Introduction

Vitamin C, or ascorbic acid, is a water-soluble antioxidant vitamin and an essential cofactor for many enzymes. It is a six-carbon lactone that is synthesized from glucose by most animals, but not by humans, non-human primates, guinea pigs, bats, some fish, and some other animals which lack the enzyme L-gulonolactone oxidase; this makes these species rely on dietary vitamin C [2, 31]. Vitamin C was discovered in the 1920s, and popularized in the 1970s as a method of treating the common cold [14, 59]. It is found primarily in fruits and vegetables, with a serving generally containing 20-120 mg, although the amount can be affected by many variables [2]. Despite the high availability of vitamin C from foods, the average daily intake in the US in males and females is 84 mg and 73 mg respectively, while the new RDA is 90 mg and 75 mg daily for men and women [2]. It is estimated that 25% of children do not receive adequate dietary vitamin C [2].

This article will give an overview of how vitamin C and antioxidants in general work, discuss the role of vitamin C supplementation in exercise, briefly cover many of the possible health benefits of vitamin C supplementation, and discuss the optimal dosage and administration strategies for vitamin C supplements.

Biological action

The biological actions of vitamin C are attributed to its antioxidant properties. Vitamin C sequentially donates electrons from the double bond between the second and third carbons on the 6-carbon molecule, becoming oxidized to the ascorbyl radical in the process. The ascorbyl radical is generally much less reactive than the free radical that was quenched. The ascorbyl radical can also be recycled back to vitamin C through three separate enzymatic pathways as well as by reducing compounds such as glutathione. Vitamin C can also aid in the recycling of other antioxidants, most notably vitamin E. Compounds which can be reduced by vitamin C include oxygen related radicals (superoxide, hydroxyl radical, peroxyl radicals), sulphur radicals, nitrogen-oxygen radicals, reactive compounds such as hypochlorous acid, nitrosamines, and other nitrosating compounds, and many others. [2]

In general, oxidative stress occurs in three general classes of biomolecules – lipid, protein, and DNA. Vitamin C has the potential to prevent oxidative stress in all of these areas, although results depend on study design, and a greater effect is generally seen in situations where health is compromised. Lipid peroxidation occurs when lipids interact with reactive oxygen species (ROS), and these lipid peroxides further react with oxygen to form peroxyl radicals which then result in lipid hydroperoxides. This process is called radical propogation, and vitamin C can prevent this by reducing the initiating ROS. Studies both in vitro and in animals have found vitamin C to reduce lipid peroxidation. Proteins can be oxidized in a variety of ways, which also leads to radical propogation, and in this case vitamin C also inhibits the initiating step. DNA can be oxidized either directly or indirectly through protein or lipid oxidation, and reactive nitrogen species can also damage proteins needed for DNA repair. Vitamin C can help prevent the formation of reactive nitrogen species, and vitamin C has also been found to reduce DNA oxidation from a variety of causes both in vitro and in vivo. [2]

Vitamin C also acts as an electron donor for eight known enzymes. Out of these, three participate in collagen hydroxylation, which increases the stability of the collagen structure, two participate in the synthesis of carnitine, one participates in the biosynthesis of norepinephrine from dopamine, one adds amide groups to peptide hormones to increase their stability, and one modulates tyrosine metabolism. [2]

Under certain conditions, vitamin C can also act as a prooxidant. This is particularly the case when vitamin C reacts with transmition metals such as iron [64]. However, studies showing prooxidant effects have generally not been replicated or used artifical conditions [2].

Vitamin C and exercise

Prolonged exercise is associated with a decrease in plasma vitamin C concentration, and this is associated with an increase in exercise-induced oxidative stress [7]. However, short-term vitamin C supplementation is generally not associated with improved performance [42]. On the other hand, although vitamin C may not offer a direct ergogenic benefit, it may have a variety of effects that would be beneficial to the athlete [42]. This may be especially true if taken with a supplement with which vitamin C is synergistic (such as ALA or vitamin E) [42].

Exercise causes a significant increase in the production of free radicals, which can originate from the mitochondria, the capillary endothelium, and oxdiative bursts from inflammatory cells [42]. Whole body oxygen consumption dramatically increases during exercise, which leads to a higher production of oxygen radicals, and can challenge the natural antioxidant defense system [66]. Although there is conflicting research, many studies have found that vitamin C supplementation decreases exercise-induced oxidative stress [52, 42, 13]. In turn, vitamin C can also blunt the immune depression caused by prolonged exercise [25, 13]. One study also reported a decrease in muscle soreness after unaccustomed exercise with vitamin C supplementation [55]. On the other hand, one study found that vitamin C and N-acetyl-cysteine (NAC) supplementation increased oxidative stress and markers of muscle damage after eccentric exercise [64]. Given that many studies have also been equivocal, further research is needed to more clearly establish the role vitamin C supplementation plays in exercise.

A final effect that has been noted, and replicated, is a reduction of serum cortisol from vitamin C supplementation in ultramarathon runners [7, 63, 13]. This only occurs when the dosage used of vitamin C is relatively high, in the 1-1.5 g range [63, 13]. This effect occurs even with carbohydrate intake, indicating additive effects [13].

Mood & stress

An interesting, and not very well known, trait of vitamin C is the ability to reduce stress and anxiety. Vitamin C has a number of stress-related effects, such as modulation of dopaminergic and noradrenergic activity, increased oxytocin secretion, and a decrease in stress-induced cortisol release [30, 58]. In an open trial, 1000 mg of vitamin C and 200 mg of vitamin E reduced serum cortisol in elderly women, replicating the results of animal studies [58]. In a randomized double-blind trial, 3 g daily of sustained release ascorbic acid lowered blood pressure, subjective stress, and state anxiety response to an acute interpersonal psychological stressor, and speeded the recovery of normal cortisol levels after the stressor [58]. The exact mechanisms for these effects are unknown, but it appears that large doses (1-3 g) are needed for them to occur.

Disease and aging

Epidemiologic studies have found associations between many disease states and both plasma vitamin C and vitamin C intake. Conditions associated with low plasma vitamin C include smoking, diabetes, myocardial infraction, high blood pressure, pancreatitis, and infections; low plasma vitamin C is also associated with an increase in all cause mortality [2, 58, 65]. While in many of these cases the state contributed to lowered vitamin C status, rather than vice versa, this lowered status can further worsen the condition. Low vitamin C intake has also been correlated with cardiovascular disease and cancer [2, 8]. While this may be due to higher fruit and vegetable intake or other lifestyle factors, statistical analysis suggests that vitamin C plays a role [2].

Oxidative stress has been implicated in many disease states. It may cause or worsen conditions such as atherosclerosis and type II diabetes, and can worsen many of the complications of diabetes. Oxidative stress may also play a role in chronic renal failure, complications of end stage renal disease and hemodialysis, rheumatoid arthritis, neurogenerative diseases, pancreatitis, organ damage during acute illness, inflammatory disorders, cataracts, and cancer [2, 64, 23]. In all of these conditions, various antioxidants have been found to have beneficial effects.

Vitamin C is also one of the most popular anti-aging nutrients. The oxidative stress hypothesis of aging suggests that aging itself is caused by oxidative stress. In animal studies, aging is associated with lowered vitamin C status, and supplementation is associated with an improvement in many age-related variables [3, 41]. The association with reduced incidence of disease and other anti-aging properties make vitamin C a cornerstone nutrient for good health.

Cardiovascular disease

There is a very large body of literature on the use of vitamin C in the treatment and prevention of cardiovascular disease, most commonly in conjunction with vitamin E. Vitamin C has numerous effects that are beneficial to the cardiovascular system. First, it can protect endothelial nitric oxide (NO) from oxidation and increase synthesis of NO, leading to improved endothelial function [1, 2]. Second, as discussed above, vitamin C is an inhibitor of lipid peroxidation. It inhibits the buildup of oxidized LDL in arteries, a major contributing factor to atherosclerosis [2]. Third, vitamin C status has been correlated with the level of homocysteine, a cardiovascular disease risk factor [40]. Finally, synergism with vitamin E may play a strong role in the cardioprotective properties of vitamin C.

In addition to the epidemiologic evidence above, a number of other studies have been conducted. In animals, coadministration of vitamin C and E decreases atherosclerosis in LDL-receptor deficient mice, cholesterol fed rabbits, and cholesterol fed primates [2]. Vitamin C reduces blood pressure in both salt-fed and fructose-fed rats [26, 33]. In healthy humans, vitamin C can restore vasodilation that is impaired by acute hyperglycemia, and another trial found that reduced serum LDL and total cholesterol and raised HDL cholesterol [2, 15]. A six year trial with 100 mg of vitamin E and 250 mg vitamin C found that the vitamins slowed the progression of atherosclerosis [22]. Other trials have found reduced blood pressure in type II diabetes patients [35] and, along with vitamin E, inhibited progression of transplant-associated arterioslcerosis [53]. Numerous other studies have been conducted on vitamin C and cardiovascular disease, but there are far too many to discuss here.

Neurological disorders

Vitamin C is concentrated in the brain, and may be neuroprotective in a variety of ways. Vitamin C protects neurons from oxidative stress directly and by sparing vitamin E [18]. It may also protect the brain by interrupting the secretion of inflammatory cytokines and by maintaining immune function [31]. Levels of vitamin C in the brain decline with age, opening the possibility that supplementation may be useful in treating or preventing age-related cognitive decline [9]. Numerous epidemiologic studies have been conducted in this regard with varying results. Higher intake of ascorbic acid has been associated with reduced risk of vascular dementia, improved cognitive performance in both normal older people and patients with dementia, and lowered risk of Alzheimer's disease and age related cognitive decline [9, 31, 34].

In a 12 month trial with 300 IU of vitamin E and 1000 mg of vitamin C, the treatment improved short-term memory, psychomotor performance, and mood in the elderly. High doses of both supplements also extended the time required before levodopa therapy was required in Parkinson's Disease patients. A recent review on the existing literature found that vitamin C and vitamin E are both useful in preventing and treating age-related cognitive deficits, and that this is particularly true when treatment is begun earlier in life. [31]

Other uses

As discussed above, vitamin C intake is associated with a lower risk of cancer. In vitro, vitamin C inhibits liver, ovarian, and other cancers [11, 21]. In rats, vitamin C reduces the incidence of gastric cancer, and also protects against aspirin-induced gastric damage [20, 67]. However, randomized trials have yet to show a benefit from oral vitamin C supplementation in cancer patients [43]. It could be that the effect, if any, is primarily preventative.

Vitamin C supplementation is very beneficial to smokers, and presumably to those exposed to high levels of air pollution. Smoking and exposure to second-hand smoke both significantly decrease vitamin C status and increase markers of oxidative stress, and vitamin C supplementation (in large doses) completely prevents these effects [32, 23]. Vitamin C status has been inversely correlated with the incidence of cough/wheeze in smokers [24]. Asthma is also associated with reduced levels of vitamin C, and a study found that supplementation improved lung function in children with asthma exposed to high levels of air pollution [29, 45].

Another reputed benefit of vitamin C supplementation is prevention and treatment of the common cold. Most of the literature in this instance indicates no benefit from vitamin C. A large-scale epidemiologic study found no correlation between vitamin C intake and risk of the common cold [60], and a study using 1 g shortly after the onset of cold found no alteration in duration or severity of symptoms [62]. However, one report indicates that large doses of vitamin C do not aid in cold prevention, but do modestly reduce duration of symptoms [36].

Vitamin C is also indicated in the prevention of cataracts. This has been demonstrated in both animal models and epidemiological studies [2, 50]. Along with vitamin E, vitamin C supplementation also improved markers of eye health in diabetic patients [37]. Vitamin C supplementation also reduced various aspects of the obesity-diabetes syndrome in an animal model [56]. Vitamin C improved bone fracture healing in rats, and use of vitamin C supplements has been positively correlated with bone mineral density in postmenopausal women [48, 57]. Vitamin C can also protect against the effects of some toxic metals, specifically arsenic and lead, in animal models [12, 16, 28]. Finally, low vitamin C status has been linked to increased risk of preterm delivery [5].

Skin health

When discussing vitamin C supplementation, not all of the news is positive. Commonly seen as a skin nutrient, some evidence indicates that vitamin C may in fact be the opposite when taken in excess, although the literature is contradictory on this point. In vitro studies find that high concentrations of vitamin C promote skin damage from UV radiation [27, 38]. A prospective study in women found that there was an increased risk of melanoma in those with higher intakes of vitamin C from food, but argued that the effect was more likely to be due to a photosensitizing agent in fruits or vegetables high in vitamin C [4]. A trial using 500 mg of supplemental vitamin C daily measured the effects on UV-induced effects on a patch of skin. It found that although the supplementation reduced levels of lipid peroxidation, it also reduced the levels of glutathione and protein thiols. It noted that it was possible that vitamin C reduced the stimulus to maintain a high cellular glutathione level, or replaced other reducing agents within the cell [39].

There is some evidence that opposes this, while some is equivocal. One study found that 3 grams daily did not change the sunburn threshold in humans [39]. Two studies in humans have found the combination of vitamin C and E to reduce skin dryness caused by UV radiation [39]. In mice, vitamin C reduced the incidence of UVR-induced skin neoplasms [39]. The effects vitamin C has on skin health are not clear, but caution is clearly advised, especially for those who are regularly exposed to UV radiation. Other supplements, such as vitamin E, EGCG (from green tea), and ALA may reduce any negative effects vitamin C has on skin health.

Iron overload

Multiple studies have found that vitamin C increases iron absorption in the intestine by keeping iron reduced [2, 10]. However, one study found that single meal studies exaggerate the effects of vitamin C on iron absorption, and that when vitamin C is given under real life circumstances the increase in absorption is much less [54]. Furthermore, vitamin C protects against iron oxidation under multiple circumstances, and there is little evidence to support the contention that vitamin C promotes oxidative damage from iron [51, 46].

Stone formation

Another concern about vitamin C supplements is the possibility of increased risk of stone formation. Reduced vitamin C can be hydrolized to 2,3 diketogulonic acid, which can then be further metabolized into oxalate, which can contribute to stone formation [2]. High intake of ascorbic acid is indeed associated with increased urinary oxalate levels in some studies. However, clinicial trials, even involving high doses for long periods, have not found increased risk of kidney stones, and two large population based studies failed to find a correlation between the two. It is still recommended that calcium oxalate stone formers limit vitamin C supplementation to less than two grams per day. [14]

Dose and suggested use

Vitamin C supplementation is associated with few side effects and no toxic side effects. High intakes may lead to diarrhea and abdominal bloating. Also, high doses are not recommended to patients with iron overload, hemochromatosis, thalessemia major, sideroblastic anemia, or other diseases requiring multiple red blood cell transufions [31]. The UL (tolerable upper limit) for vitamin C supplementation has been set at 2 grams daily [23], although this seems to be based on the dose at which gastrointestinal side effects become an issue, and higher doses are still considered to be safe.

The average body pool of vitamin C is 1500 mg, with a turnover of 3-4% daily, which suggests that 60 mg daily is needed to maintain stores. The RDA was recently raised to 75 mg, based on variability in absorption and other factors. 20-30% of the US population does not meet the RDA for vitamin C. Of course, there is a large amount of evidence that the required dose is far from optimal, and for this reason there is much literature devoted to optimal vitamin C intake. It has been estimated that our Paletolithic ancestors consumed approximately 4 g daily. Estimates for optimal dosage generally fall in the 200-1000 mg range, although some researchers argue that the amount is as high as 2-3 g. There is no solid scientific basis for doses higher than this. [31]

Pharmacokinetic studies have been generally used to determine the ideal vitamin C dosage. At intakes around the RDA, plasma concentrations are generally in the 35-45 microM, while therapeutic concentrations are considered to be at least 50 microM [23]. In dose-response studies, there is a steep curve in the 30-100 mg range, with another 30-35% increase in plasma levels from 100 to 400 mg [2]. Plasma saturation is reported to occur in the 400-500 mg range [2, 23]. Similarly, absorption significantly decreases as dose increases – 80-95% is absorbed at 100 mg/day, while only about 50% is absorbed at 1500 mg [31]. After the saturation point is reached, plasma levels can no longer be increased, as extra vitamin C is rapidly unloaded [25].

Some researchers have argued that optimal vitamin C intake is 200 mg/day, based on epidemiologic observations and plasma and tissue concentrations. In contrast to plasma, most tissues reach the saturation point at this dose [2, 31]. However, the majority argue that optimal intake is around 500 mg. One dose-response study in young, healthy, non-smoking adults that consumed about 2 servings of fruits and vegetables daily concluded that 500-1000 mg was the ideal amount for reducing oxidative stress, but found no further benefit with 2 grams daily. A dose of 325 mg did not confer the same protection as the 500 mg dose. It also pointed out that the optimal amount may increase in situations of increased oxidative stress, which would again argue against a lower dose of 200 mg [23]. A five year study compared 50 mg and 500 mg, and found significantly higher plasma concentrations in the high dose group [17]. Other studies comparing 500 mg to higher doses have found no increase in cellular absorption or effectiveness against hypertension [49, 61]. However, a few scattered studies have found increased benefits with doses higher than 500 mg, particularly in the area of cortisol reduction and neural effects. For example, in the previously mentioned study in ultramarathon runners, 1500 mg was effective where 500 mg was not [13]. This could very well be due to the high amount of oxidative stress the sample population was subjected to.

In conclusion, it would seem that the ideal dosage of vitamin C is 500-1500 mg, depending on circumstances. The higher amount should be used in circumstances of increased oxidative stress, such as intense training or sickness. Given the studies finding no benefit or increase in tissue levels from higher doses and the possibilities of stone formation and iron overload, there is little reason to exceed 2 g daily. Because vitamin C is water soluble and rapidly excreted, it should be taken throughout the day. For further antioxidant protection, vitamin C can be combined with a variety of synergistic supplements, such as Vitamin E, ALA, N-acetyl-cysteine, pantothenic acid, and many others [19, 22, 44, 47].

If you have any questions or comments regarding this article, please email dvdtlsn@bulknutrition.com.



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