D. W. Woolley, the Serotonin Hypothesis, and the Genesis of Psychopharmacology

by Eric M. Fortier, B.A. | 2018

D. W. Woolley (source: Whitaker-Azmitia, 1999)

Dilworth Wayne Woolley was a Canadian-born biochemist with impressive interdisciplinary expertise in chemistry, psychiatry and pharmacology (Hewitt, 2016). Woolley was an outstanding student; he graduated high school at the age of thirteen, published his first paper at seventeen, and graduated with honors from the University of Alberta, where he obtained an undergraduate degree in chemistry, by age nineteen. He completed his Ph.D. at the University of Wisconsin in 1939 (Miller, 1941), then joined the Rockefeller Institute for Medical Research, “a unique gathering place for elite biochemical and medical researchers, who are free to pursue virtually any avenue of inquiry they wish” (Wild and Hildebrand, 2014). A proficient writer with a serious dedication to biochemistry research, handing in twenty of his own peer-reviewed papers instead of a traditional thesis, he published 232 articles in his career, over eighty percent of which as the sole or senior author.

During his stay at the University of Wisconsin, Woolley worked with Conrad Elvehjem, studying nicotinic acid (vitamin B3; niacin) for canine black-tongue with implications for human pellagra. While investigating cases of pellagra, he recognized that a staple food of Southern United States at the time was corn, and found that an ingredient in corn was preventing the absorption of niacin. That is, something was acting as an antimetabolite. Out of this was born his first major work, A Study of Antimetabolites (1952).

This research was soon investigated by two Canadian psychiatrists, Humphrey Osmond and Abraham Hoffer, who found that vitamin B3 could cure symptoms of pellagra-induced psychosis, which at the time accounted for the majority of psychiatric hospitalizations.

The influence of biochemistry on mental illness and altered states of consciousness intrigued Woolley, as he became increasingly interested in the link between psychology and biology, and strove to integrate the two. And with the help of his understanding of antimetabolites, he eventually developed the serotonin hypothesis of schizophrenia.

Origins
It is important to root Woolley’s contributions in the somewhat mysterious historical context from which they emerged. The term schizophrenia (Greek for ‘split mind.’) was initially coined by Swiss Psychiatrist Eugene Bleuler in 1911, who was the first to conceptualize it as a metabolic disorder. This was much to the opposition of Freud’s theories at the time (who he closely studied), which he felt were too dogmatic in their focus on the impact of childhood experience and psychodynamics, and were inadequate for understanding mental illness.

Modern research on mental illness based in biochemistry mainly emerged from observations involving exogenous psychoactive substances, with a special interest in hallucinogens around the turn of the 20th century. One of the first systematic studies with hashish (a concentrated form of cannabis) on healthy and mentally ill individuals was conducted and published in 1845 by French Psychiatrist Jacques-Joseph Moreau. Also known as Moreau de Tours, he was a member of the Club des Hashischins: a Paris club of scientists, artists, and writers who were keen on exploring strange, exalting, and often hidden realms of the mind with the help of drug-induced altered states of consciousness. The results of Moreau’s controlled experiments on patients, on himself and on colleagues, led him to believe that orally ingested hashish could simulate mental illness, yet by doing so paradoxically help to treat it by revealing its origins through introspection and observation. This work was published as Du hachisch et de l’aliénation mentale: études psychologiques. Moreau was the first psychiatrist with an interest in psychopharmacology (Holmstedt, 1973), and this was the first book about a drug written by a scientist.

Shortly after the publication of Du hachisch et de l’alienation mentale, mescaline (the psychoactive ingredient of the South-American sacrament, peyote) entered the Western world and began to make its way through elite intellectual circles, somewhat also popularized by the Hashischins and their contemporaries. The effects were sometimes compared to mental and behavioral aspects of the acute schizophrenic state, and physicians and psychiatrists began to use it as a working model for psychosis.

In 1952, Osmond and Smythies discovered that compounds structurally similar to mescaline (putative endogenous compounds they called ‘Substance M’) could be produced by altering the human catecholamine metabolism, and proposed the transmethylation/catecholamine hypothesis of schizophrenia. This was presented as evidence that hallucination and psychosis were a result of faulty biochemistry.

Osmond and Smythies’ research emphasized that fantastical or otherwise hallucinatory accounts described by mental patients were not merely stories of make-believe as was often thought at the time, but appeared to the patient as real, undeniable, somatic and visceral experiences which could be elicited on demand using a hallucinogen. ‘Substance M’ was never found (Gillin et al., 1978). But this hypothesis served as a foundation for understanding the involvement of biochemistry in mental disease.

For the first half of the 20th century, much of mental illness was blamed on bad parenting–things like “refrigerator mothers” who were emotionally unavailable to their children (Nichols, 2013). Freudian theories and psychodynamics were often used to explain mental illness and split-mind phenomena, and handling severe cases often involved relatively dangerous approaches, including insulin treatment, electroconvulsive therapy, lobotomy, and eventually tranquilizers and Thorazine (Hewitt, 2016). However, it was not well understood why these treatments worked, and they were not based on empirical theories of the origins of mental illness. At the time, most scientists believed that biochemistry only affected the peripheral and not the central nervous system (Whitaker-Azmitia, 1999).

But the view that biochemistry had no stake in the brain was soon to change after a series of discoveries about serotonin in the early 1950s. Prior to this, serotonin was thought only to be involved in the periphery, acting on smooth muscle in the gastrointestinal tract and vascular systems. Once Maurice Rapport identified serotonin’s chemical structure as an indole in 1949, and Betty Twarog and Irvin Page discovered serotonin in the brain in 1953, it was proposed as a neurotransmitter. But neurochemistry was still considered a fringe discipline at the time.

It was around this time that Woolley recognized LSD’s indole structure, and imagined it could act as an antimetabolite of serotonin. He synthesized structural intermediaries between LSD and 5HT and demonstrated that all of them acted as antimetabolites of serotonin, and found behavioral effects in animals. Adding to this Twarog and Page’s discovery of serotonin in the brain along with the fact that these compounds produced mental disturbances similar to those of mescaline, Woolley proposed that low brain serotonin might play a role in the origins of schizophrenia (Woolley and Shaw, 1954).

A New Era
The serotonin hypothesis of mental disease was the first scientific application of the antimetabolite hypothesis in psychopharmacology and psychiatry, and most importantly, it was the first formal hypothesis involving brain chemistry in mental illness and behavior (Nichols, 2013). David Nichols, a pharmacologist and medical chemist from Purdue University, states, “The idea that disturbances in brain chemistry might be important to behavior was profound, and began to revolutionize thinking about the brain, and neuroscience in general.” The same hypothesis was simultaneously put forward independently by Gaddum (1953), but Woolley’s work was meticulously detailed and explained the involvement of serotonin specifically in schizophrenia, so he received most of the credit (Cozzi, 2013; Nichols, 2013; Wild and Hildebrand, 2014; Hewitt, 2016).

However, soon after this initial hypothesis, Woolley and Shaw began to see the complexity of the serotonin problem. Studies showed mixed results, and it was now uncertain whether LSD inhibited or stimulated the serotonergic system (Shaw and Woolley, 1956; Baumeiseter and Hawkins, 2004). It was later found that serotonin produced a combination of inhibition and excitation of the system at various parts in the body and brain.

Finally, based on the findings that antipsychotics (like reserpine and chlorpromazine) and monoamine-oxidase inhibitors (MAOIs) decreased serotonin levels, combined with the conclusion that psychotomimetic substances were antimetabolites of serotonin, Woolley proposed his hypothesis in further detail–namely, that bipolar psychosis could be explained by high serotonin levels being associated with psychotic excitement and low levels with symptoms of depression–in his 1962 book, The Biochemical Bases of Psychoses–or the Serotonin Hypothesis about Mental Disease.

He further believed serotonin played a role in brain development because of its resemblance to auxin (a plant hormone that stimulates cell growth and orients it toward sources of energy) and was the first to propose that serotonin dysfunctions interfered with learning and memory.

Maybe the most surprising thing about Woolley is that he simultaneously performed as head of the biochemistry department at Rockefeller, conducted and published his research (including his two major monographs on antimetabolites and serotonin), and delivered university lectures, after going entirely blind from diabetes-related complications. During this time, he would stay up to date on research by having others read it aloud to him, and was able to lecture and write on the blackboard clearly–fooling students unaware of his condition. He demonstrated his keen spatial abilities when he calmly led his Rockerfeller colleagues out of the building after a power outage. Naturally, he worked with the lights off, to the surprise of colleagues who found him working in complete darkness late into the night. Despite his blindness, Woolley’s colleagues often credited his brilliance to his knack for “seeing things” with his mind, and finding meaning in isolated and diverse facts (Whitaker-Azmitia, 1999).

Woolley’s work contributed to the shift from a view of the brain and central nervous system as primarily electrical to one deeply controlled by chemistry (Hewitt, 2016). This contributed significantly to the credibility of neurochemistry. His theories about serotonin, along with his pioneering research in antimetabolites, greatly demystified the function of metabolic mechanisms, paving new avenues for drug development.

Joel Elkes and Avrid Carlsson used Woolley’s research to further popularize the idea that the brain did, in fact, have neurotransmitters that influenced mental states and behavior, and this led to the development of antipsychotics and new drugs that control neurotransmitters. Biochemist Bernard Brodie’s discovery that reserpine (a tranquilizer) decreased serotonin levels in the animal brain further confirmed Woolley’s hypothesis, and led to the dopamine hypothesis of schizophrenia, and the development of tricyclic antidepressants (Baumeister and Hawkins, 2004; Hewitt, 2016). Eventually, Prozac (fluoxetine, a selective serotonin reuptake inhibitor) was developed and praised as a wonder drug for relieving symptoms of depression and marketed as an agent of personality change. This set the stage for the development of modern SSRIs.

Nicholas Cozzi, director of Neuropharmacology Lab at the University of Wisconsin, states (2013),

Present-day research into neurotransmitters and drugs that affect their function in the brain is directly traceable to the experiments and writings of scientists investigating the mechanisms of action of LSD, DMT, and other psychedelic compounds.

He further emphasizes that these discoveries were among the most lucrative to the pharmaceutical industry, adding that, despite the controversy, many of these have indeed helped out countless people.

The neurochemical paradigm played a substantial role in disintegrating stigma associated with mental illness–relieving parents of blame–but is often itself blamed for robbing the patient of dignified agency and dismissing important personal history and context (Hewitt, 2016).

Experimental psychosis?
The role of classical psychedelics as providing model psychoses was questioned as time went on. Experiences varied so widely that it was becoming increasingly difficult to characterize its effects, let alone use it as a model psychosis. With time, it became apparent that experiences under the effects of hallucinogens were heavily influenced by the set and setting.

For example, Walter Pahnke’s 1962 Good Friday Experiment found that Harvard divinity graduates given psilocybin (another serotonergic psychedelic) for a sermon at Marsh Chapel had mystical/religious experiences of unity rather than psychotic-type experiences of frightening mental splitting. The spiritual mindset of the participants and the religious setting heavily influenced the experience to be positive and valued among the single, or top five most meaningful events of their lives. It was eventually found that anxiety and distress experienced prior to and during psychedelic sessions predict difficult and frightening experiences (Carbonaro, 2016), and produce what is called anxious ego dissolution comparable to a splitting of the mind, as opposed to oceanic boundlessness, comparable to religious experience.

The often sterile, clinical environment under the scrutiny of researchers imposed by the experiment and the intensification of emotions caused by the drug would greatly amplify the emotional and psychological impact of every minute interaction between subject and researcher. In these strict clinical conditions, this often resulted in a paranoia, distrust in experimenters and an intense sense of dehumanization due to their treatment as simple “subjects” rather than fully living, breathing humans with rich mental worlds often impossible to verbalize, experiencing frightening visual and strange mental experiences–while others in less clinical contexts often experienced a wonderful sense of meaning, mental unity, and dissolution of boundaries between the self and the world, accompanied by lavish, beautiful imagery, and dubbed them invigorating, life-saving blessings. The profound effect of set and setting on positive and negative acute and enduring effects of psychedelics is now much better understood using environmental predictors and psychometric scales such as the Altered States of Consciousness rating scale (Studerus et al., 2010) and Mystical Experience Questionnaire. With such scales, researchers can predict the degree and likelihood of enduring positive therapeutic outcomes.

Hartogsohn (2017) explains that the idea of set and setting can be traced back as far as ancient religion, in which the (loosely defined) shaman set up a specific set of rituals, chants, symbols, and acts for a particular purpose and individual in their sociocultural context. Furthermore, Moreau actually made explicit note of the importance of set and setting in his experiments, in which for the haschisch eater, “a word, a gesture, a look, a sound or the slightest noise, by demanding his attention, will confer a special character on his illusions.”

Holy, holy, all–the irony
So as with Moreau’s insights on mental illness, gleaned from his studies in hashish and mental alienation, serotonergic psychedelics—once thought to produce mental illness–are now being used to treat it. New research on terminally-ill cancer patients with existential distress shows great promise for psychedelics with concomitant psychotherapy as one-time treatments for alleviating depression and anxiety, re-introducing a sense of meaning, and improving quality of life and personal relationships (Griffiths et al., 2016). This research has also been conducted on healthy participants with similar benefits. Recent research identifies one of the main effects of psychedelics as an amplification of meaningful thought content, which accordingly has become one of the core focuses of NYU’s psilocybin-assisted psychotherapy trials.

Psychosis and mania are characterized in part by an over-ascription of meaning, and depression with a lack of meaning, consistent with Woolley’s work on the hyper- and hypo-serotonergic effects on bipolar psychosis. The importance of set and setting in defining the character and content of the experience emphasizes the need for a more comprehensive understanding of the personal mind set, history, environment, and therapeutic paradigm which are being used to treat mental illness. This is in line with the modern humanistic approach to mental illness.

The new understanding of serotonin in the brain and the mental effects of psychedelics led to a resurgence of interest in questions of consciousness and the relationship between the mind and body (Hewitt, 2016). The current standard of treatment for depression and anxiety involving (especially serotonergic) medication recommends concomitant therapy such as psychodynamic psychotherapy. Prior to 1964, psychotherapists had used psychedelics as catalytic tools; by combining them with psychotherapy, they could accomplish in an afternoon what otherwise could have taken years. Despite these findings, many are prescribed SSRIs and similar medication without psychotherapeutic treatment. This mis-prescription has been considered a symptom of the over-medicalization of mental illness, ironically, with too great a focus on the promise of the biochemical paradigm in academic research (Hewitt, 2016).

The surprising discoveries of LSD’s activity on the central nervous system and mind fostered interest in the neurochemical paradigm and greatly amplified the field of neuropsychopharmacology. At once unveiling a biological piece of the puzzle in mental illness, and later reinforcing the need for a holistic approach to mental illness that considers the mental and environmental elements of set and setting, Woolley’s ideas exemplify “a broader paradigm shift in cultural studies toward a biopsychosocial model that acknowledges the intersections between biology and culture” (Hewitt, 2016).

Untimely end
Throughout his career, Woolley was a member of many scientific organizations, including the Federation of American Societies for Experimental Biology, American Society for Nutrition, American Society for Pharmacology and Experimental Therapeutics, and American Society of biological chemists. He received the Eli Lilly award twice—once in 1940 by the Society of American Bacteriologists for outstanding contributions to bacteriology, and again in 1948 by the American Chemical Society for his work on vitamins and antimetabolites. He won a Mead Johnson prize for his work on vitamins in 1945, as well as a research award in 1947 from the American Pharmaceutical Manufacturers Association. He was later given an honorary medical degree by the University of Alberta in 1949. In 1959, he became president of the Institute of Nutrition. He was also nominated for the Nobel Prize for his work on antimetabolites (Wild and Hildebrand, 2014; Hewitt, 2016).

Woolley died in 1966 at the age of 54 during a hike through the Andes Mountains on his way to a pharmacological conference in Brazil, only three years after the publication of The Biochemical Bases of Psychoses (Whitaker-Azmitia, 1999).

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