There are two different types of vitamin A. The first type, preformed vitamin A, is found in meat, poultry, fish, and dairy products. The second type, provitamin A, is found in fruits, vegetables, and other plant-based products. The most common type of provitamin A in foods and dietary supplements is beta-carotene.

How much vitamin A do I need?

The amount of vitamin A you need depends on your age and reproductive status. Recommended intakes for vitamin A for people aged 14 years and older range between 700 and 900 micrograms (mcg) of retinol activity equivalents (RAE) per day. Recommended intakes for women who are nursing range between 1,200 and 1,300 RAE. Lower values are recommended for infants and children younger than 14.

However, the vitamin A content of foods and dietary supplements is given on product labels in international units (IU), not mcg RAE. Converting between IU and mcg RAE is not easy. A varied diet with 900 mcg RAE of vitamin A, for example, provides between 3,000 and 36,000 IU of vitamin A depending on the foods consumed. See our Health Professional Fact Sheet on Vitamin A for more details.

For adults and children aged 4 years and older, the U.S. Food and Drug Administration has established a vitamin A Daily Value (DV) of 5,000 IU from a varied diet of both plant and animal foods. DVs are not recommended intakes; they don't vary by age and sex, for example. But trying to reach 100% of the DV each day, on average, is useful to help you get enough vitamin A. For more information on DVs, see our Frequently Asked Questions page.

What foods provide vitamin A?

Vitamin A is found naturally in many foods and is added to some foods, such as milk and cereal. You can get recommended amounts of vitamin A by eating a variety of foods, including the following:

• Beef liver and other organ meats (but these foods are also high in cholesterol, so limit the amount you eat).
• Some types of fish, such as salmon.
• Green leafy vegetables and other green, orange, and yellow vegetables, such as broccoli, carrots, and squash.
• Fruits, including cantaloupe, apricots, and mangos.
• Dairy products, which are among the major sources of vitamin A for Americans.
• Fortified breakfast cereals.
• What kinds of vitamin A dietary supplements are available?

Vitamin A is available in dietary supplements, usually in the form of retinyl acetate or retinyl palmitate (preformed vitamin A), beta-carotene (provitamin A), or a combination of preformed and provitamin A. Most multivitamin-mineral supplements contain vitamin A. Dietary supplements that contain only vitamin A are also available.

Am I getting enough vitamin A?

Most people in the United States get enough vitamin A from the foods they eat, and vitamin A deficiency is rare. However, certain groups of people are more likely than others to have trouble getting enough vitamin A:

• Premature infants, who often have low levels of vitamin A in their first year.
• Infants, young children, pregnant women, and breastfeeding women in developing countries.
• People with cystic fibrosis.

What happens if I don't get enough vitamin A?

Vitamin A deficiency is rare in the United States, although it is common in many developing countries. The most common symptom of vitamin A deficiency in young children and pregnant women is an eye condition called xerophthalmia. Xerophthalmia is the inability to see in low light, and it can lead to blindness if it isn't treated.

What are some effects of vitamin A on health?

Scientists are studying vitamin A to understand how it affects health. Here are some examples of what this research has shown.

Cancer

People who eat a lot of foods containing beta-carotene might have a lower risk of certain kinds of cancer, such as lung cancer or prostate cancer. But studies to date have not shown that vitamin A or beta-carotene supplements can help prevent cancer or lower the chances of dying from this disease. In fact, studies show that smokers who take high doses of beta-carotene supplements have an increased risk of lung cancer.

Age-Related Macular Degeneration

Age-related macular degeneration (AMD), or the loss of central vision as people age, is one of the most common causes of vision loss in older people. Among people with AMD who are at high risk of developing advanced AMD, a supplement containing antioxidants, zinc, and copper with or without beta-carotene has shown promise for slowing down the rate of vision loss.

Measles

When children with vitamin A deficiency (which is rare in North America) get measles, the disease tends to be more severe. In these children, taking supplements with high doses of vitamin A can shorten the fever and diarrhea caused by measles. These supplements can also lower the risk of death in children with measles who live in developing countries where vitamin A deficiency is common.

Can vitamin A be harmful?

Yes, high intakes of some forms of vitamin A can be harmful.

Getting too much preformed vitamin A (usually from supplements or certain medicines) can cause dizziness, nausea, headaches, coma, and even death. High intakes of preformed vitamin A in pregnant women can also cause birth defects in their babies. Women who might be pregnant should not take high doses of vitamin A supplements.

Consuming high amounts of beta-carotene or other forms of provitamin A can turn the skin yellow-orange, but this condition is harmless. High intakes of beta-carotene do not cause birth defects or the other more serious effects caused by getting too much preformed vitamin A.

The upper limits for preformed vitamin A in IU are listed below. These levels do not apply to people who are taking vitamin A for medical reasons under the care of a doctor. Upper limits for beta-carotene and other forms of provitamin A have not been established.

Are there any interactions with vitamin A that I should know about?

Yes, vitamin A supplements can interact or interfere with medicines you take. Here are several examples:

• Orlistat (Alli®, Xenical®), a weight-loss drug, can decrease the absorption of vitamin A, causing low blood levels in some people.
• Several synthetic forms of vitamin A are used in prescription medicines. Examples are the psoriasis treatment acitretin (Soriatane®) and bexarotene (Targretin®), used to treat the skin effects of T-cell lymphoma. Taking these medicines in combination with a vitamin A supplement can cause dangerously high levels of vitamin A in the blood.

Tell your doctor, pharmacist, and other health care providers about any dietary supplements and medicines you take. They can tell you if those dietary supplements might interact or interfere with your prescription or over-the-counter medicines or if the medicines might interfere with how your body absorbs, uses, or breaks down nutrients.

Vitamin A and healthful eating

People should get most of their nutrients from food, advises the federal government's Dietary Guidelines for Americans. Foods contain vitamins, minerals, dietary fiber and other substances that benefit health. In some cases, fortified foods and dietary supplements may provide nutrients that otherwise may be consumed in less-than-recommended amounts. For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture's MyPlateexternal link disclaimer.

Disclaimer

This fact sheet by the Office of Dietary Supplements provides information that should not take the place of medical advice. We encourage you to talk to your healthcare providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.

Vitamin B6

What is vitamin B6 and what does it do?

Vitamin B6 is a vitamin that is naturally present in many foods. The body needs vitamin B6 for more than 100 enzyme reactions involved in metabolism. Vitamin B6 is also involved in brain development during pregnancy and infancy as well as immune function.

How much vitamin B6 do I need?

The amount of vitamin B6 you need depends on your age. Average daily recommended amounts are listed below in milligrams (mg).

What foods provide vitamin B6?

Vitamin B6 is found naturally in many foods and is added to other foods. You can get recommended amounts of vitamin B6 by eating a variety of foods, including the following:

• Poultry, fish, and organ meats, all rich in vitamin B6.
• Potatoes and other starchy vegetables, which are some of the major sources of vitamin B6 for Americans.
• Fruit (other than citrus), which are also among the major sources of vitamin B6 for Americans.

What kinds of vitamin B6 dietary supplements are available?

Vitamin B6 is available in dietary supplements, usually in the form of pyridoxine. Most multivitamin-mineral supplements contain vitamin B6. Dietary supplements that contain only vitamin B6, or vitamin B6 with other B vitamins, are also available.

Am I getting enough vitamin B6?

Most people in the United States get enough vitamin B6 from the foods they eat. However, certain groups of people are more likely than others to have trouble getting enough vitamin B6:

• People whose kidneys do not work properly, including people who are on kidney dialysis and those who have had a kidney transplant.
• People with autoimmune disorders, which cause their immune system to mistakenly attack their own healthy tissues. For example, people with rheumatoid arthritis, celiac disease, Crohn's disease, ulcerative colitis, or inflammatory bowel disease sometimes have low vitamin B6 levels.
• People with alcohol dependence.

What happens if I don't get enough vitamin B6?

Vitamin B6 deficiency is uncommon in the United States. People who don't get enough vitamin B6 can have a range of symptoms, including anemia, itchy rashes, scaly skin on the lips, cracks at the corners of the mouth, and a swollen tongue. Other symptoms of very low vitamin B6 levels include depression, confusion, and a weak immune system. Infants who do not get enough vitamin B6 can become irritable or develop extremely sensitive hearing or seizures.

What are some effects of vitamin B6 on health?

Scientists are studying vitamin B6 to understand how it affects health. Here are some examples of what this research has shown.

Heart disease

Some scientists had thought that certain B vitamins (such as folic acid, vitamin B12, and vitamin B6) might reduce heart disease risk by lowering levels of homocysteine, an amino acid in the blood. Although vitamin B supplements do lower blood homocysteine, research shows that they do not actually reduce the risk or severity of heart disease or stroke.

Cancer

People with low levels of vitamin B6 in the blood might have a higher risk of certain kinds of cancer, such as colorectal cancer. But studies to date have not shown that vitamin B6 supplements can help prevent cancer or lower the chances of dying from this disease.

Cognitive Function

Some research indicates that elderly people who have higher blood levels of vitamin B6 have better memory. However, taking vitamin B6 supplements (alone or combined with vitamin B12 and/or folic acid) does not seem to improve cognitive function or mood in healthy people or in people with dementia.

Premenstrual Syndrome

Scientists aren't yet certain about the potential benefits of taking vitamin B6 for premenstrual syndrome (PMS). But some studies show that vitamin B6 supplements could reduce PMS symptoms, including moodiness, irritability, forgetfulness, bloating, and anxiety.

Nausea and Vomiting in Pregnancy

At least half of all women experience nausea, vomiting, or both in the first few months of pregnancy. Based on the results of several studies, the American Congress of Obstetricians and Gynecologists (ACOG) recommends taking vitamin B6 supplements under a doctor's care for nausea and vomiting during pregnancy.

Can vitamin B6 be harmful?

People almost never get too much vitamin B6 from food. But taking high levels of vitamin B6 from supplements for a year or longer can cause severe nerve damage, leading people to lose control of their bodily movements. The symptoms usually stop when they stop taking the supplements. Other symptoms of too much vitamin B6 include painful, unsightly skin patches, extreme sensitivity to sunlight, nausea, and heartburn.

The upper limits for vitamin B6 are listed below. These levels do not apply to people who are taking vitamin B6 for medical reasons under the care of a doctor.

Are there any interactions with vitamin B6 that I should know about?

Yes, vitamin B6 supplements can interact or interfere with medicines that you take. Here are several examples:

• Vitamin B6 supplements might interact with cycloserine (Seromycin®), an antibiotic used to treat tuberculosis, and worsen any seizures and nerve cell damage that the drug might cause.
• Taking certain epilepsy drugs could decrease vitamin B6 levels and reduce the drugs' ability to control seizures.
• Taking theophylline (Aquaphyllin®, Elixophyllin®, Theolair®, Truxophyllin®, and many others) for asthma or another lung disease can reduce vitamin B6 levels and cause seizures.

Tell your doctor, pharmacist, and other health care providers about any dietary supplements and medicines you take. They can tell you if those dietary supplements might interact or interfere with your prescription or over-the-counter medicines or if the medicines might interfere with how your body absorbs, uses, or breaks down nutrients.

Vitamin B6 and healthful eating

People should get most of their nutrients from food, advises the federal government's Dietary Guidelines for Americans. Foods contain vitamins, minerals, dietary fiber and other substances that benefit health. In some cases, fortified foods and dietary supplements may provide nutrients that otherwise may be consumed in less-than-recommended amounts. For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture's MyPlateexternal link disclaimer.

Disclaimer

This fact sheet by the Office of Dietary Supplements provides information that should not take the place of medical advice. We encourage you to talk to your healthcare providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.

Vitamin B12

Introduction

Vitamin B12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 exists in several forms and contains the mineral cobalt, so compounds with vitamin B12 activity are collectively called "cobalamins". Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 that are active in human metabolism .

Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis. Vitamin B12 functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase catalyzes the conversion of homocysteine to methionine. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate, an essential biochemical reaction in fat and protein metabolism. Succinyl-CoA is also required for hemoglobin synthesis.

Vitamin B12, bound to protein in food, is released by the activity of hydrochloric acid and gastric protease in the stomach. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and, thus, does not require this separation step. Free vitamin B12 then combines with intrinsic factor, a glycoprotein secreted by the stomach's parietal cells, and the resulting complex undergoes absorption within the distal ileum by receptor-mediated endocytosis. Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1-2 mcg of vitamin B12).

Pernicious anemia is an autoimmune disease that affects the gastric mucosa and results in gastric atrophy. This leads to the destruction of parietal cells, achlorhydria, and failure to produce intrinsic factor, resulting in vitamin B12 malabsorption. If pernicious anemia is left untreated, it causes vitamin B12 deficiency, leading to megaloblastic anemia and neurological disorders, even in the presence of adequate dietary intake of vitamin B12.

Vitamin B12 status is typically assessed via serum or plasma vitamin B12 levels. Values below approximately 170-250 pg/mL (120-180 picomol/L) for adults indicate a vitamin B12 deficiency. However, evidence suggests that serum vitamin B12 concentrations might not accurately reflect intracellular concentrations. An elevated serum homocysteine level (values >13 micromol/L) might also suggest a vitamin B12 deficiency. However, this indicator has poor specificity because it is influenced by other factors, such as low vitamin B6 or folate levels. Elevated methylmalonic acid levels (values >0.4 micromol/L) might be a more reliable indicator of vitamin B12 status because they indicate a metabolic change that is highly specific to vitamin B12 deficiency.

Recommended Intakes

Intake recommendations for vitamin B12 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences). DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

• Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy individuals.
• Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
• Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current RDAs for vitamin B12 in micrograms (mcg). For infants aged 0 to 12 months, the FNB established an AI for vitamin B12 that is equivalent to the mean intake of vitamin B12 in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B12

Sources of Vitamin B12

Food

Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, but fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability for vegetarians. Some nutritional yeast products also contain vitamin B12. Fortified foods vary in formulation, so it is important to read product labels to determine which added nutrients they contain.

Several food sources of vitamin B12 are listed in Table 2.

Table 2: Selected Food Sources of Vitamin B12

Dietary supplements

In dietary supplements, vitamin B12 is usually present as cyanocobalamin, a form that the body readily converts to the active forms methylcobalamin and 5-deoxyadenosylcobalamin. Dietary supplements can also contain methylcobalamin and other forms of vitamin B12.

Existing evidence does not suggest any differences among forms with respect to absorption or bioavailability. However the body's ability to absorb vitamin B12 from dietary supplements is largely limited by the capacity of intrinsic factor. For example, only about 10 mcg of a 500 mcg oral supplement is actually absorbed in healthy people.

In addition to oral dietary supplements, vitamin B12 is available in sublingual preparations as tablets or lozenges. These preparations are frequently marketed as having superior bioavailability, although evidence suggests no difference in efficacy between oral and sublingual forms.

Prescription medications

Vitamin B12, in the form of cyanocobalamin and occasionally hydroxocobalamin, can be administered parenterally as a prescription medication, usually by intramuscular injection. Parenteral administration is typically used to treat vitamin B12 deficiency caused by pernicious anemia and other conditions that result in vitamin B12 malabsorption and severe vitamin B12 deficiency.

Vitamin B12 is also available as a prescription medication in a gel formulation applied intranasally, a product marketed as an alternative to vitamin B12 injections that some patients might prefer. This formulation appears to be effective in raising vitamin B12 blood levels, although it has not been thoroughly studied in clinical settings.

Vitamin B12 Intakes and Status

Most children and adults in the United States consume recommended amounts of vitamin B12, according to analyses of data from the 1988-1994 National Health and Nutrition Examination Survey (NHANES III) and the 1994-1996 Continuing Survey of Food Intakes by Individuals. Data from the 1999-2000 NHANES indicate that the median daily intake of vitamin B12 for the U.S. population is 3.4 mcg.

Some people-particularly older adults, those with pernicious anemia, and those with reduced levels of stomach acidity (hypochlorhydria or achlorhydria) or intestinal disorders-have difficulty absorbing vitamin B12 from food and, in some cases, oral supplements. As a result, vitamin B12 deficiency is common, affecting between 1.5% and 15% of the general population. In many of these cases, the cause of the vitamin B12 deficiency is unknown.

Evidence from the Framingham Offspring Study suggests that the prevalence of vitamin B12 deficiency in young adults might be greater than previously assumed. This study found that the percentage of participants in three age groups (26-49 years, 50-64 years, and 65 years and older) with deficient blood levels of vitamin B12 was similar. The study also found that individuals who took a supplement containing vitamin B12 or consumed fortified cereal more than four times per week were much less likely to have a vitamin B12 deficiency.

Individuals who have trouble absorbing vitamin B12 from foods, as well as vegetarians who consume no animal foods, might benefit from vitamin B12-fortified foods, oral vitamin B12 supplements, or vitamin B12 injections.

Vitamin B12 Deficiency

Vitamin B12 deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss. Neurological changes, such as numbness and tingling in the hands and feet, can also occur. Additional symptoms of vitamin B12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue. The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage. During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia. Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B12 deficiency.

Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 may also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration. Overall, an individual patient's ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection. In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged.

Folic acid and vitamin B12

Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs. Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency. Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults.

Groups at Risk of Vitamin B12 Deficiency

The main causes of vitamin B12 deficiency include vitamin B12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency. However, in many cases, the cause of vitamin B12 deficiency is unknown. The following groups are among those most likely to be vitamin B12 deficient.

Older adults

Atrophic gastritis, a condition affecting 10%-30% of older adults, decreases secretion of hydrochloric acid in the stomach, resulting in decreased absorption of vitamin B12. Decreased hydrochloric acid levels might also increase the growth of normal intestinal bacteria that use vitamin B12, further reducing the amount of vitamin B12 available to the body.

Individuals with atrophic gastritis are unable to absorb the vitamin B12 that is naturally present in food. Most, however, can absorb the synthetic vitamin B12 added to fortified foods and dietary supplements. As a result, the IOM recommends that adults older than 50 years obtain most of their vitamin B12 from vitamin supplements or fortified foods. However, some elderly patients with atrophic gastritis require doses much higher than the RDA to avoid subclinical deficiency.

Individuals with pernicious anemia

Pernicious anemia, a condition that affects 1%-2% of older adults, is characterized by a lack of intrinsic factor. Individuals with pernicious anemia cannot properly absorb vitamin B12 in the gastrointestinal tract. Pernicious anemia is usually treated with intramuscular vitamin B12. However, approximately 1% of oral vitamin B12 can be absorbed passively in the absence of intrinsic factor, suggesting that high oral doses of vitamin B12 might also be an effective treatment.

Individuals with gastrointestinal disorders

Individuals with stomach and small intestine disorders, such as celiac disease and Crohn's disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores. Subtly reduced cognitive function resulting from early vitamin B12 deficiency might be the only initial symptom of these intestinal disorders, followed by megaloblastic anemia and dementia.

Individuals who have had gastrointestinal surgery

Surgical procedures in the gastrointestinal tract, such as weight loss surgery or surgery to remove all or part of the stomach, often result in a loss of cells that secrete hydrochloric acid and intrinsic factor. This reduces the amount of vitamin B12, particularly food-bound vitamin B12, that the body releases and absorbs. Surgical removal of the distal ileum also can result in the inability to absorb vitamin B12. Individuals undergoing these surgical procedures should be monitored preoperatively and postoperatively for several nutrient deficiencies, including vitamin B12 deficiency.

Vegetarians

Strict vegetarians and vegans are at greater risk than lacto-ovo vegetarians and nonvegetarians of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods. Fortified breakfast cereals are one of the few sources of vitamin B12 from plants and can be used as a dietary source of vitamin B12 for strict vegetarians and vegans.

Pregnant and lactating women who follow strict vegetarian diets and their infants

Vitamin B12 crosses the placenta during pregnancy and is present in breast milk. Exclusively breastfed infants of women who consume no animal products may have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency within months of birth. Undetected and untreated vitamin B12 deficiency in infants can result in severe and permanent neurological damage.

The American Dietetic Association recommends supplemental vitamin B12 for vegans and lacto-ovo vegetarians during both pregnancy and lactation to ensure that enough vitamin B12 is transferred to the fetus and infant. Pregnant and lactating women who follow strict vegetarian or vegan diets should consult with a pediatrician regarding vitamin B12 supplements for their infants and children.

Vitamin B12 and Health

Cardiovascular disease

Cardiovascular disease is the most common cause of death in industrialized countries, such as the United States, and is on the rise in developing countries. Risk factors for cardiovascular disease include elevated low-density lipoprotein (LDL) levels, high blood pressure, low high-density lipoprotein (HDL) levels, obesity, and diabetes.

Elevated homocysteine levels have also been identified as an independent risk factor for cardiovascular disease. Homocysteine is a sulfur-containing amino acid derived from methionine that is normally present in blood. Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation. Evidence from retrospective, cross-sectional, and prospective studies links elevated homocysteine levels with coronary heart disease and stroke.

Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to inadequate function of methionine synthase. Results from several randomized controlled trials indicate that combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels in people with vascular disease or diabetes and in young adult women. In another study, older men and women who took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels.

Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular disease. In the Women's Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular disease who took daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid, and 50 mg vitamin B6 for 7.3 years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels. The Heart Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54 years with vascular disease or diabetes, found that daily treatment with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for an average of 5 years reduced homocysteine levels and the risk of stroke but did not reduce the risk of major cardiovascular events. In the Western Norway B Vitamin Intervention Trial, which included 3,096 patients undergoing coronary angiography, daily supplements of 0.4 mg vitamin B12 and 0.8 mg folic acid with or without 40 mg vitamin B6 for 1 year reduced homocysteine levels by 30% but did not affect total mortality or the risk of major cardiovascular events during 38 months of follow-up. The Norwegian Vitamin (NORVIT) trial and the Vitamin Intervention for Stroke Prevention trial had similar results.

The American Heart Association has concluded that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk.

Dementia and cognitive function

Researchers have long been interested in the potential connection between vitamin B12 deficiency and dementia. A deficiency in vitamin B12 causes an accumulation of homocysteine in the blood and might decrease levels of substances needed to metabolize neurotransmitters. Observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer's disease and dementia. Low vitamin B12 status has also been positively associated with cognitive decline.

Despite evidence that vitamin B12 lowers homocysteine levels and correlations between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent effect on cognition. In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older with no or moderate cognitive impairment received 1,000 mcg vitamin B12, 1,000 mcg vitamin B12 plus 400 mcg folic acid, or placebo for 24 weeks. Treatment with vitamin B12 plus folic acid reduced homocysteine concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved cognitive function.

Women at high risk of cardiovascular disease who participated in the Women's Antioxidant and Folic Acid Cardiovascular Study were randomly assigned to receive daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid and 50 mg vitamin B6, or placebo. After a mean of 1.2 years, B-vitamin supplementation did not affect mean cognitive change from baseline compared with placebo. However, in a subset of women with low baseline dietary intake of B vitamins, supplementation significantly slowed the rate of cognitive decline. In a trial conducted by the Alzheimer's Disease Cooperative Study consortium that included individuals with mild-to-moderate Alzheimer's disease, daily supplements of 1 mg vitamin B12, 5 mg folic acid, and 25 mg vitamin B6 for 18 months did not slow cognitive decline compared with placebo. Another study found similar results in 142 individuals at risk of dementia who received supplements of 2 mg folic acid and 1 mg vitamin B12 for 12 weeks.

The authors of two Cochrane reviews and a systematic review of randomized trials of the effects of B vitamins on cognitive function concluded that insufficient evidence is available to show whether vitamin B12 alone or in combination with vitamin B6 or folic acid has an effect on cognitive function or dementia. Additional large clinical trials of vitamin B12 supplementation are needed to assess whether vitamin B12 has a direct effect on cognitive function and dementia.

Energy and endurance

Due to its role in energy metabolism, vitamin B12 is frequently promoted as an energy enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit.

Health Risks from Excessive Vitamin B12

The IOM did not establish a UL for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the IOM states that "no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals".

Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial).

Interactions with Medications

Vitamin B12 has the potential to interact with certain medications. In addition, several types of medications might adversely affect vitamin B12 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B12 status with their healthcare providers.

Chloramphenicol

Chloramphenicol (Chloromycetin®) is a bacteriostatic antibiotic. Limited evidence from case reports indicates that chloramphenicol can interfere with the red blood cell response to supplemental vitamin B12 in some patients.

Proton pump inhibitors

Proton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®), are used to treat gastroesophageal reflux disease and peptic ulcer disease. These drugs can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach. However, the evidence is conflicting on whether proton pump inhibitor use affects vitamin B12 status. As a precaution, health care providers should monitor vitamin B12 status in patients taking proton pump inhibitors for prolonged periods.

H2 receptor antagonists

Histamine H2 receptor antagonists, used to treat peptic ulcer disease, include cimetidine (Tagamet®), famotidine (Pepcid®), and ranitidine (Zantac®). These medications can interfere with the absorption of vitamin B12 from food by slowing the release of hydrochloric acid into the stomach. Although H2 receptor antagonists have the potential to cause vitamin B12 deficiency, no evidence indicates that they promote vitamin B12 deficiency, even after long-term use. Clinically significant effects may be more likely in patients with inadequate vitamin B12 stores, especially those using H2 receptor antagonists continuously for more than 2 years.

Metformin

Metformin, a hypoglycemic agent used to treat diabetes, might reduce the absorption of vitamin B12, possibly through alterations in intestinal mobility, increased bacterial overgrowth, or alterations in the calcium-dependent uptake by ileal cells of the vitamin B12-intrinsic factor complex. Small studies and case reports suggest that 10%-30% of patients who take metformin have reduced vitamin B12 absorption. In a randomized, placebo controlled trial in patients with type 2 diabetes, metformin treatment for 4.3 years significantly decreased vitamin B12 levels by 19% and raised the risk of vitamin B12 deficiency by 7.2% compared with placebo. Some studies suggest that supplemental calcium might help improve the vitamin B12 malabsorption caused by metformin, but not all researchers agree.

Vitamin B12 and Healthful Diets

The federal government's 2015-2020 Dietary Guidelines for Americans notes that "Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts."

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

Fish and red meat are excellent sources of vitamin B12. Poultry and eggs also contain vitamin B12.

• Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.

Milk and milk products are good sources of vitamin B12. Many ready-to-eat breakfast cereals are fortified with vitamin B12.

• Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
• Limits saturated and trans fats, added sugars, and sodium.
• Stays within your daily calorie needs.

Disclaimer

This fact sheet by the Office of Dietary Supplements provides information that should not take the place of medical advice. We encourage you to talk to your healthcare providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.

Vitamin C

Introduction

Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component.

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism . Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E). Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function and improves the absorption of nonheme iron, the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility.

The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter. Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.

Oral vitamin C produces tissue and plasma concentrations that the body tightly controls. Approximately 70%-90% of vitamin C is absorbed at moderate intakes of 30-180 mg/day. However, at doses above 1 g/day, absorption falls to less than 50% and absorbed, unmetabolized ascorbic acid is excreted in the urine. Results from pharmacokinetic studies indicate that oral doses of 1.25 g/day ascorbic acid produce mean peak plasma vitamin C concentrations of 135 micromol/L, which are about two times higher than those produced by consuming 200-300 mg/day ascorbic acid from vitamin C-rich foods. Pharmacokinetic modeling predicts that even doses as high as 3 g ascorbic acid taken every 4 hours would produce peak plasma concentrations of only 220 micromol/L.

The total body content of vitamin C ranges from 300 mg (at near scurvy) to about 2 g. High levels of vitamin C (millimolar concentrations) are maintained in cells and tissues, and are highest in leukocytes (white blood cells), eyes, adrenal glands, pituitary gland, and brain. Relatively low levels of vitamin C (micromolar concentrations) are found in extracellular fluids, such as plasma, red blood cells, and saliva.

Recommended Intakes

Intake recommendations for vitamin C and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences). DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

• Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy individuals.
• Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
• Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current RDAs for vitamin C. The RDAs for vitamin C are based on its known physiological and antioxidant functions in white blood cells and are much higher than the amount required for protection from deficiency. For infants from birth to 12 months, the FNB established an AI for vitamin C that is equivalent to the mean intake of vitamin C in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin C

Sources of Vitamin C

Food

Fruits and vegetables are the best sources of vitamin C (see Table 2). Citrus fruits, tomatoes and tomato juice, and potatoes are major contributors of vitamin C to the American diet. Other good food sources include red and green peppers, kiwifruit, broccoli, strawberries, Brussels sprouts, and cantaloupe (see Table 2). Although vitamin C is not naturally present in grains, it is added to some fortified breakfast cereals. The vitamin C content of food may be reduced by prolonged storage and by cooking because ascorbic acid is water soluble and is destroyed by heat. Steaming or microwaving may lessen cooking losses. Fortunately, many of the best food sources of vitamin C, such as fruits and vegetables, are usually consumed raw. Consuming five varied servings of fruits and vegetables a day can provide more than 200 mg of vitamin C.

Table 2: Selected Food Sources of Vitamin C

The U.S. Department of Agriculture's (USDA's) Nutrient Databaseexternal link disclaimer Web site lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin C arranged by nutrient content and by food name.

Dietary supplements

Supplements typically contain vitamin C in the form of ascorbic acid, which has equivalent bioavailability to that of naturally occurring ascorbic acid in foods, such as orange juice and broccoli. Other forms of vitamin C supplements include sodium ascorbate; calcium ascorbate; other mineral ascorbates; ascorbic acid with bioflavonoids; and combination products, such as Ester-C®, which contains calcium ascorbate, dehydroascorbate, calcium threonate, xylonate and lyxonate.

A few studies in humans have examined whether bioavailability differs among the various forms of vitamin C. In one study, Ester-C® and ascorbic acid produced the same vitamin C plasma concentrations, but Ester-C® produced significantly higher vitamin C concentrations in leukocytes 24 hours after ingestion. Another study found no differences in plasma vitamin C levels or urinary excretion of vitamin C among three different vitamin C sources: ascorbic acid, Ester-C®, and ascorbic acid with bioflavonoids. These findings, coupled with the relatively low cost of ascorbic acid, led the authors to conclude that simple ascorbic acid is the preferred source of supplemental vitamin C.

Vitamin C Intakes and Status

According to the 2001-2002 National Health and Nutrition Examination Survey (NHANES), mean intakes of vitamin C are 105.2 mg/day for adult males and 83.6 mg/day for adult females, meeting the currently established RDA for most nonsmoking adults. Mean intakes for children and adolescents aged 1-18 years range from 75.6 mg/day to 100 mg/day, also meeting the RDA for these age groups. Although the 2001-2002 NHANES analysis did not include data for breastfed infants and toddlers, breastmilk is considered an adequate source of vitamin C. Use of vitamin C-containing supplements is also relatively common, adding to the total vitamin C intake from food and beverages. NHANES data from 1999-2000 indicate that approximately 35% of adults take multivitamin supplements (which typically contain vitamin C) and 12% take a separate vitamin C supplement. According to 1999-2002 NHANES data, approximately 29% of children take some form of dietary supplement that contains vitamin C.

Vitamin C status is typically assessed by measuring plasma vitamin C levels. Other measures, such as leukocyte vitamin C concentration, could be more accurate indicators of tissue vitamin C levels, but they are more difficult to assess and the results are not always reliable.

Vitamin C Deficiency

Acute vitamin C deficiency leads to scurvy. The timeline for the development of scurvy varies, depending on vitamin C body stores, but signs can appear within 1 month of little or no vitamin C intake (below 10 mg/day). Initial symptoms can include fatigue (probably the result of impaired carnitine biosynthesis), malaise, and inflammation of the gums. As vitamin C deficiency progresses, collagen synthesis becomes impaired and connective tissues become weakened, causing petechiae, ecchymoses, purpura, joint pain, poor wound healing, hyperkeratosis, and corkscrew hairs. Additional signs of scurvy include depression as well as swollen, bleeding gums and loosening or loss of teeth due to tissue and capillary fragility. Iron deficiency anemia can also occur due to increased bleeding and decreased nonheme iron absorption secondary to low vitamin C intake. In children, bone disease can be present. Left untreated, scurvy is fatal.

Until the end of the 18th century, many sailors who ventured on long ocean voyages, with little or no vitamin C intake, contracted or died from scurvy. During the mid-1700s, Sir James Lind, a British Navy surgeon, conducted experiments and determined that eating citrus fruits or juices could cure scurvy, although scientists did not prove that ascorbic acid was the active component until 1932.

Today, vitamin C deficiency and scurvy are rare in developed countries. Overt deficiency symptoms occur only if vitamin C intake falls below approximately 10 mg/day for many weeks. Vitamin C deficiency is uncommon in developed countries but can still occur in people with limited food variety.

Groups at Risk of Vitamin C Inadequacy

Vitamin C inadequacy can occur with intakes that fall below the RDA but are above the amount required to prevent overt deficiency (approximately 10 mg/day). The following groups are more likely than others to be at risk of obtaining insufficient amounts of vitamin C.

Smokers and passive "smokers"

Studies consistently show that smokers have lower plasma and leukocyte vitamin C levels than nonsmokers, due in part to increased oxidative stress. For this reason, the IOM concluded that smokers need 35 mg more vitamin C per day than nonsmokers. Exposure to secondhand smoke also decreases vitamin C levels. Although the IOM was unable to establish a specific vitamin C requirement for nonsmokers who are regularly exposed to secondhand smoke, these individuals should ensure that they meet the RDA for vitamin C.

Infants fed evaporated or boiled milk

Most infants in developed countries are fed breastmilk and/or infant formula, both of which supply adequate amounts of vitamin C. For many reasons, feeding infants evaporated or boiled cow's milk is not recommended. This practice can cause vitamin C deficiency because cow's milk naturally has very little vitamin C and heat can destroy vitamin C.

Individuals with limited food variety

Although fruits and vegetables are the best sources of vitamin C, many other foods have small amounts of this nutrient. Thus, through a varied diet, most people should be able to meet the vitamin C RDA or at least obtain enough to prevent scurvy. People who have limited food variety-including some elderly, indigent individuals who prepare their own food; people who abuse alcohol or drugs; food faddists; people with mental illness; and, occasionally, children-might not obtain sufficient vitamin C.

People with malabsorption and certain chronic diseases

Some medical conditions can reduce the absorption of vitamin C and/or increase the amount needed by the body. People with severe intestinal malabsorption or cachexia and some cancer patients might be at increased risk of vitamin C inadequacy. Low vitamin C concentrations can also occur in patients with end-stage renal disease on chronic hemodialysis.

Vitamin C and Health

Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions. This section focuses on four diseases and disorders in which vitamin C might play a role: cancer (including prevention and treatment), cardiovascular disease, age-related macular degeneration (AMD) and cataracts, and the common cold.

Cancer prevention

Epidemiologic evidence suggests that higher consumption of fruits and vegetables is associated with lower risk of most types of cancer, perhaps, in part, due to their high vitamin C content. Vitamin C can limit the formation of carcinogens, such as nitrosamines, in vivo; modulate immune response; and, through its antioxidant function, possibly attenuate oxidative damage that can lead to cancer.

Most case-control studies have found an inverse association between dietary vitamin C intake and cancers of the lung, breast, colon or rectum, stomach, oral cavity, larynx or pharynx, and esophagus. Plasma concentrations of vitamin C are also lower in people with cancer than controls.

However, evidence from prospective cohort studies is inconsistent, possibly due to varying intakes of vitamin C among studies. In a cohort of 82,234 women aged 33-60 years from the Nurses' Health Study, consumption of an average of 205 mg/day of vitamin C from food (highest quintile of intake) compared with an average of 70 mg/day (lowest quintile of intake) was associated with a 63% lower risk of breast cancer among premenopausal women with a family history of breast cancer. Conversely, Kushi and colleagues did not observe a significantly lower risk of breast cancer among postmenopausal women consuming at least 198 mg/day (highest quintile of intake) of vitamin C from food compared with those consuming less than 87 mg/day (lowest quintile of intake). A review by Carr and Frei concluded that in the majority of prospective cohort studies not reporting a significantly lower cancer risk, most participants had relatively high vitamin C intakes, with intakes higher than 86 mg/day in the lowest quintiles. Studies reporting significantly lower cancer risk found these associations in individuals with vitamin C intakes of at least 80-110 mg/day, a range associated with close to vitamin C tissue saturation.

Evidence from most randomized clinical trials suggests that vitamin C supplementation, usually in combination with other micronutrients, does not affect cancer risk. In the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study, a randomized, double-blind, placebo-controlled clinical trial,13,017 healthy French adults received antioxidant supplementation with 120 mg ascorbic acid, 30 mg vitamin E, 6 mg beta-carotene, 100 mcg selenium, and 20 mg zinc, or placebo. After a median follow-up time of 7.5 years, antioxidant supplementation lowered total cancer incidence in men, but not in women. In addition, baseline antioxidant status was related to cancer risk in men, but not in women. Supplements of 500 mg/day vitamin C plus 400 IU vitamin E every other day for a mean follow-up period of 8 years failed to reduce the risk of prostate or total cancer compared with placebo in middle-aged and older men participating in the Physicians' Health Study II. Similar findings were reported in women participating in the Women's Antioxidant Cardiovascular Study. Compared with placebo, supplementation with vitamin C (500 mg/day) for an average of 9.4 years had no significant effect on total cancer incidence or cancer mortality. In a large intervention trial conducted in Linxian, China, daily supplements of vitamin C (120 mg) plus molybdenum (30 mcg) for 5-6 years did not significantly affect the risk of developing esophageal or gastric cancer. Moreover, during 10 years of follow-up, this supplementation regimen failed to significantly affect total morbidity or mortality from esophageal, gastric, or other cancers. A 2008 review of vitamin C and other antioxidant supplements for the prevention of gastrointestinal cancers found no convincing evidence that vitamin C (or beta-carotene, vitamin A, or vitamin E) prevents gastrointestinal cancers. A similar review by Coulter and colleagues found that vitamin C supplementation, in combination with vitamin E, had no significant effect on death risk due to cancer in healthy individuals.

At this time, the evidence is inconsistent on whether dietary vitamin C intake affects cancer risk. Results from most clinical trials suggest that modest vitamin C supplementation alone or with other nutrients offers no benefit in the prevention of cancer.

A substantial limitation in interpreting many of these studies is that investigators did not measure vitamin C concentrations before or after supplementation. Plasma and tissue concentrations of vitamin C are tightly controlled in humans. At daily intakes of 100 mg or higher, cells appear to be saturated and at intakes of at least 200 mg, plasma concentrations increase only marginally. If subjects' vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes.

Cancer treatment

During the 1970s, studies by Cameron, Campbell, and Pauling suggested that high-dose vitamin C has beneficial effects on quality of life and survival time in patients with terminal cancer. However, some subsequent studies-including a randomized, double-blind, placebo-controlled clinical trial by Moertel and colleagues at the Mayo Clinic-did not support these findings. In the Moertel study, patients with advanced colorectal cancer who received 10 g/day vitamin C fared no better than those receiving a placebo. The authors of a 2003 review assessing the effects of vitamin C in patients with advanced cancer concluded that vitamin C confers no significant mortality benefit.

Emerging research suggests that the route of vitamin C administration (intravenous vs. oral) could explain the conflicting findings. Most intervention trials, including the one conducted by Moertel and colleagues, used only oral administration, whereas Cameron and colleagues used a combination of oral and intravenous (IV) administration. Oral administration of vitamin C, even of very large doses, can raise plasma vitamin C concentrations to a maximum of only 220 micromol/L, whereas IV administration can produce plasma concentrations as high as 26,000 micromol/L. Concentrations of this magnitude are selectively cytotoxic to tumor cells in vitro. Research in mice suggests that pharmacologic doses of IV vitamin C might show promise in treating otherwise difficult-to-treat tumors. A high concentration of vitamin C may act as a pro-oxidant and generate hydrogen peroxide that has selective toxicity toward cancer cells. Based on these findings and a few case reports of patients with advanced cancers who had remarkably long survival times following administration of high-dose IV vitamin C, some researchers support reassessment of the use of high-dose IV vitamin C as a drug to treat cancer.

As discussed below, it is uncertain whether supplemental vitamin C and other antioxidants might interact with chemotherapy and/or radiation. Therefore, individuals undergoing these procedures should consult with their oncologist prior to taking vitamin C or other antioxidant supplements, especially in high doses.

Cardiovascular disease

Evidence from many epidemiological studies suggests that high intakes of fruits and vegetables are associated with a reduced risk of cardiovascular disease. This association might be partly attributable to the antioxidant content of these foods because oxidative damage, including oxidative modification of low-density lipoproteins, is a major cause of cardiovascular disease. In addition to its antioxidant properties, vitamin C has been shown to reduce monocyte adherence to the endothelium, improve endothelium-dependent nitric oxide production and vasodilation, and reduce vascular smooth-muscle-cell apoptosis, which prevents plaque instability in atherosclerosis.

Results from prospective studies examining associations between vitamin C intake and cardiovascular disease risk are conflicting. In the Nurses' Health Study, a 16-year prospective study involving 85,118 female nurses, total intake of vitamin C from both dietary and supplemental sources was inversely associated with coronary heart disease risk. However, intake of vitamin C from diet alone showed no significant associations, suggesting that vitamin C supplement users might be at lower risk of coronary heart disease. A much smaller study indicated that postmenopausal women with diabetes who took at least 300 mg/day vitamin C supplements had increased cardiovascular disease mortality.

A prospective study in 20,649 British adults found that those in the top quartile of baseline plasma vitamin C concentrations had a 42% lower risk of stroke than those in the bottom quartile. In male physicians participating in the Physicians' Health Study, use of vitamin C supplements for a mean of 5.5 years was not associated with a significant decrease in total cardiovascular disease mortality or coronary heart disease mortality. A pooled analysis of nine prospective studies that included 293,172 subjects free of coronary heart disease at baseline found that people who took =700 mg/day of supplemental vitamin C had a 25% lower risk of coronary heart disease incidence than those who took no supplemental vitamin C. The authors of a 2008 meta-analysis of prospective cohort studies, including 14 studies reporting on vitamin C for a median follow-up of 10 years, concluded that dietary, but not supplemental, intake of vitamin C is inversely associated with coronary heart disease risk.

Results from most clinical intervention trials have failed to show a beneficial effect of vitamin C supplementation on the primary or secondary prevention of cardiovascular disease. In the Women's Antioxidant Cardiovascular Study, a secondary prevention trial involving 8,171 women aged 40 years or older with a history of cardiovascular disease, supplementation with 500 mg/day vitamin C for a mean of 9.4 years showed no overall effect on cardiovascular events. Similarly, vitamin C supplementation (500 mg/day) for a mean follow-up of 8 years had no effect on major cardiovascular events in male physicians enrolled in the Physicians' Health Study II.

Other clinical trials have generally examined the effects on cardiovascular disease of supplements combining vitamin C with other antioxidants, such as vitamin E and beta-carotene, making it more difficult to isolate the potential contribution of vitamin C. The SU.VI.MAX study examined the effects of a combination of vitamin C (120 mg/day), vitamin E (30 mg/day), beta-carotene (6 mg/day), selenium (100 mcg/day), and zinc (20 mg/day) in 13,017 French adults from the general population. After a median follow-up time of 7.5 years, the combined supplements had no effect on ischemic cardiovascular disease in either men or women. In the Women's Angiographic Vitamin and Estrogen (WAVE) study, involving 423 postmenopausal women with at least one coronary stenosis of 15%-75%, supplements of 500 mg vitamin C plus 400 IU vitamin E twice per day not only provided no cardiovascular benefit, but significantly increased all-cause mortality compared with placebo.

The authors of a 2006 meta-analysis of randomized controlled trials concluded that antioxidant supplements (vitamins C and E and beta-carotene or selenium) do not affect the progression of atherosclerosis. Similarly, a systematic review of vitamin C's effects on the prevention and treatment of cardiovascular disease found that vitamin C did not have favorable effects on cardiovascular disease prevention. Since then, researchers have published follow-up data from the Linxian trial, a population nutrition intervention trial conducted in China. In this trial, daily vitamin C supplements (120 mg) plus molybdenum (30 mcg) for 5-6 years significantly reduced the risk of cerebrovascular deaths by 8% during 10 years of follow-up after the end of the active intervention.

Although the Linxian trial data suggest a possible benefit, overall, the findings from most intervention trials do not provide convincing evidence that vitamin C supplements provide protection against cardiovascular disease or reduce its morbidity or mortality. However, as discussed in the cancer prevention section, clinical trial data for vitamin C are limited by the fact that plasma and tissue concentrations of vitamin C are tightly controlled in humans. If subjects' vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes.

Age-related macular degeneration (AMD) and cataracts

AMD and cataracts are two of the leading causes of vision loss in older individuals. Oxidative stress might contribute to the etiology of both conditions. Thus, researchers have hypothesized that vitamin C and other antioxidants play a role in the development and/or treatment of these diseases.

A population-based cohort study in the Netherlands found that adults aged 55 years or older who had high dietary intakes of vitamin C as well as beta-carotene, zinc, and vitamin E had a reduced risk of AMD. However, most prospective studies do not support these findings. The authors of a 2007 systematic review and meta-analysis of prospective cohort studies and randomized clinical trials concluded that the current evidence does not support a role for vitamin C and other antioxidants, including antioxidant supplements, in the primary prevention of early AMD.

Although research has not shown that antioxidants play a role in AMD development, some evidence suggests that they might help slow AMD progression. The Age-Related Eye Disease Study (AREDS), a large, randomized, placebo-controlled clinical trial, evaluated the effect of high doses of selected antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc, and 2 mg copper) on the development of advanced AMD in 3,597 older individuals with varying degrees of AMD. After an average follow-up period of 6.3 years, participants at high risk of developing advanced AMD (i.e., those with intermediate AMD or those with advanced AMD in one eye) who received the antioxidant supplements had a 28% lower risk of progression to advanced AMD than participants who received a placebo. A follow-up AREDS2 study confirmed the value of this and similar supplement formulations in reducing the progression of AMD over a median follow-up period of 5 years.

High dietary intakes of vitamin C and higher plasma ascorbate concentrations have been associated with a lower risk of cataract formation in some studies. In a 5-year prospective cohort study conducted in Japan, higher dietary vitamin C intake was associated with a reduced risk of developing cataracts in a cohort of more than 30,000 adults aged 45-64 years. Results from two case-control studies indicate that vitamin C intakes greater than 300 mg/day reduce the risk of cataract formation by 70%-75%. Use of vitamin C supplements, on the other hand, was associated with a 25% higher risk of age-related cataract extraction among a cohort of 24,593 Swedish women aged 49-83 years. These findings applied to study participants who took relatively high-dose vitamin C supplements (approximately 1,000 mg/day) and not to those who took multivitamins containing substantially less vitamin C (approximately 60 mg/day).

Data from clinical trials are limited. In one study, Chinese adults who took daily supplements of 120 mg vitamin C plus 30 mcg molybdenum for 5 years did not have a significantly lower cataract risk. However, adults aged 65-74 years who received 180 mg vitamin C plus 30 mcg molybdenum combined with other nutrients in a multivitamin/mineral supplement had a 43% significantly lower risk of developing nuclear cataracts than those who received a placebo. In the AREDS study, older individuals who received supplements of 500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene for an average of 6.3 years did not have a significantly lower risk of developing cataracts or of cataract progression than those who received a placebo. The AREDS2 study, which also tested formulations containing 500 mg vitamin C, confirmed these findings.

Overall, the currently available evidence does not indicate that vitamin C, taken alone or with other antioxidants, affects the risk of developing AMD, although some evidence indicates that the AREDS formulations might slow AMD progression in people at high risk of developing advanced AMD.

The common cold

In the 1970s Linus Pauling suggested that vitamin C could successfully treat and/or prevent the common cold. Results of subsequent controlled studies have been inconsistent, resulting in confusion and controversy, although public interest in the subject remains high.

A 2007 Cochrane review examined placebo-controlled trials involving the use of at least 200 mg/day vitamin C taken either continuously as a prophylactic treatment or after the onset of cold symptoms. Prophylactic use of vitamin C did not significantly reduce the risk of developing a cold in the general population. However, in trials involving marathon runners, skiers, and soldiers exposed to extreme physical exercise and/or cold environments, prophylactic use of vitamin C in doses ranging from 250 mg/day to 1 g/day reduced cold incidence by 50%. In the general population, use of prophylactic vitamin C modestly reduced cold duration by 8% in adults and 14% in children. When taken after the onset of cold symptoms, vitamin C did not affect cold duration or symptom severity.

Overall, the evidence to date suggests that regular intakes of vitamin C at doses of at least 200 mg/day do not reduce the incidence of the common cold in the general population, but such intakes might be helpful in people exposed to extreme physical exercise or cold environments and those with marginal vitamin C status, such as the elderly and chronic smokers. The use of vitamin C supplements might shorten the duration of the common cold and ameliorate symptom severity in the general population, possibly due to the anti-histamine effect of high-dose vitamin C. However, taking vitamin C after the onset of cold symptoms does not appear to be beneficial.

Health Risks from Excessive Vitamin C

Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes. The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract.

In postmenopausal women with diabetes who participated in the Iowa Women's Health Study, supplemental (but not dietary) vitamin C intake (at least 300 mg/day) was significantly associated with an increased risk of cardiovascular disease mortality. The mechanism for this effect, if real, is not clear and this finding is from a subgroup of patients in an epidemiological study. No such association has been observed in any other epidemiological study, so the significance of this finding is uncertain. High vitamin C intakes also have the potential to increase urinary oxalate and uric acid excretion, which could contribute to the formation of kidney stones, especially in individuals with renal disorders. However, studies evaluating the effects on urinary oxalate excretion of vitamin C intakes ranging from 30 mg to 10 g/day have had conflicting results, so it is not clear whether vitamin C actually plays a role in the development of kidney stones. The best evidence that vitamin C contributes to kidney stone formation is in patients with pre-existing hyperoxaluria.

Due to the enhancement of nonheme iron absorption by vitamin C, a theoretical concern is that high vitamin C intakes might cause excess iron absorption. In healthy individuals, this does not appear to be a concern. However, in individuals with hereditary hemochromatosis, chronic consumption of high doses of vitamin C could exacerbate iron overload and result in tissue damage.

Under certain conditions, vitamin C can act as a pro-oxidant, potentially contributing to oxidative damage. A few studies in vitro have suggested that by acting as a pro-oxidant, supplemental oral vitamin C could cause chromosomal and/or DNA damage and possibly contribute to the development of cancer. However, other studies have not shown increased oxidative damage or increased cancer risk with high intakes of vitamin C.

Other reported effects of high intakes of vitamin C include reduced vitamin B12 and copper levels, accelerated metabolism or excretion of ascorbic acid, erosion of dental enamel, and allergic responses. However, at least some of these conclusions were a consequence of assay artifact, and additional studies have not confirmed these observations.

The FNB has established ULs for vitamin C that apply to both food and supplement intakes (Table 3). Long-term intakes of vitamin C above the UL may increase the risk of adverse health effects. The ULs do not apply to individuals receiving vitamin C for medical treatment, but such individuals should be under the care of a physician.

Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin C

Interactions with Medications

Vitamin C supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss their vitamin C intakes with their health care providers.

Chemotherapy and radiation

The safety and efficacy of the use of vitamin C and other antioxidants during cancer treatment is controversial. Some data indicate that antioxidants might protect tumor cells from the action of radiation therapy and chemotherapeutic agents, such as cyclophosphamide, chlorambucil, carmustine, busulfan, thiotepa, and doxorubicin. At least some of these data have been criticized because of poor study design. Other data suggest that antioxidants might protect normal tissues from chemotherapy- and radiation-induced damage and/or enhance the effectiveness of conventional cancer treatment. However, due to the physiologically tight control of vitamin C, it is unclear whether oral vitamin C supplements could alter vitamin C concentrations enough to produce the suggested effects. Individuals undergoing chemotherapy or radiation should consult with their oncologist prior to taking vitamin C or other antioxidant supplements, especially in high doses.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins)

Vitamin C, in combination with other antioxidants, may attenuate the increase in high-density lipoprotein levels resulting from combination niacin-simvastatin (Zocor®) therapy. It is not known whether this interaction occurs with other lipid-altering regimens. Health care providers should monitor lipid levels in individuals taking both statins and antioxidant supplements.

Vitamin C and Healthful Diets

The federal government's 2015-2020 Dietary Guidelines for Americans notes that "Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts."

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture's MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

• Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.

Fruits, particularly citrus fruits, fruit juices, and many vegetables are excellent sources of vitamin C. Some ready-to-eat breakfast cereals are fortified with vitamin C.

• Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
• Limits saturated and trans fats, added sugars, and sodium.
• Stays within your daily calorie needs

Disclaimer

This fact sheet by the Office of Dietary Supplements provides information that should not take the place of medical advice. We encourage you to talk to your healthcare providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.