MAPS Bulletin Winter 2014 Vol. 24, No. 3 – Annual Report
Alexander “Sasha” Shulgin was born in Berkeley on June 17, 1925, and received his bachelor’s (1949) and doctorate (1955) degrees from the local college, the University of California in Berkeley. Except for some time spent as an undergraduate at Harvard and a stint in the U.S. Navy during World War II, he lived his entire life either in Berkeley or nearby in the East Bay.
Sasha’s doctoral research in biochemistry at UC Berkeley developed methods for the synthesis of amino acids containing chemical isotopes of carbon and nitrogen. Isotopically labeled molecules like these are useful for investigating details of metabolic pathways, how the body manufactures this from that.
Although Sasha later wrote that his doctoral work was “uninspired” and “dull” (PiHKAL, Chapter 2), adjectives like these are commonly applied to graduate-school projects. The primary goal of doctoral research in science is generally not to accomplish one’s best and most creative work, but to muck around and build intuition in the subject area. No doubt Sasha’s intuitions about molecular structure and chemical syntheses grew immensely during this period, and he was set on his way to becoming the artistic genius of pharmaceutical chemistry that he was to be. To Sasha, molecules had personalities, and he related to their structures and properties with an intimacy that is reflected, for example, in his calling molecular-structure diagrams “dirty pictures.”
Following his Ph.D., Sasha pursued the study of pharmacology at UC San Francisco, and worked for more than a decade in industry, first at Bio-Rad Laboratories and then at Dow Chemical. While at Dow he synthesized a carbamate derivative that was marketed as an insecticide (mexacarbate, brand name Zectran®). He also began to read pretty much everything that had been written about mescaline, and became increasingly intrigued with the seemingly magical properties of this molecule that had been identified from the peyote cactus in 1897 by German pharmacologist Arthur Heffter. Then, in April 1960, in his 35th year, Sasha experienced the powerful psychoactive effects of mescaline, stating later that: “It was a day that will remain blazingly vivid in my memory, and one which unquestionably confirmed the entire direction of my life.” (PiHKAL, Chapter 2)
A century ago, mescaline was the only chemical substance known to science that today would unequivocally be called a psychedelic. By 1960, when Sasha experienced its effects, there were but a handful of additional psychedelic chemicals known: LSD (lysergic acid diethylamide) had been characterized by Albert Hofmann in 1943; psilocybin and psilocin were identified from Psilocybe mushrooms by Hofmann in 1958; lysergic acid amide had been identified, again by Hofmann, from the seeds of 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. Today, in the early 21st century, there are well over a hundred chemicals known to have psychedelic effects, some say over 200. The majority of these were discovered through chemical synthesis and testing by one man: Sasha Shulgin.
Sasha Shulgin at the workbench in his lab.
Being a chemist, Sasha was deeply intrigued by how a chemical could have such profound effects on one’s thoughts, feelings, and perceptions, and decided that the study of how molecular structure relates to a chemical’s effects on body and mind was a topic deserving rigorous scientific investigation. Taking the chemical structure of mescaline as his starting point, he made, over a period of years, numerous molecular modifications, and very carefully tested the effects of each one, using himself as research subject. He published the results of his investigations in scientific journals—several hundred chemically unique compounds that had never before been synthesized and investigated, or even imagined.
This was truly heroic work. For the most part Sasha worked alone, or with a very small number of close friends and colleagues. He used his own resources—supporting his work via lecturing and consulting—and did his chemical syntheses in a small laboratory he constructed behind his home. It is nearly impossible to do good science this way anymore: the old way—the way of Priestly, or Newton.
Neurochemists and psychopharmacologists recognize the pioneering nature of Sasha’s work. Practitioners of these disciplines in years to come are likely to have an even greater appreciation of his contributions. Work of this nature may never again be possible. Sasha so thoroughly 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.
Some of Sasha’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. 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—not to mention their effectiveness as psychotherapeutic tools, long appreciated and now again being openly researched in mainstream clinical science.
Many discoveries in science happen when knowledge and technology make it ripe for them to happen. If such-and-such an individual or individuals had not made a particular discovery, then someone else likely would have sometime soon. Joseph Priestley and Antoine Lavoisier both appreciated around the same time that there must be a previously unrecognized elemental substance involved in combustion—the discovery of oxygen. Charles Darwin and Alfred Russel Wallace independently came up with the notion of evolution through natural selection. If a cadre of physicists working at Los Alamos in the 1940s had not built the world’s first fission bomb, it would have been done elsewhere at some point. If Francis Crick and James Watson had not discovered the double-helical structure of DNA, someone else (Rosalind Franklin or Linus Pauling, for starters) soon would have.
For other discoveries it is not so clear. If Einstein had not come up with the general theory of relativity—the description of gravity in terms of a non-Euclidean geometry of spacetime—it’s not at all clear that someone else would have thought of this. If Albert Hofmann had not synthesized and then tested on himself the diethylamide derivative of lysergic acid obtained from an extract of ergot alkaloids, it is likely the world today would not know the effects of LSD. If Sasha ha
d not shuffled methoxy groups around the phenethylamine ring of mescaline and then had the wit to place substituents like bromine, iodine, and alkylthios in what he called the “magical 4-position” of the 6-carbon ring, followed by careful focus of intention in the testing of these molecules, a vast landscape of pharmaceutical chemistry would have gone uncharted. It is very possible no one else would have done these things in the way required to make the discoveries Sasha made.
These discoveries concerning relationships between specific chemical compounds, brain physiology, and mental experience are, by all objective criteria, worthy of the very highest academic kudos: National Academy of Sciences, Royal Society, Nobel Prize. A very well deserved Nobel Prize in Chemistry would have been one shared by Albert Hofmann and Sasha Shulgin: Hofmann for his discovery of LSD and its effects, contributing to kick-starting the field of biological psychiatry, and a whole lot of other things; and Sasha, for pioneering the study of chemical-structure relationships to biological activity and mental experience in humans. But such honors are not presently possible, as we continue to struggle as a society learning how to balance the complex issues stirred up by the power of psychedelics to open the psyche.
What’s true is this: Some kinds of work are simply too big for universities, government research institutes, and industries, impressive as these institutions may be. Sasha’s work was like this: too big for a multi-million dollar laboratory, instead requiring an alchemist’s den, a courageous spirit, a careful focus of intention, and a goodly dose of mystical insight. Then the stuff of legend happened. Thank you, Sasha!
David E. Presti, Ph.D.
David E. Presti, Ph.D., teaches neurobiology and cognitive science at the University of California in Berkeley. His classes on “Drugs and the Brain,” “Brain, Mind, and Behavior: An Introduction to Neuroscience,” “Neurochemistry,” and “Mind, Matter, Consciousness” reach more than 1,000 UC Berkeley students every year. For more than a decade, he worked in the clinical treatment of addiction and post-traumatic stress at the Veteran’s Administration Medical Center in San Francisco. For the past 10 years, he has also been teaching neuroscience to Tibetan monastics in India.
“I first met Sasha in 1967 at a landmark NIMH-sponsored conference on the ethnobotany of psychoactive drugs held at UCSF Medical Center. We were both on the nutmeg portion of the program. I was a senior at Harvard, writing a thesis under the direction of Dick Schultes on the psychoactivity of nutmeg; he was working on phenethylamines and was interested in nutmeg’s active principle, myristicin. We hit it off, and when I moved to San Francisco the following year to start a medical internship at Mt. Zion, began seeing him regularly. I introduced him to Schultes and my East Coast network. He introduced me to his circle on the West Coast. I have wonderful memories of time spent with Sasha and Ann at Esalen, Telluride, and other spots and of sharing knowledge and adventures with them. I will always remember Sasha’s elfin twinkle.”
—Andrew Weil, M.D