Ever since the discovery of the chemical structure of vitamin C or ascorbic acid (hexuronic acid) by Albert Szent-Gyorgyi in the early 1930s (1) interest in its medical use has steadily increased. This interest is fueled by mounting evidence, gathered in the past 30 years that diseases such as atherosclerosis, type II diabetes mellitus, chronic renal failure, rheumatoid arthritis are associated with increased oxidative damage to important cell components, i.e. lipids, proteins and nucleic acids as well as to the extracellular matrix. At the same time, patients with these conditions regularly show decreased tissue and blood plasma vitamin C concentrations. It has been suggested that low plasma ascorbate levels may reflect a poor nutrition or may be a consequence of the disease or simply associated with the condition. To date, there are no large epidemiologic studies being carried on to address these issues. On the other hand, a positive relationship between the free radicals as a causative agent and the disease has only been suggested in the case of atherosclerosis. While numerous in vitro studies have clearly demonstrated that the ascorbic acid is an effective antioxidant when lipid complexes (LDL), proteins and DNA were subjected to oxidative stress in well defined experimental conditions, the same cannot be said with certainty about the in vivo action of vitamin C in either animal or human models (2). For instance, a widely accepted model of atherogenesis in humans is the oxidation modification hypothesis, which is based on the oxidative modification of LDL as the initiating event in atherogenesis (3). Thus, it was reasoned that the pattern of LDL oxidation in vivo would be similar to the one in vitro and antioxidants capable of inhibiting the process outside the body would act inside the living cells in a similar manner. If ascorbate is the antioxidant in question then what role does it play in protecting LDL and other cell components such as proteins and DNA against modification through oxidation in vivo and how much of it is needed on a daily basis?  So far there is no definite answer to this question.

Although vitamin C is readily available in fresh fruits and vegetables and despite a massive campaign in the U.S. over the last 20 years or so to educate the public in consuming a healthy diet that includes up to five servings of fruits and vegetables per day, a substantial fraction of the population is thought to have daily vitamin C intakes at or below the RDA of about 100 mg (4). So, it appears that a lot of people do not get the necessary RDA of vitamin C every day. Is it good, is it bad? One cannot tell for sure. Medical experts are still divided over the issue. However, there are people in the scientific and medical community who think otherwise. For them the current RDA for vitamin C is far too low.

One of these people was Linus Pauling(1901-1994), the Nobel Prize winner for chemistry in 1954 and for peace in 1962. In a paper published in 1970 Pauling argues that the requirements of humans for vitamin C should be 2.3 g or more per day (5). This figure was calculated for an adult with an energy requirement of 2500 kcal/day. Pauling speculated that members of the human ancestors, primates and a few other species, which lost their ability to synthesize ascorbic acid because of a mutation in the gene that codes the enzyme L-gulonolactone oxidase, were better equipped to survive than those which did not. This was because the mutants were better off without having to support an extra metabolic activity necessary to produce ascorbic acid. In addition, there were plenty of food supplies that were rich in vitamin C to make up for the loss of synthetic activity. Most of the other vertebrates (except for the guinea pig) still produce vitamin C in their bodies at a rate that is much higher than the one we get from our food when calculated per unit body weight per day. Thus, it was estimated that the amount of ascorbic acid synthesized by rats, i.e. 58 mg/kg/day would correspond to about 4 g vitamin C per day for an adult weighing 70 kg. This is some 40 times higher than the RDA of about 100 mg/day for humans. Do animals really need so much more ascorbate in their body and we so little or is there something wrong in our estimation? Pauling and other scientists argued for much higher daily doses of vitamin C for humans, especially in cases of viral (common cold)/bacterial infections, stress and other medical conditions; they recommended 4-10 g/day or even more. Unfortunately, the proponents of megadoses of vitamin C supplementation are only supported by theoretical considerations, anectodal stories and scant evidence coming from a handful of medical practitioners who pioneered this kind of approach to disease prevention and treatment going back to the 1950s. I suggest you read one of these accounts, a paper by F. Klenner, MD entitled: "Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology", published in Journal of Applied Nutrition vol.23(3-4), 1971. This article is available here.

As if to keep the interest in the subject alive a recent medical story involving the successful treatment of a severe swine flu case with mega doses of intravenously administered vitamin C was widely publicized on New Zeeland television. The video is available on this website. Such stories pop up regularly in the popular literature and media but the reality is that we still don't have reliable clinical trials on the virtues of using mega doses of vitamin C for the treatment of conditions such as viral infections. Why is the medical profession and pharma industry so adamantly opposed to such trials remains an open question.

On the other hand, the mainstream scientific community has a different opinion when it comes to the use of megadoses of vitamin C. As pointed out in a recent review, blood plasma was completely saturated at vitamin C intakes of 400 mg/day, while the blood cells became saturated before the plasma did (2). The steady state concentration of the ascorbic acid at saturation in plasma and cells was 0.080 mM and 4 mM, respectively. It was also shown that at doses of 500 mg or higher the entire absorbed dose of vitamin C was excreted. Thus, it appears that vitamin C concentrations in plasma are tightly controlled as a function of the amount of vitamin ingested (6). However, the authors only looked at blood (cells and plasma) ascorbate level and not at the vitamin concentration in other tissues where important metabolic activities that require the presence of ascorbic acid occur. This kind of experiment is extremely difficult to conduct in humans and data from non-vitamin C producing animals such as the guinea pig are still far from complete. Moreover, it is also not clear how much ascorbic acid is consumed in metabolic activities in the animals that do produce the vitamin and how much is excreted either as such or as degradation products. Until such data become available we are left to wonder how much the vitamin C producing animals, not to mention the humans, do really need for their survival/optimal health. Meanwhile, the advocates of vitamin C supplementation at megadose levels are faced with the fact that a lot of the ingested vitamin C is wasted through excretion. We should also bear in mind that one vitamin taken in excess amounts may upset the balance of the others. In time this may lead to disturbances in cellular metabolism.

There is no question that a diet rich in fresh fruits and vegetables significantly reduces the risk of heart disease, some forms of cancer and other pathological conditions. These foods contain, besides ascorbic acid and several other antioxidant factors, minerals and many nutrients whose identity, let alone actions are unknown. The protective effects against cardiovascular disease reported for population groups having higher intakes of fruits and vegetables may be attributable to the synergystic action of all relevant nutrients and not to vitamin C alone. Vitamin C may or may not contribute to the observed effect. Epidemiological studies using large randomized population cohorts have failed to prove conclusively a positive correlation between the reduction in the risk of developing cardiovascular diseases and supplementation with either vitamin C, E or b-carotene (7). It is interesting to note that in general, beneficial effects of vitamin C supplementation at doses in excess of the current RDA have been recorded in small studies while large well-controlled and prospective studies have failed to show benefit.

The complexity of pathological processes as well as other factors may explain in part the failure of the clinical trials reported so far in the mainstream scientific literature to demonstrate clear antioxidant benefits for vitamin C. Thus, there are many antioxidant systems at play at any given moment and in order to detect clinical effects clearly attributable to the ascorbic acid alone all other antioxidant defense mechanisms would have to be exhausted. It is also important to note that the beneficial effect of vitamin C would have to be detected at the site of the disease process and not at systemic level, i.e. the body as a whole. In addition, the assay methods for the biomarkers of oxidation are not widely standardized and validated and this makes the comparison of data from different research centers very difficult.

Good health or the susceptibility of an individual to disease depends on many factors, including but not limited to the genetic make-up, nutrition, stress, environmental pressure and not the amount of vitamin C or other antioxidants present in the body as some scientists and medical experts would like us to believe. If certain animal species produce ascorbic acid in their bodies in high amount it does not necessarily follow that humans, who lack the machinery to make vitamin C, are not getting the antioxidant protection afforded by vitamin C and need much higher intakes of this vitamin from foods or supplements in order to stay healthy. Pauling suggested 2-3 g of vitamin C per day as a baseline value (5) for the healthy individual. In conditions of stress this amount should be increased. The problem is, we don't know how much ascorbic acid is used up for other metabolic activities besides fighting oxidative stress, on a daily basis. It is possible that doses lower than 4 g per day(this figure was calculated by converting the amount of vitamin C produced per unit body weight in rats to a 70 kg human being) might put a strain on certain ascorbic acid-dependent reactions, which in the long run may lead to disease. This may explain, in the opinion of the proponents of megadoses of vitamin C, why we get sick. However, this hypothesis has not been so far put to test. There is also no explanation as to why man's ancestors could live for millions of years, apparently without problems, relying only on food supplies for their vitamin C needs. Were they getting more or less than the current RDA for vitamin C? There is no answer to this question at the present time.

However, most diseases are not caused directly by free radical activity and vitamin C as a free radicals scavenger would play no essential role in preventing or curing those diseases. On the other hand, it was known for some time that lower vitamin C concentrations are associated with many human disorders. Whether this is due to poor diet habits and other factors or to the pathological process itself is not clear yet. For sure, vitamin C has many functions besides that of antioxidant and if some of those functions control vital biochemical/physiological processes it might be possible that low levels of vitamin C could result in disease. Again, this has not been explored in detail at the molecular level.

As for the debate on the use of vitamin C at megadoses level it appears that the focus is not so much on the prevention side as on the curative one. Most of the proponents of this approach belong to the so-called Alternative Medicine wave that is gaining more and more ground nowadays with the North American public. I would like you to get exposure to the pro and con arguments on the use of megadoses of vitamin C by visiting two websites that play central stage in this heated debate. They are kind of portals to hundreds of pages of information on the current research on vitamin C at both the basic and the clinical level so you can get an idea about the full dimension of this issue.
1. Vitamin C Foundation's website
2. Vitamin C - Orthomed.com

This book is primarily addressed to the young students that will become tomorrow's new generation of scientists and medical practitioners, who will put their mark on the advancement of science and medicine. Let your imagination fly and don't be afraid to challange current dogmas. Ask questions and honestly seek answers. Science is about finding the truth no matter how long it takes. Linus Pauling himself, talking to a group of students on the night of his Nobel Lecture in 1954 said:
"When an old and distinguished person speaks to you, listen to him carefully and with respect - but do not believe him. Never put your trust in anything but your own intellect. Your elder, no matter whether he has gray hair or has lost his hair, no matter whether he is a Nobel Laureate, may be wrong. The world progresses, year by year, century by century, as the members of younger generations find out what was wrong among the things that their elders said. So you must be skeptical - always think for yourself" (reproduced from the home page of Vitamin C Foundation's website).


References
1. Szent-Gyorgyi, A. Oxidation, energy transfer and vitamins (1937) Nobel Lecture, (Source: Vitamin C Foundation's
    website)
2. Padayatty, S.J., Katz, A., Wang, Y. et al.(2003) J.Am.Coll.Nutr. 22(1) 18-35. Vitamin C as an antioxidant:
    Evaluation of its role in disease prevention.
3. Witztum, J.L., Steinberg, D.(2001) Trends Cardiovasc.Med. 11, 93-102. The oxidative modification hypothesis of
    atherosclerosis: does it hold for humans?
4. Levine, M., Rumsey, S.C. et al.(1999) Criteria and recommendations for vitamin C intake. JAMA 281, 1415-1423.
5. Pauling, L.(1970) Proceedings of the National Academy of Sciences of the U.S.A., 67(4) 1643-1648. Evolution and
    the need for ascorbic acid.
6. Levine, M., Wang, Y. et al.(2001) Proc.Natl.Acad.Sci.USA 98, 9842-9846. A new recommended dietary allowance
    of vitamin C for healthy young women.
7. Jha, P., Flather, M. et al.(1995) Ann.Intern.Med. 123, 860-872. The antioxidant vitamins and cardiovascular
    disease. A critical review of epidemiologic and clinical trial data.