|Claims||Health effects of dietary supplements, particularly vitamin megadoses.|
|Original proponents||Linus Pauling (coined term)|
|This article is part of a series on|
Orthomolecular medicine is a form of alternative medicine that aims to maintain human health through nutritional supplementation. The concept builds on the idea of an optimal nutritional environment in the body and suggests that diseases reflect deficiencies in this environment. Treatment for disease, according to this view, involves attempts to correct "imbalances or deficiencies based on individual biochemistry" by use of substances such as vitamins, minerals, amino acids, trace elements and fatty acids. The notions behind orthomolecular medicine are not supported by sound medical evidence, and the therapy is not effective; even the validity of calling the orthomolecular approach a form of medicine has been questioned since the 1970s.
The approach is sometimes referred to as megavitamin therapy, because its practice evolved out of, and in some cases still uses, doses of vitamins and minerals many times higher than the recommended dietary intake. Orthomolecular practitioners may also incorporate a variety of other styles of treatment into their approaches, including dietary restriction, megadoses of non-vitamin nutrients and mainstream pharmaceutical drugs. Proponents argue that non-optimal levels of certain substances can cause health issues beyond simple vitamin deficiency and see balancing these substances as an integral part of health.
American chemist Linus Pauling coined the term "orthomolecular" in the 1960s to mean "the right molecules in the right amounts" (ortho- in Greek implies "correct"). Proponents of orthomolecular medicine hold that treatment must be based on each patient's individual biochemistry.
The scientific and medical consensus holds that the broad claims of efficacy advanced by advocates of orthomolecular medicine are not adequately tested as drug therapies. It has been described as a form of food faddism and as quackery. Proponents point to mainstream sources that have published research supporting the benefits of nutrient supplementation and to instances where conventional medicine uses vitamins as treatments for some diseases.
Some vitamins in large doses have been linked to increased risk of cardiovascular disease, cancer and death. The scientific consensus view is that for normal individuals, a balanced diet contains all necessary vitamins and minerals and that routine supplementation is not necessary outside of specific diagnosed deficiencies.
History and development
In the early 20th century, some doctors hypothesised that vitamins could cure disease, and supplements were prescribed in megadoses by the 1930s. Their effects on health were disappointing, though, and in the 1950s and 1960s, nutrition was de-emphasised in standard medical curricula. Riordon's organization cite figures from this period as founders of their movement, although the word "orthomolecular" was coined by Linus Pauling only in 1967.
Amongst the individuals described posthumously as orthomolecularists are Max Gerson, who developed a diet that he claimed could treat diseases, which the American Medical Association's 1949 Council on Pharmacy and Chemistry found ineffective; and the Shute brothers, who attempted to treat heart disease with vitamin E. Several concepts now cited by orthomolecularists, including individual biochemical variation and inborn errors of metabolism, debuted in scientific papers early in the 20th century.
In 1948, William McCormick theorized that vitamin C deficiency played an important role in many diseases and began to use large doses in patients. In the 1950s, Fred R. Klenner also tried vitamin C megadosage as a therapy for a wide range of illnesses, including polio. Irwin Stone stated that organisms that do not synthesise their own vitamin C due to a loss-of-function mutation have a disease he called "hypoascorbemia". This term is not used by the medical community, and the idea of an organism-wide lack of a biosynthetic pathway as a disease was not endorsed by Stone's contemporaries.
In the 1950s, some individuals believed that vitamin deficiencies caused mental illness. Psychiatrists Humphry Osmond and Abram Hoffer gave people having acute schizophrenic episodes high doses of niacin, while William Kaufman used niacinamide. While niacin has no known efficacy in psychiatric disease, the use of niacin in combination with statins and other medical therapies has become one of several medical treatments for cardiovascular disease.
In the late 1960s, Linus Pauling introduced the expression "orthomolecular" to express the idea of the right molecules in the right amounts. Since the first claims of medical breakthroughs with vitamin C by Pauling and others, findings on the health effects of vitamin C have been controversial and contradictory. Pauling's claims have been criticised as overbroad.
According to Abram Hoffer, orthomolecular medicine does not purport to treat all diseases, nor is it "a replacement for standard treatment. A proportion of patients will require orthodox treatment, a proportion will do much better on orthomolecular treatment, and the rest will need a skillful blend of both." Nevertheless, advocates have said that the right nutrients at the optimum dose for the individual concerned can prevent, treat, and sometimes cure a wide range of medical conditions. Conditions for which orthomolecular practitioners have claimed some efficacy are: acne, alcoholism, allergies, arthritis, autism, bee stings, bipolar disorder, burns, cancer, the common cold, depression, drug addiction, drug overdose, epilepsy, heart diseases, heavy metal toxicity, acute hepatitis, herpes, hyperactivity, hypertension, hypoglycemia, influenza, learning disabilities, mental and metabolic disorders, migraine, mononucleosis, mushroom poisoning, neuropathy & polyneuritis (including multiple sclerosis), osteoporosis, polio, a hypothesised condition called "pyroluria", radiation sickness, Raynaud's disease, mental retardation, schizophrenia, shock, skin problems, snakebite, spider bite, tetanus toxin and viral pneumonia.
Hoffer believed that particular nutrients could cure mental illness. In the 1950s, he attempted to treat schizophrenia with niacin, although proponents of orthomolecular psychiatry say that the ideas behind their approach predate Hoffer. According to Hoffer and others who called themselves "orthomolecular psychiatrists", psychiatric syndromes result from biochemical deficiencies, allergies, toxicities or several hypothetical contributing conditions which they termed pyroluria, histadelia and histapenia. These purported causes were said to be found during an "individual biochemical workup" and treated with megavitamin therapy and dietary changes including fasting. These diagnoses and treatments are not accepted by evidence-based medicine.
According to Abram Hoffer, "primitive" peoples do not consume processed foods and do not have "degenerative" diseases. In contrast, typical "Western" diets are said to be insufficient for long-term health, necessitating the use of megadose supplements of vitamins, dietary minerals, proteins, antioxidants, amino acids, ω-3 fatty acids, ω-6 fatty acids, medium-chain triglycerides, dietary fiber, short and long chain fatty acids, lipotropes, systemic and digestive enzymes, other digestive factors, and prohormones to ward off hypothetical metabolism anomalies at an early stage, before they cause disease.
Orthomolecularists say that they provide prescriptions for optimal amounts of micronutrients after individual diagnoses based on blood tests and personal histories. Lifestyle and diet changes may also be recommended. The battery of tests ordered includes many that are not considered useful by medicine.
A survey released in May, 2004 by the National Center for Complementary and Alternative Medicine focused on who used alternative medicine, what was used, and why it was used in the United States by adults age 18 years and over during 2003. The survey reported uses in the previous twelve months that include orthomolecular related uses: Nonvitamin, nonmineral, natural products 18.9%, Diet-based therapies 3.5%, Megavitamin therapy 2.8%.
Another recent CAM survey reported that 12% of liver disease patients used the antioxidant silymarin, more than 6% used vitamins, and that "in all, 74% of patients reported using CAM in addition to the medications prescribed by their physician, but 26% did not inform their physician of their CAM use."
Even though the health benefits are not established, the use of high doses of vitamins is also common in people who have been diagnosed with cancer. According to Cancer Research UK, cancer patients should always seek professional advice before taking such supplements, and using them as a substitute for conventional treatment "could be harmful to [their] health and greatly reduce the chance of curing or controlling [their] cancer".
Medical and scientific reception
Orthomolecular therapies have been criticized as lacking a sufficient evidence base for clinical use: their scientific foundations are too weak, the studies that have been performed are too few and too open to interpretation, and reported positive findings in observational studies are contradicted by the results of more rigorous clinical trials. Accordingly, "there is no evidence that orthomolecular medicine is effective". Proponents of orthomolecular medicine strongly dispute this statement by citing studies demonstrating the effectiveness of treatments involving vitamins, though this ignores the belief that a normal diet will provide adequate nutrients to avoid deficiencies, and that orthomolecular treatments are not actually related to vitamin deficiency. The lack of scientifically rigorous testing of orthomolecular medicine has led to its practices being classed with other forms of alternative medicine and regarded as unscientific. It has been described as food faddism and quackery, with critics arguing that it is based upon an "exaggerated belief in the effects of nutrition upon health and disease." Orthomolecular practitioners will often use dubious diagnostic methods to define what substances are "correct"; one example is hair analysis, which produces spurious results when used in this fashion.
Proponents of orthomolecular medicine contend that, unlike some other forms of alternative medicine such as homeopathy, their ideas are at least biologically based, do not involve magical thinking, and are capable of generating testable hypotheses. Orthomolecular is not a standard medical term, and clinical use of specific nutrients is considered a form of chemoprevention (to prevent or delay development of disease) or chemotherapy (to treat an existing condition).
Despite a lack of evidence for its efficacy, interest in intravenous high dose vitamin C therapy has not been permanently extinguished, and some research groups continue to investigate whether it has an effect as a possible cancer treatment.
Views on safety and efficacy
In general, the vitamin megadoses advocated by orthomolecular medicine are unsupported by scientific consensus. Some vitamins are toxic in high doses, including niacin (B3), cholecalciferol (D) and tocopherol (E). The view of the medical community is that there is no evidence for the efficacy of Orthomolecular medicine as a treatment for cancer, and that high vitamin doses may – on the contrary – increase overall mortality. Nutritional treatments are not generally accepted as being helpful for psychological health. Its claims have been criticized by most medical organizations, including the American Cancer Society, the American Psychiatric Association, the National Institute of Mental Health, the American Academy of Pediatrics, CHAMPUS, and the Canadian Paediatric Society. The American Medical Association describes as "myths" the ideas that adequate nutrition is not readily achievable with normal food, all food grown with pesticide is poisonous, all food additives are poisonous, vitamin and mineral deficiencies are common, that the cause of most disease is poor diet, which can be prevented by nutritional supplements. 
Similarly, the American Cancer Society comments that the current scientific evidence does not "support use of orthomolecular therapy for most of the conditions for which it is promoted." Some supplements have exhibited benefits for specific conditions, while a few have been confirmed to be harmful; the consumption of nutritious foods is the best recognized method to obtain vitamins, minerals, and nutrients crucial for good health. Barrie Cassileth, an adviser on alternative medicine to the National Institutes of Health, stated that "scientific research has found no benefit from orthomolecular therapy for any disease," and medical textbooks also report that there is "no evidence that megavitamin or orthomolecular therapy is effective in treating any disease."
A 1973 task force of the American Psychiatric Association unanimously concluded:
This review and critique has carefully examined the literature produced by megavitamin proponents and by those who have attempted to replicate their basic and clinical work. It concludes in this regard that the credibility of the megavitamin proponents is low. Their credibility is further diminished by a consistent refusal over the past decade to perform controlled experiments and to report their new results in a scientifically acceptable fashion. Under these circumstances this Task Force considers the massive publicity which they promulgate via radio, the lay press and popular books, using catch phrases which are really misnomers like "megavitamin therapy" and "orthomolecular treatment," to be deplorable.
Proponents of orthomolecular medicine counter that some vitamins and nutrients are now used in medicine as treatments for specific diseases, such as megadose niacin and fish oil for dyslipidemias, and megavitamin therapies for a group of rare inborn errors of metabolism. A review in the Annals of Internal Medicine concluded that while some therapies might be beneficial, others might be harmful or interfere with effective medical therapy. A recent study of over 161,000 individuals provided, in the words of the authors, "convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease, or total mortality in postmenopausal women." A recent meta-analysis in JAMA suggested that supplementation with combinations of antioxidant vitamins (beta-carotene, vitamin A, and vitamin E) may increase mortality, although with respect to beta-carotene this conclusion may be due to the known harmful effect in smokers.
In the United States, pharmaceuticals must be proven safe and effective to the satisfaction of the FDA before they can be marketed, whereas dietary supplements must be proven unsafe before regulatory action can be taken. A number of orthomolecular supplements are available in the US in pharmaceutical versions that are sometimes quite similar in strength and general content, or in other countries are regulated as pharmaceuticals. The US regulations also have provisions to recognize a general level of safety for established nutrients that can forgo new drug safety tests. Proponents of orthomolecular medicine argue that supplements are less likely to cause dangerous side-effects or harm, since they are normally present in the body. Some vitamins are toxic in high doses and nearly all (with the possible exception of Vitamin C) will cause adverse effects given high levels of overdosing for prolonged periods as recommended by orthomolecular practitioners. Forgoing medical care in favor of orthomolecular treatments can lead to adverse health outcomes.
Health professionals see orthomolecular medicine as encouraging individuals to dose themselves with large amounts of vitamins and other nutrients without conventional supervision, which they worry might be damaging to health. Potential risks of inappropriate vitamin and supplement regimes include an increased risk of coronary heart disease, hypertension, thrombophlebitis, peripheral neuropathy, ataxia, neurological effects, liver toxicity, congenital abnormalities, spontaneous abortion, gouty arthritis, jaundice, kidney stones, and diarrhea. In their book Trick or Treatment?, Edzard Ernst and Simon Singh conclude that "The concepts of orthomolecular medicine are not biologically plausible and not supported by the results of rigorous clinical trials. These problems are compounded by the fact that orthomolecular medicine can cause harm and is often very expensive."
Example: vitamin E
Orthomolecular proponents claim that even large doses of vitamin E pose no risk to health and are useful for the treatment and prevention of a broad list of conditions, including heart and circulatory diseases, diabetes and nephritis. Initial hopes for the usefulness of vitamin E in orthomolecular medicine were based on epidemiological studies suggesting that people who consumed more vitamin E had lower risks of chronic disease, such as coronary heart disease. These observational studies could not distinguish between whether the higher levels of vitamin E improved health themselves, or whether confounding variables (such as other dietary factors or exercise) were responsible. To distinguish between these possibilities, a number of randomized controlled trials were performed and meta-analysis of these controlled clinical trials have not shown any clear benefit from any form of vitamin E supplementation for preventing chronic disease. Further clinical studies show no benefit of vitamin E supplements for cardiovascular disease. The current position of the American National Institutes of Health is that there is no convincing evidence that vitamin E supplements can prevent or treat any disease.
Beyond the lack of apparent benefit, a series of three meta-analyses reported that vitamin E supplementation is associated with an increased risk of death; one of the meta-analyses performed by the Cochrane Collaboration also found significantly increased mortality for the antioxidant vitamins A and beta-carotene. A subsequent meta-analysis found no mortality benefit from vitamin E, but also no increase in mortality either.
Use in AIDS
Several articles in the alternative-medicine literature have suggested that orthomolecular-related dietary supplementation might be helpful for patients with HIV/AIDS. A study using 250 mg and 1000 mg doses of vitamin C along with other antioxidants to treat people with AIDS did not find any benefit.
A meta analysis in 2010 (updated in 2017 with different results) found that micronutrient supplementation decreased the risk of death and improved outcomes in pregnant women with HIV in Africa. A 2017 Cochrane review found no strong evidence to suggest that micronutrient supplementation prevents death or is effective at slowing the progression of disease for adults with HIV. It is important for people living HIV to eat a healthy adequate diet. For people with HIV that have clinically demonstrated deficiencies in micronutrients or for people who are not able to consume the recommended daily quantities of minerals and vitamins, supplementation is still encouraged. Vitamin A in children with HIV appears to be safe and beneficial. Vitamin A deficiency is found in children with HIV infection who may or may not have symptoms of AIDS. Vitamin A supplementation reduces morbidity and mortality in AIDS symptomatic children, but has no effect on asymptomatic children. It does not prevent HIV infection, cannot treat the chronic HIV infection, and will not cure AIDS.
Deaths resulting from illegal vitamin trials in South Africa
Matthias Rath has been extensively criticized for presenting his vitamin supplements as a treatment for AIDS and for testing them in illegal trials in South Africa. A former associate of Linus Pauling, Rath has promoted vitamins as a treatment for HIV infection, describing treatment with effective antiretroviral drugs as toxic and part of a global conspiracy serving the financial interests of the pharmaceutical industry. In a lawsuit that found against Rath, the South African Medical Association blamed his vitamin products for several deaths. The World Health Organization and two health agencies of the United Nations also described Rath’s advertisements as “wrong and misleading” and “an irresponsible attack on ARV (antiretroviral) therapy.” The South African Centre for Social Science Research described the trials as "state sponsored pseudo-science". Rath's trials, conducted with the aid of AIDS denialist David Rasnick, were declared unlawful by the Cape High Court; Rath, Rasnick and their foundation were barred from conducting further unauthorised clinical trials and from advertising their products.
Alleged institutional bias
Advocates of orthomolecular medicine, including Pauling, Hoffer and Ewan Cameron have claimed that their findings are actively suppressed by the medical and pharmaceutical industry. Hoffer wrote "There is no conspiracy led and directed by a single person or by a single organization. There is no Mafia in psychiatry. However, there is a conspiracy led and directed by a large number of professionals and their associations who have a common aim to protect their hard-earned orthodoxy, no matter what the cost to their opponent colleagues or to their patients."
- We had to create our own journals because it was impossible to obtain entry into the official journals of psychiatry and medicine. Before 1967 I had not found it difficult to publish reports in these journals, and by then I had about 150 articles and several books in the establishment press.
Other members of the medical community deny the existence of such an institutional prejudice. A review in the Journal of Clinical Oncology denied that physicians collude against unconventional treatments. Claims of conspiracy were limited to the now defunct Linus Pauling Institute of Science and Medicine. In its current iteration, the Linus Pauling Institute derives a significant amount of funding from the National Institutes of Health and other federal sources.
- Saul AW; Hoffer A (2008). Orthomolecular Medicine For Everyone: Megavitamin Therapeutics for Families and Physicians. Laguna Beach, California: Basic Health Publications. ISBN 978-1-59120-226-4. OCLC 232131968. OL 16944688M.
- McMichael AJ (January 1981). "Orthomolecular medicine and megavitamin therapy". Med. J. Aust. 1 (1): 6–8. doi:10.5694/j.1326-5377.1981.tb135275.x. PMID 7207301. S2CID 27461422.
- Hoffer A, Walker M (2000). Smart Nutrients. Avery. ISBN 978-0-89529-562-0.
- Skinner Patricia (2004). "Gale encyclopedia of alternative medicine: holistic medicine". Thomson Gale.
- "Orthomolecular medicine". orthomed.org. Archived from the original on 2011-08-13. Retrieved August 2013. Check date values in:
Aaronson S, et al. (2003). "Cancer medicine". In Frei Emil, Kufe Donald W, Holland James F (eds.). Cancer medicine 6. Hamilton, Ontario: BC Decker. pp. 76. ISBN 978-1-55009-213-4.
There is no evidence that megavitamin or orthomolecular therapy is effective in treating any disease.
- "NIH state-of-the-science conference statement on multivitamin/mineral supplements and chronic disease prevention". NIH Consens State Sci Statements. 23 (2): 1–30. 2006. PMID 17332802.
Lipton M, et al. (1973). "Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry". American Psychiatric Association. Cite journal requires
- Braverman Eric (1979). "Orthomolecular Medicine and Megavitamin Therapy: Future and Philosophy" (PDF). Journal of Orthomolecular Medicine. 8 (4): 265.
- Singh, S; Ernst, Edzard (2008). Trick or Treatment: The Undeniable Facts About Alternative Medicine. Norton. p. 320. ISBN 978-0-393-06661-6.
- Pauling L (April 1968). "Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease". Science. 160 (3825): 265–71. Bibcode:1968Sci...160..265P. doi:10.1126/science.160.3825.265. PMID 5641253. S2CID 20153555.
- Baumel Syd (August 2000). Dealing with depression naturally : complementary and alternative therapies for restoring emotional health (2nd ed.). Los Angeles: McGraw-Hill. ISBN 978-0-658-00291-5. OCLC 43641423.
- Williams RJ (1998). Biochemical individuality: the basis for the genetotrophic concept (2 ed.). New Canaan, Connecticut: Keats. ISBN 978-0-87983-893-5. OCLC 38239195.
- Jarvis WT (1983). "Food faddism, cultism, and quackery". Annu. Rev. Nutr. 3: 35–52. doi:10.1146/annurev.nu.03.070183.000343. PMID 6315036.
- Research Newsletter-Fall/Winter 2009 Archived 2013-04-11 at the Wayback Machine. Linus Pauling Institute. Cites research by Gesch summarized in Science magazine's The Theory? Diet Causes Violence. The Lab? Prison.
- Gesch CB, et al. (2002). "Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial". The British Journal of Psychiatry: The Journal of Mental Science. 181: 22–28. doi:10.1192/bjp.181.1.22. PMID 12091259.
- Satia JA, Littman A, Slatore CG, Galanko JA, White E (April 2009). "Long-term Use of β-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study". Am. J. Epidemiol. 169 (7): 815–28. doi:10.1093/aje/kwn409. PMC 2842198. PMID 19208726.[unreliable medical source?]
- Brody, Jane (March 23, 2009). "Extra Vitamin E: No Benefit, Maybe Harm". New York Times. Retrieved March 24, 2009.
- "High dose vitamin E death warning". BBC. November 11, 2004. Retrieved March 24, 2009.
- Duff, Roberta Larson: American Dietetic Association Complete Food and Nutrition Guide, ISBN 0470912073
- Menolascino FJ, Donaldson JY, Gallagher TF, Golden CJ, Wilson JE (1988). "Orthomolecular therapy: its history and applicability to psychiatric disorders". Child Psychiatry Hum Dev. 18 (3): 133–50. doi:10.1007/BF00709727. PMID 2898324. S2CID 38354755.
- "History of orthomolecular medicine". riordonclinic.org. Retrieved 26 August 2013.
- AMA Council on Pharmacy and Chemistry (January 8, 1949). "Report of the council: cancer and the need for facts". JAMA. 139 (2): 93–98. doi:10.1001/jama.1949.02900190023007.
- "Evan Shute & Wilfrid Shute". Hall of Fame. Riordonclinic.org. Retrieved 2013-08-26.
- Mason SF (1997). "The science and humanism of Linus Pauling (1901–1994)". Chemical Society Reviews. 26 (1): 29–39. doi:10.1039/cs9972600029. Archived from the original on 2009-05-15. Retrieved 2009-02-16.
- Magner Lois N (2005). A history of medicine (Second ed.). Washington, DC: Taylor & Francis. ISBN 978-0-8247-4074-0. OCLC 142979953.
- McCormick WJ (January 1951). "Vitamin C in the prophylaxis and therapy of infectious diseases". Arch Pediatr. 68 (1): 1–9. PMID 14800557.
- Saul AW (2007). "Hidden in plain sight: the pioneering work of Frederick Robert Klenner, M.D". Journal of Orthomolecular Medicine. 22 (1): 31–38. Retrieved 2009-02-16.
- Stone I (January 1967). "The genetic disease, hypoascorbemia. A fresh approach to an ancient disease and some of its medical implications". Acta Genet Med Gemellol. 16 (1): 52–62. doi:10.1017/S1120962300013287. PMID 6063937.
- Chatterjee IB (December 1973). "Evolution and the biosynthesis of ascorbic acid". Science. 182 (4118): 1271–2. Bibcode:1973Sci...182.1271C. doi:10.1126/science.182.4118.1271. PMID 4752221. S2CID 26992098.
- Hoffer A, Osmond H, Callbeck MJ, Kahan I (1957). "Treatment of schizophrenia with nicotinic acid and nicotinamide". Journal of Clinical and Experimental Psychopathology. 18 (2): 131–58. PMID 13439009.
- "Orthomolecular medicine". Making treatment decisions. American Cancer Society. 2007-06-19. Archived from the original on 2008-03-29. Retrieved 2008-04-04.
- Guyton JR (2007). "Niacin in cardiovascular prevention: mechanisms, efficacy, and safety". Current Opinion in Lipidology. 18 (4): 415–20. doi:10.1097/MOL.0b013e3282364add. PMID 17620858. S2CID 1647629.
- Chen Q, Espey MG, Sun AY, et al. (August 2008). "Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice". Proceedings of the National Academy of Sciences of the United States of America. 105 (32): 11105–11109. Bibcode:2008PNAS..10511105C. doi:10.1073/pnas.0804226105. PMC 2516281. PMID 18678913.
- Heaney ML, Gardner JR, Karasavvas N, et al. (October 2008). "Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs". Cancer Research. 68 (19): 8031–8. doi:10.1158/0008-5472.CAN-08-1490. PMC 3695824. PMID 18829561. Lay summary – New York Times (2008-10-01).
- Barrett, SJ (2001-05-05). "The dark side of Linus Pauling's legacy". Quackwatch. Retrieved 2008-04-04.
- Kidd PM (September 2007). "Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids". Alternative Medicine Review. 12 (3): 207–27. PMID 18072818.
- Huemer RP (August 1977). "A theory of diagnosis for orthomolecular medicine". J Theor Biol. 67 (4): 625–35. doi:10.1016/0022-5193(77)90250-8. PMID 904336.
- Moyad Mark A (September 24, 2007). "Clinical data shows vitamin C may reduce risks of cancer, heart disease and variety of other health disorders". Genetic Engineering & Biotechnology News (reporting on seminars in preventive and alternative medicine ed.). 3 (1): 25–35. Retrieved October 2007. Check date values in:
- Leung Lit-Hung (1997). "A stone that kills two birds: how pantothenic acid unveils the mysteries of acne vulgaris and obesity". J Orthomol Med. 12 (2): 99–114. ISSN 0834-4825. OCLC 15726974.
- Francis Hartigan (2000). Bill W. : a biography of Alcoholics Anonymous cofounder Bill Wilson. New York: Thomas Dunne Books. pp. 204–209. ISBN 978-0-312-20056-5. OCLC 42772358.
- Cameron Ewan; Pauling Linus (1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proceedings of the National Academy of Sciences. 73 (10): 3685–9. Bibcode:1976PNAS...73.3685C. doi:10.1073/pnas.73.10.3685. PMC 431183. PMID 1068480. (self published)
- Cameron Ewan; Pauling Linus (1979). Cancer and vitamin C : a discussion of the nature, causes, prevention, and treatment of cancer with special reference to the value of vitamin C. New York: Norton. ISBN 978-0-393-50000-4. OCLC 5788147.
- Princeton Brain Bio Center. Brochure, distributed to patients. Skillman, New Jersey, 1983, The Center.
- Plaza, S. M.; Lamson, D. W. (2005). "Vitamin K2 in bone metabolism and osteoporosis". Alternative Medicine Review. 10 (1): 24–35. PMID 15771560.
- Klenner FR (1971). "Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology". J Appl Nutr. 23: 61–88. as reprinted with edits in Hoffer A, ed. (1998). "Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology" (PDF). J Orthomol Med. 13 (4): 198–210. ISSN 0834-4825. OCLC 15726974. (self published)
- Reiter, PJ (1927). "Behandlung von Dementia praecox mit Metallsalzen a. m. Walbum. I. Mangan". Zeitschrift für die Gesamte Neurologie und Psychiatrie. 108: 464–80. doi:10.1007/bf02863975. as cited in Pfeiffer, C; LaMola, S (1983). "Zinc and Manganese in the Schizophrenias". Journal of Orthomolecular Psychiatry. 12 (3).
- Kay Lily E (1993). The molecular vision of life: Caltech, the Rockefeller Foundation, and the rise of the new biology. Oxford: Oxford University Press. ISBN 978-0-19-511143-9.
- Edelman Eva (2001). Natural healing for schizophrenia: and other common mental disorders. Borage. ISBN 978-0-9650976-7-3.
- Barrett, Stephen (2000-07-12). "Orthomolecular therapy". Quackwatch. Retrieved 2008-01-02.
- Weston Price (2008). [Nutrition and Physical Degeneration] (8th ed.). Price Pottenger Nutrition. ISBN 978-0-916764-20-3.
- Cassileth Barrie R (1999). The alternative medicine handbook: the complete reference guide to alternative and complementary therapies. New York: W.W. Norton. pp. 67. ISBN 978-0-393-31816-6. OCLC 40880206.
- Wunderlich RC. "Orthomolecular Medicine Revisited" (PDF). Orthomolecular Medicine Online. Retrieved 2009-03-02.
- Barnes PM, Powell-Griner E, McFann K, Nahin RL (May 2004). "Complementary and alternative medicine use among adults: United States, 2002" (PDF). Adv Data (343): 1–19. PMID 15188733.
- Strader DB, Bacon BR, Lindsay KL, et al. (September 2002). "Use of complementary and alternative medicine in patients with liver disease". Am J Gastroenterol. 97 (9): 2391–7. PMID 12358262.
- Velicer CM, Ulrich CM (2008). "Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review". J Clin Oncol. 26 (4): 665–73. doi:10.1200/JCO.2007.13.5905. PMID 18235127.
- "The safety of vitamins and diet supplements". Cancer Research UK. Retrieved August 2013. Check date values in:
- "Vitamin C for SARS?". Canadian Statistical Assessment Service. June 12, 2003. Archived from the original on September 25, 2005.
- Leibovici L (1999). "Alternative (complementary) medicine: a cuckoo in the nest of empiricist reed warblers". BMJ. 319 (7225): 1629–32. doi:10.1136/bmj.319.7225.1629. PMC 1127092. PMID 10600974.
- Sampson W, Atwood K (2005). "Propagation of the Absurd: demarcation of the Absurd revisited" (PDF). Med J Aust. 183 (11–12): 580–1. doi:10.5694/j.1326-5377.2005.tb00040.x. PMID 16336135. S2CID 43272637.
- Task Force on Complementary; Alternative Medicine; Burch T; et al. (2000). "Report on complementary and alternative medicine" (PDF). Frankfort, Kentucky: Legislative Research Commission.CS1 maint: multiple names: authors list (link)
- Jarvis WT (1983). "Food faddism, cultism, and quackery". Annu Rev Nutr. 3 (1): 35–52. doi:10.1146/annurev.nu.03.070183.000343. PMID 6315036.
- Jukes TH (1990). "Nutrition science from vitamins to molecular biology". Annual Review of Nutrition. 10 (1): 1–20. doi:10.1146/annurev.nu.10.070190.000245. PMID 2200458. A short summary is in the journal's preface.
- Braganza SF; Ozuah PO (2005). "Fad therapies". Pediatrics in Review. 26 (10): 371–376. doi:10.1542/pir.26-10-371. PMID 16199591.
- Lindeman M, Keskivaara P, Roschier M (April 1, 2000). "Assessment of magical beliefs about food and health". Journal of Health Psychology. 5 (2): 195–209. doi:10.1177/135910530000500210. PMID 22049010. S2CID 23255517.
- Jonas WB (1999). "Magic and methodology: when paradigms clash". The Journal of Alternative and Complementary Medicine. 5 (4): 319–21. doi:10.1089/acm.1999.5.319. PMID 10471010.
- Martínez ME, Marshall JR, Giovannucci E (2008). "Diet and cancer prevention: the roles of observation and experimentation". Nature Reviews Cancer. 8 (9): 694–703. doi:10.1038/nrc2441. PMID 19143054. S2CID 376975.
- Ohno, S; Ohno, Y; Suzuki, N; Soma, G; Inoue, M (2009). "High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer". Anticancer Research. 29 (3): 809–15. PMID 19414313.
- Levine, M.; Padayatty, S. J.; Espey, M. G. (2011). "Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries". Advances in Nutrition. 2 (2): 78–88. doi:10.3945/an.110.000109. ISSN 2156-5376. PMC 3065766. PMID 22332036.
- Nutrition Committee; Canadian Paediatric Society (January 1, 1990). "Megavitamin and megamineral therapy in childhood. Nutrition Committee, Canadian Paediatric Society". Canadian Medical Association Journal. 143 (10): 1009–13. PMC 1452516. PMID 1699646.
- National Library of Medicine (March 2009). "Niacin". MedlinePlus Encyclopedia. National Library of Medicine. Retrieved 2010-04-28.
Large doses of niacin can cause liver damage, peptic ulcers, and skin rashes. Even normal doses can be associated with skin flushing. It can be prescribed as a treatment for elevated total cholesterol and other types of lipid disorders, but it should only be used with medical supervision due to its potential for severe side effects.
- National Library of Medicine (March 2009). "Vitamin D". MedlinePlus Encyclopedia. National Library of Medicine. Retrieved 2010-04-28.
Vitamin D deficiency can lead to osteoporosis in adults or rickets in children. Too much vitamin D can make the intestines absorb too much calcium. This may cause high levels of calcium in the blood. High blood calcium can lead to calcium deposits in soft tissues such as the heart and lungs. This can reduce their ability to function. Kidney stones, vomiting, and muscle weakness may also occur in someone who has too much vitamin D.
- National Library of Medicine (March 2009). "Vitamin E". MedlinePlus Encyclopedia. National Library of Medicine. Retrieved 2010-04-28.
In November, 2004, the American Heart Association stated that high amounts of vitamin E can be harmful. Taking 400 IU per day, or higher, may increase the risk of death. Taking smaller amounts, such as those found in a typical multivitamin, was not harmful.
- Bjelakovic, G; Nikolova, D; Simonetti, RG; Gluud, C (16 July 2008). "Antioxidant supplements for preventing gastrointestinal cancers". The Cochrane Database of Systematic Reviews (3): CD004183. doi:10.1002/14651858.CD004183.pub3. PMID 18677777.
- Miller M (1996). "Diet and psychological health". Altern Ther Health Med. 2 (5): 40–8. PMID 8795935.
- Bennett, Forrest C (November 1983). "Vitamin and mineral supplementation in Down's syndrome". Pediatrics. 72 (5): 707–713. PMID 6226926.
- Council on Scientific Affairs (June 1997). "Report 12: Alternative medicine". American Medical Association. Retrieved 2009-02-18.
- Frei Emil; Kufe Donald W; Holland James F (2003). "20.76. Complementary and alternative cancer therapies". Cancer medicine 6. Hamilton, Ontario: BC Decker. pp. 76. ISBN 978-1-55009-213-4. Retrieved 2008-04-04.
- Lipton M, et al. (1973). Task force report on megavitamin and orthomolecular therapy in psychiatry. Washington DC: American Psychiatric Association.; as cited in Barrett, Stephen (2000-07-12). "Orthomolecular Therapy". Quackwatch. Retrieved 2008-01-02.
- American Academy of Pediatrics Committee on Nutrition (1976). "Megavitamin therapy for childhood psychoses and learning disabilities". Pediatrics. 58 (6): 910–2. PMID 995522.
- Eisenberg DM, Cohen MH, Hrbek A, Grayzel J, Van Rompay MI, Cooper RA (December 2002). "Credentialing complementary and alternative medical providers". Ann Intern Med. 137 (12): 965–73. doi:10.7326/0003-4819-137-12-200212170-00010. PMID 12484712. S2CID 7780006.
- Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. (February 2009). "Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts". Arch Intern Med. 169 (3): 294–304. doi:10.1001/archinternmed.2008.540. PMC 3868488. PMID 19204221.
- Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007). "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis". JAMA. 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526. See also the letter to JAMA by Philip Taylor and Sanford Dawsey and the reply by the authors of the original paper.
- "Dietary Supplement Health and Education Act of 1994". Food and Drug Administration. 1994-10-25. Retrieved 2008-04-04.
- Padayatty, S. J.; Sun, A. Y.; Chen, Q.; Espey, M. G.; Drisko, J.; Levine, M. (2010). Gagnier, Joel Joseph (ed.). "Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects". PLOS ONE. 5 (7): e11414. Bibcode:2010PLoSO...511414P. doi:10.1371/journal.pone.0011414. PMC 2898816. PMID 20628650.
- Rosenbloom, M (2007-12-12). "Toxicity, vitamin". eMedicine. Retrieved 2008-04-04.
- Rapola JM, Virtamo J, Ripatti S, et al. (1997). "Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction". Lancet. 349 (9067): 1715–20. doi:10.1016/S0140-6736(97)01234-8. PMID 9193380. S2CID 54392389.
- Huang HY, Caballero B, Chang S, et al. (September 2006). "The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference". Ann Intern Med. 145 (5): 372–85. doi:10.1001/archinte.145.2.372. PMID 16880453.
- Arroyave G (1988). "[Abuse of megadoses of vitamins]". Arch Latinoam Nutr (in Spanish). 38 (3): 589–98. PMID 3153129.
- Blair KA (1986). "Vitamin supplementation and megadoses". Nurse Pract. 11 (7): 19–26, 31–6. doi:10.1097/00006205-198607000-00003. PMID 3737019.
- Roberts HJ; Roberts, H (1995). "Vitamin E". Lancet. 345 (8951): 737. doi:10.1016/S0140-6736(95)90913-3. PMID 7885163. S2CID 5410582.
- Bégin M, Kaegi E (1999). "Unconventional therapies and cancer" (PDF). Canadian Medical Association Journal. 161 (6): 686–7. PMC 1230613. PMID 10513271.
- "Vitamin E: Safe, Effective, and Heart-Healthy". Orthomolecular Medicine News Service. 2005-03-23.
- Traber MG (November 2006). "How much vitamin E?... Just enough!". Am J Clin Nutr. 84 (5): 959–60. doi:10.1093/ajcn/84.5.959. PMID 17093143.
- Gaziano JM (December 2004). "Vitamin E and cardiovascular disease: observational studies". Ann N Y Acad Sci. 1031 (1): 280–91. Bibcode:2004NYASA1031..280G. doi:10.1196/annals.1331.028. PMID 15753154. S2CID 26369772.
- Hemilä H, Miller ER (July 1, 2007). "Evidence-based medicine and vitamin E supplementation". Am J Clin Nutr. 86 (1): 261–2, author reply 262–4. doi:10.1093/ajcn/86.1.261. PMID 17616790.
- Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003). "Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials". The Lancet. 361 (9374): 2017–23. doi:10.1016/S0140-6736(03)13637-9. PMID 12814711. S2CID 41982547.
- Stocker R (2007). "Vitamin E". Dietary Supplements and Health. Novartis Found Symp. Novartis Foundation Symposia. 282. pp. 77–87, discussion 87–92, 212–8. doi:10.1002/9780470319444.ch6. ISBN 978-0-470-31944-4. PMID 17913225.
- Cherubini A, Vigna GB, Zuliani G, Ruggiero C, Senin U, Fellin R (2005). "Role of antioxidants in atherosclerosis: epidemiological and clinical update". Curr Pharm Des. 11 (16): 2017–32. doi:10.2174/1381612054065783. PMID 15974956.
- Kline K, Lawson KA, Yu W, Sanders BG (2007). "Vitamin E and cancer". Vitamin E. Vitam Horm. Vitamins & Hormones. 76. pp. 435–61. doi:10.1016/S0083-6729(07)76017-X. ISBN 9780123735928. PMID 17628185.
- Sesso HD, Buring JE, Christen WG, et al. (November 2008). "Vitamins E and C in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II Randomized Trial". Journal of the American Medical Association. 300 (18): 2123–33. doi:10.1001/jama.2008.600. PMC 2586922. PMID 18997197.
- "Vitamin E". National Institutes of Health. 2009.
- Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2012). "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". Cochrane Database Syst Rev. 3 (3): CD007176. doi:10.1002/14651858.CD007176.pub2. hdl:10138/136201. PMID 22419320.
- Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality". Ann Intern Med. 142 (1): 37–46. doi:10.7326/0003-4819-142-1-200501040-00110. PMID 15537682.
- Bjelakovic G, Nikolova D, Gluud L, Simonetti R, Gluud C (2007). "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis". Journal of the American Medical Association. 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526.
- Abner, E. L.; Schmitt, F. A.; Mendiondo, M. S.; Marcum, J. L.; Kryscio, R. J. (2011). "Vitamin E and all-cause mortality: A meta-analysis". Current Aging Science. 4 (2): 158–170. doi:10.2174/1874609811104020158. PMC 4030744. PMID 21235492.
- Patrick Lyn (December 1999). "Nutrients and HIV: part one -- beta carotene and selenium" (PDF). Altern Med Rev. 4 (6): 403–13. PMID 10608913. Archived from the original (PDF) on 2008-10-06. Retrieved 2008-08-25.
- Lichtenstein BS (1995). "Nutrition and HIV". STEP Perspect. 7 (1): 2–5. PMID 11362399.
- Batterham M, Gold J, Naidoo D, et al. (February 2001). "A preliminary open label dose comparison using an antioxidant regimen to determine the effect on viral load and oxidative stress in men with HIV/AIDS". Eur J Clin Nutr. 55 (2): 107–14. doi:10.1038/sj.ejcn.1601124. PMID 11305623.
- Irlam, James H.; Visser, Marianne Me; Rollins, Nigel N.; Siegfried, Nandi (2010-12-08). Irlam, James H (ed.). "Micronutrient supplementation in children and adults with HIV infection". The Cochrane Database of Systematic Reviews (12): CD003650. doi:10.1002/14651858.CD003650.pub3. ISSN 1469-493X. PMID 21154354.
- Visser, Marianne E.; Durao, Solange; Sinclair, David; Irlam, James H.; Siegfried, Nandi (18 May 2017). "Micronutrient supplementation in adults with HIV infection". The Cochrane Database of Systematic Reviews. 5: CD003650. doi:10.1002/14651858.CD003650.pub4. ISSN 1469-493X. PMC 5458097. PMID 28518221.
- Irlam, James H.; Siegfried, Nandi; Visser, Marianne E.; Rollins, Nigel C. (2013-10-11). "Micronutrient supplementation for children with HIV infection". The Cochrane Database of Systematic Reviews (10): CD010666. doi:10.1002/14651858.CD010666. ISSN 1469-493X. PMID 24114375.
- Grotto I, Mimouni M, Gdalevich M, Mimouni D (March 2003). "Vitamin A supplementation and childhood morbidity from diarrhea and respiratory infections: a meta-analysis". J Pediatr. 142 (3): 297–304. doi:10.1067/mpd.2003.116. PMID 12640379.
- Mehta Saurabh; Fawzi Wafaie (2007). Effects of vitamins, including vitamin A, on HIV/AIDS patients. Vitam Horm. Vitamins & Hormones. 75. pp. 355–83. doi:10.1016/S0083-6729(06)75013-0. ISBN 978-0-12-709875-3. PMID 17368322.
- Kapp C (November 2006). "South Africans hope for a new era in HIV/AIDS policies". Lancet. 368 (9549): 1759–60. doi:10.1016/S0140-6736(06)69717-1. PMID 17120343. S2CID 37147734.
- Smith TC, Novella SP (August 2007). "HIV Denial in the Internet Era". PLOS Med. 4 (8): e256. doi:10.1371/journal.pmed.0040256. PMC 1949841. PMID 17713982.
Boseley Sarah (May 14, 2005). "Discredited doctor's 'cure' for Aids ignites life-and-death struggle in South Africa". The Guardian. Manchester.
*"Apartheid a pharmaceutical plot - Rath". Independent Online. Cape Town. May 10, 2007.
- Watson J (January 2006). "Scientists, activists sue South Africa's AIDS 'denialists'". Nat Med. 12 (1): 6. doi:10.1038/nm0106-6a. PMID 16397537. S2CID 3502309.
- "TAC hails ruling on Rath". Independent Online. Cape Town. June 13, 2008.
- Reed John (July 25, 2005). "HIV fight focuses on ads". Los Angeles Times.
- Geffen N (2005). "Echoes of Lysenko: State-sponsored pseudo-science in South Africa" (PDF). Social Dynamics. 31 (2): 183–210. doi:10.1080/02533950508628713. hdl:11427/19344. S2CID 143821379.
- "South African court bans AIDS vitamin trials". Reuters. June 13, 2008. Retrieved June 20, 2008.
- Hoffer A (1987). "Is there a conspiracy?" (PDF). J Orthomol Med. 2 (3): 158.
- Thomas Hager (1995). Force of nature: the life of Linus Pauling. New York: Simon & Schuster. ISBN 978-0-684-80909-0.
- Hoffer Abram. "History". J Orthomol Med. Archived from the original on 2007-11-01. (via archive.org) archived on November 1, 2007
- Razzouk N, Seitz V (2003). "Marketing to the heart: a practical approach to dealing with health care quackery" (PDF). Clinical Research and Regulatory Affairs. 20 (4): 469–478. doi:10.1081/CRP-120026128. S2CID 73219671.
- Weitzman S (1998). "Alternative nutritional cancer therapies". Int J Cancer Suppl. 11: 69–72. doi:10.1002/(SICI)1097-0215(1998)78:11+<69::AID-IJC20>3.0.CO;2-7. PMID 9876483.
- Gertz MA, Bauer BA (May 2003). "Caring (really) for patients who use alternative therapies for cancer". J Clin Oncol. 21 (9 Suppl): 125s–128s. doi:10.1200/JCO.2003.01.195. PMID 12743218.
- Frei, Balz (June 2006). "From the Director". LPI Research Newsletter (Spring 2006). Archived from the original on 2011-09-19. Retrieved 2006-09-21.
- Hoffer Abram; with Pauling Linus (2004). Healing cancer : complementary vitamin & drug treatments. Toronto: Canadian College of Naturopathic Medicine. ISBN 978-1-897025-11-6. OCLC 56682217.
- Barrett Stephen (1980). The health robbers : how to protect your money and your life (Second ed.). Philadelphia: G. F. Stickley. pp. 52. ISBN 978-0-89313-023-7. OCLC 6994138.
- Cassileth Barrie R (1998). Alternative medicine handbook: the complete reference guide to alternative and complementary therapies. New York: W.W. Norton. ISBN 978-0-393-04566-6. OCLC 36727947.
- Bender David A (2003). Nutritional biochemistry of the vitamins (Second ed.). Cambridge; New York: Cambridge University Press. p. 230. ISBN 978-0-521-80388-5. OCLC 50948594.
- Gratzer Walter B (2005). Terrors of the table: the curious history of nutrition. Oxford; New York: Oxford University Press. pp. 210. ISBN 978-0-19-280661-1. OCLC 60837725.