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Optimum nutrition and orthomolecular medicine are nutritional health and medical approaches 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. Many of the substances used are essential nutrients.

Orthomolecular medicine is explicitly practiced by relatively few conventional medical practitioners. Orthomolecular treatments are also utilized 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 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 treatments and recommendations. 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.

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 nor hope.. Orthomolecular psychiatry began to be developed in the early 1950's by a group of biochemists and psychiatrists who identified a number of biochemical abnormalities associated with mental illness and treated a number of mental disorders using high dosages of certain vitamins. Before Linus Pauling wrote his seminal article in Science, Otto Heinrich Warburg a two time Nobel laureate advocated the use of vitamins and minerals to treat illness, but found that his ideas were ignored. Orthomolecular megavitamin therapies, such as with tocopherols and ascorbates, 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". 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 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 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. 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.

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.

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."

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, run by the Journal of Orthomolecular Medicine, discusses differences between orthomolecular medicine and current mainstream medicine, which the website refers to as allopathic medicine.

Amongst the differences, mainstream medicine attaches great importance to rigorous double-blind randomized controlled trials to prove a treatment is effective and to exclude the placebo effect. Orthomolecular medicine proponents, on the other hand, believe that such studies overemphasize presupposed minimization of uncertainty in measurement and have instead led to false-negative results from otherwise poorly designed and executed studies that resulted in misrepresented "authoritative" disparagement of nutritional treatments. 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. 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, with claims such as "Scientific research has found no benefit from orthomolecular therapy for any disease" despite strong counterexamples such as megadose niacin for dyslipidemias (1955).

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 reduce the overall incidence of cancers

• Studies finding that greater than 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 Bruce Ames and by others in a JAMA review article for "chronic disease prevention in adults"

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.

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, 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.

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. 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.

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. 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 without any conventional medical trials of such intravenous vitamin C treatments.

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 or suffered from other special conditions, contamination, populations or statistical treatment often not clearly published in the documentation.

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.

• Orthomolecular medicine
• Biologically based therapies