Pauling’s Study of Schizophrenia: Support

[Ed Note: The Pauling Blog becomes a teenager this week! On March 4, 2008 we introduced ourselves to the world with our first post. Thirteen years later, we’re thrilled to be publishing post 5 of 9 in our series on schizophrenia, and post number 810 overall. Our continuing thanks to the many readers who have helped make this such a rewarding experience for the duration.]

As we have seen, Linus Pauling’s work on the use of orthomolecular therapies as a treatment for schizophrenia never attracted anything like widespread acceptance from mainstream psychiatric and psychological professional organizations. But despite this, Pauling’s ideas did attract attention and respect from other corners of the mental health profession, both individuals and groups.

In addition to Abram Hoffer and Humphry Osmond, another early proponent of the orthomolecular approach to schizophrenia was Harry Vanderkamp, who worked for the Veterans Administration Hospital in Battle Creek, Michigan. Notably, in 1966 Vanderkamp published an article in the journal Neuropsychiatry titled, “A Biochemical Abnormality in Schizophrenia involving Ascorbic Acid.” The paper, which Pauling noted and which actually preceded his own first publication on the topic by about two years, echoed the basics of Pauling’s core thesis; that schizophrenia could be successfully treated through megavitamin dosing. In the article, Vanderkamp specifically argued that schizophrenia patients could “metabolize ten times as much [vitamin C]” as those without schizophrenia and that, as such, one might reasonably draw a connection between schizophrenia diagnosis and low levels of vitamin C.

The ideas of Vanderkamp and others informed Pauling’s first formal paper on the subject, “Orthomolecular Psychiatry: Varying the Concentrations of Substances Normally Present in the Human Body May Control Mental Disease.” The article appeared in the April 1968 issue of Science, and attracted a great deal of interest. One particular outcome was a series of invitations to speak on the topic at Tulane University, which invited Pauling to address the school’s entire medical school in May 1970 and again in March 1971. Pauling was chosen for this honor by unanimous decision of the school’s faculty and students, and in both instances the title of his lecture was simply, “Orthomolecular Medicine.” The same was true for a spring 1971 lecture at the University of New Brunswick, as well as four other major talks delivered between 1968-1972.

Pauling also found traction with the American Schizophrenia Foundation following the 1968 publication. Shortly after it appeared, the organization (which later changed its name to the American Schizophrenia Association), offered Pauling space in its newsletter to expand upon his academic work and defend his ideas as necessary. Pauling took advantage of this offer and in the October 1968 issue wrote that megadosing was safe and effective, and that any “psychiatrist who refused to try the methods of orthomolecular psychiatry, in addition to the usual methods, is failing in his duty as a physician.”

Two-and-a-half years later, despite the negative press that Pauling was receiving, the ASA granted Pauling an undisclosed monetary award and provided an additional $1,000 to Stanford University – where Pauling was working at the time – to support continued research on the orthomolecular approach to schizophrenia. Later that same month, the association’s journal, which had been titled Schizophrenia, changed its name to the Journal of Orthomolecular Medicine. At the time of the change, the journal was being edited by Abram Hoffer, who wrote to Pauling that the new name “more accurately reflects the spectrum of [the publication’s] concern.”

Other academic support for Pauling came from the Journal of Autism and Childhood Schizophrenia. Founded in 1971, the journal’s first editor was Leo Kanner, a leading figure in child psychiatry. From the start, Kanner wanted Pauling to serve on the journal’s board as a contributing editor. Pauling accepted this offer and remained a member of the board until 1979, when the mission of the publication changed. But during those years of association, Kanner stressed that Pauling’s role as a contributing editor boosted the publication’s name recognition and, importantly, its credibility. Pauling seemed to enjoy the connection as well, joking at one point that, “Years ago I was a member of the Editorial Board of J.A.C.S. It was, however, the Journal of the American Chemical Society.”

In 1973, when negative press surrounding megadosing crested in the wake of the American Psychiatric Association’s damning task force report, a second round of support for Pauling and orthomolecular medicine emerged in response. In private correspondence, colleagues like J.B. Drori, Chairman of the Committee of Education at John Muir Memorial Hospital, wrote that despite the fact that Pauling’s ideas “have not been widely accepted,” they still “seem to make a lot of sense to me.” Likewise Dr. C. David Geer, chair of the New Jersey Schizophrenia Foundation, who publicly lauded Pauling’s work, noting to a reporter that his own research on megadosing had come to pass as a result of the momentum that Pauling had brought to the field.

And Pauling naturally retained the support of his friends. High among them was Humphry Osmond, who often rallied around Pauling and offered public praise. So too Abram Hoffer who, in a piece detailing historical advances in schizophrenia treatment, wrote of the late 1960s that “Dr. Linus Pauling’s concept of orthomolecular psychiatry seemed most appropriate at the time and still does.” For Hoffer, Pauling was clearly “a major historical root” for the field.

Hoffer and Pauling’s professional connection eventually evolved into a tight friendship. In 1986, for example, Hoffer was invited to celebrate the launch of an endowed orthomolecular chair at Ben Gurion University in Israel. In agreeing to do so, Hoffer further suggested that Pauling’s presence would be a “a major attraction” and “a marvelous opportunity to promote [his] books.” (and thus the benefits of orthomolecular medicine). Hoffer, who often referred to Pauling simply as “Linus” in their correspondence, ultimately covered the full cost of Pauling’s trip to Israel.

On another occasion, Hoffer arranged for a “Linus Pauling Reception Dinner,” which was held to raise funds for the Canadian Schizophrenia Foundation, with Pauling set to receive half of the proceeds. At a rate of $25 per person and $45 per couple, Pauling’s share of the gate was $4,275.46. This model of generating support and raising money for orthomolecular causes was so successful that the foundation set up another lecture series for Pauling in 1992. Even though Pauling announced that he had cancer in February of that year, he was determined to attend the event to support Hoffer and to help raise funds for an organization that he believed in.

Pauling’s Study of Schizophrenia: A Program of Work

[Part 3 of 9]

I feel, accordingly, that it is the duty of every psychiatrist to add megavitamin therapy, orthomolecular methods, to his armamentarium, and to make use of these vitamins, to try them out in proper amounts, not just by doubling the recommended daily allowance, but in the proper amounts as discussed by Dr. Hoffer and others here as having been found to be effective for many patients.

-Linus Pauling, speech to the American Schizophrenia Association, July 1971

Upon learning about the potential that vitamin megadosing might have for improving the lives of people suffering from schizophrenia, Linus Pauling quickly began thinking about a new research program. This process was only accelerated by his interactions with Irwin Stone, who introduced vitamin C as a potential tool for attacking mental disease, among other health maladies. One piece that Pauling still needed however, was a more complete understanding of how best to run the types of experimental trials that he had in mind. To bridge this gap, Pauling once again turned to the literature, reading everything that he could find that was even remotely related to orthomolecular protocols.

One interesting resource that Pauling consulted amidst his information gathering process was the Veteran’s Administration. Specifically, in June 1967 Pauling asked the VA’s chief of psychobiology research, Arthur Cherkin, to provide a digest of all research that had been done by the federal agency on the correlation between mental disorders with nutrition, protein deficiencies, and vitamin deficiencies. Cherkin was happy to help, supplying Pauling with notes on some 500 different studies that involved these topics.

A few months later, Pauling also reached out to Humphry Osmond to ask if he knew of any “psychiatrists, especially in California, who are sympathetic to the use of nicotinic acid, nicotinamide, and ascorbic acid in the treatment of schizophrenia.” What seems to be clear in these exchanges is that even though Pauling had read reports about the design and effectiveness of other trials, he was still pondering how best to organize his own experimental approach.

By December 1967, Pauling was feeling more ready to begin his research. His careful reading of the literature had convinced him that schizophrenia could be caused by a nutritional imbalance of nutrients, and that orthomolecular therapy could be of great benefit. He also had a good idea about the analytical tool that would drive his experiments.

From the beginning, Pauling worked closely with his University of California – San Diego colleague (and former Caltech student) Art Robinson. Together they collaborated with County University Hospital in San Diego to conduct human trial nutrient tests on patients with schizophrenia. The study initially tested the trial group’s capacity to absorb vitamin C, and was later repeated to analyze absorption of vitamins B3, B6, and B12. Importantly, as he had done in the 1940s, Pauling once again relied upon urinalysis to compile his data. In the County University Hospital trials, subjects’ urine was collected and analyzed both before and after dosing with vitamin C, which was ingested in the form of orange juice.

Art Robinson, 1974.

Though the urinalysis approach had proven unsuccessful in the 1940s work, Pauling was inspired to try it again as a result of his more contemporary reading. In one particularly relevant research notebook entry, dated July 25, 1967, Pauling analyzed a 1966 paper in which author H. VanderKamp reported on his use of urine sampling to investigate ascorbic acid and thorazine treatments for schizophrenia patients. The idea was clearly enticing for Pauling, who wrote in his journal that day, “Could a urine test be useful in diagnosis?” The answer proved to be yes, and by the time Pauling was running his human subjects trials in San Diego, he had fine tuned his approach. To test the amount of vitamin C present in a urine sample, Pauling and Robinson would use gas chromatography to detect the presence and quantities of aromatic compounds that are created when vitamin C reacts with alcohols.

The initial trials showed promise, with “all patients elevat[ing] to normal levels [of vitamin C] after eight days” of treatment. This finding aligned with Pauling’s hypothesis that vitamin C levels in schizophrenics were too low, and that through supplementation they would be able to reach “normal” levels in a relatively short period of time.

Pauling and Robinson’s first data set was exciting enough that they decided to apply for funding to expand the scale of their project. In mid-1968, the duo submitted a grant proposal titled “Orthomolecular Psychiatry – Diagnosis and Therapy” to the National Institutes of Health, requesting $336,945 (roughly $2.7 million in 2020 dollars) to support work conducted from January 1, 1969 to December 31, 1973.

The proposal outlined a plan that would follow the same general procedure as before, centering around the administration of “oral doses of substances and then to analyze samples of urine” using “chemical, microbiological, spectrophotometric, and gas chromatographic methods.” The substances that Pauling and Robinson planned to test were “ascorbic acid [vitamin C], nicotinamide [B3], pantothenic acid [B5], cyanocobalamin [B12], and pyridoxine [B6].” However, unlike the previous study, this project would also make use of controls – people who did not have schizophrenia – including “nurses, physicians, students, [and] faculty members.”

In justifying the proposal, Pauling admitted to grand ambitions, stating that

We are not attempting to carry out a definitive test of a well-defined hypothesis, but rather to discover something about mental disease. I hope that it will turn out that what we are doing now is analogous to what my coworkers and I did between 1945, when I had an idea about the nature of sickle-cell anemia, and 1949, when Drs. Itano, Singer, and Wells and I published our paper, “Sickle Cell Anemia, a Molecular Disease.”

The study was funded, and also happened to coincide with a period of rapid change for Pauling, whose institutional home shifted from UCSD to Stanford to the Institute for Orthomolecular Medicine (co-founded by Pauling and Robinson) during the lifetime of the grant. Despite all these transitions, Pauling published a number of papers as a result of the grant, all of which emphasized a positive relationship between vitamin megadosing and improved health for schizophrenia patients. As its profile rose, the work also began to attract interest from additional funding sources including, as communicated in a 1978 letter from Art Robinson, “the Multiple Sclerosis Society, the Educational Foundation of America, the National Cancer Institute, and the National Institute of General Medical Sciences.”

As the program moved forward, Pauling continued to devote time and energy to perfecting experimental design and minimizing side effects for trial participants. In his correspondence with Humphry Osmond for example, regular attention is given to defining proper dosages and best practices for maximum absorption. Taking supplements with Coca-Cola was, for instance, ill-advised, and so too with caffeinated coffee. Concerns were also raised about the sugar content in fruit juices, and eventually pure glucose was used to sweeten the vitamin C trial drinks. Likewise, milk was not recommended for any person of African or Asian descent, and at least two or three grams of bran were to be given to all patients per day “to help avoid the use of laxatives” often needed by those taking high doses of antipsychotic drugs.

One major trial that involved Pauling and Robinson as collaborators was titled “Urine Biochemistry in Schizophrenia and the Effects of Vitamin Loading,” and was carried out at the Agnews state mental hospital in Santa Clara, California. Pauling and Robinson were primarily asked to take charge of analyzing urine samples collected from the 200 schizophrenic patients recruited into the study, but the importance of Pauling’s past work clearly permeated the new trial. In the study’s introduction, lead researcher Maurice Rappaport pointed out that

Pauling, on the basis of previous research, has reached the conclusion that there are differences in the metabolism of ascorbic acid, nicotinic acid and pyridoxine between those who are in good mental health and those who are in poor mental health. Specifically he reports that among the mentally ill as compared to the mentally well, ‘there is a much larger group of people with unusually high requirements for one or another of these three vitamins.’

The sum result was

a theory of mental ill health based upon the fact that a man’s normal diet does not always supply the amount of essential nutrilites necessary to establish an optimal molecular environment for his mind. Further, [Pauling] has suggested that there are biochemical variations in some men which cause their requirements for essential nutrilites to be so unusual that the failure of their diet to satisfy these requirements results in mental illness.

Clearly Pauling’s work had made a significant impact in a short period of time. But, as we shall see, signs of trouble were soon to appear.

Pauling’s Study of Schizophrenia: A New Model Vitamin

Irwin Stone. (Image by Oscar Falconi)

[Part 2 of 9]

“I have decided, on the basis of the evidence presented by Irwin Stone, that there is very strong evidence now, that most human beings are suffering from hypoascorbemia, a mild sort of deficiency of ascorbic acid in the blood; perhaps it is wrong for me to call it a mild sort. The point that I call to your attention is that I believe that for all or almost all human beings, the amount of vitamin C that is contained in the food is less that the optimum amount, and that the state of health of almost all human beings is not so good as it would be if they were to ingest a larger amount.”

-Linus Pauling, speech to the American Schizophrenia Association, July 1971.

Linus Pauling’s chance encounter with the work of Abram Hoffer and Humphry Osmond convinced him that metabolic diseases could be treated by megadosing with certain vitamins; a practice that he labeled “orthomolecular medicine.” As Pauling’s interest in the topic grew, he sought out as much of the existing scientific literature as he could find, and quickly began to see a pattern.

As early as the 1940s, there seemed to be evidence of a positive correlation between increased niacin intake and improvement of certain psychoses in patients. The literature also supported Hoffer and Osmond’s finding that vitamin megadosing was not likely to cause significant side effects. On the contrary, many of the era’s commonly prescribed anti-psychotic drugs often caused severe side effects, sometimes even at low doses. The benefit of this new alternative was made clear by Osmond in a 1970 letter to Pauling, in which he noted that

[we are] dealing with a set of highly physiologically active substances [such as niacin] which do not, however, seem to produce the sort of danger which one finds in most physiologically active substances.

Though Pauling was convinced that orthomolecular therapy was effective, his continuing review of the literature cast doubt on whether or not niacin was, in fact, the most effective vitamin to use in treating patients with psychoses, such as schizophrenia. Though niacin was clearly safe, certain investigators had reported marginal success rates with their patients. Enough data of this sort had been reported to lead Pauling away from niacin and in the direction of a new vitamin. It was here that Irwin Stone entered his life.

In March 1966, Pauling traveled to New York to accept an award from the Carl Neuberg Society for International Scientific Relations. In his speech, Pauling – then sixty-five years old – expressed hope that he might live for another twenty years, so that he might witness the scientific advances that he believed to be forthcoming. Irwin Stone, a biochemist who worked mostly in the brewing industry, was in the audience that evening, and he felt as though he could virtually guarantee another twenty years or more for Pauling.

In a letter that he wrote after the speech, Stone told Pauling about research that he had been conducting on the health effects of vitamin C, stressing that he had been megadosing with the vitamin for the past few years and was healthier than ever as a result. In relaying this, Stone acknowledged that the story seemed implausible and admitted that he had remained a bit skeptical himself until he was involved in a car accident. Buoyed by his high dose vitamin C regimen, Stone recovered from the incident far faster than he or his doctors believed possible, and from then on he had been convinced. In Stone’s view, vitamin C would easily buy Pauling another twenty years, and maybe up to fifty!

When Stone sent his letter, he could not have known that Pauling was hatching his own interest in orthomolecular medicine; Pauling’s first paper on the subject did not appear until a year later. As such, Pauling knew that Stone’s testimony was not informed or biased by previous knowledge of his work. The letter did, however, add to Pauling’s growing belief in power of high dose supplementation in the treatment of disease. Likewise, Pauling had also been given a new model that he might explore for mental illness in lieu of the niacin trials conducted by Hoffer, Osmond and others. The next step then, was to see how effective megadoses of vitamin C might be for patients suffering from schizophrenia.

Pauling’s Study of Schizophrenia: Origins from Hoffer and Osmond

Abram Hoffer and Linus Pauling at the symposium, “Adjuvant Nutrition in Cancer Treatment,” Tulsa, Oklahoma, November 1992.

[Part 1 of 9]

“If there is evidence, for example, that an increased intake of ascorbic acid decreases the amount of illness with the common cold and other diseases, and the evidence is in fact strong, it is not improper to recommend that parents give vitamin C to their children, to see if it leads to an improvement in their health. In the same way orthomolecular (megavitamin) treatment of schizophrenia, in addition to the conventional methods of treatment, is justified by the facts that a good number of psychiatrists have reported it to be of value and there is little danger in serious side effects from the vitamins.”

-Linus Pauling for the Journal of Autism and Childhood Schizophrenia, November 1974    

Orthomolecular Medicine, loosely defined as the pursuit of optimal health through the intake of the “right molecules” in the “right amounts,” is the discipline that defined Linus Pauling’s work for the last three decades of his life. The undertaking marked a dramatic shift away from the research that Pauling had pursued previously; work that garnered him a reputation as one of the leading scientists of the twentieth century. The shift was made all the more dramatic by the level of commitment that Pauling made to pursuing this new area of study: not only did he write multiple books on the topic, he also co-founded an institute to explore new ideas on orthomolecular medicine.

Today, the bulk of Pauling’s research output on orthomolecular topics centers on the use of vitamin C to treat the common cold and cancer. Less known is the fact that Pauling’s initial foray into orthomolecular topics focused on the treatment of schizophrenia.

One might propose that Pauling first became interested in orthomolecular treatments for mental disorders as the result of happenstance and boredom. In 1965 Pauling visited a psychiatrist friend in Carmel, California for a party. When his interest in socializing began to wane, Pauling wandered the house and picked up a book that seemed interesting, Niacin Therapy in Psychiatry, by the Canadian scientist, Abram Hoffer. As Pauling would soon learn, the book focused on treating schizophrenia with vitamins, specifically niacin. This idea was new to Pauling and provoked considerable interest.

Humphry Osmond, 1972

In his book, Hoffer detailed the experimental work that he and a colleague, Humphry Osmond, had conducted to demonstrate the positive impact that high levels of niacin – one of the B vitamins – made on the mental functioning of patients with schizophrenia. In these trials, Hoffer and Osmond had treated their patients with megadoses of niacin and other vitamins that were routinely more than a thousand times higher than the recommended daily allowance. The duo reported that, through years of megadosing, their patients never experienced negative side effects and often found relief from their illness. In effect, Osmond and Hoffer had seemed to find an effective treatment for schizophrenia that bore few to no side-effects. This accidental book that Pauling picked up would help start him down a path to studying the orthomolecular treatment of mental illness.  

Even though Pauling had found Hoffer and Osmond’s book interesting, he did not initially understood how his own scientific background could be applied towards orthomolecular approaches. But a bit of further reflection on work that he had done decades earlier helped to clarify the connection and prompt a new round of investigations.

In the 1940s, Pauling had tried to see if he could diagnose phenylketonuria (PKU) through a simple urine test. PKU is a birth defect that diminishes one’s ability to properly break down amino acids. If left untreated, the resulting build-up of amino acids can lead to mental disabilities, seizures, and even death. Pauling thought that it might be possible to diagnose PKU patients by conducting laboratory analyses of enzymes that were naturally excreted through urine. Though this specific project ultimately proved unsuccessful, Pauling believed that his failures were not due to problems with the theory, but instead could be sourced to inferior technologies of the era that were not sensitive enough to make a proper analysis. Years later, when reading about Hoffer and Osmond, Pauling realized that he could apply urinalysis to their work.

For PKU patients suffering from an enzyme imbalance, health could be restored by ingesting doses of supplemental enzymes. Pauling extended this model to Osmond and Hoffer’s results, suggesting that niacin succeeded in reducing patients’ symptoms precisely because schizophrenics were suffering from an imbalance of enzymes; megadosing was a means of restoring balance in their brains.

In a 1967 paper, Pauling made it public that he had been working and ruminating on the concept of megadosing. He used the same publication to define this specific type of orthomolecular therapy as, “the treatment of mental disease by the provision of the optimum molecular environment for the mind, especially the optimum concentration of substances normally present in the human body.” He would go on to posit that “The functioning of the brain and nervous tissue is more sensitively dependent on the rate of chemical reactions than the functioning of other organs and tissues.” As such, “I believe that mental disease is for the most part caused by abnormal reaction rates, as determined by genetic constitution and diet, and by abnormal molecular concentrations of essential substances.”

Pauling’s realization that his past urinalysis work could connect with orthomolecular therapy was just one reason why he became involved in the research. Pauling was also driven by a fundamental belief that the human need for certain vitamins, such as vitamin C, was an evolutionary phenomenon. According to Pauling,

the process of evolution does not necessarily result in the normal provision of optimum molecular concentrations. Let us use ascorbic acid [vitamin C] as an example. Of the mammals that have been studied in this respect, the only species that have lost the power to synthesize ascorbic acid and that accordingly require it in the diet [in addition to humans] are many other primates (rhesus monkey, Formosan long-tail monkey, and ring-tail or brown capuchin monkey), the guinea pig, and an Indian fruit-eating bat.

By extension, this evolutionary precedent might also imply that, even though certain enzymes are essential, they are still not readily produced in the quantities that we need. Pauling postulated from there that mental imbalances, sometimes manifesting in illnesses such as schizophrenia, could be a result of inherited enzyme imbalances.

Pauling also knew that deficiency diseases such as scurvy (which results from a deficiency in vitamin C) and pellagra (which results from a deficiency in niacin) can both manifest as mental illnesses. People with scurvy often suffer from mood changes and depression, and people with pellagra are sometimes beset by hallucinations or dementia. This correlation between mental illness and nutritional deficiency was echoed by Abram Hoffer, who wrote that, “if niacin was removed entirely from food, everyone would become psychotic in one year.”

Eventually, numerous other maladies would fall under Pauling’s definition of an orthomolecular disease. Diabetes, for instance, was the result of an insulin imbalance and its treatment entailed the injection of insulin, therefore it was an orthomolecular disease. Goiters too were seen as an orthomolecular disease because they occur as a result of iodine imbalance and were treated with iodine dosing. Even cavities could be viewed through an orthomolecular lens, given their prevention with supplemental fluoride. Possibilities of this sort fascinated Pauling and would consume much of his time in the years to come.

The Decline of Orthomolecular Psychiatry

Abram Hoffer and Linus Pauling at the symposium, "Adjuvant Nutrition in Cancer Treatment," Tulsa, Oklahoma, November 1992.

Abram Hoffer and Linus Pauling at the symposium, “Adjuvant Nutrition in Cancer Treatment,” Tulsa, Oklahoma, November 1992.

We have written before on both the orthomolecular psychiatry of Linus Pauling and the birth of orthomolecular medicine, which has its roots in nutritional (later called orthomolecular) psychiatry. This post delves further into how orthomolecular psychiatry came to be, as well as its marginalization out of the scientific mainstream.

It all began with Albert Hofmann, the Swiss scientist who, in 1938, famously synthesized LSD and discovered its psychedelic properties. After several trials, some on himself, Hofmann developed the hypothesis that LSD mimics the effects of psychosis.

Hofmann’s idea inspired two English psychiatrists, Dr. Humphry Osmond and Dr. John Smythies, to further his research in the late 1940s. Using mescaline (derived from the peyote cactus) as their basic compound, the duo took Hofmann’s work a step further, eventually conjecturing that schizophrenics suffered from an overdose of an endogenous (made in the body) toxin that was similar in structure to mescaline and LSD.

Finding no sympathy in England – at the dominated by Freudian thought – Osmond and Smythies took their work to Saskatchewan, Canada, relocating there in late 1951. Once in Canada, Osmond met Abram Hoffer, a fellow psychiatrist with whom he would collaborate for decades. Together, Hoffer and Osmond ran the psychiatric sciences and therapies divisions of the psychiatric hospital in Weyburn, Saskatchewan, which housed a number of schizophrenic patients.

Hoffer and Osmond eventually discovered the toxin that Osmond and Smythies had suspected was causing the psychoses present in schizophrenics: adrenochrome, a byproduct of the body’s metabolic oxidization of adrenaline and noradrenaline. The next step in helping their patients, the doctors felt, was to find some way to alleviate the psychoses brought about by schizophrenia. This led them to nicotinic acid, also known as vitamin B3 or niacin. Niacin, they learned, was known anecdotally to help patients with neuropsychiatric disorders. This fit with the fact that pellagra, a disease caused by a deficiency of niacin, sometimes presents with psychiatric symptoms.

Eager to test their theory that vitamin B3 could help alleviate mental disease, Hoffer and Osmond began experimentation, dosing their schizophrenic patients with large amounts of niacin by adding it to their daily diets in the first double-blind tests performed in psychiatry. Once the experimentation was finished, Hoffer and Osmond followed their patients for ten years, measuring the effectiveness of their added-vitamin therapy in terms of readmission rates and ability to find outside employment once released from the hospital.

In 1962 Hoffer and Osmond published the book Niacin Therapy in Psychiatry, the text that introduced Linus Pauling to the duo’s megavitamin work. The book revivified his interest in the biochemical basis of mental illness, which he had been studying for a decade, having previously learned that phenylketonuria is a molecular disease in much the same way as sickle-cell anemia.

By the time Pauling read the niacin book, anecdotes about megavitamin therapy, as it was then called, had begun to spread. Additionally, it had already been discovered that niacin could lower cholesterol levels. When added to his prior knowledge, these facts led Pauling to find the evidence presented in the book compelling enough to merit further investigation. The final ingredient to Pauling’s interest appeared the next year, when Dr. Irwin Stone introduced Pauling to the potential health benefits of large doses of Vitamin C. .

It wasn’t until 1967 that Pauling coined the term “orthomolecular,” using it in print for the first time in a paper titled “Orthomolecular Methods in Medicine.” In 1968 Pauling wrote his more famous paper on the subject, “Orthomolecular Psychiatry,” published in the journal Science. Pauling, of course, went on to found the Institute of Orthomolecular Medicine with Art Robinson in 1973, (soon after renamed the Linus Pauling Institute of Science and Medicine) and co-edit the book Orthomolecular Psychiatry: Treatment of Schizophrenia in the same year. Around this time, Pauling also began broadening his theory of orthomolecular medicine to include the whole body, not just the mind.

But what happened to Hoffer and Osmond? The answer to this question plays a part in understanding why many doctors today still refuse to consider orthomolecular medicine a legitimate form of treatment.

In 1967 Hoffer and Osmond formed both the Canadian Schizophrenia Foundation and the American Schizophrenia Association. The two doctors had recently been encountering a great deal of resistance to the publication of their ideas, so they started their own journal, the Journal of Schizophrenia, in the same year. They asked Pauling to serve on the editorial board; Pauling agreed, participating in that capacity for the rest of his professional life.

In 1973 orthomolecular psychiatry was dealt a serious blow by the American Psychological Association Task Force. That year, the group published a report titled “Megavitamin and Orthomolecular Therapy in Psychiatry,” condemning the practice as unsupported at best and “deplorable” at worst. Hoffer and Osmond were subjected to humiliation and orthomolecular psychiatry was deemed unworthy of study or application. The following year, Pauling responded to the report, pointing out a number of flaws, including errors in methodology, lack of research, confusion of focus, and bias:

Orthomolecular psychiatry is the achievement and preservation of good mental health by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the human body, such as the vitamins….The APA task force report Megavitamin and Orthomolecular Therapy in Psychiatry discusses vitamins in a very limited way (niacin only) and deals with only one or two aspects of the theory. Its arguments are in part faulty and its conclusions unjustified.

But Pauling, Hoffer, and Osmond’s expressions of outrage at perceived mistreatment by the APA weren’t enough to overcome further obstacles that lay ahead. For one, in the mid-1970s, orthomolecular psychiatry, rather than sticking to megavitamin doses, expanded to include diet in the treatment of mental health, as well as avoiding stimulants like nicotine. However, no consensus was reached within the community with regard to precise standards for the practice, so recommendations varied from doctor to doctor, making the efficacy of orthomolecular psychiatry difficult to evaluate.

The mainstream introduction of tranquilizers and the phasing out of electroconvulsive therapy in the treatment of mental illness also proved a barrier to the orthomolecular community. Tranquilizers, unlike megavitamins, were immediately successful in alleviating symptoms, making orthomolecular medicine, which took time to work, appear ineffective by comparison.

Eventually, whenever a patient would ask about megavitamin or orthomolecular therapy as an alternative treatment, many doctors would simply cite the APA report, claiming that it had disproven orthomolecular methods. After a while, most patients simply stopped asking.

The American Schizophrenia Association eventually became the Huxley Institute for Biosocial Research, still led by Abram Hoffer. Dr. Hoffer asked Pauling to serve on its board of directors but Pauling declined, by then more interested in pursuing Vitamin C in the treatment of cancer and colds.  The flagging in his energy for the discipline of orthomolecular psychiatry was indicative of the lack of momentum within the field, a situation that persisted for the remainder of Pauling’s life.

Humphry Osmond, the Original Psychedelic Psychiatrist

Humphry Osmond (front row seated, far left), with the Paulings and others at a gathering in Tulsa, Oklahoma. June 1972.

Humphry Osmond (front row seated, far left), with the Paulings and others at a gathering in Tulsa, Oklahoma. April 1972.

Dr. Humphry Fortescue Osmond, while never a direct collaborator of Linus Pauling’s, was nonetheless a professional influence in his life and a friend. Alongside Dr. Abram Hoffer, Osmond helped to establish orthomolecular psychiatry, the precursor to the larger body of work on orthomolecular medicine that consumed Pauling for close to three decades. Later in life, Pauling and Osmond wrote numerous letters back and forth, in which Osmond often shared interesting articles on the uses of vitamin C, schizophrenia, nutrition, and orthomolecular medicine.

Osmond is famous to both the medical community and to the public for related, yet separate reasons. In the field of medicine, Osmond, along with Abram Hoffer, is best known for his work in orthomolecular psychiatry. Working together, the two doctors performed extensive studies on schizophrenic patients in psychiatric hospitals in Saskatchewan, Canada, using niacin (vitamin B3) and ascorbic acid (vitamin C) as potential cures for the disease. Osmond is also known for his work with lysergic acid diethylamide, or LSD, in the treatment of alcoholism and as a way for psychiatrists and psychologists to experience something approximating what he believed to be the state that schizophrenics experience as they struggle with their illnesses.

To the public however, Humphry Osmond will forever be known as the man who coined the term “psychedelic” and the man who “turned on,” in the words of the famous LSD advocate Timothy Leary, acclaimed British author Aldous Huxley, a man with whom he developed a close friendship. In the early 1950s, Huxley approached Osmond after reading an article on his research with mescaline; Huxley expressed a desire for Osmond to run a human trial of the drug with Huxley as subject. Osmond wasn’t fond of the proposal, not relishing “the possibility, however remote, of finding a small but discreditable niche in literary history as the man who drove Aldous Huxley mad.” Despite his misgivings, Osmond dosed Huxley with 400 mg of mescaline in 1953.  The result was recorded in Huxley’s cult hit The Doors of Perception (1954), a book that both takes its name from William Blake’s poem “The Marriage of Heaven and Hell” and inspired the name of the legendary 1960s rock band, The Doors.

Later, when discussing his flight of hallucinogenic fancy, Huxley, writing to Osmond, penned this bit of verse:

To make this mundane world sublime, / take half a gram of phanerothyme.

The word phanerothyme, cobbled together from the Greek, translates roughly to “manifest spirit.”

In response Osmond wrote some poetry of his own, in the process coining a term that soon spread around the world:

To fathom Hell or soar Angelic, / just take a pinch of psychedelic.

Psychedelic – again from Greek etymology – translates to “mind-manifesting.” By 1957 Osmond had introduced the word to the medical community as a way to describe the euphoric, perception-altering, mind-expanding effects of hallucinogenic drugs like LSD, mescaline, DMT, and psilocybin. Previously the only well-known description of this concept was “psychotomimetic,” a mimicry of the symptoms of psychosis.

Humphry Osmond was born in July 1917 in Surrey, England, gaining his primary and secondary education from Haileybury, a long-established boarding school in Hertfordshire. After Haileybury, Osmond earned his medical degree from Guy’s Hospital Medical School, London, in 1942, and from there joined the Royal Navy, commissioning as a surgeon-lieutenant and training to be a ship’s psychiatrist.

After the Second World War concluded in 1945, Osmond returned home and accepted a position as a resident psychiatrist at St. George’s Hospital, Tooting. It was here that he met his future wife, Amy “Jane” Roffey, and his first major research partner, Dr. John Smythies. Together, Smythies and Osmond performed a number of studies in the late 1940s on the chemical composition and effects of the drug mescaline – a hallucinogenic derived from the peyote cactus – having been inspired by the work of Albert Hofmann, who had discovered the hallucinogenic properties of LSD a decade prior.

From their research, Smythies and Osmond hypothesized that because the experience of subjects on mescaline seemingly mimicked the symptoms of schizophrenia, and that because mescaline is structurally related to adrenaline, it could be possible that schizophrenics were over-producing a chemical related to both mescaline and adrenaline. They called this hypothesis, fittingly, the “M-hypothesis.” The idea, when presented to the British psychiatric medical community – which at the time was dominated by Freudian thinking – was not well received. Feeling isolated in the UK, in 1951 Humphry and Jane Osmond, along with John Smythies, immigrated to Canada, where Osmond had been offered a job as the clinical director of the psychiatric hospital in Weyburn, Saskatchewan.

"How to Live with Schizophrenia," by Abram Hoffer and Humphry Osmond, 1966.

“How to Live with Schizophrenia,” by Abram Hoffer and Humphry Osmond, 1966.

It was at Weyburn that Osmond met Dr. Abram Hoffer, director of psychiatry at the hospital, with whom Osmond would collaborate for the next decade. Working together with the patients at Weyburn and at neighboring hospitals, Osmond and Hoffer developed what became known as the “Hoffer-Osmond Adrenochrome-Hypothesis.” Using the M-hypothesis as their basis, Osmond and Hoffer claimed that it was adrenochrome, a byproduct of adrenaline that is structurally similar to mescaline and other hallucinogens, that schizophrenics were overproducing.  In theory, schizophrenics were suffering from their disease either as a result of their bodies producing too much adrenochrome or through an inability to properly metabolize adrenaline.

Working from this hypothesis, Osmond and Hoffer next searched for a way to reduce the overproduction of adrenochrome, hoping to find a cure for schizophrenia as well as additional evidence for their idea. Learning that niacin might limit the production of adrenaline, they decided to dose their schizophrenic patients with “megavitamin” amounts of B3, adding it to their diets in the first double-blind studies ever conducted in the field of psychiatry. The results were encouraging: according to their studies, the recovery rate for the schizophrenics that they treated over the next few years doubled from 35% to 75%.

In addition, the Osmond and Hoffer studies provided data that added to the finding that niacin could reduce cholesterol, a result that was replicated and confirmed by the Mayo Clinic in 1956. This finding is now globally accepted and niacin is presently used in the treatment of high cholesterol all over the world.

An example of Hoffer's "memos," October 1976.

An example of Hoffer’s “memos,” October 1976.

In 1967 Linus Pauling – who had learned of Hoffer’s work on niacin two years before – read the Osmond and Hoffer studies and, finding the subject interesting enough to pursue further, wrote to the duo asking for more information.  The data that he received was eventually included by Pauling alongside his own theories in his seminal paper, “Orthomolecular Psychiatry” (published in Science in 1968) as well as in the book that he co-edited with Dr. David Hawkins, Orthomolecular Psychiatry: Treatment of Schizophrenia (1973). Over time, Pauling expanded his orthomolecular theory from the study of the mind to include the whole body, thus creating the field of orthomolecular medicine.

This initial contact between Drs. Pauling and Osmond led to a nearly thirty-year correspondence between the two men, with Osmond regularly sending to Pauling selected copies of his “memos” – commentaries in which Osmond would paste a news article onto the left side of a sheet of blank paper, then cover the right side and the back with prodigious, elegant essays on the context, significance, and meaning of the article. (These memos were collected into a book, Predicting the Past, and published in 1981). Osmond made special effort to forward to Pauling those memos concerning ways in which orthomolecular medicine was being used around the world as well as any material on mental illnesses.

Exchanges between the two men were often personal as well as professional. For example, after learning of Ava Helen Pauling’s trouble with cataracts, Osmond sent Dr. Pauling any information that he could find on the ocular malady, of which Osmond was also a sufferer. Osmond also wrote letters filled with his thoughts on Pauling’s activism and increasing celebrity, including a letter in which he agreed with Pauling’s negative assessment of physicist Edward Teller, a major advocate for U.S. nuclear armament and the hydrogen bomb, as well as a letter congratulating Pauling on his 1977 appearance on NOVA.


In 1961 Osmond was appointed Director of the Bureau of Research in Neurology and Psychiatry at Princeton University. While there, he continued his research into schizophrenia as a physical illness. In 1970, hallucinogenic drugs like mescaline, LSD, and DMT were declared controlled substances, and studies on the effects of these drugs on psychiatric patients was curtailed.

In 1971 Osmond resigned his position at Princeton and moved to Alabama, where he taught at the University of Alabama, Birmingham as a professor of psychiatry. He worked there alongside his old friend, John Smythies. Osmond also consulted at Bryce Hospital in Tuscaloosa, the oldest and largest in-patient psychiatric hospital in Alabama. He retired from the university and the hospital in 1992. A decade later, by then an octogenarian, Osmond granted an interview for a documentary on the history of LSD, titled “Hofmann’s Potion.” Not long after, in February 2004, Osmond died of natural causes at his daughter’s home in Appleton, Wisconsin. Abram Hoffer wrote an obituary on the event of Osmond’s passing, which was featured in the British newspaper, The Guardian.

Some of Humphry Osmond’s more well-known books include The Chemical Basis of Clinical Psychiatry (with Abram Hoffer, 1960); How to Live with Schizophrenia (with Hoffer, 1966); Psychedelics: The Uses and Implications of Hallucinogenic Drugs (with Bernard Aaronson, 1970); and Models of Madness, Models of Medicine (with Miriam Siegler, 1974). A complete bibliography of his works can be found here.