Frequently used in complementary and alternative medicine and orthomolecular medicine, megavitamin therapy also employs nutrients such as dietary minerals, enzymes, amino acids, essential fatty acids, natural antioxidants and fermentable dietary fiber for short chain fatty acids. Historically megavitamin therapies have been stigmatized, proponents say unfairly, by mainstream medical organizations and their associates.
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 Tentative experiments in the 1930s with larger doses of vitamin C were superseded by Fred R. Klenner's development of megadose intravenous vitamin C treatments in the 1940s.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, critics point out that there is no strong evidence that ingesting once a day supplements of 1 to 3 grams of Vitamin C is effective in treating the common cold for ordinary people. There is some evidence that similar intermediate dosages might help some stressed or compromised subpopulations and that 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.
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, and in the case of K3 large doses may cause hemolytic anemia. Hemolytic anemia 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, forms 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 not orthomolecular type megavitain treatments.
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
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 a dispute over scientific proof. In response to criticisms about the potential dangers of these therapies, megavitamin proponents point to the almost zero level of autopsied deaths caused by overdosing with vitamins compared to the significant numbers from pharmaceuticals, including a number of over-the-counter items.
Administration of very large doses of vitamin A, vitamin C, vitamin D, and pyridoxine (Vitamin B6) may have adverse side effects, usually when used alone rather than balanced with other vitamins or in large, non-orthmolecular overdoses.
The United States Department of Agriculture establishes a maximum intake level for most vitamins, at which no adverse effects should occur. These are part of the Dietary Reference Intake recommendation.
- 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
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- 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 
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- Irwin Stone (1972) The Healing Factor: Vitamin C Against Disease, GD/Perigee Books (Putnam Pub) ISBN 0-399-50764-7 
- Wilfred Shute (1980) Complete Updated Vitamin E Book. New Canaan, CT: Keats Publishing, ISBN 0-87983-151-0
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- Klenner, F. R., Virus Pneumonia and Its Treatment With Vitamin C, So. Medicine & Surgery, Vol. 110, February, 1948, No. 2, pp. 36-38, 46
- Klenner, F. R., Significance Of High Daily Intake Of Ascorbic Acid In Preventive Medicine, 1974 paper
- Lendon H. Smith, MD (1988) Clinical Guide to the Use of Vitamin C - The Clinical Experiences of Frederick R. Klenner, MD 
- William Kaufman (1943) Common Forms of Niacinamide Deficiency Disease: Aniacinamidosis. New Haven, CT: Yale University Press
- William Kaufman (1949) The Common Form of Joint Dysfunction: Its Incidence and Treatment. E.L. Hildreth and Co., Brattleboro, Vermont 
- R. Altschul, A. Hoffer, J.D. Stephen, Arch. Biochem. Biophys., 54, 558, 1955.
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- abstract Goodwin JS, et al. Battling quackery: attitudes about micronutrient supplements in American academic medicine. Arch Intern Med 1998;158:2187-2191. academic MD questions and shows conventional medicine's enduring antipathy and double standard toward nutrients
- 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.
- |RF Cathcart, Vitamin C, Titrating to Bowel Tolerance, Anascorbemia, and Acute Induced Scurvy, Medical Hypotheses, 7:1359-1376, 1981
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-  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
- Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed, Ch 63.
- "Vitamin Therapy, Megadose / Orthomolecular Therapy" British Columbia Provincial Health Services Authority 2000
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