DR. Linus Pauling Vitamin C

http://lpi.oregonstate.edu/mic/vitamins/vitamin-C

DR. Linus Pauling Vitamin C

Summary

• 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 ascorbic acid and must obtain vitamin C from the diet.

• Inside our bodies, vitamin C functions as an essential cofactor in numerous enzymatic reactions, e.g., in the biosynthesis of collagen, carnitine, and catecholamines, and as a potent antioxidant. (More information)

• Prospective cohort studies indicate that higher intakes of vitamin C from either diet or supplements are associated with a reduced risk of cardiovascular disease (CVD), including coronary heart disease and stroke. (More information)

• Observational prospective cohort studies report no or modest inverse associations between vitamin C intake and the risk of developing a given type of cancer. Randomized controlled trials have shown no effect of vitamin C supplementation on cancer outcomes. (More information)

• Prospective cohort studies indicate that higher blood levels of vitamin C are associated with lower risk of death from all-causes, cancer, and CVD. (More information)

• Pharmacological doses of vitamin C administered intravenously are generally safe and well tolerated in cancer patients. The potential for intravenous ascorbic acid as an adjunct to cancer therapies is currently under investigation in phase II clinical trials. (More information)

• Overall, there is evidence that regular use of vitamin C supplements shortens the duration of the common cold, but the effect in cold treatment may be limited. (More information)

• Vitamin C supplements are available in many forms, but there is little scientific evidence that any one form is better absorbed or more effective than another. (More information)

• There is no scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults) exert any adverse or toxic effects. An upper level of 2 grams/day is recommended in order to prevent some adults from experiencing diarrhea and gastrointestinal disturbances. (More information)

• Supplemental vitamin C increases urinary oxalate levels, but whether an increase in urinary oxalate elevates the risk for kidney stones is not yet known. Those predisposed for kidney stone formation may consider avoiding high-dose (≥1,000 mg/day) vitamin C supplementation. (More information)
  

Function

Vitamin C is a potent reducing agent, meaning that it readily donates electrons to recipient molecules. Related to this oxidation-reduction (redox) potential, two major functions of vitamin C are as an antioxidant and as an enzyme cofactor (1, 2).

Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma and tissues (1, 2). 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 radicalsand reactive oxygen species (ROS) that are generated during normal metabolism, by active immune cells, and through exposure to toxins and pollutants (e.g., certain chemotherapy drugs and cigarette smoke). Vitamin C also participates in redox recycling of other important antioxidants; for example, vitamin C is known to regenerate vitamin E from its oxidized form (3, 4).

Vitamin C’s role as a cofactor is also related to its redox potential. By maintaining enzyme-bound metals in their reduced forms, vitamin C assists mixed-function oxidases in the synthesis of several critical biomolecules (1, 2). Symptoms of vitamin C deficiency, such as poor wound healing and lethargy, result from impairment of these enzymatic reactions and insufficient collagen, carnitine, and catecholamine synthesis (see Deficiency). 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 (5).

Finally, vitamin C increases the bioavailability of iron from foods by enhancing intestinal absorption of non-heme iron (1) (see the article on Iron).

Bioavailability

Depletion-repletion pharmacokinetic experiments demonstrated that plasma vitamin C concentration is tightly controlled by three primary mechanisms: intestinal absorption, tissue transport, and renal reabsorption (6). In response to increasing oral doses of vitamin C, plasma vitamin C concentration rises steeply at doses between 30 and 100 mg/day and reaches a steady-state concentration (60 to 80 μmol/L) at doses of 200 to 400 mg/day in healthy young adults (7, 8). One hundred percent absorption efficiency is observed when ingesting vitamin C at doses up to 200 mg at a time. Once plasma ascorbic acid levels reach saturation, additional vitamin C is largely excreted in the urine. Notably, intravenous administration of vitamin C bypasses absorptive control in the intestine such that very high concentrations of ascorbic acid can be achieved in the plasma; over time, renal excretion restores vitamin C to baseline plasma levels (9) (see Cancer Treatment).

While plasma vitamin C concentration reflects recent dietary intake, leukocyte (white blood cell) vitamin C is thought to more closely reflect tissue stores. However, a recent randomized controlled trial (RCT) demonstrated that human skeletal muscle, a major body pool for vitamin C, is highly labile and more responsive to vitamin C intake than neutrophils or mononuclear cells (encompassing the major types of leukocytes) (10). Thus, leukocyte vitamin C concentration does not accurately reflect skeletal muscle ascorbic acid, and may underestimate muscle tissue ascorbic acid uptake. However, plasma concentrations of ascorbic acid ≥50 μmol/L are sufficient to saturate muscle tissue vitamin C.

Due to the pharmacokinetics and tight regulation of plasma ascorbic acid, supplementation with vitamin C will have variable effects in vitamin C-replete (plasma levels near saturation) versus sub-optimal (plasma levels <50 μmol/L), marginally deficient (plasma levels <28 μmol/L), or severely deficient (plasma levels <11 μmol/L) individuals. Scientific studies investigating vitamin C efficacy to prevent or treat disease need to assess baseline vitamin C status before embarking on an intervention or statistical analysis (6, 11-13).

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

Deficiency

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 ascorbic acid would not be isolated until the early 1930s. Symptoms of scurvy include subcutaneous bleeding, poor wound closure, 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 the catecholaminenorepinephrine (see Function). Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily (14). However, cases have occurred in children and the elderly on very restricted diets (15, 16).

The Recommended Dietary Allowance (RDA)

In the US, 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 (Table 1). The RDA is based on the amount of vitamin C intake necessary to maintain neutrophil concentration with minimal urinary excretion of ascorbic acid, presumed to provide sufficient antioxidant protection (17). The recommended intake for smokers is 35 mg/day higher than for nonsmokers, because smokers are under increased oxidative stress from the toxins in cigarette smoke and generally have lower blood levels of vitamin C.

Table 1. Recommended Dietary Allowance (RDA) for Vitamin CLife StageAgeMales (mg/day)Females (mg/day)Infants0-6 months40 (AI)40 (AI)Infants7-12 months50 (AI)50 (AI)Children1-3 years1515Children4-8 years2525Children9-13 years4545Adolescents14-18 years7565Adults19 years and older9075Smokers19 years and older125110Pregnancy18 years and younger-80Pregnancy   19 years and older-85Breast-feeding    18 years and younger-115Breast-feeding19 years and older-120

Disease Prevention

The amount of vitamin C required to help prevent chronic disease is higher than the amount required for prevention of scurvy. Information regarding vitamin C and the prevention of chronic disease is based on both observational prospective cohort studies and randomized controlled trials (RCTs) (3, 11). Prospective cohort studies assess vitamin C intake or body status in large numbers of people who are followed over time to determine whether they develop a specific chronic disease outcome. RCTs evaluate the effect of vitamin C supplementation on the reduction of chronic disease in participants randomly assigned to receive either vitamin C or placebo for a given length of time.

Cardiovascular disease

Coronary heart disease

Coronary heart disease (CHD) is characterized by the build-up of plaque inside the arteries that supply blood to the heart (atherosclerosis). Over years of build-up and accumulated damage to the coronary arteries, CHD may culminate in a myocardial infarction or heart attack. Many prospective cohort studies have examined the relationship between vitamin C intake from diet and supplements and CHD risk, the results of which have been pooled and analyzed in two separate studies (18, 19). In 2004, a pooled analysis of nine prospective cohort studies found that supplemental vitamin C intake (≥400 mg/day for a mean of 10 years), but not dietary vitamin C intake, was inversely associated with CHD risk (18). Conversely, a 2008 meta-analysis of 14 cohort studies concluded that dietary, but not supplemental, vitamin C intake was inversely related to CHD risk (19). The most recent large prospective cohort study found an inverse association between dietary vitamin C intake and CHD mortality in Japanese women, but not in men (20). In spite of the variable association depending on source, these analyses indicate an overall inverse association between higher vitamin C intakes and CHD risk.

Limitations inherent to dietary assessment methodology, such as recall bias, measurement error, and residual confounding, may account for some of the inconsistent associations between vitamin C intake and CHD risk. In order to overcome such limitations, some prospective studies measured plasma or serum levels of vitamin C as a more reliable index of vitamin C intake and biomarker of body vitamin C status. The European Investigation into Cancer and Nutrition (EPIC)-Norfolk prospective cohort study investigated the relationship between vitamin C status and incident heart failure in healthy adults (9,187 men and 11,112 women, aged 58.1±9.2 years) (21). After a mean follow-up of 12.8 years, plasma vitamin C was inversely associated with incident cases of heart failure. Specifically, plasma vitamin C ranged from approximately 23-70 μmol/L in men and 33-82 μmol/L in women; across this range, every 20 μmol/L increase in plasma vitamin C was associated with a 9% reduction in risk of heart failure. Self-reported consumption of fruit and vegetables assessed by food frequency questionnaire was not associated with heart failure, consistent with the notion that limitations associated with dietary assessment methods may be overcome by using biomarkers of nutrient intake (22, 23).

A meta-analysis of 13 randomized controlled trials (RCTs) assessed the effect of vitamin C supplementation on serum cholesterol and triglycerides — established risk factors for cardiovascular disease (CVD) (24). The analysis included 549 hypercholesterolemic subjects, with an age range of 48-82 years, who received vitamin C supplements or placebo at doses ranging from 500 to 2,000 mg/day for 4 to 24 weeks. Overall, vitamin C supplementation significantly reduced serum levels of low-density lipoprotein cholesterol (LDL-C) (-7.9 mg/dL, 95% Confidence Interval (CI): -12.3 to -3.5) and serum triglycerides (-20.1 mg/dL, 95% CI: -33.3 to -6.8), but had no effect on serum levels of high-density lipoprotein cholesterol (HDL-C). On the other hand, an RCT 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 (25). Notably, this study had several limitations (26), including no measurement of vitamin C status and the recruitment of a well-nourished study population. See the Linus Pauling Institute’s Response to the PHS II Study for a more extensive discussion.

Overall, results of individual and pooled analyses of large prospective studies in conjunction with pharmacokinetic data of vitamin C in humans (see Bioavailability) and RCTs suggest that maximal reduction of CHD risk may require vitamin C intakes of 400 mg/day or more (27).

Stroke

A cerebrovascular event, or stroke, can be classified as hemorrhagic or ischemic. Hemorrhagic stroke occurs when a weakened blood vessel ruptures and bleeds into the surrounding brain tissue. Ischemic stroke occurs when an obstruction within a blood vessel blocks blood flow to the brain. Most (~80%) cerebrovascular events are ischemic in nature and associated with atherosclerosis as an underlying condition (28).

With respect to vitamin C and cerebrovascular disease, a prospective cohort study that 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 (29). 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. Similarly, the EPIC-Norfolk study, a 10-year prospective cohort study in 20,649 adults, found that individuals with plasma vitamin C levels in the top quartile (25%) had a 42% lower risk of stroke compared to those in the lowest quartile (30). In both the Japanese (29) and EPIC-Norfolk (30) populations, 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 from the effects of other components of fruit and vegetables, emphasizing the benefits of a diet rich in fruit and vegetables in reducing stroke risk. For example, potassium—found at high levels in bananas, potatoes, and other fruit and vegetables—is known to be important in blood pressure regulation, and elevated blood pressure is a major risk factor for stroke (see the article on Potassium). 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.

Some studies have investigated the effect of vitamin C supplementation on specific types of stroke. A small RCT performed in 60 ischemic stroke patients demonstrated that intravenous vitamin C supplementation (500 mg/day for 10 days, initiated day 1 post-stroke) had no effect on serum markers of oxidative stress or neurological outcomes compared to placebo, which was administered to both ischemic stroke patients and healthy controls (31). A randomized, double-blind, placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study II (PHS II) found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on the incidence of or mortality from any type of stroke (25). However, this study had numerous limitations that make it difficult to draw conclusions for the general population (26); see the Linus Pauling Institute’s Response to the PHS II Study.

Hypertension

In an analysis that combined data from three, large, independent prospective cohorts: (1) Nurses' Health Study 1 (NHS1; 88,540 women, median age 49 years); (2) Nurses' Health Study 2 (NHS2; 97,315 women, median age 36 years); and (3) Health Professionals Follow-up Study (HPFS; 37,375 men, median age 52 years), higher intakes of fructose and vitamin C were not associated with the risk for developing hypertension (32). On the other hand, when plasma vitamin C concentration is measured, thus overcoming some of the limitations of dietary assessment (23), cross-sectional studies consistently indicate that plasma vitamin C concentration is inversely related to blood pressure in both men and women (33-35).

Cancer

Overall, observational prospective cohort studies report no or modest inverse associations between vitamin C intake and the risk of developing a given type of cancer (3, 36-38). Additional detail is provided below for those cancer subtypes with substantial scientific information obtained from prospective cohort studies. Randomized, double-blind, placebo-controlled trials that have tested the effect of vitamin C supplementation (alone or in combination with other antioxidant nutrients) on cancer incidence or mortality have shown no effect (39).

Breast cancer

Two large, prospective studies found dietary vitamin C intake to be inversely associated with breast cancer incidence 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 (40). 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 (41). More recent prospective cohort studies have found no association between dietary and/or supplemental vitamin C intake and breast cancer (42-44).

Stomach cancer

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 N-nitroso compounds in the stomach (45-47). A nested case-control study in the EPIC study found an inverse association between plasma vitamin C and gastric cancer incidence in the highest (≥51 μmol/L) versus lowest (<29 μmol/L) quartiles of plasma vitamin C concentration (Odds Ratio (OR): 0.55, 95% CI: 0.31-0.97); no association between dietary vitamin C intake and gastric cancer risk was observed (48).

Infection with the bacteria, Helicobacter pylori (H. pylori), is known to increase the risk of stomach cancer and is associated with lower vitamin C content of stomach secretions (49, 50). Although two intervention studies did not find a decrease in the occurrence of stomach cancer with vitamin C supplementation (17), 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 (51). Because vitamin C can inactivate urease, an enzyme that facilitates H. pylori survival and colonization of the gastric mucosa at low pH, vitamin C may be most effective as a prophylactic agent in those without achlorhydria (52).

Colon cancer

By pooling data from 13 cohort studies comprising 676,141 participants, it was determined that dietary intake of vitamin C was not associated with colon cancer, while total intake of vitamin C (i.e., from food and supplements) was associated with a modestly reduced risk of colon cancer (Relative Risk (RR): 0.81, 95% CI: 0.71-0.92, >600 vs. ≤100 mg/day) (53). Each of the cohort studies used self-administered food frequency questionnaires at baseline to assess vitamin C intake. Although the analysis adjusted for several lifestyle and known risk factors, the authors note that other healthy behaviors and/or folate intake may have confounded the association.

Non-Hodgkin lymphoma (NHL)

A population-based, prospective study, the Iowa Women’s Health Study, collected baseline data on diet and supplement use in 35,159 women (aged 55-69 years) and evaluated the riskof developing NHL after 19 years of follow-up (54). Overall, an inverse association between fruit and vegetable intake and risk of NHL was observed. Additionally, dietary, but not supplemental, intake of vitamin C and other antioxidant nutrients (carotenoids, proanthocyanidins, and manganese) was inversely associated with NHL risk, suggesting that the association of NHL with these individual antioxidants may be mediated through food sources. The Women's Health Initiative was a large, multi-center, prospective study that assessed the association between antioxidant nutrient intake and risk of NHL, among other chronic diseases, in 154,363 postmenopausal women (55). After 11 years of follow-up, dietary and supplemental vitamin C intake at baseline was inversely associated with diffuse B-cell lymphoma, a subtype of NHL.

Alzheimer's disease

The majority of large, population-based studies examining the relationship of ascorbic acid intake or supplementation with Alzheimer's disease (AD) incidence have reported null results (56). Notably, these types of studies are limited by subjective measures of ascorbic acid exposure, which may be even less reliable in cognitively impaired study participants. To overcome this study limitation, the relationship between plasma vitamin C (a marker of body vitamin C status) and cognitive function has been examined in some observational studies. Overall, higher plasma ascorbic acid is associated with better cognitive function or lower risk of cognitive impairment (56), and plasma ascorbic acid concentration tends to be lower in AD patients (57).

Few studies have measured ascorbic acid concentration in the cerebrospinal fluid (CSF), which is thought to more closely reflect the vitamin C status of the brain. Ascorbic acid is concentrated in the brain through a combination of active transport into brain tissue and retention via the blood-brain barrier (BBB) (56). Although CSF vitamin C is maintained at levels several-fold higher than plasma vitamin C, the precise function of vitamin C in cognitive function and AD etiology is not yet known. In a small, longitudinal biomarker study in 32 individuals with probable AD, a higher CSF to plasma ascorbic acid ratio at baseline was associated with a slower rate of cognitive decline at one year of follow-up (58). The strength of this relationship was modified by the CSF Albumin Index, a marker of BBB integrity; this suggests that BBB dysfunction may lead to diffusion of AA from the central nervous system and impair the brain’s ability to maintain a high CSF:plasma ascorbic acid ratio. The significance of the CSF:plasma ascorbic acid ratio in AD progression requires further study.

The effect of vitamin C supplementation, in combination with other antioxidants, on CSF biomarkers and cognitive function has been tested in two trials involving AD patients. In a small (n=23), open-label trial, combined supplementation with vitamin C (1,000 mg/day) and vitamin E (400 IU/day) to AD patients taking a cholinesterase inhibitor significantly increased antioxidant levels and decreased lipoprotein oxidation in CSF after one year, but had no effect on the clinical course of AD compared to controls (59). A similar finding was obtained in a double-blind, randomized controlled trial (RCT) in which combined supplementation with vitamin C (500 mg/day), vitamin E (800 IU/day), and alpha-lipoic acid (900 mg/day) for 16 weeks reduced lipoprotein oxidation in CSF, but elicited no clinical benefit in individuals with mild-to-moderate AD (n=78) (60). In this latter trial, a greater decline in Mini Mental State Examination (MMSE) score was observed in the supplemented group, however, the significance of this observation remains unclear.

At this time, avoidance of ascorbic acid deficiency or insufficiency, rather than supplementation in replete individuals, seems prudent for the promotion of healthy brain aging (57).

Cataracts

The lens of the eye focuses light, producing a clear, sharp image on the retina, a layer of tissue on the inside back wall of the eyeball. Age-related changes to the lens (thickening, loss of flexibility) and oxidative damage contribute to the formation of cataract, cloudiness or opacity in the lens that interferes with the clear focusing of images on the retina.

Decreased vitamin C levels in the lens of the eye have been associated with increased severity of cataracts (61). Some, but not all, observational studies have reported that increased dietary intake (62-64) or increased concentration of vitamin C in the blood (65, 66) is associated with decreased risk of cataract formation. 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 (3).

A 2012 Cochrane review of RCTs concluded that there is no evidence that single or mixed antioxidant vitamin supplements (beta-carotene, vitamin C, and vitamin E) influence the development or progression of age-related cataract (67). In fact, two prospective cohort studies in Swedish men (68) and women (69) reported that high-dose single nutrient supplements of vitamin C were associated with increased risk of cataract, especially in those on corticosteroid therapy.

Although RCTs have not supported the use of high-dose supplementation with vitamin C in cataract prevention, there is a consistent inverse association observed between high daily intake of fruit and/or vegetables (>5 servings/day) and risk of cataract (64).

Gout

Gout, a condition that afflicts more than 4% of US adults (70), is characterized by abnormally high blood levels of uric acid (urate) (71). 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 (72). In an observational study that included 1,387 men, higher intakes of vitamin C were associated with lower serum levels of uric acid (73). 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 incidence of gout, with higher intakes being associated with greater risk reductions (74). The results of this study also indicated that supplemental vitamin C may be helpful in the prevention of gout (74).

A recent meta-analysis of 13 RCTs revealed that vitamin C supplementation (a median dose of 500 mg/day for a median duration of 30 days) modestly reduced serum uric acid concentrations by -0.35 mg/dL compared to placebo (95% CI: -0.66, -0.03) (75). Though lowering serum uric acid may help prevent incident and recurrent gout, more studies are needed to test this possibility.

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 (76-80) and function (81, 82) of leukocytes(white blood cells), especially neutrophils, lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (82), chemotaxis (81, 82), and phagocytosis (81). Neutrophils, mononuclear phagocytes, and lymphocytes accumulate vitamin C to high concentrations, which can protect these cell types from oxidative damage (80, 83, 84). 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 (85). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from self-inflicted oxidative damage (86). Phagocytic leukocytes also produce and release cytokines, including interferons, which have antiviral activity (87). Vitamin C has been shown to increase interferon levels in vitro (88).

It is widely thought by the general public that vitamin C boosts immune function, yet human studies published to date are conflicting. Additional controlled clinical trials are necessary to conclusively demonstrate that supplemental vitamin C enhances the function of the immune system in adequately nourished individuals.

Mortality

Two large prospective cohort studies assessed the relationship between vitamin C intake from both dietary and supplemental sources and mortality. In the Vitamins and Lifestyle Study, 55,543 men and women (aged 50-76 years) were questioned at baseline on their use of dietary supplements during the previous 10 years (89). After five years of follow-up, vitamin C supplement use was associated with a small decreased risk of total mortality, though no association was found with CVD- or cancer-specific mortality. In the second prospective cohort study, the Diet, Cancer and Health Study, 55,543 Danish adults (aged 50-64 years) were questioned at baseline about their lifestyle, diet, and supplement use during the previous 12 months (90). No association between dietary or supplemental intake of vitamin C and mortality was found after approximately 14 years of follow-up.

In contrast to these dietary assessment studies, a strong inverse association between plasma ascorbic acid and mortality from all-causes, CVD, and ischemic heart disease (and cancer in men only) was observed in the EPIC-Norfolk multicenter, prospective cohort study (91). After approximately four years of follow-up in 19,496 men and women (aged 45-79 years), a continuous relationship was observed such that each 20 μmol/L increase in plasma ascorbic acid was associated with an ~20% risk reduction in all-cause mortality. Similarly, higher serum vitamin C levels were associated with decreased risks of cancer- and all-cause mortality in 16,008 adults from NHANES III (1994-1998) (92).

Disease Treatment

Cardiovascular disease

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 (93). 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 (3, 94-96). Improved vasodilation has been demonstrated at an oral dose of 500 mg of vitamin C daily (94).

Hypertension

A recent meta-analysis of 29 short-term trials (each trial included 10 to 120 participants) indicated that vitamin C supplementation at a median dose of 500 mg/day for a median duration of eight weeks reduced blood pressure in both healthy, normotensive and hypertensive adults (97). In normotensive individuals, the pooled changes in systolic and diastolic blood pressure were -3.84 mm Hg and -1.48 mm Hg, respectively; in hypertensive participants, corresponding reductions were -4.85 mm Hg and -1.67 mm Hg. The significance of the blood pressure-lowering effect of vitamin C on CVD risk has not yet been determined (98). It is important for individuals with significantly elevated blood pressure not to rely on vitamin C supplementation alone to treat their hypertension, but to seek or continue therapy with anti-hypertensive medication and through diet and lifestyle changes in consultation with their health care provider. For information on dietary and lifestyle strategies to control blood pressure, see the article in the Spring/Summer 2009 Research Newsletter.

Diabetes mellitus

A strong inverse association between plasma vitamin C and risk of diabetes mellitus has been reported in a cohort of 21,831 men and women from the EPIC study (99). Additionally, two large, population-based cross-sectional studies reported an inverse association between serum or plasma vitamin C concentration and hemoglobin A1c level, an indicator of glucosecontrol (100, 101).

Cardiovascular disease (CVD) 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 of antioxidant nutrients could help decrease CVD risk in diabetic individuals. A 16-year prospective 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 (102). In contrast, a 15-year prospective study of postmenopausal women found that diabetic women (N = 1,923) 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 CVD (RR: 1.69, 95% CI: 1.09, 2.44), coronary artery disease (RR: 2.07, 95% CI: 1.27, 3.38), and stroke (RR: 2.37, 95% CI: 1.01, 5.57) than those who did not take vitamin C supplements (103). Vitamin C supplement use was not associated with a significant increase in CVD mortality in the cohort as a whole. Randomized controlled trials have not found antioxidant supplementation that included vitamin C to reduce the risk of CVD in diabetic or other high-risk individuals (101, 105).

It is possible that genetic differences may influence the effect of vitamin C supplementation on CVD risk in diabetic patients. 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 (106).

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 infused intravenously for 10 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 (107). Controversy surrounding the efficacy of vitamin C in cancer treatment ensued, leading to the recognition that the route of vitamin C administration is critical (6, 108). Compared to orally administered vitamin C, intravenous vitamin C can result in 30 to 70-fold higher plasma levels of vitamin C (9). The higher plasma levels achieved via intravenous ascorbic acid administration are comparable to those that are toxic to cancer cells in culture. The anticancer mechanism of intravenous vitamin C action is under investigation. It may involve the production of high levels of hydrogen peroxide, selectively toxic to cancer cells (6, 109-111), or the deactivation of hypoxia inducible factor, a prosurvival transcription factor that protects cancer cells from various forms of stress (108, 112, 113).

Currently, results from controlled clinical trials indicate that intravenous vitamin C is generally safe and well tolerated in cancer patients. Four 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 and 70-80 g/m2 was well tolerated and safe in pre-screened patients (114-117). A retrospective analysis of breast cancer patients reported that complementary intravenous ascorbic acid treatment reduced quality-of-life related side effects of chemotherapy(118). A phase I study in nine patients with metastatic pancreatic cancer showed that millimolar levels of plasma ascorbic acid could be reached safely when administered in conjunction with the cancer chemotherapy drugs, gemcitabine and erlotinib (116).

In a pilot study performed in 15 patients with refractory myelodisplastic syndrome or acute myeloid leukemia, an alternating ascorbic acid depletion/intravenous repletion protocol was safe and elicited a clinical response in a subset of nine patients (119). Retrospective in vitro colony formation assays revealed that patient leukemic cells displayed variable sensitivity to ascorbic acid treatment: leukemic cells from seven out of the nine patients who experienced a significant clinical benefit were sensitive to ascorbic acid in vitro (i.e., "responders"); the leukemic cells from the remaining six patients were not sensitive to ascorbic acid (i.e., "non-responders"). Thus, in vitro ascorbic acid sensitivity assays may provide predictive value for the clinical response to intravenous vitamin C treatment. The mechanisms underlying differential sensitivity to ascorbic acid are under investigation. In vitro experiments performed using 11 different cancer cell lines demonstrated that sensitivity to ascorbic acid correlated with the expression of catalase, an enzyme involved in the decomposition of hydrogen peroxide (120). Approximately half of the cell lines tested were resistant to ascorbic acid cytotoxicity, a response associated with high levels of catalase activity. Sensitivity to ascorbic acid may also be determined by the expression of sodium-dependent vitamin C transporter-2 (SVCT-2), which transports ascorbic acid into cells (121). Higher SVCT-2 levels were associated with enhanced sensitivity to L-ascorbic acid in nine different breast cancer cell lines. Moreover, SVCT-2 was significantly expressed in 20 breast cancer tissue samples, but weakly expressed in normal tissues.

These pilot and phase I study results motivate larger, longer-duration phase II clinical trials that test the efficacy of intravenous ascorbic acid in disease progression and overall survival. Such phase II clinical trials are currently under way (122). Because different cancer subtypes may be recalcitrant or require different doses of intravenous vitamin C, phase II trials are necessary before use of intravenous vitamin C as an anti-tumor agent can be fully realized (123). For information about the use of high-dose intravenous vitamin C as an adjunct in cancer treatment, visit The University of Kansas Medical Center Program in Integrative Medicine website.

Common cold

The work of Linus Pauling stimulated public interest in the use of large doses (greater than 1 gram/day) of vitamin C to prevent the common cold (124). In the past 40 years, numerous placebo-controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A recent meta-analysis of 53 placebo-controlled trials evaluated the effect of vitamin C supplementation on the incidence, duration, or severity of the common cold when taken as a continuous daily supplement (43 trials) or as therapy upon onset of cold symptoms (10 trials) (125). Regarding the incidence of colds, a distinction was observed between two groups of participants: regular supplementation with vitamin C (0.25 to 2 grams/day) did not reduce the incidence of colds in the general population (23 trials); however, in participants undergoing heavy physical stress (e.g., marathon runners, skiers, or soldiers in subarctic conditions), vitamin C supplementation halved the incidence of colds (5 trials; RR: 0.48, 95% CI: 0.35-0.64). A benefit of regular vitamin C supplementation was also seen in the duration of colds, with a greater benefit in children than in adults: the pooled effect of vitamin C supplementation was a 14% reduction in cold duration in children and an 8% reduction in adults. Finally, no significant effect of vitamin C supplementation (1-8 grams/day) was observed in therapeutic trials in which vitamin C was administered after cold symptoms occurred.

Asthma

Evidence for an effect of vitamin C on respiratory health comes from a meta-analysis of three RCTs that evaluated the effect of vitamin C on exercise-induced bronchoconstriction (126). Exercise-induced bronchoconstriction is a transient narrowing of the airways that occurs after exercise and is indicated by a ≥10% decline in Forced Expiratory Volume in 1 second (FEV1). The trials encompassed 40 asthmatic participants who received either vitamin C (a 0.5 g dose on two subsequent days in one trial; a single dose of 2 grams in the second trial; 1.5 g daily for 2 weeks in the third trial) or placebo before exercise. Compared to placebo, vitamin C administration significantly reduced the exercise-induced decline in FEV1 by 48% (95% CI: 0.33-0.64).

Lead toxicity

Although the use of lead paint and leaded gasoline has been discontinued in the US, 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.

Several cross-sectional studies report an inverse association between vitamin C status and blood lead level (BLL). In a study of 747 older men, BLL was 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 (127). A much larger study of 19,578 people, including 4,214 children from 6 to 16 years of age, found higher serum vitamin C levels to be associated with significantly lower BLL (128). A US national survey of more than 10,000 adults found that BLL were inversely related to serum vitamin C levels (129).

Cigarette smoking or second-hand exposure to cigarette smoke contributes to increased BLL and a state of chronic low-level lead exposure. An intervention trial in 75 adult male smokers found that supplementation with 1,000 mg/day of vitamin C resulted in significantly lower BLL over a four-week treatment period compared to placebo (130). A lower dose of 200 mg/day did not significantly affect BLL, despite the finding that serum vitamin C levels were not different from those in the group who took 1,000 mg/day.

The mechanism for the relationship between vitamin C intake and BLL is not known, although it has been postulated that vitamin C may inhibit intestinal absorption (130) or enhance urinary excretion of lead.

Sources

Food sources

As shown in Table 2, different fruit and vegetables vary in their vitamin C content (131), but five servings (2½ cups) of fruit 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.

Table 2. Some Food Sources of Vitamin CFoodServingVitamin C (mg)Orange juice¾ cup (6 ounces)62-93Grapefruit juice¾ cup (6 ounces)62-70Kiwifruit, gold1 fruit (86 g)91Orange1 medium70Grapefruit½ medium38Strawberries1 cup, whole85Tomato1 medium16Sweet red pepper½ cup, raw chopped95Broccoli½ cup, cooked51Potato1 medium, baked17Spinach1 cup, raw8

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 its sodium salt, called sodium ascorbate. Natural and synthetic L-ascorbic acid are chemically identical and there are no known differences in their biological activities or bioavailabilities (132).

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 fruit and vegetables, especially citrus fruit (see the article on Flavonoids). There is little evidence that the bioflavonoids in most commercial preparations increase the bioavailability or efficacy of vitamin C (133). Studies in cell culture indicate that a number of flavonoids inhibit the transport of vitamin C into cells (134-136), and supplementation of rats with quercetin and vitamin C decreased the intestinal absorption of vitamin C (134). More research is needed to determine the significance of these findings in humans.

Ascorbic acid and vitamin C metabolites

One supplement, Ester-C®, contains mainly calcium ascorbate but also contains small amounts of the vitamin C metabolites dehydroascorbic acid (oxidized ascorbic acid), calcium threonate, and trace levels of xylonate and lyxonate. Although these metabolites are purported 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 (133). Ester-C® should not be confused with ascorbyl palmitate, which is also marketed as "vitamin C ester." 

Ascorbyl palmitate

Ascorbyl palmitate is a vitamin C ester (i.e., ascorbic acid linked 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 (137) (see the separate article, Vitamin C and Skin Health). 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 (138). Ascorbyl palmitate is also marketed as "vitamin C ester," which should not be confused with Ester-C®.

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 in subsequent studies, 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 concern of kidney stone formation with vitamin C supplementation is discussed below.

With the latest RDA published in 2000, a tolerable upper intake level (UL) for vitamin C was set for the first time (Table 3). A UL of 2 grams (2,000 milligrams) daily was recommended in order to prevent most adults from experiencing diarrhea and gastrointestinal disturbances (17). Such symptoms are not generally serious, especially if they resolve with temporary discontinuation or reduction of high-dose vitamin C supplementation. 

Table 3. Tolerable Upper Intake Level (UL) for Vitamin CAge GroupUL (mg/day)Infants 0-12 monthsNot possible to establish*Children 1-3 years400Children 4-8 years650Children 9-13 years 1,200Adolescents 14-18 years1,800Adults 19 years and older2,000*Source of intake should be from foods or formula only.

Kidney stones

Because oxalate is a metabolite of vitamin C, there is some concern that high vitamin C intake could increase the risk of calcium oxalate kidney stones. Some (7, 139, 140), but not all (141-143), 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 several epidemiological studies. Two large prospective cohort studies, one following 45,251 men for 6 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 (144, 145). On the other hand, two other large prospective studies reported that a high intake of ascorbic acid was associated with an increased risk of kidney stone formation in men (146, 147). Specifically, in the Health Professionals Follow-Up Study, 45,619 male health professionals (aged 40-75 years) reported vitamin C intake from food and supplemental sources every four years (146). After 14 years of follow-up, men 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. In the Cohort of Swedish Men study, self-reported use of single-nutrient ascorbic acid supplements (taken 7 or more times per week) at baseline was associated with a 2-fold higher risk of incident kidney stones among 48,840 men (aged 45-79 years) followed for 11 years (147). 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 (148).

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 (149).

Antioxidant supplements and HMG-CoA reductase inhibitors (statins)

A three-year randomized controlled trial (RCT) in 160 patients with documented coronary heart disease and low HDL levels found that a combination of simvastatin (Zocor) and niacinincreased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke(150). Surprisingly, when an antioxidant combination (1,000 mg vitamin C, 800 IU alpha-tocopherol, 100 μg 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 RCT 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 five-year period (151). 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).

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 (152, 153), 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 (154).

Linus Pauling Institute Recommendation

Based on the combined evidence from metabolic, pharmacokinetic, and observational studies and from randomized controlled trials, it has been argued that sufficient scientific evidence exists to support an optimum, daily vitamin C intake of at least 200 mg/day, which is substantially higher than the current RDA (11). Studies conducted at the National Institutes of Health showed that plasma and circulating cells in healthy, young subjects attained near-maximal concentrations of vitamin C at a dose of 400 mg/day (11). Because of the very high benefit-to-risk ratio of vitamin C supplementation, and to ensure tissue and body saturation of vitamin C in almost all healthy people, the Linus Pauling Institute recommends a vitamin C intake of at least 400 mg daily for adult men and women. Consuming at least five servings (2½ cups) of fruit and vegetables daily provides about 200 mg of vitamin C. Most multivitamin/mineral 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 (>50 years)

Although it is not yet known with certainty whether older adults have higher requirements for vitamin C, 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 age-related 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 (aged 60-96 years) have considerably lower plasma levels of vitamin C following a certain intake of vitamin C compared with younger individuals (aged 15-65 years) (155), suggesting that older adults have higher vitamin C requirements. 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 (156). 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.

For more information on the difference between Dr Linus Pauling's recommendation and the Linus Pauling Institute's recommendation for vitamin C intake, select the highlighted text.

Authors and Reviewers

Originally written in 2000 by: Jane Higdon, Ph.D.  Linus Pauling Institute  Oregon State University

Updated in November 2002 by:   Jane Higdon, Ph.D.   Linus Pauling Institute   Oregon State University

Updated in September 2003 by:   Jane Higdon, Ph.D.   Linus Pauling Institute   Oregon State University

Updated in December 2004 by:   Jane Higdon, Ph.D.   Linus Pauling Institute   Oregon State University

Updated in January 2006 by:  Jane Higdon, Ph.D.  Linus Pauling Institute  Oregon State University

Updated in September 2009 by: Victoria J. Drake, Ph.D. Linus Pauling Institute  Oregon State University

Updated in November 2013 by:  Giana Angelo, Ph.D.  Linus Pauling Institute  Oregon State University

Reviewed in November 2013 by:  Balz Frei, Ph.D.  Director and Endowed Chair, Linus Pauling Institute  Joan H. Facey Linus Pauling Institute Professor  Distinguished Professor, Dept. of Biochemistry and Biophysics  Oregon State University

Reviewed in November 2013 by:  Alexander J. Michels, Ph.D.  Research Associate, Linus Pauling Institute  Oregon State University

The 2013 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Last updated 1/14/14  Copyright 2000-2018  Linus Pauling Institute

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