The origins of orthomolecular psychiatry date to the 1920s, and the work of Abram Hoffer in the 1950s established the orthodoxy of the field. Hoffer's therapies focused on using niacin, among other nutrients, to treat acute schizophrenia, which was identified using the Hoffer-Osmond test. In 1973, a task force of the American Psychiatric Association examined and rejected the practice and it has been considered an alternative therapy since that time. However, the conclusions of this APA report were strongly criticized by proponents of orthomolecular psychiatry for being politically motivated and scientifically unfounded. Currently there is a clinical trial being conducted on the basis that previous trials were done without taking into account Hoffer's distinction between acute and chronic schizophrenia.
Since Hoffer's early work, other possible nutritional treatments for mental illnesses from both inside and outside the orthomolecular community, and some mainly preliminary current scientific research is consistent with some the hypotheses advanced by orthomolecular psychiatrists, but most orthomolecular practices have not been extensively tested by conventional clinical trials, instead practitioners rely on their interpretations of biochemical research, case reports and clinical series.
The origins of orthomolecular psychiatry can be traced to as early as 1927, and the broad roots of modern orthomolecular medicine involving Linus Pauling trace back to the 1930s. Orthomolecular psychiatry per se is generally accepted to have begun in the 1950s with the work of Abram Hoffer and Humphry Osmond, continued by the work of Carl Pfeiffer. For a time in the late 1950s and early 1960s, research into orthmolecular treatments was given much more prominence but the availability of faster acting orthodox tranquilizers and antidepressants, with clinically proven effects, began to dominate conventional psychiatric practice. In 1968, Linus Pauling gave the name and principle to the discipline of 'orthomolecular psychiatry'.
The earliest assertions by proponents of orthomolecular psychiatry were rejected in 1973 by a panel of the American Psychiatric Association. The protocols used by the APA to test the theories of orthomolecular psychiatry involved populations with chronic schizophrenia as well as populations not expected to benefit from the approach (notably populations with schizoaffective and bipolar disorder). Orthomolecular psychiatry has subsequently found scant support in mainstream psychiatry and is currently considered to be an unproven system of treatments. After 1975, research directly associated with orthomolecular psychiatry was primarily reported in Orthomolecular Psychiatry, now the Journal of Orthomolecular Medicine. A National Institute of Mental Health listed, randomized controlled trial of treatment, with two additional orthomolecular related nutrients originated later in the 1950s, is being tested, and is expected to be complete in 2009.
Orthomolecular methods have been claimed as effective in treating bipolar disorder, schizophrenia, ADHD and some of its sub-types., and tardive dyskinesia. The Journal of Orthomolecular Medicine has also referred to a reported case of a recovery from a diagnosis of Alzheimer's attributed partly to orthomolecular treatment to chelate and reduced exposure to aluminium.
According to orthomolecular psychiatry, the causes of psychotic disorders include pyroluria, histadelia (elevated histamine and basophiles), histapenia with high serum copper (low histamine with high copper), food allergy, hypoglycemia, hypothyroidism in the presence of normal thyroid values, heavy metal intoxications, as well as other rarer conditions.
Hoffer and Osmond developed and used the "Hoffer-Osmond Diagnostic test" of perception, their biochemical research as available in the 1950s and 1960s, and length of illness, acute vs. chronic, to identify, differentiate and monitor schizophrenic patients' progress, with more specific classifications in schizophrenia for orthomolecular treatment than the then accepted, broader classifications of the schizophrenizas. Many orthomolecular physicians still prescribe an initial course of antipsychotics for schizophrenic patients with the long-term goal returning patients to health, and avoiding antipsychotics due to their side-effects. Orthomolecular psychiatry's goal of weaning patients from conventional neuroleptic drugs follows 'Pfeiffer's Law', "For every drug that benefits a patient, there is a natural substance that can achieve the same effect".
A single study of megavitamin and dietary therapy to treat schizophrenia was tested in 1999 and found to be effective at increasing serum levels of vitamins, but did not show any impact on symptoms of schizophrenia.
The orthomolecular treatment of depression generally consists of treating histadelia, which can cause depression without psychosis, with methionine, or augmenting other amino acid imbalances.
The coenzyme S-adenosyl methionine is effective in treating some forms of depression. One paper in the Lancet reported that S-adenosylmethionine was as effective as conventional antidepressants, and linked depression to a disorder of methylation. Pfeiffer and others advocate the use of methionine, which is a precursor to S-adenosyl methionine, to treat some forms of depression, but have not published any clinical trials that would test the effectiveness of this therapy.
The amino acid tryptophan, a precursor of serotonin, is also used to treat some forms of depression; significant differences were found between plasma tryptophan levels in patients suffering from depression and healthy controls. Mainstream psychiatry often treats depression with selective serotonin reuptake inhibitors. There are reports that tryptophan is effective in the treatment of mania.
A 1973 task force of the American Psychiatric Association charged with investigating orthomolecular claims, but instead focused on niacin monotherapeutically (the earliest version of treatment, ca. 1952) for a different kind of patient population, 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.
A study of the effectiveness of an orthomolecular treatment for acute schizophrenia began in 2005, attempting to adequately address the failings of previous APA studies to use an appropriate treatment group and intervention.
Controlled studies using the orthomolecular approach have been few. Those that were done were performed in chronic schizophrenia or in populations that included bipolar and schizoaffective patients. Both of these diagnostic groups are not today considered to benefit from the orthomolecular approach. Moreover, some negative studies of high-dose niacin were done in patients who were not otherwise given general counseling for good diet."; compared with a basic, modern orthomolecular regimen.
Proponents consider the 1973 APA task force report error laden with sweeping, scientifically unfounded conclusions, highly politicized, and that its studies failed to use similar methods, materials and subjects as the original work. The APA report's criticism alleges inadequate controlled trials because Hoffer quit running additional blinded tests that he had come to view as unethical for his patients, especially since the results of his previous double blinded tests went unheeded. The APA's assertion is made despite Hoffer's claim to have run the first double blind controlled test in psychiatry, on megavitamin therapies, with a total four double blinded tests, up to 19 years before the APA task force report, as well as being supported by two independent double blinded tests and an extensive biochemical research program. One of the APA report's five authors, psychologist JR Wittenborn, reacting to Hoffer's specific criticisms, later re-analyzed his original double blind study favorably with respect to orthomolecular psychiatry, obtaining the same result as Hoffer, and never received NIMH or APA support again. According to Hoffer, APA task force co-author Thomas Ban was well known for his tranquilizer studies and that Ban previously stated that much of his income derived from grants from companies and other sources interested in selling tranquilizers. APA task force co-author, then NIMH member Loren Mosher, prior to the serving on the panel, had stated forcibly that if every psychiatrist in the USA believed that megavitamin therapy helped schizophrenic patients, he would not believe it. Mosher later resigned from the American Psychiatric Association in total disgust for reasons unrelated to orthomolecular psychiatry, and referred to the organization as a "drug company patsy. In any event, allegations of misconduct surround panels that influence mainstream psychiatry to this day.
A 2006 literature review noted that studies had found that the frequency of schizophrenia in patients with celiac disease to be significantly above average; one study found schizophrenia to occur in patients with celiac disease 3.2 times as often as in the general population. The review reported that some studies suggest that removal of gluten from the diet of a subset of schizophrenic patients may reduce symptoms in a subset of patients, but that others have seen no effect from dietary changes. It noted that the sample sizes in the studies that found no improvement were very small, so that if only a relatively small subset of schizophrenics do improve, the odds of these studies, one of which was otherwise flawed, not including any of these less common cases was between 48% and 75%. The review attributed the hesitancy with which these positive results have been been received to the fact that many of them had been reported by a group lead by the same researcher, FC Dohan. Dohan reported in one study of 102 patients that 62% of the patients in a locked ward could be discharged to an unlocked ward within 7 days compared to only 36% on a high cereal diet. Another study found that after 90 days, 37.2% of the patients on a gluten and milk-free diet had been discharged from the locked ward compared to 16.1% on a diet rich in cereals. Neither study was double blind, however secretly adding gluten unbeknownst to patients or staff was found to negate the observed different rate of recovery. Other studies not conducted by Dohan have reported similar findings, or symptom improvement on a gluten-free diet which dramatically worsened when gluten was reintroduced.
Also mentioned was a 1997 article about a woman with schizophrenia and celiac disease who experienced a remission of both illnesses when gluten was removed from her diet. SPECT scans before and after the adoption of a gluten-free diet change showed a remarkable resolution of the decreased blood flow to the brain's cortex, which is associated with schizophrenia. The review concluded that large randomized clinical trials (RCTs) will be required to verify if there is a genuine causal relationship between diet and schizophrenia. The problem is that RCTs are very costly, and since it is impossible to patent a diet, there is no motivation for the pharmaceutical or other industry to fund such a trial. Removing gluten and other allergens had long been recommended by orthomolecular psychiatrists when indicated.
A scientist specifically pursuing research in orthomolecular psychiatry has found that women who suffer from postpartum depression on average have a strongly significant higher level of plasma copper than women who haven't suffered from postpartum depression, and that males with a history of violence and assault have a significantly higher median blood copper / zinc ratio.
Carl Pfeiffer posited the existence of a syndrome called "histadelia"; this is claimed to be marked by unnaturally high blood levels of the naturally occurring chemical messenger histamine as well as so-called "undermethylation", which Pfeiffer suggested might cause depression and psychosis. Pfeiffer gave the amino acid methionine to people that he considered had this syndrome. Although there is no published scientific evidence that methionine is effective in the treatment of these mental illnesses, one trial has been published that suggested the coenzyme S-adenosyl methionine is effective in the treatment of depression.
Between 1997 and 1999 the Journal of Orthomolecular Medicine published articles that suggested there was a correlation between amalgam fillings and schizophrenia, bipolar disorder, and multiple sclerosis. Anecdotal accounts also suggested similar ideas, with in 1998 a dentist publishing that a patient who had been diagnosed with multiple sclerosis, but whose symptoms resolved after her amalgam fillings were replaced. The patient's neurologist subsequently concluded that she had never suffered from multiple sclerosis. Another patient described in this study had been almost completely unable to work because of psychological and physical ailments deemed to be psychosomatic, almost completely recovered after her amalgam fillings were removed. Another dentist has written a book describing what he claims are recoveries from multiple sclerosis after the removal of amalgam fillings. A paper on the effects of amalgam fillings on the immune system reported that they can cause the appearance of basophil granulocytes, which are seldom seen in amalgam-free patients. Pfeiffer reported that some schizophrenic patients had extremely high basophil counts. These ideas are not accepted in mainstream science, and a recent meta-analysis of four epidemiological studies found significant differences between the findings of the individual studies, but on average only a slight but insignificant association between amalgam fillings and multiple sclerosis. The United States Public Health Service and American Dental Association's position statements on dental amalgams is that they do not pose a significant risk of adverse health consequences and are a cost-effective, durable and effective option for dental fillings, though an FDA panel felt that there was insufficient research for an unequivocal statement on the safety of amalgams for children, pregnant women and individuals sensitive to mercury.