Vitamin C

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin. Unlike most mammals and other animals, humans do not have the ability to make their own vitamin C. Therefore, we must obtain vitamin C through our diet.

Function

Vitamin C is required for the synthesis of collagen, an important structural component of blood vessels, tendons, ligaments, and bone. Vitamin C also plays an important role in the synthesis of the neurotransmitter, norepinephrine. Neurotransmitters are critical to brain function and are known to affect mood. In addition, vitamin C is required for the synthesis ofcarnitine, a small molecule that is essential for the transport of fat into cellular organelles called mitochondria, where the fat is converted to energy(1). Research also suggests that vitamin C is involved in the metabolism of cholesterol to bile acids, which may have implications for blood cholesterol levels and the incidence of gallstones (2).

Vitamin C is also a highly effective antioxidant. Even in small amounts vitamin C can protect indispensable molecules in the body, such as proteins, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA), from damage by free radicals and reactive oxygen species that can be generated during normal metabolism as well as through exposure to toxins and pollutants (e.g., cigarette smoke). Vitamin C may also be able to regenerate other antioxidants such as vitamin E (1). One recent study of cigarette smokers found that vitamin C regenerated vitamin E from its oxidized form (3).

Deficiency

Scurvy

Severe vitamin C deficiency has been known for many centuries as the potentially fatal disease, scurvy. By the late 1700s the British navy was aware that scurvy could be cured by eating oranges or lemons, even though vitamin C would not be isolated until the early 1930s. Symptoms of scurvy include bleeding and bruising easily, hair and tooth loss, and joint pain and swelling. Such symptoms appear to be related to the weakening of blood vessels, connective tissue, and bone, which all contain collagen. Early symptoms of scurvy like fatigue may result from diminished levels of carnitine, which is needed to derive energy from fat, or from decreased synthesis of theneurotransmitter norepinephrine (see Function). Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily(4). However, cases have occurred in children and the elderly on very restricted diets (5, 6).

The Recommended Dietary Allowance (RDA)

In the U.S., the recommended dietary allowance (RDA) for vitamin C was revised in 2000 upward from the previous recommendation of 60 mg daily for men and women. The RDA continues to be based primarily on the prevention of deficiency disease, rather than the prevention of chronic disease and the promotion of optimum health. The recommended intake for smokers is 35 mg/day higher than for nonsmokers, because smokers are under increasedoxidative stress from the toxins in cigarette smoke and generally have lower blood levels of vitamin C (7).

Recommended Dietary Allowance (RDA) for Vitamin C
Life Stage	Age	Males (mg/day)	Females (mg/day)
Infants	0-6 months	40 (AI)	40 (AI)
Infants	7-12 months	50 (AI)	50 (AI)
Children	1-3 years	15	15
Children	4-8 years	25	25
Children	9-13 years	45	45
Adolescents	14-18 years	75	65
Adults	19 years and older	90	75
Smokers	19 years and older	125	110
Pregnancy	18 years and younger	-	80
Pregnancy	19 years and older	-	85
Breast-feeding	18 years and younger	-	115
Breast-feeding	19 years and older	-	120

Disease Prevention

The amount of vitamin C required to prevent chronic disease appears to be more than that required for prevention of scurvy. Much of the information regarding vitamin C and the prevention of chronic disease is based onprospective studies, in which vitamin C intake is assessed in large numbers of people who are followed over time to determine whether they develop specific chronic diseases.

Cardiovascular Diseases

Coronary Heart Disease

Until recently, the results of most prospective studies indicated that low or deficient intakes of vitamin C were associated with an increased risk ofcardiovascular diseases, and that modest dietary intakes of about 100 mg/day were sufficient for maximal reduction of cardiovascular disease risk among nonsmoking men and women (1). A recent meta-analysis of 14 cohort studies concluded that dietary vitamin C intake, but not supplemental vitamin C intake, was inversely related to coronary heart disease (CHD) risk (8). Thus, some studies did not find significant reductions in CHD risk among vitamin C supplement users in well-nourished populations (9-11). One notable exception was the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (12). This study found that the risk of death from cardiovascular diseases was 42% lower in men and 25% lower in women who consumed more than 50 mg/day of dietary vitamin C and regularly took vitamin C supplements, corresponding to a total vitamin C intake of about 300 mg/day (13). Results from the Nurses’ Health Study (NHS), based on the follow-up of more than 85,000 women over 16 years, also suggested that higher vitamin C intakes may be cardioprotective (14). In this study, vitamin C intake of more than 359 mg/day from diet plus supplements or supplement use itself was associated with a 27-28% reduction in CHD risk. However, in those women who did not take vitamin C supplements, dietary vitamin C intake was not significantly associated with CHD risk. Hence, both the NHANES I Epidemiologic Follow-up Study (12, 13)and NHS (14) do not support the conclusions of the above meta-analysis (8). Another pooled analysis of nine prospective cohort studies, including more than 290,000 adults who were free of CHD at baseline and followed for an average of ten years, found that those who took more than 700 mg/day of supplemental vitamin C had a 25% lower risk of CHD than those who did not take vitamin C supplements (15). Additionally, a randomized, double-blind,placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study II found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on major cardiovascular events, total myocardial infarction, or cardiovascular mortality(16). However, this study had several limitations (17); see the Linus Pauling Institute’s response to this study. Data from pharmacokinetic studies of vitamin C at the National Institutes of Health (NIH) indicate that plasma and circulating cells—and thus, presumably, total body pool—in healthy, young subjects became fully saturated with vitamin C at a dose of about 400 mg/day (18). Therefore, the results of the pooled analysis of prospective cohort studies as well as individual, large prospective studies, such as the NHANES I Epidemiologic Follow-up Study (12, 13) and NHS (14), together with pharmacokinetic data of vitamin C in humans (18), suggest that maximal reduction of CHD risk may require vitamin C intakes of 400 mg/day or more(19).

Stroke

With respect to vitamin C and cerebrovascular disease, a prospective studythat followed more than 2,000 residents of a rural Japanese community for 20 years found that the risk of stroke in those with the highest serum levels of vitamin C was 29% lower than in those with the lowest serum levels of vitamin C (20). Additionally, the risk of stroke in those who consumed vegetables 6-7 days of the week was 54% lower than in those who consumed vegetables 0-2 days of the week. In this population, serum levels of vitamin C were highly correlated with fruit and vegetable intake. Therefore, as in many studies of vitamin C intake and chronic disease risk, it is difficult to separate the effects of vitamin C on stroke risk from the effects of other components of fruits and vegetables, emphasizing the benefits of a diet rich in fruits and vegetables in reducing stroke risk. Hence, plasma vitamin C levels may be a good biomarker for fruit and vegetable intake and other lifestyle factors that contribute to a reduced risk of stroke. A recent 10-year prospective study in 20,649 adults found that those in the top quartile of plasma vitamin C concentrations had a 42% lower risk of stroke compared to those in the lowest quartile (21). A randomized, double-blind, placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study II found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on stroke death, ischemic stroke, or hemorrhagic stroke (16). However, this study had numerous limitations that make it difficult to draw conclusions for the general population(17); see the Linus Pauling Institute’s response to this study.

Cancer

A large number of studies have shown that increased consumption of fresh fruits and vegetables is associated with a reduced risk for most types ofcancer (22). Such studies were the basis for dietary guidelines endorsed by the U.S. Department of Agriculture and the National Cancer Institute, which recommended at least five servings of fruits and vegetables per day. U.S. government organizations currently recommend eating a variety of fruits and vegetables daily; the recommended serving number depends on total caloric intake, which is governed by age, gender, body composition, and physical activity level (23). A number of case-control studies have investigated the role of vitamin C in cancer prevention.  Most have shown that higher intakes of vitamin C are associated with decreased incidence of cancers of the mouth, throat and vocal chords, esophagus, stomach, colon-rectum, and lung. Because the possibility of bias is greater in case-control studies, prospective cohort studies are generally given more weight when evaluating the effect of nutrient intake on disease. In general, prospective studies in which the lowest intake group consumed more than 86 mg of vitamin C daily have not found differences in cancer risk, while studies finding significant cancer risk reductions found them in people consuming at least 80 to 110 mg of vitamin C daily (1).

A prospective study that followed 870 men over a period of 25 years found that those who consumed more than 83 mg of vitamin C daily had a striking, 64% reduction in lung cancer compared with those who consumed less than 63 mg per day (24). However, a pooled analysis of eight prospective studies concluded that dietary vitamin C was not related to lung cancer when the analysis was controlled for other dietary factors (25). Although most large prospective studies observed no association between breast cancer and vitamin C intake, two studies found dietary vitamin C intake to be inversely associated with breast cancer risk in certain subgroups. In the Nurses' Health Study, premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of vitamin C from foods had a 63% lower risk of breast cancer than those who consumed an average of 70 mg/day (26). In the Swedish Mammography Cohort, overweight women who consumed an average of 110 mg/day of vitamin C had a 39% lower risk of breast cancer compared to overweight women who consumed an average of 31 mg/day (27). A number of observational studies have found increased dietary vitamin C intake to be associated with decreased risk of stomach cancer, and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic compounds in the stomach (28, 29). Infection with the bacteria, Helicobacter pylori (H. pylori), is known to increase the risk of stomach cancer and also appears to lower the vitamin C content of stomach secretions. Although two intervention studies did not find a decrease in the occurrence of stomach cancer with vitamin C supplementation (7), more recent research suggests that vitamin C supplementation may be a useful addition to standard H. pylori eradication therapy in reducing the risk of gastric cancer (30, 31). Another intervention trial, a randomized, double-blind, placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study (PHS) II, reported vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on total cancer or site-specific cancers, including colorectal, lung, and prostate cancer(32). However, the PHS II had several limitations; see the Linus Pauling Institute’s response to the PHS II.

Cataracts

Cataracts are a leading cause of visual impairment throughout the world. In the U.S., cataract-related expenditures are estimated to exceed $3 billion annually (33). Cataracts occur more frequently and become more severe as people age. Decreased vitamin C levels in the lens of the eye have been associated with increased severity of cataracts in humans. Some, but not all, studies have observed increased dietary vitamin C intake (34, 35) and increased blood levels of vitamin C (36, 37) to be associated with decreased risk of cataracts. In general, those studies that have found a relationship suggest that vitamin C intake may have to be higher than 300 mg/day for a number of years before a protective effect can be detected (1). A 7-year controlled intervention trial in 4,629 men and women found that a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene had no effect on the development and progression of age-related cataracts compared to a placebo (38). Therefore, the relationship between vitamin C intake and the development of cataracts requires further clarification before specific recommendations can be made.

Gout

Gout, a condition that afflicts more than 1% of U.S. adults, is characterized by abnormally high blood levels of uric acid (urate) (39). Urate crystals may form in joints, resulting in inflammation and pain, as well as in the kidneys and urinary tract, resulting in kidney stones. The tendency to develop elevated blood uric acid levels and gout is often inherited; however, dietary and lifestyle modification may be helpful in both the prevention and treatment of gout (40). In an observational study that included 1,387 men, higher intakes of vitamin C were associated with lower serum levels of uric acid (41). More recently, a prospective study that followed a cohort of 46,994 men for 20 years found that total daily vitamin C intake was inversely associated with risk of gout, with higher intakes being associated with greater risk reductions(42). The results of this study also indicate that supplemental vitamin C may be helpful in the prevention of gout (42). Interestingly, a randomized, double-blind, placebo-controlled trial in 184 adult nonsmokers reported that vitamin C supplementation (500 mg/day) for two months lowered serum concentrations of uric acid compared to placebo (43).

Lead toxicity

Although the use of lead paint and leaded gasoline has been discontinued in the U.S., lead toxicity continues to be a significant health problem, especially in children living in urban areas. Abnormal growth and development have been observed in infants of women exposed to lead during pregnancy, while children who are chronically exposed to lead are more likely to develop learning disabilities, behavioral problems, and to have a low IQ. In adults, lead toxicity may result in kidney damage, high blood pressure, and anemia. In a study of 747 older men, blood lead levels were significantly higher in those who reported total dietary vitamin C intakes averaging less than 109 mg/day compared to those who reported higher vitamin C intakes (44). A much larger study of 19,578 people, including 4,214 children from six to 16 years of age, found higher serum vitamin C levels to be associated with significantly lower blood lead levels (45). A U.S. national survey of more than 10,000 adults found that blood lead levels were inversely related to serum vitamin C levels (46). An intervention trial that examined the effects of vitamin C supplementation on blood lead levels in 75 adult male smokers found that 1,000 mg/day of vitamin C resulted in significantly lower blood lead levels over a four-week treatment period compared to placebo (47). A lower dose of 200 mg/day did not significantly affect blood lead levels, despite the finding that serum vitamin C levels were not different than those in the group who took 1,000 mg/day. The mechanism for the relationship between vitamin C intake and blood lead levels is not known, although it has been postulated that vitamin C may inhibit intestinal absorption or enhance urinary excretion of lead.

Role in Immunity

Vitamin C affects several components of the human immune system; for example, vitamin C has been shown to stimulate both the production (48-52)and function (53, 54) of leukocytes (white blood cells), especially neutrophils,lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (54), chemotaxis (53, 54), and phagocytosis(53). Neutrophils, which attack foreign bacteria and viruses, seem to be the primary cell type stimulated by vitamin C, but lymphocytes and other phagocytes are also affected (55). Additionally, several studies have shown that supplemental vitamin C increases serum levels of antibodies (56, 57)and C1q complement proteins (58-60) in guinea pigs, which—like humans—cannot synthesize vitamin C and hence depend on dietary vitamin C. However, some studies have reported no beneficial changes in leukocyte production or function with vitamin C treatment (61-64). Vitamin C may also protect the integrity of immune cells. Neutrophils, mononuclear phagocytes, and lymphocytes accumulate vitamin C to high concentrations, which can protect these cell types from oxidative damage (52, 65, 66). In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid (“bleach”), and peroxynitrite; these reactive oxygen species kill pathogens and, in the process, can damage the leukocytes themselves (67). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from such effects of autooxidation (68). Phagocytic leukocytes also produce and releasecytokines, including interferons, which have antiviral activity (69). Vitamin C has been shown to increase interferon levels in vitro (70).

It is widely thought by the general public that vitamin C boosts the function of the immune system, and accordingly, may protect against viral infections and perhaps other diseases. While some studies suggest the biological plausibility of vitamin C as an immune enhancer, human studies published to date are conflicting. Further, controlled clinical trials of appropriate statistical power would be necessary to determine if supplemental vitamin C boosts the immune system.

Disease Treatment

Cardiovascular Diseases

Vasodilation

The ability of blood vessels to relax or dilate (vasodilation) is compromised in individuals with atherosclerosis. Damage to the heart muscle caused by a heart attack and damage to the brain caused by a stroke are related, in part, to the inability of blood vessels to dilate enough to allow blood flow to the affected areas. The pain of angina pectoris is also related to insufficient dilation of the coronary arteries. Impaired vasodilation has been identified as an independent risk factor for cardiovascular disease (71). Many randomized,double-blind, placebo-controlled studies have shown that treatment with vitamin C consistently results in improved vasodilation in individuals with coronary heart disease as well as those with angina pectoris, congestive heart failure, diabetes, high cholesterol, and high blood pressure (1, 72-74). Improved vasodilation has been demonstrated at an oral dose of 500 mg of vitamin C daily (72).

Hypertension

Individuals with high blood pressure (hypertension) are at increased risk of developing cardiovascular diseases. Several, but not all, studies have demonstrated a blood pressure lowering effect of vitamin C supplementation(75). A small study in individuals with hypertension found that vitamin C supplementation with 500 mg/day for six weeks slightly decreased systolic blood pressure (1.8 mm Hg reduction) compared to a placebo (76). Another study in individuals with elevated blood pressure found that a daily supplement of 500 mg of vitamin C resulted in an average drop in systolic blood pressure of 9% after four weeks (77). It should be noted that those participants who were taking antihypertensive medications continued taking them throughout the four-week study. Because the findings regarding vitamin C and high blood pressure have not yet been replicated in larger studies, it is important for individuals with significantly elevated blood pressure to continue current therapy (medication, lifestyle changes, etc.) in consultation with their health care provider.

Cancer

Studies in the 1970s and 1980s conducted by Linus Pauling, Ewan Cameron, and colleagues suggested that very large doses of vitamin C (10 grams/day intravenously for ten days followed by at least 10 grams/day orally indefinitely) were helpful in increasing the survival time and improving the quality of life of terminal cancer patients (78). However, two randomized placebo-controlled studies conducted at the Mayo Clinic found no differences in outcome between terminal cancer patients receiving 10 grams/day of vitamin C orally or placebo (79, 80). There were significant methodological differences between the Mayo Clinic and Pauling's studies, and recently, researchers from the NIH suggested that the route of administration (intravenous versus oral) may have been the key to the discrepant results. Intravenous (IV) administration can result in much higher blood levels of vitamin C than oral administration, and vitamin C levels that are toxic to cancer cells in culture can be achieved in humans only with intravenous but not oral administration of vitamin C (81). Dr. Mark Levine and colleagues at NIH have investigated the anticancer mechanism responsible for vitamin C and reported that it involves production of hydrogen peroxide, which is selectively toxic to cancer cells (82-84). Thus, it appears reasonable to reevaluate the use of high-dose vitamin C as adjunctive cancer therapy.

Currently, there are no results from controlled clinical trials indicating that vitamin C would adversely affect the survival of cancer patients. Recently, two phase I clinical trials in patients with advanced cancer found that intravenous administration of vitamin C at doses up to 1.5 g/kg of body weight was well tolerated and safe in pre-screened patients (85, 86); other phase I trials are ongoing (87). Additionally, phase II clinical trials evaluating the efficacy of vitamin C in cancer treatment are currently under way (87). Some case reports have suggested that intravenous vitamin C may aid in cancer treatment (88, 89). However, vitamin C should not be used in place of therapy that has been demonstrated effective in the treatment of a particular type of cancer, for example, chemotherapy or radiation therapy. If an individual with cancer chooses to take vitamin supplements, it is important that the clinician coordinating his or her treatment is aware of the type and dose of each supplement. While research is under way to determine whether combinations of antioxidant vitamins might be beneficial as an adjunct to conventional cancer therapy, definitive conclusions are not yet possible (90). For more information about intravenous vitamin C and cancer, see the Linus Pauling Institute Spring/Summer 2006 Research Newsletter.

In a presentation at a meeting of the American Cancer Society, a scientist suggested that supplemental vitamin C might enhance the growth of cancer cells or protect them from cell-killing free radicals produced by radiation and some forms of chemotherapy. An article published in the Spring/Summer 2000 issue of the Linus Pauling Institute Newsletter, Is vitamin C harmful for cancer patients?, provides additional insight on this topic.

For information about the clinical use of high-dose intravenous vitamin C as an adjunct in cancer treatment, visit the University of Kansas Medical Center Program in Integrative Medicine Web site.

Diabetes Mellitus

Cardiovascular diseases (heart disease and stroke) are the leading cause of death in individuals with diabetes. Evidence that diabetes is a condition of increased oxidative stress led to the hypothesis that higher intakes ofantioxidant nutrients could help decrease cardiovascular disease risk in diabetic individuals. In support of this hypothesis, a 16-year study of 85,000 women, 2% of whom were diabetic, found that vitamin C supplement use (400 mg/day or more) was associated with significant reductions in the risk of fatal and nonfatal coronary heart disease in the entire cohort as well as in those with diabetes (14). In contrast, a 15-year study of postmenopausal women found that diabetic women who reported taking at least 300 mg/day of vitamin C from supplements when the study began were at significantly higher risk of death from coronary heart disease and stroke than those who did not take vitamin C supplements (91). Vitamin C supplement use was not associated with a significant increase in cardiovascular disease mortality in the cohort as a whole. Although a number of observational studies have found that higher dietary intakes of vitamin C are associated with lower cardiovascular disease risk, randomized controlled trials have not found antioxidant supplementation that included vitamin C to reduce the risk of cardiovascular disease in diabetic or other high-risk individuals (92, 93).

It is possible that genetic differences may influence the effect of vitamin C supplementation on cardiovascular disease. When the results of one randomized controlled trial were reanalyzed based on haptoglobin genotype, antioxidant therapy (1,000 mg/day of vitamin C + 800 IU/day of vitamin E) was associated with improvement of coronary atherosclerosis in diabetic women with two copies of the haptoglobin 1 gene but worsening of coronary atherosclerosis in those with two copies of the haptoglobin 2 gene (94). The significance of these findings is not entirely clear, but they suggest that there may be a subpopulation of people with diabetes who will benefit from antioxidant therapy, while others may not benefit or could actually be harmed.

Common cold

The work of Linus Pauling stimulated public interest in the use of large doses (greater than 1 gram/day, also sometimes called "mega-doses") of vitamin C to prevent the common cold (95). In the past 30 years, numerous placebo-controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A meta-analysis of 30 placebo-controlled prevention trials found that vitamin C supplementation in doses up to 2 grams/day did not decrease the incidence of colds (96). However, in a subgroup of marathon runners, skiers, and soldiers training in the Arctic, doses ranging from 250 mg/day to 1 gram/day decreased the incidence of colds by 50%. Overall, the preventive use of vitamin C supplementation reduced the duration of colds by about 8% in adults and 14% in children. Most of the prevention trials used a dose of 1 gram/day. When treatment was started at the onset of symptoms, vitamin C supplementation did not shorten the duration of colds in seven placebo-controlled trials at doses ranging from 1-4 grams/day. Additionally, the same authors completed a meta-analysis of the 15 trials that assessed the effect of vitamin C on cold severity; no consistent evidence that vitamin C was beneficial in ameliorating cold symptoms was found in this analysis. Thus, the overall conclusion of this meta-analysis was that vitamin C is ineffective as a prophylactic against the common cold, but individuals under stress, such as those exposed to strenuous physical exercise or cold weather, may experience some therapeutic benefit (96). More recently, a randomized, double-blind (but not placebo-controlled) study reported that those who took 500 mg/day of supplemental vitamin C had a 66% lower risk for contracting three or more colds in a five-year period compared to those who took 50 mg/day of supplemental vitamin C (97). The authors of this study did not find any significant differences in the two groups when analyzing data regarding cold severity or duration. However, the doses used in this study were smaller than those used in most of the previous studies.

Some authors have asserted that the studies included in the above mentioned meta-analysis (96) utilized daily doses of vitamin C that would be too low to observe a therapeutic benefit (98, 99). Additionally, results of a recent pharmacokinetic study suggest that dividing the daily dose and administering it several times throughout the day, thereby increasing dose frequency, would better sustain plasma ascorbate levels (81). Large-scale, controlled clinical trials using pharmacological doses of vitamin C are necessary to determine whether or not higher doses of vitamin C have any therapeutic value in preventing or treating the common cold. For a more detailed discussion on vitamin C and the common cold, see the Linus Pauling Institute's Spring/Summer 2006 Research Newsletter.

Sources

Food Sources

As shown in the table below, different fruits and vegetables vary in their vitamin C content (100), but five servings (2½ cups) of fruits and vegetables should average out to about 200 mg of vitamin C. If you wish to check foods for their nutrient content, search the USDA food composition database.

Food	Serving	Vitamin C (mg)
Orange juice	¾ cup (6 ounces)	62-93
Grapefruit juice	¾ cup (6 ounces)	62-70
Orange	1 medium	70
Grapefruit	½ medium	38
Strawberries	1 cup, whole	85
Tomato	1 medium	16
Sweet red pepper	½ cup, raw chopped	95
Broccoli	½ cup, cooked	51
Potato	1 medium, baked	17

Supplements

Vitamin C (L-ascorbic acid) is available in many forms, but there is little scientific evidence that any one form is better absorbed or more effective than another. Most experimental and clinical research uses ascorbic acid or sodium ascorbate.

Natural vs. synthetic vitamin C

Natural and synthetic L-ascorbic acid are chemically identical and there are no known differences in their biological activities or bioavailabilities (101).

Mineral ascorbates

Mineral salts of ascorbic acid are buffered and, therefore, less acidic than ascorbic acid. Some people find them less irritating to the gastrointestinal tract than ascorbic acid. Sodium ascorbate and calcium ascorbate are the most common forms, although a number of other mineral ascorbates are available. Sodium ascorbate provides 111 mg of sodium (889 mg of ascorbic acid) per 1,000 mg of sodium ascorbate, and calcium ascorbate generally provides 90-110 mg of calcium (890-910 mg of ascorbic acid) per 1,000 mg of calcium ascorbate.

Vitamin C with bioflavonoids

Bioflavonoids are a class of water-soluble plant pigments that are often found in vitamin C-rich fruits and vegetables, especially citrus fruits. There is little evidence that the bioflavonoids in most commercial preparations increase the bioavailability or efficacy of vitamin C (102). Studies in cell culture indicate that a number of flavonoids inhibit the transport of vitamin C into cells (103-105), and supplementation of rats with quercetin and vitamin C decreased the intestinal absorption of vitamin C (103). More research is needed to determine the significance of these findings in humans.

Ascorbate and vitamin C metabolites

One supplement, Ester-C^® contains mainly calcium ascorbate, but also contains small amounts of the vitamin C metabolites dehydroascorbate (oxidized ascorbic acid), calcium threonate, and trace levels of xylonate and lyxonate. Although the metabolites are supposed to increase the bioavailability of vitamin C, the only published study in humans addressing this issue found no difference between Ester-C^® and commercially available ascorbic acid tablets with respect to the absorption and urinary excretion of vitamin C (102). Ester-C^® should not be confused with ascorbyl palmitate, which is also marketed as "vitamin C ester" (see below).

Ascorbyl palmitate

Ascorbyl palmitate is actually a vitamin C ester (i.e., vitamin C that has been esterified to a fatty acid). In this case, vitamin C is esterified to the saturated fatty acid, palmitic acid, resulting in a fat-soluble form of vitamin C. Ascorbyl palmitate has been added to a number of skin creams due to interest in its antioxidant properties as well as its importance in collagen synthesis (106). Although ascorbyl palmitate is also available as an oral supplement, it is likely that most of it is hydrolyzed (broken apart) to ascorbic acid and palmitic acid in the digestive tract before it is absorbed (107). Ascorbyl palmitate is also marketed as "vitamin C ester," which should not be confused with Ester-C^®(see above).

For a more detailed review of scientific research on the bioavailability of different forms of vitamin C, see The Bioavailability of Different Forms of Vitamin C.

Safety

Toxicity

A number of possible problems with very large doses of vitamin C have been suggested, mainly based on in vitro experiments or isolated case reports, including genetic mutations, birth defects, cancer, atherosclerosis, kidney stones, "rebound scurvy," increased oxidative stress, excess iron absorption, vitamin B₁₂ deficiency, and erosion of dental enamel. However, none of these alleged adverse health effects have been confirmed, and there is no reliable scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults) are toxic or detrimental to health. The concerns of kidney stone formation with vitamin C supplementation are discussed below. With the latest RDA published in 2000, a tolerable upper intake level (UL) for vitamin C was set for the first time. A UL of 2 grams (2,000 milligrams) daily was recommended in order to prevent most adults from experiencing diarrhea andgastrointestinal disturbances (7). Such symptoms are not generally serious, especially if they resolve with temporary discontinuation or reduction of high-dose vitamin C supplementation. For a more thorough discussion of the Linus Pauling Institute's response to the UL for vitamin C, see the article, The New Recommendations for Dietary Antioxidants: A Response and Position Statement by the Linus Pauling Institute, in the Spring/Summer 2000 Newsletter. A more detailed discussion of vitamin C and the risk of kidney stones can be found below and in the article, What About Vitamin C and Kidney Stones?, in the Fall/Winter 1999 Newsletter.

Tolerable Upper Intake Level (UL) for Vitamin C
Age Group	UL (mg/day)
Infants 0-12 months	Not possible to establish*
Children 1-3 years	400
Children 4-8 years	650
Children 9-13 years	1,200
Adolescents 14-18 years	1,800
Adults 19 years and older	2,000

*Source of intake should be from foods or formula only.

Does vitamin C promote oxidative damage under physiological conditions?Vitamin C is known to function as a highly effective antioxidant in living organisms. However, in test tube experiments, vitamin C can interact with some free metal ions to produce potentially damaging free radicals. Although free metal ions are not generally found under physiological conditions, the idea that high doses of vitamin C might be able to promote oxidative damage in vivo has received a great deal of attention. Widespread publicity has been given to a few studies suggesting a pro-oxidant effect of vitamin C (108, 109), but these studies turned out to be either flawed or of no physiological relevance. A comprehensive review of the literature found no credible scientific evidence that supplemental vitamin C promotes oxidative damage under physiological conditions or in humans (110). Studies that report a pro-oxidant effect for vitamin C should be evaluated carefully to determine whether the study system was physiologically relevant and to rule out the possibility of methodological and design flaws.

For example, a study in the June 15, 2001 issue of the journal Sciencereported that lipid hydroperoxides (rancid fat molecules) can react with vitamin C to form products that could potentially harm DNA, although the reaction of these products with DNA was not demonstrated in this study(108). To find out why the Linus Pauling Institute considers the study's conclusions unwarranted, see Vitamin C doesn't cause cancer! in the Linus Pauling Institute Newsletter.

Kidney Stones

Because oxalate is a metabolite of vitamin C, there is some concern that high vitamin C intake could increase the risk of oxalate kidney stones. Some (111-113), but not all (114-116), studies have reported that supplemental vitamin C increases urinary oxalate levels. Whether any increase in oxalate levels would translate to an elevation in risk for kidney stones has been examined in epidemiological studies. Two large prospective studies, one following 45,251 men for six years and the other following 85,557 women for 14 years, reported that consumption of ≥1,500 mg of vitamin C daily did not increase the risk of kidney stone formation compared to those consuming <250 mg daily. However, a more recent prospective study that followed 45,619 men for 14 years found that those who consumed ≥1,000 mg/day of vitamin C had a 41% higher risk of kidney stones compared to men consuming <90 mg of vitamin C daily—the current recommended dietary allowance (see RDA;(117)). In this study, low intakes (90-249 mg/day) of vitamin C (primarily from the diet) were also associated with a significantly elevated risk. Supplemental vitamin C intake was only weakly associated with increased risk of kidney stones in this study (117). Despite conflicting results, it may be prudent for individuals predisposed to oxalate kidney stone formation to avoid high-dose vitamin C supplementation.

Drug Interactions

A number of drugs are known to lower vitamin C levels, requiring an increase in its intake. Estrogen-containing contraceptives (birth control pills) are known to lower vitamin C levels in plasma and white blood cells. Aspirin can lower vitamin C levels if taken frequently. For example, taking two aspirin tablets every six hours for a week has been reported to lower vitamin C levels in white blood cells by 50%, primarily by increasing urinary excretion of vitamin C (118).

There is some evidence, though controversial, that vitamin C interacts with anticoagulant medications (blood thinners) like warfarin (Coumadin). Large doses of vitamin C may block the action of warfarin, requiring an increase in dose to maintain its effectiveness. Individuals on anticoagulants should limit their vitamin C intake to 1 gram/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy. Because high doses of vitamin C have also been found to interfere with the interpretation of certain laboratory tests (e.g., serum bilirubin, serum creatinine, and the guaiac assay for occult blood), it is important to inform one's health care provider of any recent supplement use (119).

Antioxidant Supplements and HMG-CoA Reductase Inhibitors (Statins)

A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL₂ levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction (heart attack) and stroke (120). Surprisingly, when an antioxidant combination (1,000 mg vitamin C, 800 IU alpha-tocopherol, 100 mcg selenium, and 25 mg beta-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of vitamin C cannot be determined. In contrast, a much larger randomized controlled trial in more than 20,000 men and women with CHD or diabetes found that simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) did not diminish the cardioprotective effects of simvastatin therapy over a 5-year period (121). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering drugs, such as HMG-CoA reductase inhibitors (statins).

Linus Pauling Institute Recommendation

For healthy men and women, the Linus Pauling Institute recommends a vitamin C intake of at least 400 mg daily. Consuming at least five servings (2½ cups) of fruits and vegetables daily provides about 200 mg of vitamin C. Most multivitamin supplements provide 60 mg of vitamin C. To make sure you meet the Institute’s recommendation, supplemental vitamin C in two separate 250-mg doses taken in the morning and evening is recommended.

Older adults (65 years and older)

Although it is not yet known with certainty whether older adults have higher requirements for vitamin C than younger people, some older populations have been found to have vitamin C intakes considerably below the RDA of 75 and 90 mg/day for women and men, respectively. A vitamin C intake of at least 400 mg daily may be particularly important for older adults who are at higher risk for chronic diseases. In addition, a meta-analysis of 36 publications examining the relationship between vitamin C intake and plasma concentrations of vitamin C concluded that older adults (age 60-96 years) have considerably lower plasma levels of vitamin C following a certain intake of vitamin C compared with younger individuals (age 15-65 years) (122), suggesting that older adults may have higher vitamin C requirements. Studies conducted at the National Institutes of Health indicated that plasma and circulating cells in healthy, young subjects attain near-maximal concentrations of vitamin C at a dose of about 400 mg/day—a dose much higher than the current RDA. Pharmacokinetic studies in older adults have not yet been conducted, but evidence suggests that the efficiency of one of the molecular mechanisms for the cellular uptake of vitamin C declines with age(123). Because maximizing blood levels of vitamin C may be important in protection against oxidative damage to cells and biological molecules, a vitamin C intake of at least 400 mg daily is particularly important for older adults who are at higher risk for chronic diseases caused, in part, by oxidative damage, such as heart disease, stroke, certain cancers, and cataract.