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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 Recommended Dietary Allowance of 90 mg/day, and often well beyond the Tolerable upper intake level of 2000 mg/day.^[1] 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.

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 other mammalian relatives, 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,^[2]^[3] but the available scientific evidence does not support these claims.^[4] Some trials show some effect in combination with other therapies, but this does not imply vitamin C megadoses in themselves have therapeutic effect.^[5]

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.^[6] 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.^[7] Vitamin C is an antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.^[8] Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.^[9] Certain animal species, including haplorhine primates (which includes humans),^[10]^[11] members of the Caviidae family of rodents (including guinea pigs and capybaras),^[12] most species of bats,^[13] many passerine birds,^[14] and about 96% of fish (the teleosts),^[14] do not synthesize vitamin C internally.

Since its discovery, vitamin C has been considered almost a panacea by some,^[15] although this led to suspicions of it being overhyped by others.^[16] 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.^[17] 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.^[18]

About 70-90% of vitamin C is adsorbed by the body when taken orally at normal levels (30–180 mg daily). Adsorption is only about 50% for daily doses of 1 g. Oral administration, even of mega doses, cannot raise blood concentration above 0.22 mM.^[19]

Relative deficiency hypothesis

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^[20] 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.^[21]^{[unreliable medical source?]}

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^[10] believed 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.^[26]

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."^[27]

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.^[28] 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.^[27]
Because oxalic acid is produced in the metabolism of vitamin C, hyperoxaluria can be caused by intravenous administration of ascorbic acid.^[27]

Blood levels of vitamin C remain steady at approximately 200 mg per day.^{[clarification needed]} 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.^[29]

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.^[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]^[35]

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.^[36]

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.^[37]^[38] 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.^[38]^[39]

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.^[27] 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."^[39]

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."^[38]

Burns

One study performed in 2000 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,^[40] but despite being described as promising, it has not been replicated by independent institutions and thus is not a widely accepted treatment.^[41] 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.^[42] 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.^[40]

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 ^[43] ^[44]^[45]^[46]. However, five randomized studies did not find benefit in the USA, so that the benefit was restricted to less wealthy countries ^[46]^[47].

References

^ ^a ^b ^c Institute of Medicine (2000). "Vitamin C". Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. pp. 95–185. ISBN 0-309-06935-1. Retrieved 2017-09-01.
^ Bad Science, Ben Goldacre
^ Trick Or Treatment, Simon Singh & Edzard Ernst
^ The Dark Side Of Linus Pauling's Legacy, Quackwatch
^ David Gorski, Science Based Medicine, 18 Aug 2008
^ Vitamin and mineral requirements in human nutrition (PDF) (2nd ed.). World Health Organization. 2004. p. 138. ISBN 9241546123. Retrieved 31 December 2014.
^ Gropper SS, Smith JL, Grodd JL (2004). Advanced Nutrition and Human Metabolism (4th ed.). Belmont, CA. US: Thomson Wadsworth. pp. 260–275.
^ Yeom CH, Jung GC, Song KJ (2007). "Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration". J. Korean Med. Sci. 22 (1): 7–11. doi:10.3346/jkms.2007.22.1.7. PMC 2693571. PMID 17297243.
^ "Vitamin C (Ascorbic Acid)". University of Maryland Medical Center. April 2002. Retrieved 2007-02-19.
^ ^a ^b Pauling L (1970). "Evolution and the need for ascorbic acid". Proc. Natl. Acad. Sci. USA. 67 (4): 1643–1648. Bibcode:1970PNAS...67.1643P. doi:10.1073/pnas.67.4.1643. PMC 283405. PMID 5275366.
^ Pollock, J. I.; Mullin, R. J. (1987). "Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.
^ R. Eric Miller; Murray E. Fowler (2014-07-31). Fowler's Zoo and Wild Animal Medicine, Volume 8. p. 389. ISBN 9781455773992. Retrieved 2016-06-02.
^ Jenness R, Birney E, Ayaz K (1980). "Variation of l-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. 67 (2): 195–204. doi:10.1016/0305-0491(80)90131-5.
^ ^a ^b Martinez del Rio C (July 1997). "Can passerines synthesize vitamin C?". The Auk. 114 (3): 513–16. doi:10.2307/4089257. JSTOR 4089257.
^ Levy, Thomas (2011). Primal Panacea. MedFox Publishing. p. 352. ISBN 0983772800.
^ Harri Hemilä (January 2006). "Do vitamins C and E affect respiratory infections?" (PDF). University of Helsinki. Retrieved 2007-02-21.
^ "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived from the original (PDF) on March 16, 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.
^ "Office of Dietary Supplements - Vitamin C". ods.od.nih.gov. Retrieved 2016-02-26.
^ "My Love Affair with Vitamin C" (PDF).
^ Stone, I. (1979). "Homo sapiens ascorbicus, a biochemically corrected robust human mutant". Medical Hypotheses. 5 (6): 711–721. doi:10.1016/0306-9877(79)90093-8. PMID 491997.
^ Rath M, Pauling L (1990). "Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig". Proc Natl Acad Sci USA. 87 (23): 9388–9390. Bibcode:1990PNAS...87.9388R. doi:10.1073/pnas.87.23.9388. PMC 55170. PMID 2147514.
^ Rath M, Pauling L (1990). "Hypothesis: lipoprotein(a) is a surrogate for ascorbate". Proc. Natl. Acad. Sci. USA. 87 (16): 6204–6207. Bibcode:1990PNAS...87.6204R. doi:10.1073/pnas.87.16.6204. PMC 54501. PMID 2143582.
^ Rath M, Pauling L (1992). "A unified theory of human cardiovascular disease leading the way to the abolition of this disease as a cause for human mortality" (PDF). Journal of Orthomolecular Medicine. 7 (1): 5–15.
^ Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap. ISBN 0-448-11693-6. OCLC 3967737.
^ Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN 0-380-70289-4. OCLC 154663991.
^ ^a ^b ^c ^d Verrax J, Calderon PB (December 2008). "The controversial place of vitamin C in cancer treatment". Biochem. Pharmacol. 76 (12): 1644–52. doi:10.1016/j.bcp.2008.09.024. PMID 18938145.
^ Rees; Kelsey, Richards (March 1993). "Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency" (PDF). British Medical Journal. 306 (6881): 841–2. doi:10.1136/bmj.306.6881.841. PMC 1677333. PMID 8490379.
^ Nankivell, BJ; Murali KM (2008). "Renal failure from vitamin C after transplantation" (PDF). The New England Journal of Medicine. 358 (4): e4. doi:10.1056/NEJMicm070984. PMID 18216350.
^ "Safety (MSDS) data for ascorbic acid". Oxford University. October 9, 2005. Retrieved 2007-02-21.
^ E. B. Henry, A. Carswell, A. Wirz, V. Fyffe & K. E. L. Mccoll (September 2005). "Proton pump inhibitors reduce the bioavailability of dietary vitamin C". Alimentary Pharmacology and Therapeutics. 22 (6). Alimentary Pharmacology & Therapeutics: 539–45. doi:10.1111/j.1365-2036.2005.02568.x. PMID 16167970. Retrieved 2007-02-21.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ C. Mowat; A. Carswell; A. Wirz; K.E. McColl (April 1999). "Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice". Gastroenterology. 116 (4). Alimentary Pharmacology & Therapeutics: 813–22. doi:10.1016/s0016-5085(99)70064-8. PMID 10092303.
^ Loh HS, Watters K; Wilson CW (1 November 1973). "The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings". J Clin Pharmacol. 13 (11): 480–486. doi:10.1002/j.1552-4604.1973.tb00203.x. PMID 4490672. {{cite journal}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help)
^ Basu TK (1982). "Vitamin C-aspirin interactions". Int J Vitam Nutr Res Suppl. 23: 83–90. PMID 6811490.
^ Ioannides C, Stone AN, Breacker PJ & Basu TK (1982). "Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs". Biochem Pharmacol. 31 (24): 4035–4038. doi:10.1016/0006-2952(82)90652-9. PMID 6818974.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ "Dietary Supplement Health and Education Act of 1994".
^ Cameron E, Pauling L (October 1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proc. Natl. Acad. Sci. USA. 73 (10): 3685–3689. Bibcode:1976PNAS...73.3685C. doi:10.1073/pnas.73.10.3685. PMC 431183. PMID 1068480.
^ ^a ^b ^c "Vitamin C". American Cancer Society.
^ ^a ^b Cabanillas, F (2010). "Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later?". Puerto Rico Health Sciences Journal. 29 (3): 215–7. PMID 20799507.
^ ^a ^b Berger MM (October 2006). "Antioxidant micronutrients in major trauma and burns: evidence and practice". Nutr Clin Pract. 21 (5): 438–49. doi:10.1177/0115426506021005438. PMID 16998143.
^ Greenhalgh DG (2007). "Burn resuscitation". J Burn Care Res. 28 (4): 555–65. doi:10.1097/bcr.0b013e318093df01. PMID 17665515.
^ Pham TN, Cancio LC, Gibran NS (2008). "American Burn Association practice guidelines burn shock resuscitation". J Burn Care Res. 29 (1): 257–66. doi:10.1097/BCR.0b013e31815f3876. PMID 18182930.
^ Baker, W. L; Coleman, C. I (2016). "Meta-analysis of ascorbic acid for prevention of postoperative atrial fibrillation after cardiac surgery". American Journal of Health-System Pharmacy. 73 (24): 2056. doi:10.2146/ajhp160066. PMID 27806938.
^ Polymeropoulos, Evangelos; Bagos, Pantelis; Papadimitriou, Maria; Rizos, Ioannis; Patsouris, Efstratios; Toumpoulis, Ioannis (2016). "Vitamin C for the Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis". Advanced Pharmaceutical Bulletin. 6 (2): 243. doi:10.15171/apb.2016.033. PMID 27478787.
^ Hu, Xiaolan; Yuan, Linhui; Wang, Hongtao; Li, Chang; Cai, Junying; Hu, Yanhui; Ma, Changhua (2017). "Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials". International Journal of Surgery. 37: 58–64. doi:10.1016/j.ijsu.2016.12.009. PMID 27956113.
^ ^a ^b Hemilä, Harri; Suonsyrjä, Timo (2017). "Vitamin C for preventing atrial fibrillation in high risk patients: A systematic review and meta-analysis". BMC Cardiovascular Disorders. 17. doi:10.1186/s12872-017-0478-5.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Hemilä, Harri (2017). "Publication bias in meta-analysis of ascorbic acid for postoperative atrial fibrillation". American Journal of Health-System Pharmacy. 74 (6): 372–373. doi:10.2146/ajhp160999. PMID 28274978.

External links

Quackwatch article critical of megadosing for cold prevention, Charles W. Marshall, Ph.D. Accessed 2016-06-02.

[DRItext-1] Institute of Medicine (2000). "Vitamin C". Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. pp. 95–185. ISBN 0-309-06935-1. Retrieved 2017-09-01.

[2] Bad Science, Ben Goldacre

[3] Trick Or Treatment, Simon Singh & Edzard Ernst

[4] The Dark Side Of Linus Pauling's Legacy, Quackwatch

[5] David Gorski, Science Based Medicine, 18 Aug 2008

[6] Vitamin and mineral requirements in human nutrition (PDF) (2nd ed.). World Health Organization. 2004. p. 138. ISBN 9241546123. Retrieved 31 December 2014.

[Gropper-7] Gropper SS, Smith JL, Grodd JL (2004). Advanced Nutrition and Human Metabolism (4th ed.). Belmont, CA. US: Thomson Wadsworth. pp. 260–275.

[pmid17297243-8] Yeom CH, Jung GC, Song KJ (2007). "Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration". J. Korean Med. Sci. 22 (1): 7–11. doi:10.3346/jkms.2007.22.1.7. PMC 2693571. PMID 17297243.

[UMM-9] "Vitamin C (Ascorbic Acid)". University of Maryland Medical Center. April 2002. Retrieved 2007-02-19.

[pmid5275366-10] Pauling L (1970). "Evolution and the need for ascorbic acid". Proc. Natl. Acad. Sci. USA. 67 (4): 1643–1648. Bibcode:1970PNAS...67.1643P. doi:10.1073/pnas.67.4.1643. PMC 283405. PMID 5275366.

[11] Pollock, J. I.; Mullin, R. J. (1987). "Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.

[12] R. Eric Miller; Murray E. Fowler (2014-07-31). Fowler's Zoo and Wild Animal Medicine, Volume 8. p. 389. ISBN 9781455773992. Retrieved 2016-06-02.

[13] Jenness R, Birney E, Ayaz K (1980). "Variation of l-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. 67 (2): 195–204. doi:10.1016/0305-0491(80)90131-5.

[Martinez_del_Rio_1997-14] Martinez del Rio C (July 1997). "Can passerines synthesize vitamin C?". The Auk. 114 (3): 513–16. doi:10.2307/4089257. JSTOR 4089257.

[15] Levy, Thomas (2011). Primal Panacea. MedFox Publishing. p. 352. ISBN 0983772800.

[16] Harri Hemilä (January 2006). "Do vitamins C and E affect respiratory infections?" (PDF). University of Helsinki. Retrieved 2007-02-21.

[17] "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived from the original (PDF) on March 16, 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[JapanDRI-18] Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.

[19] "Office of Dietary Supplements - Vitamin C". ods.od.nih.gov. Retrieved 2016-02-26.

[20] "My Love Affair with Vitamin C" (PDF).

[Stone-21] Stone, I. (1979). "Homo sapiens ascorbicus, a biochemically corrected robust human mutant". Medical Hypotheses. 5 (6): 711–721. doi:10.1016/0306-9877(79)90093-8. PMID 491997.

[pmid2147514-22] Rath M, Pauling L (1990). "Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig". Proc Natl Acad Sci USA. 87 (23): 9388–9390. Bibcode:1990PNAS...87.9388R. doi:10.1073/pnas.87.23.9388. PMC 55170. PMID 2147514.

[pmid2143582-23] Rath M, Pauling L (1990). "Hypothesis: lipoprotein(a) is a surrogate for ascorbate". Proc. Natl. Acad. Sci. USA. 87 (16): 6204–6207. Bibcode:1990PNAS...87.6204R. doi:10.1073/pnas.87.16.6204. PMC 54501. PMID 2143582.

[Rath,_Pauling_1992-24] Rath M, Pauling L (1992). "A unified theory of human cardiovascular disease leading the way to the abolition of this disease as a cause for human mortality" (PDF). Journal of Orthomolecular Medicine. 7 (1): 5–15.

[25] Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap. ISBN 0-448-11693-6. OCLC 3967737.

[Pauling_book-26] Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN 0-380-70289-4. OCLC 154663991.

[Verrax-27] Verrax J, Calderon PB (December 2008). "The controversial place of vitamin C in cancer treatment". Biochem. Pharmacol. 76 (12): 1644–52. doi:10.1016/j.bcp.2008.09.024. PMID 18938145.

[28] Rees; Kelsey, Richards (March 1993). "Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency" (PDF). British Medical Journal. 306 (6881): 841–2. doi:10.1136/bmj.306.6881.841. PMC 1677333. PMID 8490379.

[29] Nankivell, BJ; Murali KM (2008). "Renal failure from vitamin C after transplantation" (PDF). The New England Journal of Medicine. 358 (4): e4. doi:10.1056/NEJMicm070984. PMID 18216350.

[30] "Safety (MSDS) data for ascorbic acid". Oxford University. October 9, 2005. Retrieved 2007-02-21.

[31] E. B. Henry, A. Carswell, A. Wirz, V. Fyffe & K. E. L. Mccoll (September 2005). "Proton pump inhibitors reduce the bioavailability of dietary vitamin C". Alimentary Pharmacology and Therapeutics. 22 (6). Alimentary Pharmacology & Therapeutics: 539–45. doi:10.1111/j.1365-2036.2005.02568.x. PMID 16167970. Retrieved 2007-02-21.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[32] C. Mowat; A. Carswell; A. Wirz; K.E. McColl (April 1999). "Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice". Gastroenterology. 116 (4). Alimentary Pharmacology & Therapeutics: 813–22. doi:10.1016/s0016-5085(99)70064-8. PMID 10092303.

[33] Loh HS, Watters K; Wilson CW (1 November 1973). "The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings". J Clin Pharmacol. 13 (11): 480–486. doi:10.1002/j.1552-4604.1973.tb00203.x. PMID 4490672. {{cite journal}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help)

[34] Basu TK (1982). "Vitamin C-aspirin interactions". Int J Vitam Nutr Res Suppl. 23: 83–90. PMID 6811490.

[35] Ioannides C, Stone AN, Breacker PJ & Basu TK (1982). "Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs". Biochem Pharmacol. 31 (24): 4035–4038. doi:10.1016/0006-2952(82)90652-9. PMID 6818974.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[36] "Dietary Supplement Health and Education Act of 1994".

[PNAS1976-37] Cameron E, Pauling L (October 1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proc. Natl. Acad. Sci. USA. 73 (10): 3685–3689. Bibcode:1976PNAS...73.3685C. doi:10.1073/pnas.73.10.3685. PMC 431183. PMID 1068480.

[ACS-38] "Vitamin C". American Cancer Society.

[Cabanillas-39] Cabanillas, F (2010). "Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later?". Puerto Rico Health Sciences Journal. 29 (3): 215–7. PMID 20799507.

[Berger-40] Berger MM (October 2006). "Antioxidant micronutrients in major trauma and burns: evidence and practice". Nutr Clin Pract. 21 (5): 438–49. doi:10.1177/0115426506021005438. PMID 16998143.

[41] Greenhalgh DG (2007). "Burn resuscitation". J Burn Care Res. 28 (4): 555–65. doi:10.1097/bcr.0b013e318093df01. PMID 17665515.

[ABA-42] Pham TN, Cancio LC, Gibran NS (2008). "American Burn Association practice guidelines burn shock resuscitation". J Burn Care Res. 29 (1): 257–66. doi:10.1097/BCR.0b013e31815f3876. PMID 18182930.

[Baker2016-43] Baker, W. L; Coleman, C. I (2016). "Meta-analysis of ascorbic acid for prevention of postoperative atrial fibrillation after cardiac surgery". American Journal of Health-System Pharmacy. 73 (24): 2056. doi:10.2146/ajhp160066. PMID 27806938.

[Polymeropoulos2016-44] Polymeropoulos, Evangelos; Bagos, Pantelis; Papadimitriou, Maria; Rizos, Ioannis; Patsouris, Efstratios; Toumpoulis, Ioannis (2016). "Vitamin C for the Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis". Advanced Pharmaceutical Bulletin. 6 (2): 243. doi:10.15171/apb.2016.033. PMID 27478787.

[Hu2017-45] Hu, Xiaolan; Yuan, Linhui; Wang, Hongtao; Li, Chang; Cai, Junying; Hu, Yanhui; Ma, Changhua (2017). "Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials". International Journal of Surgery. 37: 58–64. doi:10.1016/j.ijsu.2016.12.009. PMID 27956113.

[Hemila2017-46] Hemilä, Harri; Suonsyrjä, Timo (2017). "Vitamin C for preventing atrial fibrillation in high risk patients: A systematic review and meta-analysis". BMC Cardiovascular Disorders. 17. doi:10.1186/s12872-017-0478-5.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Hemila2017b-47] Hemilä, Harri (2017). "Publication bias in meta-analysis of ascorbic acid for postoperative atrial fibrillation". American Journal of Health-System Pharmacy. 74 (6): 372–373. doi:10.2146/ajhp160999. PMID 28274978.

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@@ Line 9: / Line 9: @@
 ==Background==
-The [[World Health Organization]] recommends a daily intake of 45 mg/day of vitamin C for healthy adults, and 25–30&nbsp;mg/day in infants.<ref>{{cite book|title=Vitamin and mineral requirements in human nutrition|date=2004|publisher=World Health Organization |isbn=9241546123 |page=138 |edition=2nd |url=http://whqlibdoc.who.int/publications/2004/9241546123.pdf|accessdate=31 December 2014}}</ref> The [[Vitamin C]] article provides examples of recommendations from individual countries. None exceed 110 mg/day. Vitamin C is necessary for [[Biosynthesis|production]] of [[collagen]] and other biomolecules, and for the prevention of [[scurvy]].<ref name = Gropper>{{Cite book|vauthors=Gropper SS, Smith JL, Grodd JL |year=2004 |title=Advanced Nutrition and Human Metabolism |edition=4th |publisher=Thomson Wadsworth |location=Belmont, CA. US |pages=260–275}}</ref> Vitamin C is an [[antioxidant]], which has led to its endorsement by some researchers as a complementary therapy for improving [[quality of life]].<ref name="pmid17297243">{{cite journal |vauthors=Yeom CH, Jung GC, Song KJ |title=Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration |journal=J. Korean Med. Sci. |volume=22 |issue=1 |pages=7–11 |year=2007 |pmid=17297243 |doi= 10.3346/jkms.2007.22.1.7|pmc=2693571}}</ref> Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.<ref name=UMM>{{cite web |url=https://web.archive.org/web/20051231142109/http://www.umm.edu/altmed/ConsSupplements/VitaminCAscorbicAcidcs.html |title=Vitamin C (Ascorbic Acid) |accessdate=2007-02-19 |date=April 2002 |publisher=University of Maryland Medical Center }}</ref>  Certain animal species, including [[Haplorhini|haplorhine primates]] (which includes [[humans]]),<ref name=pmid5275366>{{cite journal |author=Pauling L |title=Evolution and the need for ascorbic acid |journal=[[Proc. Natl. Acad. Sci. USA]] |volume=67 |issue=4 |pages=1643–1648 |year=1970 |pmid=5275366 |doi= 10.1073/pnas.67.4.1643 |pmc=283405 |bibcode= 1970PNAS...67.1643P }}</ref><ref>{{cite journal |last=Pollock |first=J. I. |authorlink= |last2=Mullin |first2 = R. J. |year=1987 |title=Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity of ''Tarsius'' |journal=American Journal of Physical Anthropology |volume=73 |issue=1 |pages=65–70 |doi=10.1002/ajpa.1330730106 |pmid=3113259 |quote= }}</ref> members of the [[Caviidae]] family of rodents (including [[guinea pigs]] and [[capybaras]]),<ref>{{cite book|author1=R. Eric Miller |author2=Murray E. Fowler |title=Fowler's Zoo and Wild Animal Medicine, Volume 8|page=389|url=https://books.google.com/books?id=llBcBAAAQBAJ&pg=PA389&lpg=PA389&dq=Caviidae+%22vitamin+C%22&source=bl&ots=ofF-Bu-mx-&sig=nPEZZ68O7v26lmGS9eAGfmaUZ1o&hl=en&sa=X&ved=0ahUKEwiIk471gInNAhUT0WMKHWlpAqAQ6AEISDAH#v=onepage&q=Caviidae%20%22vitamin%20C%22&f=false|accessdate=2016-06-02}}</ref> most species of bats,<ref>{{cite journal | doi=10.1016/0305-0491(80)90131-5 | title=Variation of l-gulonolactone oxidase activity in placental mammals | year=1980 |vauthors=Jenness R, Birney E, Ayaz K | journal = Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology | volume=67 | issue=2 | pages=195–204 }}</ref> many [[passerine]] birds,<ref name = "Martinez del Rio_1997">{{cite journal | title = Can passerines synthesize vitamin C? | author = Martinez del Rio C | journal =  The Auk |date=July 1997 | volume = 114 | issue = 3 | pages = 513–16 | jstor = 4089257 | doi = 10.2307/4089257 }}</ref> and about 96% of fish (the [[teleosts]]),<ref name = "Martinez del Rio_1997"/> do not synthesize vitamin C internally.
+The [[World Health Organization]] recommends a daily intake of 45 mg/day of vitamin C for healthy adults, and 25–30&nbsp;mg/day in infants.<ref>{{cite book|title=Vitamin and mineral requirements in human nutrition|date=2004|publisher=World Health Organization |isbn=9241546123 |page=138 |edition=2nd |url=http://whqlibdoc.who.int/publications/2004/9241546123.pdf|accessdate=31 December 2014}}</ref> The [[Vitamin C]] article provides examples of recommendations from individual countries. None exceed 110 mg/day. Vitamin C is necessary for [[Biosynthesis|production]] of [[collagen]] and other biomolecules, and for the prevention of [[scurvy]].<ref name = Gropper>{{Cite book|vauthors=Gropper SS, Smith JL, Grodd JL |year=2004 |title=Advanced Nutrition and Human Metabolism |edition=4th |publisher=Thomson Wadsworth |location=Belmont, CA. US |pages=260–275}}</ref> Vitamin C is an [[antioxidant]], which has led to its endorsement by some researchers as a complementary therapy for improving [[quality of life]].<ref name="pmid17297243">{{cite journal |vauthors=Yeom CH, Jung GC, Song KJ |title=Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration |journal=J. Korean Med. Sci. |volume=22 |issue=1 |pages=7–11 |year=2007 |pmid=17297243 |doi= 10.3346/jkms.2007.22.1.7|pmc=2693571}}</ref> Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.<ref name=UMM>{{cite web |url=https://web.archive.org/web/20051231142109/http://www.umm.edu/altmed/ConsSupplements/VitaminCAscorbicAcidcs.html |title=Vitamin C (Ascorbic Acid) |accessdate=2007-02-19 |date=April 2002 |publisher=University of Maryland Medical Center }}</ref>  Certain animal species, including [[Haplorhini|haplorhine primates]] (which includes [[humans]]),<ref name=pmid5275366>{{cite journal |author=Pauling L |title=Evolution and the need for ascorbic acid |journal=[[Proc. Natl. Acad. Sci. USA]] |volume=67 |issue=4 |pages=1643–1648 |year=1970 |pmid=5275366 |doi= 10.1073/pnas.67.4.1643 |pmc=283405 |bibcode= 1970PNAS...67.1643P }}</ref><ref>{{cite journal |last=Pollock |first=J. I. |authorlink= |last2=Mullin |first2 = R. J. |year=1987 |title=Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity of ''Tarsius'' |journal=American Journal of Physical Anthropology |volume=73 |issue=1 |pages=65–70 |doi=10.1002/ajpa.1330730106 |pmid=3113259 |quote= }}</ref> members of the [[Caviidae]] family of rodents (including [[guinea pigs]] and [[capybaras]]),<ref>{{cite book|author1=R. Eric Miller |author2=Murray E. Fowler |title=Fowler's Zoo and Wild Animal Medicine, Volume 8|page=389|url=https://books.google.com/?id=llBcBAAAQBAJ&pg=PA389&lpg=PA389&dq=Caviidae+%22vitamin+C%22#v=onepage&q=Caviidae%20%22vitamin%20C%22&f=false|accessdate=2016-06-02|isbn=9781455773992 |date=2014-07-31 }}</ref> most species of bats,<ref>{{cite journal | doi=10.1016/0305-0491(80)90131-5 | title=Variation of l-gulonolactone oxidase activity in placental mammals | year=1980 |vauthors=Jenness R, Birney E, Ayaz K | journal = Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology | volume=67 | issue=2 | pages=195–204 }}</ref> many [[passerine]] birds,<ref name = "Martinez del Rio_1997">{{cite journal | title = Can passerines synthesize vitamin C? | author = Martinez del Rio C | journal =  The Auk |date=July 1997 | volume = 114 | issue = 3 | pages = 513–16 | jstor = 4089257 | doi = 10.2307/4089257 }}</ref> and about 96% of fish (the [[teleosts]]),<ref name = "Martinez del Rio_1997"/> do not synthesize vitamin C internally.
 Since its discovery, vitamin C has been considered almost a [[panacea (medicine)|panacea]] by some,<ref>{{cite book|last=Levy|first=Thomas|title=Primal Panacea|year=2011|publisher=MedFox Publishing|isbn=0983772800|pages=352}}</ref> although this led to suspicions of it being overhyped by others.<ref>{{cite web |url=http://ethesis.helsinki.fi/julkaisut/laa/kansa/vk/hemila/dovitami.pdf |title=Do vitamins C and E affect respiratory infections? |accessdate=2007-02-21 |date=January 2006 |author=Harri Hemilä |publisher=University of Helsinki |format=PDF}}</ref> 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 medicine|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.<ref name="DRItext">{{cite book | last1 = [[Institute of Medicine]] | title = Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids | chapter = Vitamin C | publisher = The National Academies Press | year = 2000 | location = Washington, DC | pages = 95-185 | url = https://www.nap.edu/read/9810/chapter/7 | accessdate = 2017-09-01 | isbn = 0-309-06935-1}}</ref> 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.<ref>{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| deadurl = no| archiveurl = https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| archivedate = March 16, 2016| df = mdy-all}}</ref> 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.<ref name=JapanDRI>[https://www.jstage.jst.go.jp/article/jnsv/59/Supplement/59_S67/_pdf Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins] Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.</ref>
+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.<ref name="DRItext">{{cite book | last1 = [[Institute of Medicine]] | title = Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids | chapter = Vitamin C | publisher = The National Academies Press | year = 2000 | location = Washington, DC | pages = 95–185 | url = https://www.nap.edu/read/9810/chapter/7 | accessdate = 2017-09-01 | isbn = 0-309-06935-1}}</ref> 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.<ref>{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| deadurl = no| archiveurl = https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| archivedate = March 16, 2016| df = mdy-all}}</ref> 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.<ref name=JapanDRI>[https://www.jstage.jst.go.jp/article/jnsv/59/Supplement/59_S67/_pdf Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins] Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.</ref>
 About 70-90% of vitamin C is adsorbed by the body when taken orally at normal levels (30–180&nbsp;mg daily). Adsorption is only about 50% for daily doses of 1 g. Oral administration, even of mega doses, cannot raise blood concentration above 0.22 mM.<ref>{{Cite web
@@ Line 58: / Line 58: @@
 == Interactions ==
-Pharmaceuticals designed to reduce stomach acid, such as the [[proton pump inhibitor|proton-pump inhibitor]]s (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.<ref>{{cite web |url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2036.2005.02568.x?cookieSet=1&journalCode=apt |title=Proton pump inhibitors reduce the bioavailability of dietary vitamin C |accessdate=2007-02-21 |date=September 2005 |author= E. B. Henry, A. Carswell, A. Wirz, V. Fyffe & K. E. L. Mccoll |publisher=Alimentary Pharmacology & Therapeutics }}</ref> In another study, 40&nbsp;mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7&nbsp;µg/mL.<ref>{{cite journal | title=Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice. |date=April 1999 |author1=C. Mowat |author2=A. Carswell |author3=A. Wirz |author4=K.E. McColl | publisher=Alimentary Pharmacology & Therapeutics |pmid=10092303 |volume=116 |journal=Gastroenterology |pages=813–22 |doi=10.1016/s0016-5085(99)70064-8}}</ref>
+Pharmaceuticals designed to reduce stomach acid, such as the [[proton pump inhibitor|proton-pump inhibitor]]s (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.<ref>{{Cite journal|url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2036.2005.02568.x?cookieSet=1&journalCode=apt |title=Proton pump inhibitors reduce the bioavailability of dietary vitamin C |journal=Alimentary Pharmacology and Therapeutics |volume=22 |issue=6 |pages=539–45 |accessdate=2007-02-21 |date=September 2005 |author= E. B. Henry, A. Carswell, A. Wirz, V. Fyffe & K. E. L. Mccoll |publisher=Alimentary Pharmacology & Therapeutics |doi=10.1111/j.1365-2036.2005.02568.x |pmid=16167970 }}</ref> In another study, 40&nbsp;mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7&nbsp;µg/mL.<ref>{{cite journal | title=Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice |date=April 1999 |author1=C. Mowat |author2=A. Carswell |author3=A. Wirz |author4=K.E. McColl | publisher=Alimentary Pharmacology & Therapeutics |pmid=10092303 |volume=116 |issue=4 |journal=Gastroenterology |pages=813–22 |doi=10.1016/s0016-5085(99)70064-8}}</ref>
 Aspirin may also inhibit the absorption of [[vitamin C]].<ref>{{Cite journal|author1=Loh HS, Watters K  |author2=Wilson CW  |lastauthoramp=yes |date=1 November 1973|title=The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings |journal=J Clin Pharmacol |volume=13 |issue=11 |pages=480–486 |pmid=4490672 |url=http://jcp.sagepub.com/cgi/content/abstract/13/11/480 |doi=10.1002/j.1552-4604.1973.tb00203.x}}</ref><ref>{{Cite journal|author=Basu TK |year=1982 |title=Vitamin C-aspirin interactions |journal=Int J Vitam Nutr Res Suppl |volume=23 |pages=83–90 |pmid=6811490}}</ref><ref>{{Cite journal|author=Ioannides C, Stone AN, Breacker PJ & Basu TK |year=1982 |title=Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs |journal=Biochem Pharmacol |volume=31 |issue=24 |pages=4035–4038 |pmid=6818974 |doi=10.1016/0006-2952(82)90652-9}}</ref>
@@ Line 87: / Line 87: @@
 One study performed in 2000 used high intravenous doses of vitamin C (66&nbsp;mg/kg/hour over 24 hours, for a total dose of around 110&nbsp;grams) after severe burn injury,<ref name=Berger/> but despite being described as promising, it has not been [[Replication (scientific method)|replicated]] by independent institutions and thus is not a widely accepted treatment.<ref>{{cite journal |author=Greenhalgh DG |title=Burn resuscitation |journal=J Burn Care Res |volume=28 |issue=4 |pages=555–65 |year=2007 |pmid=17665515 |doi= 10.1097/bcr.0b013e318093df01|url=}}</ref>  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.<ref name=ABA>{{cite journal |vauthors=Pham TN, Cancio LC, Gibran NS |title=American Burn Association practice guidelines burn shock resuscitation |journal=J Burn Care Res |volume=29 |issue=1 |pages=257–66 |year=2008 |pmid=18182930 |doi=10.1097/BCR.0b013e31815f3876 |url=}}</ref>  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.<ref name=Berger>{{cite journal |author=Berger MM |title=Antioxidant micronutrients in major trauma and burns: evidence and practice |journal=Nutr Clin Pract |volume=21 |issue=5 |pages=438–49 |date=October 2006 |pmid=16998143 |doi= 10.1177/0115426506021005438|url=}}</ref>
+===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 <ref name=Baker2016>{{cite journal|doi=10.2146/ajhp160066|pmid=27806938|title=Meta-analysis of ascorbic acid for prevention of postoperative atrial fibrillation after cardiac surgery|journal=American Journal of Health-System Pharmacy|volume=73|issue=24|pages=2056|year=2016|last1=Baker|first1=W. L|last2=Coleman|first2=C. I}}</ref>
+<ref name= Polymeropoulos2016>{{cite journal|doi=10.15171/apb.2016.033|pmid=27478787|title=Vitamin C for the Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis|journal=Advanced Pharmaceutical Bulletin|volume=6|issue=2|pages=243|year=2016|last1=Polymeropoulos|first1=Evangelos|last2=Bagos|first2=Pantelis|last3=Papadimitriou|first3=Maria|last4=Rizos|first4=Ioannis|last5=Patsouris|first5=Efstratios|last6=Toumpoulis|first6=Ioannis}}</ref><ref name=Hu2017>{{cite journal|doi=10.1016/j.ijsu.2016.12.009|pmid=27956113|title=Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials|journal=International Journal of Surgery|volume=37|pages=58–64|year=2017|last1=Hu|first1=Xiaolan|last2=Yuan|first2=Linhui|last3=Wang|first3=Hongtao|last4=Li|first4=Chang|last5=Cai|first5=Junying|last6=Hu|first6=Yanhui|last7=Ma|first7=Changhua}}</ref><ref name=Hemila2017>{{cite journal|doi=10.1186/s12872-017-0478-5|title=Vitamin C for preventing atrial fibrillation in high risk patients: A systematic review and meta-analysis|journal=BMC Cardiovascular Disorders|volume=17|year=2017|last1=Hemilä|first1=Harri|last2=Suonsyrjä|first2=Timo}}</ref>. However, five randomized studies did not find benefit in the USA, so that the benefit was restricted to less wealthy countries <ref name=Hemila2017></ref><ref name=Hemila2017b>{{cite journal|doi=10.2146/ajhp160999|pmid=28274978|title=Publication bias in meta-analysis of ascorbic acid for postoperative atrial fibrillation|journal=American Journal of Health-System Pharmacy|volume=74|issue=6|pages=372–373|year=2017|last1=Hemilä|first1=Harri}}</ref>.
 == See also ==