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The world’s very first LSD trip, and the only one undertaken with no prior expectations, was the one Albert Hofmann took in 1943. While it left him uncertain whether he had experienced madness or transcendence, Hofmann immediately sensed the potential importance of this compound for neurology and psychiatry. So Sandoz, the pharmaceutical company for which he worked at the time of his discovery, did something unusual: in effect, it crowd-sourced a worldwide research effort to figure out what in the world Delysid—its brand name for LSD-25—might be good for. Hoping someone somewhere would hit upon a commercial application for its spookily powerful new compound, Sandoz offered to supply, free of charge, however much LSD any researcher requested. The company defined the term “researcher” liberally enough to include any therapist who promised to write up his or her clinical observations. This policy remained more or less unchanged from 1949 to 1966 and was in large part responsible for setting off the first wave of psychedelic research—the one that crashed in 1966, when Sandoz, alarmed at the controversy that had erupted around its experimental drug, abruptly withdrew Delysid from circulation.

So what was learned during that fertile and freewheeling period of investigation? A straightforward question, and yet the answer is complicated by the very nature of these drugs, which is anything but straightforward. As the literary theorists would say, the psychedelic experience is highly “constructed.” If you are told you will have a spiritual experience, chances are pretty good that you will, and, likewise, if you are told the drug may drive you temporarily insane, or acquaint you with the collective unconscious, or help you access “cosmic consciousness,” or revisit the trauma of your birth, you stand a good chance of having exactly that kind of experience.

Psychologists call these self-fulfilling prophecies “expectancy effects,” and they turn out to be especially powerful in the case of psychedelics. So, for example, if you have ever read Aldous Huxley’s Doors of Perception, which was published in 1954, your own psychedelic experience has probably been influenced by the author’s mysticism and, specifically, the mysticism of the East to which Huxley was inclined. Indeed, even if you have never read Huxley, his construction of the experience has probably influenced your own, for that Eastern flavoring—think of the Beatles song “Tomorrow Never Knows”—would come to characterize the LSD experience from 1954 on. (Leary would pick up this psychedelic orientalism from Huxley and then greatly amplify it when he and his Harvard colleagues wrote a bestselling manual for psychedelic experience based on the Tibetan Book of the Dead.) Further complicating the story and adding another feedback loop, Huxley was inspired to try psychedelics and write about the experience by a scientist who gave him mescaline in the explicit hope that a great writer’s descriptions and metaphors would help him and his colleagues make sense of an experience they were struggling to interpret. So did Aldous Huxley “make sense” of the modern psychedelic experience, or did he in some sense invent it?

This hall of epistemological mirrors was just one of the many challenges facing the researchers who wanted to bring LSD into the field of psychiatry and psychotherapy: psychedelic therapy could look more like shamanism or faith healing than medicine. Another challenge was the irrational exuberance that seemed to infect any researchers who got involved with LSD, an enthusiasm that might have improved the results of their experiments at the same time it fueled the skepticism of colleagues who remained psychedelic virgins. Yet a third challenge was how to fit psychedelics into the existing structures of science and psychiatry, if indeed that was possible. How do you do a controlled experiment with a psychedelic? How do you effectively blind your patients and clinicians or control for the powerful expectancy effect? When “set” and “setting” play such a big role in the patient’s experience, how can you hope to isolate a single variable or design a therapeutic application?

Part I: The Promise The drugs weren’t called “psychedelics” at the beginning; that term wasn’t introduced until 1957. In the same way that Sandoz couldn’t figure out what it had on its hands with LSD, the researchers experimenting with the drug couldn’t figure out what to call it. Over the course of the 1950s, this class of drugs underwent a succession of name changes as our understanding of the chemicals and their action evolved, each new name reflecting the shifting interpretation—or was it a construction?—of what these strange and powerful molecules meant and did.

The first name was perhaps the most awkward: beginning around 1950, shortly after LSD was made available to researchers, the compound was known as a psychotomimetic, which is to say, a mind drug that mimicked psychoses. This was the most obvious and parsimonious interpretation of a psychedelic’s effects. Viewed from the outside, people given doses of LSD and, later, psilocybin exhibited many of the signs of a temporary psychosis. Early researchers reported a range of disturbing symptoms in their LSD volunteers, including depersonalization, loss of ego boundaries, distorted body image, synesthesia (seeing sounds or hearing sights), emotional lability, giggling and weeping, distortion of the sense of time, delirium, hallucinations, paranoid delusions, and, in the words of one writer, “a tantalizing sense of portentousness.” When researchers administered standardized psychiatric tests to volunteers on LSD—such as the Rorschach ink blots or the Minnesota Multiphasic Personality Inventory test—the results mirrored those of psychotics and, specifically, schizophrenics. Volunteers on LSD appeared to be losing their minds.

This suggested to some researchers that LSD held promise as a tool for understanding psychosis, which is precisely how Sandoz initially marketed Delysid. Although the drug might not cure anything, the resemblance of its effects to the symptoms of schizophrenia suggested that the mental disorder might have a chemical basis that LSD could somehow illuminate. For clinicians, the drug promised to help them better understand and empathize with their schizophrenic patients. That of course meant taking the drug themselves, which seems odd, even scandalous, to us today. But in the years before 1962, when Congress passed a law giving the FDA authority to regulate new “investigational” drugs, this was in fact common practice. Indeed, it was considered the ethical thing to do, for to not take the drug yourself was tantamount to treating your patients as guinea pigs. Humphry Osmond wrote that the extraordinary promise of LSD was to allow the therapist who took it to “enter the illness and see with a madman’s eyes, hear with his ears, and feel with his skin.”

Born in Surrey, England, in 1917, Osmond is a little-known but pivotal figure in the history of psychedelic research,* probably contributing more to our understanding of these compounds and their therapeutic potential than any other single researcher. In the years following World War II, Osmond, a tall reed of a man with raucous teeth, was practicing psychiatry at St. George’s Hospital in London when a colleague named John Smythies introduced him to an obscure body of medical literature about mescaline. After learning that mescaline induced hallucinations much like those reported by schizophrenics, the two researchers began to explore the idea that the disease was caused by a chemical imbalance in the brain. At a time when the role of brain chemistry in mental illness had not yet been established, this was a radical hypothesis. The two psychiatrists had observed that the molecular structure of mescaline closely resembled that of adrenaline. Could schizophrenia result from some kind of dysfunction in the metabolism of adrenaline, transforming it into a compound that produced the schizophrenic rupture with reality?

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