Vitamin C megadosage

Vitamin C megadosage is a term describing the consumption or injection of vitamin C (ascorbic acid) in doses well beyond the current Recommended Dietary Allowance of 90 mg/day, and often well beyond the Tolerable upper intake level of 2,000 mg/day.[1] There is no scientific evidence that megadosage helps to cure or prevent cancer, the common cold, or a variety of other medical conditions.[2][3]

Chemical structure of vitamin C
3D molecular model of vitamin C

Historic advocates of vitamin C megadosage include Linus Pauling, who won the Nobel Prize in Chemistry in 1954. Pauling argued that, due to a non-functional form of L-gulonolactone oxidase, an enzyme required to make vitamin C that is functional in most mammals, humans have developed a number of adaptations to cope with the relative deficiency. These adaptations, he argued, ultimately shortened lifespan but could be reversed or mitigated by supplementing humans with the hypothetical amount of vitamin C that would have been produced in the body if the enzyme were working.

Vitamin C megadoses are claimed by alternative medicine advocates including Matthias Rath and Patrick Holford to have preventative and curative effects on diseases such as cancer and AIDS,[4][5] but the available scientific evidence does not support these claims.[3] Some trials show some effect in combination with other therapies, but this does not imply vitamin C megadoses in themselves have therapeutic effect.[6]

Background

The World Health Organization recommends a daily intake of 45 mg/day of vitamin C for healthy adults, and 25–30 mg/day in infants.[7] The Vitamin C article provides examples of recommendations from individual countries. None exceed 110 mg/day. Vitamin C is necessary for production of collagen and other biomolecules, and for the prevention of scurvy.[8] Vitamin C is an antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.[9] Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.[10] Certain animal species, including haplorhine primates (which includes humans),[11][12] members of the Caviidae family of rodents (including guinea pigs and capybaras),[13] most species of bats,[14] many passerine birds,[15] and about 96% of fish (the teleosts),[15] do not synthesize vitamin C internally.

Since its discovery, vitamin C has been considered almost a panacea by some,[16] although this led to suspicions of it being overhyped by others.[17] 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. In the United States and Canada, a tolerable upper intake level (UL) was set at 2000 mg/day, referencing this mild laxative effect as the reason for establishing the UL.[1] However, the European Food Safety Authority (EFSA) reviewed the safety question in 2006 and reached the conclusion that there was not sufficient evidence to set a UL for vitamin C.[18] The Japan National Institute of Health and Nutrition reviewed the same question in 2010 and also reached the conclusion that there was not sufficient evidence to set a UL.[19]

About 70-90% of vitamin C is absorbed by the body when taken orally at normal levels (30–180 mg daily). Absorption is only about 50% for daily doses of 1 g. Oral administration, even of mega doses, cannot raise blood concentration above 0.22 mM.[20]

Relative deficiency hypothesis
Linus Pauling's popular and influential book How to Live Longer and Feel Better, first published in 1986, advocated very high doses of vitamin C.

Humans and other species that do not synthesize vitamin C carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. In the anthropoids lineage, this mutation likely occurred 40 to 25 million years ago. 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[21] 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 and published two articles discussing the possible relationship between lipoprotein and vitamin C with Pauling.[22][23] 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.[24]

Stone[25] and Pauling[11] believed that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day. For comparison, the FDA's recommended daily allowance of vitamin C is 90 milligrams.[1]

Adverse effects

Although sometimes considered free of toxicity, there are known side effects from vitamin C intake, and it has been suggested that intravenous injections should require "a medical environment and trained professionals."[26]

  • 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.[27] G6PD deficiency test is a common laboratory test.
  • Vitamin C administration may acidify the urine, that could promote the precipitation of kidney stones or drugs in the urine.[26]
  • Because oxalic acid is produced in the metabolism of vitamin C, hyperoxaluria can be caused by intravenous administration of ascorbic acid.[26]

Blood levels of vitamin C remain steady at approximately 200 mg per day. Although vitamin C can be well tolerated at doses well above what government organizations recommend, adverse effects can occur at doses above 3 grams per day. 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.[1] 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.[28]

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.[29] The American Association of Poison Control Centers has reported zero deaths from vitamin C.[30]

Interactions

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.[31] In another study, 40 mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7 µg/mL.[32] Aspirin may also inhibit the absorption of vitamin C.[33][34]

Regulation

There are regulations in most countries that limit the claims on the treatment of disease that can be placed on food and dietary supplement product labels. For example: Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the United States Food and Drug Administration even if substance has gone through well conducted clinical trials with positive outcomes. Claims are limited to Structure:Function phrasing ("Helps maintain a healthy immune system") and the following notice is mandatory on food and dietary supplement product labels that make these types of 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.[35]

Research

Cancer

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.[36][2] 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.[2][37] However, the trials at the Mayo Clinic were conducted with oral doses of ascorbate, not IV ascorbate as was done in the original trial. This difference in the way the treatment was administered to subjects is a possible reason for the failure of the Mayo Clinic trials to replicate the original trial results.[38]

More recently, in vivo findings from animal models have furnished evidence that high-dose intravenous ascorbic acid 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.[26] 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."[37]

The American Cancer Society has stated, "Although high doses of vitamin C have been suggested as a cancer treatment, the available evidence from clinical trials has not shown any benefit."[2]

Burns

One clinical trial 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,[39] but despite being described as promising, it has not been replicated by independent institutions and thus is not a widely accepted treatment.[40] 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.[41]

Cardiac effects

Atrial fibrillation (AF) is a common cardiac rhythm disturbance and it is associated with oxidative stress. Four meta-analyses have concluded that there is strong evidence that 1-2 g/day of vitamin C before and after cardiac operations can decrease the risk of post-operative AF.[42][43][44][45] However, five randomized studies did not find benefit in the USA, so that the benefit was restricted to less wealthy countries.[45][46]

Exercise-induced bronchoconstriction

Exercise-induced bronchoconstriction (EIB) indicates acute narrowing of the airways as a result of vigorous exercise. EIB seems to be caused by the loss of water caused by increased ventilation, which may lead to the release of mediators such as histamine, prostaglandins and leukotrienes, all of which cause bronchoconstriction. Vitamin C participates in the metabolism of these mediators and might thereby influence EIB.[47] A meta-analysis showed that 0.5 to 2 g/day of vitamin C before exercise decreased EIB by half.[48]

Endothelial function

A meta-analysis showed a significant positive effect of vitamin C on endothelial function. Benefit was found of vitamin C in doses in the range from 0.5 to 4 g/day, whereas lower doses from 0.09 to 0.5 g/day were not effective.[49]

Common cold

A meta-analysis calculated that large doses of vitamin C do not prevent the common cold in the general community, although 0.25 to 1 g/day of vitamin C halved the incidence of colds in people under heavy short-term physical stress.[50] Another meta-analysis calculated that in children 1-2 g/day vitamin C shortened the duration of colds by 18%, and in adults 1-4 g/day vitamin C shortened the duration of colds by 8%.[50] There is evidence of linear dose-dependency in the effect of vitamin C on common cold duration up to 6-8 g/day.[51] As of 2014, at least 16 studies had found that vitamin C supplements did not prevent the common cold and had minimal effect at best in shortening cold lengths.[3]

See also

References
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