The Drugs Meant to Induce Madness, a Review
How experimentation with psychedelics changed the course of American psychiatry.
Updated April 28, 2026 | Reviewed by Lybi Ma
In the spring of 1965, notes Justin Garson in The Madness Pill: One Doctor’s Quest to Understand Schizophrenia, published today by St Martin’s Press, several leading researchers at the National Institute of Mental Health set up an experiment with a small colony of squirrel monkeys, then with a slightly larger group of humans. Giving high doses of hallucinogens like LSD to each, they hoped to induce schizophrenia in their subjects, the better to study its underlying mechanism.
Two and three years later, before Institutional Review Boards in the 1970s would have stopped the experiments, they ran a similar one with STP, a street drug popular in the Bay Area. Later, they did the same with a cluster of amphetamines given to volunteers, including postdocs and lab workers. This time, hoping to cause amphetamine psychosis , they looked to confirm a causal relationship between dopamine flooding and a “schizophrenic reaction,” the phrase appearing in DSM -II , the field’s diagnostic manual, recently updated in 1968.
The researchers included scientists such as Bellevue psychiatrist Burton Angrist and Johns Hopkins professor Solomon (“Sol”) Snyder. Buoyed by optimism over other breakthroughs in neuroscience , they undertook the experiments in hopes of finding a cure for schizophrenia. Less hubristically, they wanted to improve its treatment, as first-generation antipsychotics like Thorazine, Mellaril, and Haldol came with a litany of side effects, from catatonia and drooling to tardive dyskinesia, a motor impairment causing involuntary spasms and twitches.
A short-term, drug-induced psychosis
The researchers assumed that the drug-induced psychosis would be short-term only and sufficiently similar to its organic counterpart for their differences not to matter. As Garson confirmed to me over email, amphetamine (speed), LSD (acid), and STP were by then “in wide circulation as street drugs, so that may have made them feel confident that any psychoactive effects would be temporary.”
“Something that I understood after talking with Snyder and Angrist,” Garson added, “was that they genuinely believed that they were on the verge of finding the biological cause of schizophrenia and potentially curing it. They had an optimism about the idea of a magic bullet that we no longer share today.”
The Madness Pill opens with Garson’s moving account of his father’s adverse reactions to first-generation antipsychotics, from a diagnosis of paranoid schizophrenia received when Justin was just 2 months old. The focus shifts to in-depth reporting on much of the lab work and experimentation to come. The “ethical dilemma” of inducing LSD and amphetamine psychosis from largely untested drugs is explored from the perspective that the experiments nonetheless took place, were carefully documented, and the results published in leading journals such as Science and the Proceedings of the National Academy of Sciences . In that respect, the work set the stage for influential single-agent hypotheses about schizophrenia, depression , and other mental conditions that, though incorrect and later disproven, fueled the widespread overprescribing of SSRIs , amphetamines, and atypical antipsychotics from the late 1980s and all decades since.
The “poster child” for new disorders and their hypotheses
Revising a 1954 research proposal on a “serotonin hypothesis of schizophrenia,” Snyder’s “Dopamine Hypothesis of Schizophrenia” (1970), and Harvard psychiatrist Joseph Schildkraut’s 1965 “Serotonin Hypothesis of Depression” failed differently over evidence and causality. But as Schildkraut’s hypothesis met with greater initial skepticism, Snyder’s became the standard-bearer for later illness modeling and awareness campaigns, including for ADHD , generalized anxiety disorder, and social anxiety disorder (“Is She Just Shy? and “Imagine Being Allergic to Other People”).
“One of the real far-reaching harms of the dopamine hypothesis,” Garson writes in the same email, is that “it lent some justification to [these] other, now-failed theories.”
Historians like David Healy and Anne Harrington have suggested as well that the dopamine hypothesis became a “poster child” for the emerging chemical imbalance paradigm. It helped lock in that paradigm in the scientific and even public imagination [and] gave doctors and researchers a sense that “this is a viable paradigm for understanding most other mental disorders, too.”
Despite Snyder's many setbacks in trying to prove his hypothesis, and ethical and evidential issues troubling his earlier research, he would later corroborate exceptional results in neuroscience, including by identifying the brain’s dopamine receptor in 1975, and—with the aid of his research assistant Candace Pert—its specialized opioid counterpart in 1972. As the latter receptor plays a distinct role in opioid dependency, its recognition paved the way for opioid antagonists such as Naloxone and for safer, more reliable tapering and deprescribing.
The foundational importance of this experimental research
Part detective story over experimental research and its results, part history and recovery of a dynamic chapter of American psychopharmacology when theory and practice were still further apart, The Madness Pill is a riveting, sometimes unnerving read. It takes us far into the lived history and effects of hallucinogens, amphetamines, and a range of other street drugs, and assesses their foundational importance to psychiatric research at the time.
A fellow contributor to this publication, the author also of The Biological Mind and Madness: A Philosophical Exploration, Garson pulls on detailed in-depth research and an impressive number of threads to trace the drugs’ importance to American psychiatry and its well-documented history of overprescribing.
Among the book’s many achievements, including the compelling way it puts schizophrenia, ambition, and delusion at the heart of its story, it captures how rapidly fads and bandwagons took off in the Age of Prozac and “cosmetic psychopharmacology,” with slick, expensive marketing campaigns reducing complexity to simple metaphors like a “chemical imbalance” in a “broken brain.” And as Garson notes wryly, the notion that brains are “broken” by schizophrenia isn’t very far from assuming that they are made “defective” as a result, an assumption fueling much of the stigma and fear attached to the condition in the 1940s and 50s.
“We absolutely should feel relieved that the dopamine hypothesis never became firmly established,” Garson concludes in his reply to me, “in the sense that we never found solid evidence for dopamine abnormalities in drug-naïve patients. I hope the reader comes away with a better understanding of why these chemical imbalance theories took hold to the extent that they did—they were largely a product of the 1960s drug subculture and a group of doctors who were willing to engage in risky experiments and far-reaching speculation. I also hope the reader can appreciate that these were quite brilliant scientists, and that they did have noble intentions, despite the fact that their theories haven’t stood the test of time.”
Garson, J (4.28.2026). The Madness Pill: One Doctor’s Quest to Understand Schizophrenia. New York: St Martin’s.
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Christopher Lane, Ph.D., is a Professor Emeritus of Medical Humanities at Northwestern University.
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