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Frequently used in complementary and alternative medicine and orthomolecular medicine, megavitamin therapists also may employ nutrients[How to reference and link to summary or text] such as dietary minerals, enzymes, amino acids, essential fatty acids, natural antioxidants, fermentable dietary fiber or short chain fatty acids.
The use of large doses of vitamins is medically supported for several dozen specific medical conditions. Historically, some megadose treatments with non-orthomolecular vitamin forms used in conventional medicine have been known to cause harm. The broad claims of effectiveness of many other treatments made by advocates of alternative medicine are considered inadequately substantiated by mainstream medicine.
In the 1930s and 1940s, some scientific and clinical evidence suggested that there might be beneficial uses of vitamins C, E and B-3 in large doses. Beginning in the 1930s, the Shutes in Canada developed a megadose vitamin E therapy for cardiovascular and circulatory complaints, naming it the "Shute protocol" . Tentative experiments in the 1930s with larger doses of vitamin C were superseded by Fred R. Klenner's development of megadose intravenous vitamin C treatments in the 1940s. William Kaufman, MD, PhD, published two books in the 1940s that detailed his treatment of arthritis with frequent, high doses of niacinamide.
In 1954, Professor R. Altschul and Abram Hoffer, MD, PhD, applied large doses of the immediate release form of niacin (Vitamin B-3) to treat hypercholesterolemia (high cholesterol). High dose niacin was shown to be more effective than conventional treatments in the Canner study of the Coronary Drug Project, a large scale, prospective, randomized, controlled trial to reduce long term total mortality, showed 11% reduction in mortality at 15 years follow up with only 6 years of niacin treatment. The other conventional approaches (two estrogen regimens, dextrothyroxine and clofibrate) —treatments that are no longer standard of care—were ineffective.. Niacin is used to treat hypercholesterolemia because of its low cost and its unique ability to broadly improve lipid profiles for ApoB, LDL, small dense LDL, HDL, HDL2b (extremely good cholesterol), Lp(a), fibrinogen and trigycerides.
The 1956 publication of Roger J. Williams Biochemical Individuality<i> introduced concepts for individualized megavitamins and nutrients. In the 1960s, biochemist Irwin Stone, author of The Healing Factor, observed that vitamin C's utility in the megadose treatments of human disease parallels the amounts of vitamin C physiologically produced in most animals and postulated humans' evolutionary loss of this capability. Megavitamin therapies were also publicly advocated by Linus Pauling in the late 1960s.
Several orthomolecular megavitamin protocols have been publicized. While formal medical recognition of niacin therapy for hypercholesterolemia followed confirmation by William Parsons of the Mayo Clinic (1956) and the Canner study (1986), the success of several popular books since the 1980s has made the public more aware of niacin's effective megavitamin therapy for dyslipidemias (abnormal lipid levels in the blood). Pauling's advocacy of megadoses of vitamin C for colds, beginning in the 1960s, and later for cancer, made millions aware of the concept of megavitamin treatment in disease. Pauling's vitamin C recommendations are lower than some modern recommendations.
Other treatments include orthomolecular oral dosing schedules for an early, "abortive" treatment of a cold at onset, and for bowel tolerance for more established colds, typically using 40 to 100+ grams per day in hourly doses as recommended as effective by orthomolecular practitioners.
Usage of therapy
An American cottage industry in the late 20th century, the evolving megavitamin therapy are integrated with orthomolecular and naturopathic medicine. Although megavitamin therapy still largely remains outside of the structure of conventional medicine and the pharmaceutical industry, they are increasingly used by patients, with or without the approval of their treating physicians. In the 21st century, proposed megavitamin therapies with vitamin C are being evaluated for their possible use in cancer.
Criticism and side effects
The effectiveness of various megavitamin therapies has been disputed by many conventional medical personnel, including about safety, definition and validation of efficacy. For example, some critics claim that there is no evidence that ingesting once a day supplements of 1 to 3 grams of Vitamin C is significant in treating the common cold for ordinary people. Reviews and re-examinations by Colchrane Collection author, Harri Hemilä, have meticulously documented that many previous "expert" statements on vitamin C have suffered from serious mathematical errors, selection bias, and misinterpretation, and that even these infrequent, intermediate "megadoses", although much lower than the dosages recommended by vitamin C megavitamin advocates, do show statistically significant benefit. There has been more general agreement that such intermediate dosages may help some stressed or compromised subpopulations. The orthomolecular advocates publish, and use, much higher, more frequent oral dose recommendations for vitamin C, in the 40 to 100+ grams per day range for treating colds and around 150 grams per day for flu.
The term "megavitamin therapy" itself was criticized by opponents of orthomolecular psychiatry in the early 1970s as misleading, because they believed the term falsely implied therapeutic benefit, because of still unresolved disputes over scientific rigor and efficacy for the early 1950s treatment of a carefully specified type of acute schizophrenia.
Some megadose vitamin uses, often older pharmaceutical ones such as neonatal use of synthetic menadione, "a synthetic lipid soluble product which was once called vitamin K3",  can cause toxicity. In the specific case of synthetic K3, large doses may cause hemolytic anemia, which occurs when the red blood cells die more quickly than the body can reproduce. In addition, K3 speeds liver damage, producing jaundice, deafness, and severe neurological problems, including retardation in infants. There is no record that the other two, natural series of Vitamin K, have produced toxic levels. The pharmaceutical synthetic, K3, is now banned in most countries for neonatal or general human use. These were previously conventional medical therapeutics, not orthomolecular type megavitamin treatments.
The United States Department of Agriculture establishes a maximum intake level for most vitamins, at which no adverse effects should occur including many infrequent or minor effects. These are part of the Tolerable upper intake level (UL) recommendations. Extremely high dose vitamin A for previous conventional pediatrics and dermatology practices, beyond orthomolecular therapy ranges, have been deprecated by some medical organizations of minor political units as ineffective and potentially toxic Administration of very large doses of vitamin A, vitamin C, vitamin D, and pyridoxine (Vitamin B6) may have adverse side effects .
- Codex Alimentarius
- Essential nutrient
- Health freedom movement
- Life extension
- Naturopathic medicine
- Orthomolecular medicine
- Schizophrenia - Adrenochrome hypothesis mega doses of vitimin C and niacin may treat schizophrenia?
- Vitamin C megadosage
- ↑ 1.0 1.1 Menolascino FJ, et al. "Orthomolecular Therapy: Its History and Applicability to Psychiatric Disorders", Child Psychiatry and Human Development, Vol.18(3), Spring 1988, pp 140-1
- ↑ http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1339500&blobtype=pdf
- ↑ Canadian Paediatric Society (CPS), "Vitamin D supplementation: Recommendations for Canadian mothers and infants", Paediatrics & Child Health 2007;12(7): 583-589
- ↑ Barker BM, Bender DA (1980, 1982) The Vitamins in Medicine, 4th ed, Vols 1 & 2, William Heinemann Medical Books, London.
- ↑ Report 12 of the Council on Scientific Affairs: Alternative medicine American Medical Association June 1997, Accessed 21 March 2008
- ↑ Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W in J Am Coll Cardiol 1986 Dec;8(6):1245-55 PMID: 3782631 “With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004).” Dose used = 2g – 3g/day for 6 years. The drop in mortality was only evident after 6-8 years.
- ↑ Cancer Survival - Cancer Help
- ↑ |RF Cathcart, Vitamin C, Titrating to Bowel Tolerance, Anascorbemia, and Acute Induced Scurvy, Medical Hypotheses, 7:1359-1376, 1981
- ↑ Robert Landwehr, The Origin of the 42-Year Stonewall of Vitamin C J Orthomolecular Medicine, Vol 6, No. 2, 1991, pp. 99-103
- ↑ 10.0 10.1 Hemilä H. "Do vitamins C and E affect respiratory infections?" Univ. of Helsinki, Dissertation, Faculty of Medicine, Dept. of Public Health. 2006.
- ↑ Surefire Cures for the Common Cold or the Flu!, Vitamin C Foundation, accessed online 27 Feb 2008.
- ↑ Cathcart RF, Vitamin C, Titrating to Bowel Tolerance, Anascorbemia, and Acute Induced Scurvy, Medical Hypotheses, 7:1359-1376, 1981.
- ↑ Orthomolecular Therapy
- ↑ Lipton M and others. Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry. Washington D.C., 1973, American Psychiatric Association.
- ↑ Megavitamin Therapy In Reply To Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry. Canadian Schizophrenia Foundation. August 1976
- ↑  FDA, Environmental Assessment: Vitamin K Active Substances, Section 220.127.116.11. Animal Toxicity, "Phylloquinone[K1] and menaquinone [K2] are nontoxic to animals even when given in large doses. For example, mice receiving a single oral dose of 15-25 g phylloquinone/kg BW showed no adverse effects (Molitor and Robinson, 1940).
- ↑  DrugBank, Vitamin K3, University of Alberta
- ↑ Vitamin K, Innvista
- ↑ FDA, Environmental Assessment: Vitamin K Active Substances
- ↑ CA Burtis, ER Ashwood, DE Bruns (2005) Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, p. 1089, Elsevier-Saunders; 4th ed. ISBN 0721601898 "The use of high doses of naturally occurring vitamin K (K1 and K2) appears to have no untoward effect; however, menadione (K3) treatment can lead to the formation of erythrocyte cytoplasmic inclusions known as Heinz bodies and hemolytic anemia....As no adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals, the U.S. Institute of Medicine has reported that a quantitative risk assessment cannot be performed, and thus a UL cannot be derived for vitamin K"
- ↑ Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed, Ch 63.
- ↑ "Vitamin Therapy, Megadose / Orthomolecular Therapy" British Columbia Provincial Health Services Authority 2000
- ↑ Penniston KL, Tanumihardjo SA (2006) The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 83:191-201. PMID: 16469975
- Abram Hoffer (1998) Putting It All Together: The New Orthomolecular Nutrition, McGraw-Hill, ISBN 0-87983-633-4
- Pauling, Linus (1986) How to Live Longer and Feel Better, W. H. Freeman and Company, ISBN 0-380-70289-4
- Roger J. Williams, Dwight K. Kalita (1979) Physician's Handbook on Orthomolecular Medicine, Keats Publishing, ISBN 0-87983-199-5
- Roger J Williams (1998) Biochemical Individuality: The Basis for the Genetotrophic Concept. 2nd ed. Keats Publishing. ISBN 0-87983-893-0
- Canner, P.L., Berge, K.G., Wenger, N.K., et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol, 1986, 8: 1245-1255.
- Meyers, et al, Varying Cost and Free Nicotinic Acid Content in Over-the-Counter Niacin Preparations for Dyslipidemia, Annals of Internal Med. 2003 Dec 16;139(12):996-1002 
- Guyton, J. R., Blazing, M.A., Hagar, J., et al. Extended-release niacin vs Gemfibrozil for the treatment of low levels of high density lipoprotein cholesterol. Arch Intern Med, 2000, 160: 1177-1184.
- Kamanna, V.S., Kashyap, M.L., Mechanism of Action of Niacin on Lipoprotein Metabolism, Current Atherosclerosis Reports 2000, 2:36-46
- Heady JA, Morris JN, Oliver MF. WHO clofibrate/cholesterol trial: clarifications. Lancet 1992; 340: 1405-1406.
- Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237-1245.
- Irwin Stone (1972) The Healing Factor: Vitamin C Against Disease, GD/Perigee Books (Putnam Pub) ISBN 0-399-50764-7