Orthomolecular medicine

From Wikipedia, the free encyclopedia

Optimum nutrition and orthomolecular medicine are nutritional health and medical approaches<ref name="saul">The War Against Vitamin Therapy doctoryourself.com , Andrew Saul, PhD - Accessed, August 2006</ref> which posit that many diseases and abnormalities result from various chemical imbalances or deficiencies and can be prevented, treated, or sometimes cured by achieving optimal levels of naturally occurring chemical substances, such as vitamins, dietary minerals, enzymes, antioxidants, amino acids, lipotropes, essential fatty acids, prohormones, dietary fiber and intestinal short chain fatty acids.<ref>The American Heritage Stedman's Medical Dictionary, 2nd Edition, 2004.</ref> Many of the substances used are essential nutrients. <ref name="orthomed"> Definition of Orthomolecular medicine at www.orthomed.org Accessed June 2006 </ref> <ref name="oregon"> What is Orthomolecular Medicine?, Linus Pauling Inst. Oregon State University , Accessed August 2006 </ref>

Orthomolecular medicine is explicitly practiced by relatively few conventional medical practitioners.<ref name="cassileth"> Cassileth BR. Alternative medicine handbook: the complete reference guide to alternative and complementary therapies. New York: W.W.Norton & Co., 1998:67.</ref><ref name="qw">Orthomolecular Therapy, Barrett S, Quackwatch, accessed 6 Nov 2006 criticism of two early, orthomolecular psychiatry treatments</ref><ref name="wund">Orthomolecular Medicine Revisited, Wunderlich RC, Orthomolecular Medicine Online, accessed 6 Nov 2006 </ref> Orthomolecular treatments are also utilized in complementary and alternative medicine fields, increasingly being integrated into OTC retail products, naturopathic medical textbooks and mainstream pharmaceuticals.<ref name="omacorx">OMACOR^®(omega-3-acid ethyl esters), Reliant Pharmaceuticals, Inc.</ref><ref>Greene R, Cortez MF. Abbott to Buy Kos Pharmaceuticals for $3.7 Billion (Update2). Bloomberg.com, 6 Nov 2006.</ref> The controversial field of orthomolecular psychiatry deals with the use of orthomolecular medicine to treat psychiatric problems.

The orthomolecular field is based on research in biochemistry, nutrition, medicine, and pharmaceuticals combined with the clinical experience of a number of physicians and physician scientists. It remains controversial among mainstream medical organizations and physicians, who consider many aspects to be complementary, alternative or integrative medicine . Orthomolecular proponents argue that many mainstream nutritional studies, both recent and historical, provide investigational and clinical support for their theories.<ref> Orthomolecular Medicine News Service (OMNS) Listing or research and news items favourable to the Orthomolecular point of view </ref> They also argue that orthomolecular therapies are intrinsically less likely to cause dangerous side-effects or harm, since they utilize only molecules which are normally present in the body through healthy diet or normal metabolism.<ref name="orthomed"/><ref name="oregon"/><ref> How safe are vitamins? Orthomolecular Medicine News Service, November 9, 2005 - Accessed August 2006 </ref>

[edit] History and development

Orthomolecular type treatments typically have been experimentally or empirically introduced by physicians with advanced scientific or research backgrounds when conventional medical treatments offered neither solution<ref>Observations On the Dose and Administration of Ascorbic Acid When Employed Beyond the Range of a Vitamin in Human Pathology</ref><ref>Alpha-Lipoic Acid (Thioctic Acid): My Experience</ref> nor hope.<ref>Reduction of Cholesterol and Lp(A) in Regression of Coronary Artery Disease: A Case Study </ref><ref>Coenzyme Q10: A Novel Cardiac Antioxidant (1997)</ref> Orthomolecular megavitamin therapies, such as with tocopherols<ref>New/Old Findings on Unique Vitamin E</ref> and ascorbates,<ref>AscorbateWeb: Timeline from 1935 to 1939</ref> date back to the 1930s.

The term "orthomolecular" was first used by Linus Pauling in 1968 to express the "idea of the right molecules in the right amounts within the context of psychiatry".<ref name="pauling1968"> Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease,Science 1968 Apr 19;160(825):265-71.(PMID 5641253) [1]</ref> "Orthomolecular medicine" was subsequently defined as "the treatment of disease by the provision of the optimum molecular environment, especially the optimum concentrations of substances normally present in the human body" or as "the preservation of good health and the treatment of disease by varying the concentrations in the human body of substances that are normally present in the body and are required for health."<ref> Definition of Orthomolecular medicine at www.orthomed.org Accessed June 2006 and What is Orthomolecular Medicine?, Linus Pauling Inst.</ref>

Since 1968 the orthomolecular field has diversified, but the term is still often closely associated with Pauling's advocacy of multi-gram doses of vitamin C for optimal health. Partly for this reason, detractors of orthomolecular ideas have described them entirely in terms of megadose nutrient therapy. Cassileth, a widely quoted critic of Pauling's ideas, states: "In 1968, the Nobel-prize-winning scientist Linus Pauling coined the term "orthomolecular" to describe the treatment of disease with large quantities of nutrients."<ref name="cassileth"/> In this way, criticism of orthomolecular medicine has, to a large extent, been confused with much older medical traditions of high-dose vitamin therapies, such as earlier "megadose" usages of retinol and ergocalciferol or synthetic pharmaceutical analogues, such as menadione. However, such definitions of orthomolecular therapy are not synonymous with Pauling's ideas.

Based on investigational scientific studies, single blinded and double blinded randomized controlled trials, clinical experience, and case histories, claims have been made that therapeutic nutrition can treat, or sometimes cure, acne, bee sting, burns, cancer, common cold, drug addiction, drug overdose, heart diseases, acute hepatitis, herpes, influenza, mononucleosis, mushroom poisoning, neuropathy & polyneuritis (including Multiple sclerosis), osteoporosis,<ref>Plaza SW, Lamson DW. [www.thorne.com/pdf/journal/10-1/vit_k10-1.pdf Vitamin K2 in Bone Metabolism and Osteoporosis]. Alt Medicine Review, Vol 10, No 1.</ref> polio, "alcoholism,<ref>Hoffer A, et al. Treatment Protocol for Alcoholism. Orthomolecular Medicine News Service, 1 Jul 2005</ref> allergies, arthritis, autism, epilepsy, hypertension, hypoglycemia, migraine, clinical depression, learning disabilities, retardation, mental and metabolic disorders, skin problems, and hyperactivity,"<ref>Princeton Brain Bio Center. Brochure, distributed to patients. Skillman, N.J., 1983, The Center.</ref><ref name="qw"/> Raynaud's disease, heavy metal toxicity, radiation sickness, * Pyroluria, schizophrenia,<ref>Skinner P, "Orthomolecular Medicine", Gale Encyclopedia of Alternative Medicine: Holistic medicine, Thomson Gale, 2004.</ref> shock, snakebite, spider bite, tetanus toxin and viral pneumonia.

[edit] Method

Orthomolecular medicine argues that some diseases reflect biochemical anomalies and that it is advantageous to recognize and to correct these anomalies at an early stage, before they result in recognizable diseases. Orthomolecular medicine posits that many typical diets are insufficient for long term health; thus, orthomolecular medical diagnoses and treatment often focus on use of natural substances found in a normal diet such as vitamins, dietary minerals, enzymes, antioxidants, amino acids, ω-3 fatty acids, ω-6 fatty acids, lipotropes, prohormones, dietary fiber and short and long chain fatty acids.

Orthomolecular therapy consists in attempting to provide optimal amounts of substances normal to the body, most commonly by oral administration. Most often, "optimal" has been a matter of the clinical judgment of the orthomolecular practitioner, who gave nutrients in accord with the clinical symptoms of the patient and his or her judgement of what is appropriate. The modern orthomolecular practitioner also uses a wide range of laboratory analyses, including those for amino acids, organic acids, vitamins and minerals, functional vitamin status, hormones, immunology, microbiology, and gastrointestinal function. However, many of these tests have not been accepted by mainstream medicine for common diagnostic use.

In the early days of orthomolecular medicine, supplementation usually meant high-dose, single-agent nutrient therapy.<ref name="qw"/> Most often today, the orthomolecular practitioner uses many substances: amino acids, enzymes, non-essential nutrients, hormones, vitamins, minerals, or derivate substances in a therapeutic effort to restore optimum levels for healthy young persons.<ref name="kunin">http://orthomed.org/kunin.html Principles That Identify Orthormolecular Medicine: A Unique Medical Specialty by Richard A. Kunin</ref>

Frequently supplementation with relatively large doses of vitamins is given, and the name megavitamin therapy is popularly associated with the area. Megavitamin therapy is the administration of large amounts of vitamins, often many times greater than the recommended dietary allowance (RDA). The nominal ratio of dose to RDA to qualify for the term "megavitamin therapy" has been a matter of minor semantic debate.

Administration of short-chain fatty acids in orthomolecular practice is usually accomplished by fiber supplementation. The fatty acids are produced by fermentation of dietary fiber in the colon, then absorbed and utilized. This process is often aided by a combination of probiotics, prebiotics and "glyconutrients" added to the diet. Administration of long chain fatty acids, such as the omega-3 fatty acids alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) may be accomplished by dietary means, or by supplementation with the appropriate fats or fatty acid esters in capsule form.

Nutritional substances may also be administered by changing the diet to emphasize certain foods high in nutrients, by dietary supplementation with oral preparations such as tablets or capsules, or by intravenous injection of nutrient solutions.

[edit] Popularity

A survey released in May 2004 by the National Center for Complementary and Alternative Medicine focused on who used complementary and alternative medicine (CAM), what was used, and why it was used in the United States by adults age 18 years and over during 2002. The survey reported uses in the previous 12 months that include orthomolecular related uses: Nonvitamin, nonmineral, natural products 18.9%, Diet-based therapies 3.5%, Megavitamin therapy 2.8%.<ref>NCCAM.NIH table 1 on page 8 </ref> The survey did not include other popular related categories such as juicing, supplemental antioxidants, essential fatty acids, amino acids, enzymes and others.

Another recent CAM survey reported 12% of liver disease patients using the antioxidant silymarin, more than 6% used megavitamins among others, and "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."<ref>Strader DB, Bacon BR, Lindsay KL, La Brecque DR, Morgan T, Wright EC, Allen J, Khokar MF, Hoofnagle JH, Seeff LB.

Use of complementary and alternative medicine in patients with liver disease. Am J Gastroenterol. 2002 Sep;97(9):2391-7.</ref>

[edit] Relation to mainstream medicine

Orthomolecular medicine claims an evolving nutritional pharmacology that overlaps between natural medicine and mainstream medicine. The International Society for Orthomolecular Medicine has conventionally-trained doctors among its members and authors. However, the leading orthomolecular medicine website, Orthomolecular Medicine Online,<ref>http://orthomed.org Orthomolecular Medicine Online</ref> run by the Journal of Orthomolecular Medicine, discusses differences between orthomolecular medicine and current mainstream medicine,<ref name="kunin"> Principles That Identify Orthormolecular Medicine: A Unique Medical Specialty</ref> which the website refers to as allopathic medicine.<ref name="wund">http://orthomed.org/wund.html</ref>

Amongst the differences, mainstream medicine attaches great importance to rigorous double-blind randomized controlled trials<REF>Smith GCS, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003;327:1459-1461 (20 December)</REF> to prove a treatment is effective and to exclude the placebo effect. Orthomolecular medicine proponents, on the other hand, believe that such studies overemphasize<REF>DJ Hess, Complementary or Alternative? Stronger vs Weaker Integration Policies Am J Public Health. 2002 October; 92(10): 1579–1581.</REF> presupposed minimization of uncertainty in measurement and have instead led to false-negative results from otherwise poorly designed and executed studies<ref>Lexchin J, Light DW. Commercial influence and the content of medical journalsBMJ 2006;332:1444-1447 (17 June)</ref> that resulted in misrepresented "authoritative" disparagement of nutritional treatments.<REF>The Acid Test For Schizophrenia, essay, 2005, accessed September 10, 2006</REF><REF>Hoffer's Home Page -The Schizophrenias, accessed September 10, 2006</REF><REF>P. Scott, E. Richards, B. Martin, Captives of Controversy: The Myth of the Neutral Social Researcher in Contemporary Scientific Controversies, Science, Technology, & Human Values, Vol. 15, No. 4, Fall 1990, pp. 474-494, accessed September 10, 2006</REF> Mainstream medicine avoids use of new, unproven xenobiotic molecules whose effects are unknown, instead favoring extensively tested, clinically proven drugs, of which 20% may subsequently have unrecognized, serious adverse reactions requiring the later addition of the "black box warning", or withdrawal from market.<REF>Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of New Black Box Warnings and Withdrawals for Prescription Medications. JAMA. 2002;287:2215-2220.</REF> Orthomolecular medicine holds that natural equivalent molecules, as non-toxic nutritional therapies, are often useful in the interim, before extremely expensive, time-consuming authoritative tests are available.

Individual mainstream medical proponents are sometimes dismissive of orthomolecular medicine: "Scientific research has found no benefit from orthomolecular therapy for any disease"<ref name="cassileth"> Cassileth BR. Alternative medicine handbook: the complete reference guide to alternative and complementary therapies. New York: W.W.Norton & Co., 1998:67.</ref> despite strong counterexamples such as megadose niacin for dyslipidemias (1955).<ref>http://www.doctoryourself.com/hoffer_cardio.html</ref>

Supporters claim that some aspects of orthomolecular medicine, and in particular the optimal nutrition subset, have support in mainstream scientific research in a variety of areas:

• Studies finding that greater than RDA of selenium<ref name="se15">Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR. JAMA 1996 ;276:1957-63 PMID 8971064 200ug/d of selenium for 4.5 years resulted in a 17% reduction of totality mortality by over 11 years (in total), due to a 50% reduction of (all) cancer mortality, 37% reduction in (all) cancer occurrence </ref><ref name="se71a">Reduction of cancer mortality and incidence by selenium supplementation. Combs GF Jr, Clark LC, Turnbull BW in Med Klin 1997 ;92 Suppl 3:42-5. PMID 9342915</ref><ref name="se71b">Reduction of cancer risk with an oral supplement of selenium. Combs GF Jr, Clark LC, Turnbull BW in Biomed Environ Sci 1997;10:227-34 PMID 9315315 </ref> reduce the overall incidence of cancers

• Studies finding that greater than RDA of "A, B₆, C and E plus zinc",<ref name="lamm99">J Urol. 1994 Jan;151(1):21-6.

Megadose vitamins in bladder cancer: a double-blind clinical trial.Lamm DL, Riggs DR, Shriver JS, vanGilder PF, Rach JF, DeHaven JI. PMID 8254816 "The 5-year estimates of tumor recurrence are 91% in the RDA arm and 41% in the megadose arm"</ref> folic acid<ref name="folatecancer98">Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC; Ann Intern Med" 1998 Oct 1;129(7):517-24 PMID 9758570 Long-term use (>15 years) of folate-containing multivitamin supplements produced an almost 5-fold reduction in the incidence of colon cancer.</ref> and selenium<ref name="se15">Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR. JAMA 1996 ;276:1957-63 PMID 8971064 200ug/d of selenium for 4.5 years resulted in a 17% reduction of totality mortality by over 11 years (in total), due to a 50% reduction of (all) cancer mortality, 37% reduction in (all) cancer occurrence </ref><ref name="se71a">Reduction of cancer mortality and incidence by selenium supplementation. Combs GF Jr, Clark LC, Turnbull BW in Med Klin 1997 ;92 Suppl 3:42-5. PMID 9342915</ref><ref name="se71b">Reduction of cancer risk with an oral supplement of selenium. Combs GF Jr, Clark LC, Turnbull BW in Biomed Environ Sci 1997;10:227-34 PMID 9315315 </ref> reduce the incidence of specific cancers

• Studies finding that supplementation of long-chain omega-3 essential fatty acids<ref>Ridker PM; Ballantyne CM. MD)[http://www.lipidsonline.org/slides/slide01.cfm?q=omacor&dpg=1

Effects of n-3 Fatty Acid Therapy on Lipids and sCAMs], slide, Lipids Online, Baylor College of Medicine, 3 Oct 2001, accessed 10 Nov 2006 </ref> reduced the incidence of cardiac mortality in secondary prevention trials<ref>http://www.ajcn.org/cgi/content/full/77/2/279?ijkey=9ab8b23f0bdf45f83af656d8623815f69608ad01&keytype2=tf_ipsecsha</ref><ref>GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–55.[PMID 10465168]</ref><ref>Orthomolecular Research</ref>

• Early studies finding that vitamin E alone<ref name="vitCE"> Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Losonczy KG, Harris TB, Havlik RJ in Am J Clin Nutr 1996 Aug;64(2):190-6 PMID: 8694019 over 9 years of vitamin E found a 34% reduction in total mortality along with a 47% reduction coronary disease mortality; over 9 years from vitamin C & E use found a 42% reduction in total mortality with a 53% reduction in coronary disease mortality</ref> and vitamin C & E together<ref name="vitCE"/> reduce coronary disease mortality

• Studies finding that niacin<ref name="niacin27g">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.</ref>, selenium<ref name="se15"/>, zinc<ref name="znb">Associations of Mortality With Ocular Disorders and an Intervention of High-Dose Antioxidants and Zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. AREDS Research Group (Authors: Traci E. Clemons, PhD; Natalie Kurinij, PhD; Robert D. Sperduto, MD.) in Arch Ophthalmol. 2004 May;122(5):716-26. PMID: 15136320 "Participants randomly assigned to receive zinc [80mg/d] had lower mortality than those not taking zinc (RR, 0.73; 95% CI, 0.61-0.89)."</ref>, vitamin C<ref name="vitC92"> Vitamin C intake and mortality among a sample of the United States population. Enstrom JE, Kanim LE, Klein MA in Epidemiology 1992 May;3(3):194-202 (PMID 1591317) 35% reduction in mortality over 10 years from vitamin C use</ref> alone and vitamin E<ref name="vitCE"/> alone and vitamin C & E together<ref name="vitCE"/> reduce overall mortality rates

• Bruce Ames's studies on the effects of vitamins on genetic diseases and biochemical aging processes<ref>Bruce N Ames, Ilan Elson-Schwab and Eli A Silver (2002). "High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms". American Society for Clinical Nutrition 75: 616-658. Retrieved on 2006-08-12.</ref><ref name="ames37a">Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Liu J, Killilea DW, Ames BN in Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1876-81 (PMID 11854488)</ref><ref name="ames37b">Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN in Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. (PMID 11854529) </ref><ref name="ames37c">Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN in Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. (PMID 11854487) </ref>

• The advocacy of daily multivitamins in cancer prevention by Bruce Ames<ref name="amesjuvon">http://www.juvenon.com/pdfs/june05_ames-prescrip.pdf</ref><ref name="postrel">http://reason.com/amesint.shtml</ref> and by others in a JAMA review article for "chronic disease prevention in adults"<ref name="fairchild82a">Vitamins for chronic disease prevention in adults: clinical applications. Fletcher RH, Fairfield KM in JAMA 2002 Jun 19;287(23):3127-9 (PMID 12069676) “Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements.[….] We recommend that all adults take one multivitamin daily.[…..] It is reasonable to consider a dose of 2 ordinary [i.e. RDA levels] multivitamins daily in the elderly” </ref><ref name="fairchild82b"> Vitamins for chronic disease prevention in adults: scientific review. Fairfield KM, Fletcher RH in JAMA 2002 Jun 19;287(23):3116-26 (PMID: 12069675) “Although the clinical syndromes of vitamin deficiencies are unusual in Western societies, suboptimal vitamin status is not [unusual].”

</ref>

Some of these findings have reported as not consistent with other studies. For example, see Vitamin E controversy below, a subsequent meta-analysis found a lack of benefit to single isomeric alpha tocopheryl ester forms of vitamin E supplementation.<ref>Vivekananthan D, Penn M, Sapp S, Hsu A, Topol E (2003). "Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials.". Lancet 361 (9374): 2017-23. PMID 12814711.</ref> Indeed, alpha tocopheryl ester supplementation might increase the risk for congestive heart failure.<ref>Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold J, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais G (2005). "Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.". JAMA 293 (11): 1338-47. PMID 15769967.</ref> The Shutes decades earlier did specifically caution about tocopherol dosage and slow buildup rates for CHF patients and those with pre-exisiting rheumatic heart problems; modern orthomolecular medicine has different specific nutrient recommendations for CHF patients.<ref>[2]</ref> Reconciling and confirming the conclusions of individual nutritional studies is a subject of ongoing research.

These studies all come from mainstream medical sources that do not claim to support orthomolecular doctrine, and in at least some cases, explicitly reject claims of orthomolecular proponents that nutritional supplements are desirable.<ref>Spencer JW, Jacobs JJ. Complementary/alternative medicine: an evidence based approach. Toronto: Mosley, 1999:134,137; The selenium shocker. University of California at Berkeley Wellness Letter 1997;13:8-9; http://www.news.cornell.edu/releases/Jan97/selenium.ssl.html</ref> Ames supports daily USRDA multivitamin supplements as a public-policy solution to the lack of vegetables in United States diets, but has not endorsed global use of megavitamin therapy propounded by orthomolecular medicine.<ref name="amesjuvon"/><ref name="postrel"/>

The skepticism about orthomolecular medicine comes in part because some of its proponents make claims more broad than those supported by double-blind randomized controlled studies,<ref name="cassileth"/><ref name="bccancer"/><ref name="qw"/><ref>http://www.tinussmits.nl/english/dynamic.htm?main=http://www.tinussmits.com/english/autism.htm</ref><ref>http://www.canstats.org/readdetail.asp?id=542</ref> additionally considering observational studies, clinical and anecdotal experience, single blinded controlled tests, and case histories. Proponents of orthomolecular medicine argue that, despite the extensive and expensive testing of pharmaceuticals, a number of medications have recently been withdrawn after approval due to serious adverse events, and the FDA regulatory methodology and relationship with the pharmaceutical industry has been criticized.<ref>Marcia Angell, (August 24, 2004) The Truth About the Drug Companies: How They Deceive Us and What to Do About It, Random House, 1st ed, ISBN 0-375-50846-5</ref>

Nutritional supplements, such as those used in orthomolecular medicine, are less regulated than pharmaceuticals in the United States. Pharmaceuticals must be proven safe and effective to the satisfaction of the FDA before they can be marketed, whereas supplements must be proven unsafe before regulatory action can be taken.<ref>Text of the Dietary Supplement Health and Education Act of 1994, legislating that vitamin supplements are regulated as foods rather than as medications. Accessed 21 Sept 2006.</ref> A number of orthomolecular US supplements are available in pharmaceutical versions that are sometimes quite similar in strength and general content, or in other countries are 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 nutritional supplement use have argued that the lower level of regulation results in cost savings for American consumers, pointing to higher supplement prices in Europe, where supplements are more tightly regulated or even unavailable.<ref>Falloon W. What Do “Regulated” Supplements Cost. LE Magazine (online archives), July 2005, p 1</ref>

[edit] Criticism and controversy

The conventional view amongst mainstream medical physicians is that most orthomolecular therapies are insufficiently proven for clinical use, that the scientific foundations are weak, and that the studies that have been performed are too few and too open to disputed interpretation.<ref name="bccancer">"Vitamin Therapy, Megadose / Orthomolecular Therapy" British Columbia Provincial Health Services Authority 2000</ref> Orthomolecular proponents, such as Robert Cathcart who predicts that 120+ grams per day intravenous vitamin C should cure SARS<ref>The Ascorbate Effect in Infectious and Autoimmune Diseases Fourth World Conference on Nutritional Medicine, San Francisco, June 2004.</ref> and has used up to 250 grams IV vitamin C per day, have been criticised without any conventional medical trials of such intravenous vitamin C treatments.<ref>Hasslberger S. Vitamin C could be effective against SARS. New Media Explorer. 6 June 2003 includes republication of article: Mawhinney J. "Vitamin C touted to fight virus." Toronto Star, 30 May 2003.</ref>

Proponents of orthomolecular medicine argue that many mainstream physicians are unfamiliar with the concepts and clinical background of orthomolecular medicine. They dispute the interpretation of results of many mainstream studies, arguing that those interpretations or studies are "strawmen", using much lower doses, frequencies, duration or assimilable forms than they recommend<ref>Saul A, How to Spot Anti- Vitamin Research: Ten Ways to Spot Anti-Vitamin Biases in a Scientific Study, DoctorYourself.com, accessed 1 Nov 2006</ref> or suffered from other special conditions, contamination, populations or statistical treatment often not clearly published in the documentation.<ref>Hoffer A, FACTS AND FACTOIDS: An Information Sheet for Patients, DoctorYourself.com, accessed 1 Nov 2006</ref><ref>Pauling L, (1976) Vitamin C, the Common Cold, and the Flu, W H Freeman & Co , ISBN 0-7167-0361-0</ref><ref name="ref1">Douglas RM, Hemila H (2005). "Vitamin C for preventing and treating the common cold". PLoS Med 2 (6): e168; quiz e217. PMID 15971944.</ref>

The orthomolecular field remains controversial among mainstream 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. A number of individuals and organizations contest the claims, benefits, degree of evidence and toxicity.<ref name="qw"/><ref name="bccancer"/><ref name="cassileth"/><ref name="acs">American Cancer Society 2006 "Orthomolecular Medicine has not been definitively or authoritatively proven to help many of the conditions for which it recommends treatments. However, vitamins, minerals, and other supplements have been and continue to be studied to see if they can help or prevent many types of illness." [3] </ref><ref> Nutrition Committee, Canadian Paediatric Society. Megavitamin and megamineral therapy in childhood. Canadian Medical Association Journal 143:1009-13, 1990, reaffirmed April 2000.</ref> Linus Pauling has been criticized for making overbroad claims<ref>The Dark Side of Linus Pauling's Legacy by Stephen Barrett</ref> for the efficacy of vitamin C but has received some support for modified claims in the last few years.<ref>Padayatty SL et al., Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use Ann Intern Med 2004;140:533-7.</ref><ref name="ref1"/>

The relationship of mainstream medicine to orthomolecular proponents has often been adversarial; orthomolecular proponents argue that mainstream medical claimants confuse orthomolecular medicine with other, less science based modalities.<ref name="kunin"/> The American Academy of Pediatrics labelled orthomolecular medicine a "cult" in 1976, in response to claims that orthomolecular medicine could cure childhood psychoses and learning disorders.<ref>Committee on Nutrition, American Academy of Pediatrics. Megavitamin therapy for childhood psychoses and learning disabilities. Pediatrics 58:910­912, 1976. PMID 995522</ref> Conventional health professionals see orthomolecular medicine as encouraging individuals to dose themselves with large amounts of vitamins and other nutritients without conventional supervision, which they worry might be damaging to health.<ref name="bccancer"/> Rare risks<ref>emedicine - Toxicity statistics, 2003</ref> of non-orthomolecular "mega" dosages of vitamin relatives, which frequently involved pharmaceutical analogues such as synthetic menadione, unsupervised misuse, deliberate abuse and earlier medical treatments, may include increased risk of coronary heart disease<ref>Rapola JM, et al. Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997;349;1715-20.</ref>, hypertension, thrombophlebitis, peripheral neuropathy, ataxia, neurological effects, liver toxicity, congenital abnormalities, spontaneous abortion, gouty arthritis, jaundice, kidney stones, and diarrhea.<ref name="bccancer"/><ref>PMID 3153129</ref> <ref>PMID 3737019</ref><ref> Roberts HJ. Vitamin E [letter]. Lancet 1995 Mar 18;345:737</ref><ref> Kaegi E, on behalf of the Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. Unconventional therapies to cancer: 5. Vitamins A, C, and E. Canadian Medical Association 1998; 158:1483-88.</ref><ref>http://www.quackwatch.org/01QuackeryRelatedTopics/DSH/colds.html</ref> Megavitamin proponents point<REF>http://www.doctoryourself.com/testimony.htm TESTIMONY by Andrew W. Saul before the Government of Canada, House of Commons Standing Committee on Health, regarding natural health product safety (Ottawa, May 12, 2005). </REF> to an almost zero level of deaths caused by vitamins, even with large overdoses, compared to the significant numbers from pharmaceuticals, including a number of over-the-counter items.<REF>http://www.emedicine.com/EMERG/topic638.htm</REF>

[edit] Vitamin E controversy

The accumulated evidence of randomized clinical trials with conventional, chemically-modified alpha tocopheryl esters, containing only one kind of natural vitamin E (of eight vitamers) in the stabilized (chemically inactivated) ester form<REF>Horwitt MK, et al, Serum concentrations of a-tocopherol after ingestion of various vitamin E preparations, Am J Clin Nutr 1984;40: 240-245. The rat-fetal-resorption test currently is used to assess the biological activity of vitamin E compounds. Previous studies in humans, however, suggest that rat assays underestimate the potency of free tocopherol relative to the acetate ester form and of RRR-a-tocopheryl acetate relative to all-rac-a-tocopheryl acetate. Therefore, we studied...20 adult human subjects. Measurements...of 800 IU of the various preparations...at 24 h...mean increase in concentration of a-tocopherols (mg/g lipid) in 24 h was 71.2% after RRR-a-tocopherol, 63.3% after RRR-a-tocopher[yl] acetate plus apple pectin, 60.9% after RRR-a-tocopher[yl] acetate, 31.6% after all-rac-a-tocopher[yl] acetate, and 41.2% after RRR-a-tocopher[yl] succinate. Animal assay data do not correlate with data from studies of absorption and retention in serum of a-tocopherols ingested by humans.</REF> (usually acetate) have been controverted. Initial hopes for alpha tocopheryl esters (usually acetate) were based on suppositional grounds and epidemiological data that often involved the natural, full spectrum dietary forms of vitamin E (mixed R,R,R tocopherols - alpha- beta- gamma-, delta- isomers).<REF>Jiang Q et al.Gamma tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001; 74: 714-22.</REF><REF>JM Gaziano, Vitamin E and Cardiovascular Disease: Observational Studies, Ann. N.Y. Acad. Sci. 1031: 280–291 (2004) "</REF> Meta analysis of several randomized clinical trials of manufactured antioxidants, including alpha tocopheryl esters (acetate, succinate) not in an antioxidant form, have not shown any benefit to alpha tocopheryl ester supplementation for preventing coronary heart disease.<ref name="viv">Vivekananthan D, Penn M, Sapp S, Hsu A, Topol E (2003). "Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials.". 'Lancet' 361: 2017-23. PMID 12814711.</ref> Orthomolecular recommendations for the full vitamin E complex typically include an additional 25% to 200% w/w of beta-, gamma-, and delta-tocopherols.<ref>M Walker, New/Old Findings on Unique Vitamin E, Townsend Letter for Doctors and Patients, No. 111, 1992, p. 826</ref> Recent scientific and medical research shows gamma-tocopherol, the most common vitamer of natural vitamin E, has unique beneficial functions and "gamma tocopherol is considered an integral component of the nutrient-based recommendations in many EU member countries."<ref>L MacWilliam,What Makes Gamma Tocopherol Superior to Alpha Tocopherol, LE Magazine, Report, April 2006</ref>

A controversial meta-analysis<ref name="meta-analysis-mythology">M. Houston, “Meta-Analysis, Metaphysics and Mythology” JANA Vol. 8 No. 1, 2005 original</ref> published in 2005 claimed that "high dose" alpha tocopheryl esters (>=400 units/day) were associated with an all-cause mortality risk difference of 39 per 10,000 persons)<ref name="miller">Miller E, Pastor-Barriuso R, Dalal D, Riemersma R, Appel L, Guallar E (2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.". 'Ann Intern Med' 142: 37-46. PMID 15537682.</ref>. Furthermore, a significant relationship was claimed between dose and all-cause mortality, with increased risk with doses exceeding 150 I.U. per day. This meta-analysis, however, was criticized on a number of grounds.<ref>Carter, T. Responses and Comments: High-Dosage Vitamin E Supplementation and All-Cause Mortality, Ann Intern Med. 2005 Jul 19;143(2):155; responses 150-160</ref> One of several criticisms which the authors did not rebut was that the mortality effect was a confounder resulting entirely from excess mortality in a few studies of combined alpha-tocopheryl ester and synthetic beta carotene in heavy smokers. Known for decades,<ref>Dam HCP. Influence of antioxidants and redox substances on signs of vitamn E defciency. Pharmacol Rev 1957 9: 1-16.</ref> that "[t]he antagonisms that exist between...carotene and vitamin E are complicated",<ref>Hoskins FH. (1980) Antinutrients, Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition, John Wiley & Sons, New York, pp 213-214</ref> this supplement and smoking exposure combination once had some academic support<ref>PMID 16027469</ref> but synthetic "beta carotene...has previously been shown to be harmful"<ref>Jialal I, Devaraj S. Antioxidants and atherosclerosis: don't throw out the baby with the bath water. Circulation. 2003 Feb 25;107(7):926-8. (Comment on: Circulation. 2003 Feb 25;107(7):947-53.) PMID 12600900</ref> in smokers, a subpopulation with high oxidative stress.<ref>Schectman G, Byrd JC, Gruchow HW. The influence of smoking on vitamin C status in adults. Am J Public Health. 1989 February; 79(2): 158–162.</ref> Long commercialized, multiple antioxidant megavitamin combinations, such as "ACES", that also include antioxidants vitamin C<ref> Stone I. Smoker’s Scurvy: Orthomolecular Preventive Medicine in Cigarette Smoking. Orthomolecular Psychiatry, 1976, Vol 5, No 1, pp. 35-42</ref> and selenium<ref>Hercberg S, Galan P, et al, The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2005 Feb 14;165(3):286.</ref> to recycle the first two antioxidants and aid liver peroxide detoxification, were not tested or measured.<ref name="meta-analysis-mythology"/>

The orthomolecularly-preferred "vitamin E", mixed (natural) R,R,R tocopherols,<ref name="meta-analysis-mythology"/> available for two-thirds of a century, remain to be authoritatively evaluated in tests controlled for bile, pancreatic function, certain specific heart problems and risk factors, blood levels and cofactors (vitamins C, D_{3, K1, K2,<REF>JM Geleijnse, C Vermeer, DE Grobbee, LJ Schurgers, MHJ Knapen, IM van der Meer, A Hofman, JCM Witteman, Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study J. Nutr. 134:3100-3105, November 2004</REF> selenium, co-enzyme Q10, etc.) in the common orthomolecular range, 600 - 3200 IU alpha tocopherol plus<i> 25%-200% by weight of other R,R,R tocopherols. With the exception of controlling for standard comorbidities such as heart disease, controlling for pancreatic function, various vitamin cofactors, etc. has not been felt by conventional medicine to be clinically relevant nor routinely done in clinical trials. However, naturopathic medicine texts <REF>Pizzorno JE, Murray MT (November 2005) Textbook of Natural Medicine, 3rd edition, Churchill Livingstone, ISBN 0-443-07300-7, Chapters 12, 14, 24, 59, 181</REF> and naturopathic physicians routinely recommend such laboratory tests<REF>Educational Documents, CDSA 2.0 Universal Kit Guide, Digestive Analysis Solution Center, Genova Diagnostics, accessed 2 Nov 2006</REF> of biliary and pancreatic functions in their orthomolecular-related modalities.}

Abram Hoffer 
Fred R. Klenner 
Robert Cathcart 

David Horrobin 
Carl Pfeiffer 
 Hugh D. Riordan

es:Medicina Ortomolecular fr:Médecine orthomoléculaire nl:Orthomoleculaire therapie