Science & Technology

The Nobel Prize that wasn’t

David Presti

A year ago the Campus Bookstore at UC Berkeley hosted what seemed an historic event.  On a sunny Saturday afternoon (June 18, 2011), between one hundred and two hundred people showed up to a book-signing party for an 800-plus page, highly technical compendium of chemical esoterica entitled The Shulgin Index (1).  It was among the best-attended book events in anyone’s memory at the UCB bookstore.

The principal author of the book, Alexander (Sasha) Shulgin, is one of the truly outstanding pharmaceutical chemists of history.  Shulgin was born in Berkeley in 1925, and received both his bachelor’s degree (1949) and his doctorate in biochemistry (1955) from UC Berkeley.  Following his doctoral work, he continued the academic study of pharmacology and also was employed in industry: at Dow Chemical, he worked on the chemical synthesis of new pesticides.  Then, in 1960, at the age of 35, he experienced the effects of mescaline, a powerful psychoactive chemical isolated from the peyote cactus.

At the beginning of the 20th century, there were a very small number of psychedelic substances known to science: there was mescaline, which had been isolated and identified from the peyote cactus in 1897; there was the Cannabis plant, the psychoactive components of which (the cannabinoids) would not be identified for another 60 years; some might even count the anesthetic gas nitrous oxide as having psychedelic-like properties.  Thus, two or three things.  By 1960, there were a handful more: LSD (lysergic acid diethylamide) had been synthesized and characterized by Albert Hofmann in 1943; psilocybin and psilocin were identified from Psilocybe mushrooms in 1958, again by Hofmann; lysergic acid amide had been identified, again by Hofmann, from the seeds of certain morning glories, used for shamanic healing ceremonies in Mexico; and DMT (dimethyltryptamine) had been characterized from several species of plants employed for their psychoactive effects by Amazonian shamans.  Now, at the beginning of the 21st century, there are well over a hundred chemicals known to be psychedelically active.  The vast majority of these were discovered through synthesis and testing by one man: Alexander Shulgin.

Shulgin’s initial experience with mescaline was one of the most powerful and interesting experiences he had ever had.  And it had somehow resulted from the actions of a single pure chemical.  As a chemist, he was intrigued, and decided that the study of how molecular structure is related to a chemical’s effects on body and mind was a question worthy of rigorous scientific investigation.  And thus began a quest that would occupy him for many decades.  Starting with the mescaline molecule, he made, over a period of many years, numerous chemical modifications, testing the effects of each and every one (very, very carefully) on himself.  And publishing his results in scientific journals.  Several hundred chemically unique compounds, never before synthesized, never before investigated (2).  It was truly heroic work.  Notably, Shulgin for the most part worked alone or with a very small number of close colleagues.  Largely he used his own resources, in a small laboratory of his own construction that had the feel of an alchemist’s den.  It’s increasingly difficult to do good science that way: the old way – the way of Priestley, or Newton.

Alexander Shulgin in his laboratory in 2005.

Neurochemists and psychopharmacologists already appreciate that Shulgin’s work is truly pioneering.  Practitioners of these disciplines in years to come are likely to have an even greater appreciation of his contributions.  This kind of work will never again be possible.  Shulgin has explored such a vast array of chemical structures related to the neurotransmitters serotonin, dopamine, and norepinephrine, that the field is to a large extent fully cultivated.  He characterized compounds that appear to have specific effects on certain perceptual modalities, such as auditory or visual systems; and others that have specific effects on various aspects of emotion.

Some of Shulgin’s compounds are used in neurobiology to investigate the role of serotonin receptors in the brain.  The chemicals DOM (2,5-dimethoxy-4-methylamphetamine) and DOI (2,5-dimethoxy-4-iodoamphetamine), for example, are used to activate particular subtypes of serotonin receptors and study their relation to conditions like depression and psychosis, including exploration of mechanisms of action of antidepressant and antipsychotic medications.  DOI has been shown to induce the rapid growth and reorganization of dendritic spines and synaptic connections with other neurons, processes known to underlie what has come to be referred to as neuroplasticity (3).  The power of these chemicals as tools to explore the complexities of the brain and the relationships between brain physiology and mental experience is only beginning to be tapped.

Molecular structures of (clockwise, beginning at high noon) mescaline, DOM, DOI, dopamine, serotonin, and 4-OH-MiPT (4-hydroxy-methylisopropyltryptamine). For several years Shulgin taught a class on “Forensic Toxicology” at UC Berkeley. When lecturing on chemistry, he called molecular structures “dirty pictures.” An excellent documentary film called Dirty Pictures, about Shulgin’s life and work, was recently made (4).

These discoveries concerning relationships between specific chemical compounds, brain physiology, and mental experience would, by objective criteria, be worthy of the highest academic kudos – Nobel Prize kind of stuff.  Among my perennial candidates have long been Albert Hofmann (who died in 2008 at the age of 102 years) and Shulgin: Hofmann for his discovery of LSD and its effects, contributing to kick-starting what is now the field of biological psychiatry, and a whole lot of other things; and Shulgin, for pioneering the study of chemical-structure relationships to biological activity and mental experience in humans.  However, due to the complex circumstances that followed the emergence of the use of psychedelic chemicals in the wider culture, such honorific considerations became off limits.  Shulgin himself stopped conducting his structure-activity research in the late 1980s, after the Federal Controlled Substances Analogue Act made it illegal to synthesize and test any new psychoactive compounds in humans.

After several decades of legal restriction, very slowly and with cautious attention to the complexities, human research with psychedelically-active compounds is returning to the scientific mainstream – exploring their neurobiology (5) and their profound therapeutic potential (6).  There is much good work to be done in this terrain.

Alexander Shulgin celebrates 87 years of life on June 17, 2012.  Happy birthday, Sasha!

Notes and references:

(1)   Alexander Shulgin, Tania Manning, & Paul Daley, The Shulgin Index: Volume One, Psychedelic Phenethylamines and Related Compounds, Transform Press (2011).

(2)  Shulgin’s many chemical and psychological investigations have been summarized in two volumes written together with his wife, Ann – PiHKAL: A Chemical Love Story, Transform Press (1991) and TiHKAL: The Continuation, Transform Press (1994).

(3)  KA Jones et al “Rapid modulation of spine morphology by the 5HT2A serotonin receptor through kalirin-7 signaling” Proceedings of the National Academy of Sciences 106: 19575-19580 (2009).

(4)  The film Dirty Pictures was shown during the 2011 San Francisco Documentary Film Festival.

(5)  Recent example: RL Carhart-Harris et al “Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin” Proceedings of the National Academy of Sciences 109: 2138-2143 (2012).

(6)  Recent example: “How psychedelic drugs can help patients face death” by L Slater in the New York Times Sunday Magazine, 20 April 2012.

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