Orthomolecular medicine
Orthomolecular medicine is a form of alternative medicine, which aims to restore the optimum environment of the body by correcting imbalances or deficiencies based on individual biochemistry using substances natural to the body such as vitamins, dietary minerals, proteins, antioxidants, amino acids, -3 fatty acids, -6 fatty acids, lipotropes, prohormones, dietary fiber and short and long chain fatty acids. It holds that such imbalances or deficiencies can be prevented, treated, or sometimes cured by achieving optimum bodily levels of these substances, either through diet or metabolism. 

# Basics
Orthomolecular medicine is practiced by few conventional medical practitioners. Orthomolecular treatments are instead more common in complementary and alternative medicine fields, increasingly being integrated into over the counter retail products, naturopathic medical textbooks and mainstream pharmaceuticals. 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, which is interpreted in the light of the clinical experience of its practitioners. Orthomolecular medicine and optimum nutrition are based on the idea of individual variation in humans, with individual nutrient requirements varying widely with health, genetic and environmental influences. Aspects of orthomolecular therapy remain controversial among mainstream medical organizations and physicians, who consider many aspects to be lacking sufficient  RCT based evidence. In contrast, orthomolecular proponents argue that many mainstream nutritional studies, both recent and historical, provide investigational and clinical support for their treatments and recommendations. They also argue that orthomolecular therapies are intrinsically less likely to cause dangerous side-effects or harm, since they utilize only chemicals that are normally present in the body.

# History and development
Orthomolecular treatments typically have been experimentally or empirically introduced by physicians or researchers when conventional medical treatments offered neither solution nor hope.
Orthomolecular psychiatry began to be developed in the early 1950s by a group of biochemists and psychiatrists who identified a number of biochemical abnormalities that they thought were associated with mental illness and treated a number of mental disorders using high dosages of certain vitamins.  Orthomolecular megavitamin therapies, such as with tocopherols and ascorbates, date back to the 1930s.
Frederick Klenner, (1907  1984) was an American medical researcher and doctor in general practice in Reidsville, North Carolina. From the 1940s on he experimented with the use of vitamin C megadosage as a therapy for a wide range of illnesses, most notably polio. He authored 28 research papers during his career. He is considered one of the originators of orthomolecular medicine, but his work remains largely unacknowledged by established medicine.
In the late 1950s, Irwin Stone stated published his belief that scurvy was not a dietary disturbance, but a potentially fatal problem that had been misunderstood by nutritionists. Ascorbate was not a trace vitamin but was required in humans in large daily amounts. He produced four papers, between 1965 and 1967, describing the human requirement for ascorbate as genetic defect which he named hypoascorbemia.
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". Pauling subsequently defined "orthomolecular medicine" 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."
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, asserts: "In 1968, the Nobel-prize-winning scientist Linus Pauling coined the term "orthomolecular" to describe the treatment of disease with large quantities of nutrients." 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 definition.
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 prevent,  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, polio, "alcoholism, allergies, arthritis, autism, epilepsy, hypertension, hypoglycemia, migraine, clinical depression, learning disabilities, retardation, mental and metabolic disorders, skin problems, and hyperactivity," Raynaud's disease, heavy metal toxicity, radiation sickness, - Pyroluria, schizophrenia, shock, snakebite, spider bite, tetanus toxin and viral pneumonia.

# Method
Orthomolecular medicine argues that it is preferable to recognize and correct any possible anomalies in metabolism at an early stage, before they cause disease. Orthomolecular medicine posits that many typical diets are insufficient for long term health; thus, orthomolecular medical diagnoses and treatment often focus on use of nutrients such as vitamins, dietary minerals, proteins, antioxidants, amino acids, -3 fatty acids, -6 fatty acids, lipotropes, prohormones, dietary fiber and short and long chain fatty acids.
Orthomolecular therapy attempts to provide what are seen as optimal amounts of these nutrients. Most often, "optimal" has been a matter of the clinical judgment of the orthomolecular practitioner, who gives nutrients in accord with the clinical symptoms of the patient and the practioner's judgment of what is appropriate, rather than the published dietary reference intakes of these nutrients. 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.  Most often today, orthomolecular practitioners use many substances: amino acids, enzymes, hormones, vitamins, minerals, or derivate substances in an effort to supply what they see as optimum levels of these substances.
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 done by increasing the level of dietary fiber. The fatty acids are produced by fermentation of the fiber in the colon, then absorbed into the body. Attempts are also made to aid this process by a combination of probiotics, prebiotics and "glyconutrients". Long chain fatty acids, such as the omega-3 fatty acids alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), may also be given directly, in food or in capsules.

# 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%.  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."

# Criticism

## Methodology
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, run by the Journal of Orthomolecular Medicine, discusses differences between orthomolecular medicine and mainstream medicine, which the website refers to as allopathic medicine.
Amongst the differences, mainstream medicine attaches great importance to evidence-based medicine, particularly to rigorous double-blind randomized controlled trials that test if a treatment is effective and exclude the placebo effect. Orthomolecular medicine proponents, on the other hand, believe that such studies overemphasize certainty and underemphasise patient choice and health freedom.  Mainstream medicine also avoids the use of new treatments whose effects are unknown, instead favoring extensively tested, clinically proven drugs.  They point out that, even with extensive testing, up to 20% of drugs may subsequently have unrecognized, serious adverse reactions, requiring the later addition of the "black box warning", or withdrawal from market.  Orthomolecular medicine holds that their approach may be useful in treating new or incurable diseases, before conventional medical treatments are available.
The skepticism about orthomolecular medicine comes in part because some of its proponents make claims more broad than those supported by scientific research, particularly claims that contradict clinical trials  and instead consider observational studies, clinical and anecdotal experience, single blinded controlled tests, and case histories.  Proponents of orthomolecular medicine argue that, despite the extensive testing of pharmaceuticals, some medications are withdrawn after approval, due to serious adverse events, and the FDA regulatory methodology and relationship with the pharmaceutical industry has been criticized.

## Views on Safety and Efficacy
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.  Some mainstream medical practitioners dismiss orthomolecular medicine.  For example, an adviser on alternative medicine to the National Institutes of Health, once stated that "Scientific research has found no benefit from orthomolecular therapy for any disease" Proponents of orthomolecular medicine counter that vitamins are used in conventional medicine as treatments for a few diseases, such niacin for dyslipidemias (1955).
Nutritional supplements, such as those used in orthomolecular medicine, are less regulated than pharmaceuticals in the United States. Furthermore, a recent meta-analysis in JAMA has suggested that supplementation with combinations of beta carotene, vitamin A, and vitamin E may increase mortality, and this risk may be particularly high in smokers. An essential regulatory difference is that 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.  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 some supplements are more tightly regulated or even unavailable.

# Relation to mainstream medicine
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:
- Greater than the RDA of selenium may reduce the overall incidence of cancers; this effect is strongest in people who had low selenium levels before treatment.
- Greater than the RDA of vitamin D may reduce the risk of cancer in post-menopausal women. It may also increase the immune response to a wide range of viruses, fungi and bacteria.  
- Greater than the RDA of "A, B6, C and E plus zinc", folic acid and selenium  reduce the incidence of specific cancers
- Studies finding that supplementation of long-chain omega-3 essential fatty acids reduced the incidence of cardiac mortality in secondary prevention trials
- Early studies finding that vitamin E alone and vitamin C & E together reduce coronary disease mortality
- Studies finding that niacin, selenium, zinc, vitamin C alone and vitamin E alone and vitamin C & E together reduce overall mortality rates
- Bruce Ames's studies on the effects of vitamins on genetic diseases and biochemical aging processes
- The advocacy of daily multivitamins in cancer prevention by Professor Bruce Ames, by a JAMA review article for "chronic disease prevention in adults", and by an NEJM Editorial. 
Some of these findings have been reported as not consistent with other studies. For example, (see Vitamin E controversy below), a subsequent meta-analysis failed to find benefit to single isomeric alpha tocopheryl ester forms of vitamin E supplementation. Indeed, alpha tocopheryl ester supplementation might increase the risk for congestive heart failure.  The Shutes decades earlier did specifically caution about tocopherol dosage and slow buildup rates for CHF patients and those with pre-existing rheumatic heart problems; modern orthomolecular medicine has different specific nutrient recommendations for CHF patients.  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.  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.
Orthomolecular proponents, such as Robert Cathcart, who predicts that 120+ grams per day intravenous vitamin C should cure SARS and has used up to 250 grams IV vitamin C per day, have been criticised for not having any conventional medical trials of such intravenous vitamin C treatments.
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.  Based on testing with dosages well below orthomolecular recommendations, Linus Pauling has been criticized for making overbroad claims for the efficacy of vitamin C but Paulings' claims have received some support from tests closer to the orthomolecular recommendations during the last few years.
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. 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.
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.  Rare risks 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, hypertension, thrombophlebitis, peripheral neuropathy, ataxia, neurological effects, liver toxicity, congenital abnormalities, spontaneous abortion, gouty arthritis, jaundice, kidney stones, and diarrhea.
  Megavitamin proponents point 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.

## 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 (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). 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.  Orthomolecular recommendations for the full vitamin E complex typically include an additional 25% to 200% w/w of beta-, gamma-, and delta-tocopherols. 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."
A controversial meta-analysis 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.  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. 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, that "he antagonisms that exist between...carotene and vitamin E are complicated", this supplement and smoking exposure combination once had some academic support but synthetic "beta carotene...has previously been shown to be harmful" in smokers, a subpopulation with high oxidative stress.  Long commercialized, multiple antioxidant megavitamin combinations, such as "ACES", that also include antioxidants vitamin C and selenium to recycle the first two antioxidants and aid liver peroxide detoxification, were not tested or measured.
The orthomolecularly-preferred "vitamin E", mixed (natural) R, R,R tocopherols, 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, D3, K1, K2,   selenium, co-enzyme Q10, etc.) in the common orthomolecular range, 600 - 3200 IU alpha tocopherol plus 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   and naturopathic physicians routinely recommend such laboratory tests of biliary and pancreatic functions in their orthomolecular-related modalities.

## Time and therapeutic priority
Conventional physicians express concern that megavitamin and orthomolecular therapies used solely as alternative treatments by other practitioners, if not successful, may create dangerous delays in obtaining conventional treatments, such as radiation and chemotherapy for cancer.  For example, in a highly publicized Canadian case, the chemotherapy and orthomolecular treatments of a 13-year-old cancer patient, Tyrell Dueck, were delayed, possibly fatally, due to his parents' religious beliefs, interest in alternative treatments, and lengthy legal battles.   Orthomolecular medical practitioners and  orthomolecular oriented naturopaths have long expressed similar concerns about conventional medicine, particularly with gut related and chronic diseases as well as viral diseases.: The use of conventional medical treatments, if not successful, may create dangerous delays in people obtaining orthomolecular treatments.  It is usually possible, however, to combine orthomolecular and conventional treatments.

## Other benefits
Several orthomolecular related AIDS approaches such as multivitamins, selenium and amino acids are used with reported improvements in patients. High dose vitamin C treatments have long been used clinically by some orthomolecular practitioners to treat AIDS patients; a minor 1994 in vitro laboratory study raised questions that sustained megadoses of vitamin C might inhibit some immune cells. In these situations, mainstream medical criticism arises when orthomolecular approaches are advocated as substitutes for, rather than complements to, current medical treatments.

## Economic interests and politics
Some orthomolecular proponents claim partisan politics, pharmaceutical industry influence, and competitive considerations to be significant factors. Some prominent orthomolecular proponents sell lines of orthomolecular products and accept some tests questioned about their benefit that vary by medical affiliation.  The Linus Pauling Institute's funding comes mostly from National Institutes of Health. Several orthomolecular therapies have been officially sanctioned within Europe and Japan

# Orthomolecular doctors
- Glen Dettman
- Abram Hoffer
- David Horrobin
- Archie Kalokerinos
- Carl Pfeiffer
- Matthias Rath
- Julian Whitaker

# Orthomolecular scientists
- Abram Hoffer
- Linus Pauling
- Irwin Stone
- Albert Szent-Gyorgyi

# Orthomolecular Journals
The Journal of Orthomolecular Medicine, founded in 1967 as the Journal of Schizophrenia, is the main publication of those involved in Orthomolecular Medicine.  Abram Hoffer has written that "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."

# Bibliography

## Advocates
- Abram Hoffer (1998) Putting It All Together: The New Orthomolecular Nutrition, McGraw-Hill,  ISBN 0-87983-633-4
- Abram Hoffer, M.D. with Linus Pauling (2004) Healing Cancer: Complementary Vitamin & Drug Treatments, CCNM Press,  ISBN 1-897025-11-4
- David Moss (2000) Ph.D, Antioxidants Against Cancer, Equinox Press , ISBN 1881025284
- Pauling, Linus (1986) How to Live Longer and Feel Better, W. H. Freeman and Company, ISBN 0-380-70289-4
- Roger J. Williams, Dwight K. Kalita (1979)  Physician's Handbook on Orthomolecular Medicine, Keats Publishing, ISBN 0-87983-199-5
- J. Alexander (2001) LABORATORY EVALUATIONS IN MOLECULAR MEDICINE: Nutrients, Toxicants and Cell Regulators. Inst. for Advances in Mol. Med., ISBN 0967394910
- Melvyn R. Werbach, Jeffrey Moss (1999) Textbook of Nutritional Medicine,  Third Line Press, ISBN 0-9618550-9-6
- Joseph E. Pizzorno, Jr., Michael T. Murray (November 2005)   Textbook of Natural Medicine, 3rd edition, Churchill Livingstone, ISBN 0-443-07300-7  2368pp

## Critics
- Barrie R. Cassileth (1998) Alternative medicine handbook: the complete reference guide to alternative and complementary therapies. New York: W.W.Norton & Co., ISBN 0-393-04566-8