Vitamin C megadosage
Vitamin C megadosage is a term describing the consumption or injection of vitamin C (ascorbate) in doses comparable to the amounts produced by the livers of most other mammals. Such dosages correspond to amounts well beyond the current Dietary Reference Intake. Oral dosages are usually divided and consumed in portions over the day. Injections of hundreds of grams per day are advocated by some physicians for the treatment of certain conditions, poisonings, or recovery from trauma. People who practice vitamin C megadosage may consume many vitamin C pills throughout each day or dissolve pure vitamin C crystals in water or juice and drink it throughout the day.
Vitamin C megadoses are claimed by alternative medicine advocates including Matthias Rath and Patrick Holford to have effects on diseases such as cancer and AIDS, but there isn't conclusive scientific evidence to back these claims. Some trials show some effect in combination with other therapies, but this does not imply vitamin C megadoses in themselves have therapeutic effect.
The World Health Organization recommends a daily intake of 45 mg/day of vitamin C for healthy adults. Vitamin C is necessary for production of collagen and other biomolecules, and for the prevention of scurvy. Vitamin C is an antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life. Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.
Primates, including humans, and guinea pigs do not synthesize vitamin C internally. Nearly all other animals synthesize vitamin C internally, maintaining cellular vitamin C concentrations that are considerably higher than those achieved with the Recommended Daily Intake set for humans. Irwin Stone coined the term hypoascorbia to describe the low level of vitamin C maintained in humans through their diet compared to the level other animals maintain through their internal production. He proposed that hypoascorbia is caused by a genetic defect in humans and most primates. Animals that produce ascorbate internally produce considerably higher amounts when they are stressed.
Vitamin C has been promoted in alternative medicine as a treatment for the common cold, cancer, polio and various other illnesses. The evidence for these claims is mixed. Orthomolecular-based megadose recommendations for vitamin C are based mainly on theoretical speculation and observational studies, such as those published by Fred R. Klenner from the 1940s through the 1970s. There is a strong advocacy movement for such doses of vitamin C, and there is an absence of large scale, formal trials in the 10 to 200+ grams per day range. The single repeatable side effect of oral megadose vitamin C is a mild laxative effect if the practitioner attempts to consume too much too quickly. A tolerable upper limit (UL) of vitamin C was set at 2 grams for the first time in the year 2000, referencing this mild laxative effect as the reason for establishing the UL. This 2 g UL restricts the acceptance of formal vitamin C megadose trials by Institutional review boards.
Common cold 
The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine prophylaxis is not justified. Vitamin C could be useful for people exposed to brief periods of severe physical exercise. While the prophylaxis trials have consistently shown that vitamin C reduces the duration and alleviates the symptoms of colds, this was not replicated in the few therapeutic trials that have been carried out.
Heart disease 
Clinical trials investigating the use of vitamin C in the prevention of coronary disease or strokes have produced equivocal results, with positive, negative and neutral outcomes. Issues with methodology, patient selection and study design make the results of the studies difficult to interpret.
The use of vitamin C in high doses as a treatment for cancer was promoted by Linus Pauling, based on a 1976 study published with Ewan Cameron which reported intravenous vitamin C significantly increased lifespans of patients with advanced cancer. This trial was criticized by the National Cancer Institute for being designed poorly, and three subsequent trials conducted at the Mayo Clinic could not replicate these results.
More recently, in vitro data in animal models suggests intravenous ascorbic acid at high doses may hold some promise in the treatment of cancer, however this has not been supported in more rigorous clinical trials in humans. Preliminary clinical trials in humans have shown that it is unlikely to be a "miracle pill" for cancer and more research is necessary before any definitive conclusions about efficacy can be reached. A 2010 review of 33 years of research on vitamin C to treat cancer stated "we have to conclude that we still do not know whether Vitamin C has any clinically significant antitumor activity. Nor do we know which histological types of cancers, if any, are susceptible to this agent. Finally, we don't know what the recommended dose of Vitamin C is, if there is indeed such a dose, that can produce an anti-tumor response."
Treatment of phencyclidine psychosis 
Large dosages of vitamin C can be used to augment an antipsychotic in the treatment of acute phencyclidine (PCP) psychosis. Usually, 1000–2000 mg. of vitamin C are given intravenously over the course of 5–10 minutes. It is given in combination with a DA-2 antagonist such as haloperidol or risperidone. The antagonist is given intramuscularly and not combined with vitamin C. The vitamin acts synergistically with phencyclidine or its metabolites.
Due to the unique metabolic conditions after severe burns, short term intravenous administration of vitamin C has been suggested as an adjuvant treatment. One study used high intravenous doses of vitamin C (66 mg/kg/hour over 24 hours, for a total dose of around 110 grams) after severe burn injury, but despite being described as promising, it has not been replicated by independent institutions and thus is not a widely accepted treatment. Based on that study, the American Burn Association (ABA) considers high dose ascorbic acid an "option" to be considered for adjuvant therapy in addition to the more accepted standard treatments. Guidelines released by the ABA noted there is likely no benefit beyond decreased intravenous fluid volume needs and there needs to be larger multicenter trials to replicate this study result before vitamin C is accepted as a standard treatment. However, one medical review article noted vitamin C at the doses studied can be toxic, and recommended further validation by future studies before this therapy is clinically used, and another noted that this therapy is not a mainstream treatment although the study results can be meaningful to physicians experienced in treating severe burns.
Prevention of chronic severe pain after injury 
Clinical trials using various daily doses of vitamin C to prevent complex regional pain syndrome (CRPS) in wrist-fracture patients have, preliminarily, shown promising initial results; however, as the cause of CRPS is not known at this time (nor the optimal vitamin C dosage), further research is necessary.
Possible adverse effects 
Although sometimes considered free of toxicity, there are known side effects from vitamin C intake, and it has been suggested that any administration should require "a medical environment and trained professionals."
- A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD) can cause sufferers to develop hemolytic anemia after using intravenous vitamin C treatment. G6PD deficiency test is a common laboratory test.
- Vitamin C administration can acidify the urine, promoting the precipitation of kidney stones or drugs in the urine.
- Because oxalic acid is produced in the metabolism of vitamin C, hyperoxaluria can be caused by intravenous administration of ascorbic acid.
Side effects 
Blood levels of vitamin C remain steady at approximately 200 mg per day. Although vitamin C can be well tolerated at doses well above the RDA recommendations, adverse effects can occur at doses above 3 grams per day though overload is unlikely. The common 'threshold' side effect of megadoses is diarrhea. Other possible adverse effects include increased oxalate excretion and kidney stones, increased uric acid excretion, systemic conditioning ("rebound scurvy"), preoxidant effects, iron overload, reduced absorption of vitamin B12 and copper, increased oxygen demand and acid erosion of the teeth with chewing ascorbic acid tablets. In addition, one case has been noted of a woman who had received a kidney transplant followed by high-dose vitamin C and died soon afterwards as a result of calcium oxalate deposits that destroyed her new kidney. Her doctors concluded that high-dose vitamin C therapy should be avoided in patients with renal failure.
Chance of overdose 
As discussed previously, vitamin C generally exhibits low toxicity. The LD50 (the dose that will kill 50% of a population) is generally accepted to be 11900 milligrams [11.9 grams] per kilogram in rat populations.
Conflicts with prescription drugs 
Pharmaceuticals designed to reduce stomach acid, such as the proton pump inhibitors (PPIs), are among the most widely-sold drugs in the world. One PPI, omeprazole (Prilosec), has been found to lower the bioavailability of vitamin C by 12% after 28 days of treatment, independent of dietary intake. The probable mechanism of vitamin C reduction, intragastric pH elevated into alkalinity, would apply to all other PPI drugs, though not necessarily to doses of PPIs low enough to keep the stomach slightly acidic. In another study, 40 mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7 mcg/mL.
Genetic deficiency and broad spectrum hypotheses 
Humans and higher primates, as well as guinea pigs and small number of other animal species, carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. This mutation likely occurred 40 to 25 million years ago (in the anthropoids lineage). The three surviving enzymes continue to produce the precursors to vitamin C, but the process is incomplete and the body then disassembles them.
In the 1960s, the Nobel-Prize-winning chemist Linus Pauling, after contact with Irwin Stone, began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10 grams per day orally, thus approaching the amounts released by the liver directly into the circulation in other mammals: an adult goat, a typical example of a vitamin-C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and much more when stressed.
Matthias Rath is a controversial German physician who worked with Pauling and published in the Proceedings of the National Academy of Sciences. He is an active proponent and publicist for high dose vitamin C. Pauling's and Rath's extended theory states that deaths from scurvy in humans during the ice age, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol provided by lipoprotein(a), a lipoprotein found in vitamin C-deficient species (higher primates and guinea pigs).
Genetic rationales for high doses 
Four gene products are necessary to manufacture vitamin C from glucose. The loss of activity of the gene for the last step, Pseudogene ΨGULO (GLO), the terminal enzyme responsible for manufacture of vitamin C, has occurred separately in the history of several species. The loss of this enzyme activity is responsible for the inability of guinea pigs to synthesize vitamin C enzymatically, but this event happened independently of the loss in the haplorrhini suborder of primates, including humans. The remains of this non-functional gene with many mutations are, however, still present in the genome of the guinea pigs and in primates, including humans. GLO activity has also been lost in all major families of bats, regardless of diet. In addition, the function of GLO appears to have been lost several times, and possibly reacquired, in several lines of passerine birds, where ability to make vitamin C varies from species to species.
Loss of GLO activity in the primate order supposedly occurred about 63 million years ago, at about the time it split into the suborders haplorrhini (which lost the enzyme activity) and the more primitive strepsirrhini (which retained it). The haplorrhini ("simple nosed") primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The suborder strepsirrhini (bent or wet-nosed prosimians), which are still able to make vitamin C enzymatically, include lorises, galagos, pottos, and to some extent, lemurs.
Stone and Pauling calculated, based on the diet of primates (similar to what our common ancestors are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.
Pauling criticized the established US Recommended Daily Allowance, pointing out that it is based on the known quantities that will prevent acute scurvy but is not necessarily the dosage for optimal health.
Regulation of vitamin C 
There are regulations in most countries which limit the claims on the treatment of disease that can be placed on food, drug, and nutrient product labels. Regulations include:
- Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the Food and Drug Administration in the USA, and by the corresponding regulatory agencies in other countries, unless the substance has gone through a well established clinical trial with neutral oversight.
- In the United States, the following notice is mandatory on food, drug, and nutrient product labels which make health claims: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
Advocacy arguments 
Vitamin C advocates argue that there is a large body of scientific evidence that the vitamin has a wide range of health and therapeutic benefits but that this belief is rejected by current science and medical research.
There is some evidence regarding the applications and efficacy of vitamin C, but recommended governmental agency doses and frequency of intake have remained relatively fixed. This has led some researchers to challenge the recommendations. In 2003, Steve Hickey and Hilary Roberts of the Manchester Metropolitan University published a fundamental criticism of the approach taken to fix the nutritional requirement of vitamin C. In 2004, they again argued that the RDA, which is based on blood plasma and white blood cell saturation data from the National Institutes of Health (NIH), was based on flawed data. According to these authors, the doses required to achieve blood, tissue and body "saturation" are much larger than previously believed.
See also 
- Ascorbic acid
- Megavitamin therapy
- Orthomolecular medicine
- Uric acid
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- Trick Or Treatment, Simon Singh & Edzard Ernst
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