Psilocybin Research

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Psilocybin research names the modern laboratory and clinical study of psilocybin, a naturally occurring compound, found in many species of mushroom, that acts on the brain’s serotonin system. The field has a peculiar shape. The thing it studies was a working medicine for centuries before any chemist handled it, and its central discovery to date is not a molecule or a mechanism but a measurement: the lasting benefit of the drug appears to track an experience the trial instruments can only call mystical.

The deep background is Mazatec. In the Sierra Mazateca of Oaxaca, in southern Mexico, the mushrooms — los niños santos, “the holy children” — were taken in a nocturnal ceremony of healing and divination called the velada, a rite descended from practices documented in the sixteenth century and observed by outsiders in modern times only from 1938, when the anthropologist Jean Bassett Johnson attended one at Huautla de Jiménez. The mushrooms were a sacrament — communion with the sacred, in the tradition’s framing — taken to heal the sick and to locate the lost: missing people, missing things. The century’s most renowned practitioner was María Sabina, who called herself not a curandera but a sabia, a wise one; she had tried the ordinary healer’s path and judged it not hers.

What carried the velada into the modern world was a New York banker. R. Gordon Wasson, a vice-president of J.P. Morgan whose interest in mushrooms began on his honeymoon in 1927, traveled to Huautla in 1955 and, with the photographer Allan Richardson, became among the first outsiders ever admitted to the ceremony. Admission rested on a lie: Wasson told María Sabina he was anxious for news of his son back home, a deception he later admitted. On 13 May 1957 Life magazine ran his photo-essay “Seeking the Magic Mushroom” — an editor inserted the phrase over Wasson’s objection, and it has never left the language. Among those the essay drew toward Mexico was a Harvard psychologist named Timothy Leary.

What it brought María Sabina belongs in the account. The article had withheld her name and her village; a later limited edition of Wasson’s work disclosed both, completing the breach of a consent that had been obtained by deception in the first place. From 1962 the visitors descended on Huautla — hippies, scientists, the merely curious. The Mexican police, watching the influx, suspected her of selling drugs. Her own community blamed her for what had come: she was ostracized, her house was burned down, her son was murdered, and she was briefly jailed. From 1967 to 1977 the army blocked the roads into the town to keep strangers out. Wasson, by the 1970s, had come to regret what the publicity had done to the ritual; he maintained that his only aim had been knowledge, and documents released later showed that his 1955 expedition had been partly funded, without his knowledge at the time, through the CIA’s MKUltra program. María Sabina’s own verdict was exact: “Before Wasson, nobody took the children simply to find God. They were always taken to cure the sick.” She died in poverty, suffering from malnutrition, in 1985. From the indigenous side of the ledger the episode has since been described plainly, as extraction, cultural appropriation, bioprospecting, colonization. The science that follows stands on this ground.

The chemistry came quickly. Mushroom material from the expeditions, cultivated by the French mycologist Roger Heim, reached the Sandoz laboratories in Basel, where Albert Hofmann — already famous for LSD — isolated, named, and synthesized the active agents, psilocybin and psilocin, in 1958. Sandoz supplied the pure compound to researchers, and where it landed first, most consequentially, was Harvard. From 1960 to 1962 Timothy Leary and Richard Alpert — later Ram Dass — ran the Harvard Psilocybin Project, with a founding circle that included Aldous Huxley. Two studies became famous: the Concord Prison Experiment, which asked whether psilocybin could lower recidivism among inmates, and the Marsh Chapel or “Good Friday” experiment, in which Walter Pahnke, a divinity-school graduate student, tested whether it could occasion genuine religious experience in divinity students — those who received the drug reported exactly that. The project then collapsed on its own conduct. Colleagues objected to the researchers’ use of the drugs themselves, to the want of randomized sampling, to pressure on students to take part, and to psilocybin reaching undergraduates against university rules; two students were hospitalized; The Harvard Crimson aired the matter in February 1962, and Leary and Alpert were dismissed in 1963. The scandal did not stay at Harvard. It helped turn elite and public opinion against the drugs altogether.

The shutdown that followed was thorough. Sandoz halted production in 1966, the year American law first prohibited the hallucinogens; in 1970 the Comprehensive Drug Abuse Prevention and Control Act placed psilocybin in Schedule I, illegal for any purpose including scientific research; in 1971 the UN Convention on Psychotropic Substances made the listing international. For roughly a generation there was, in effect, no sanctioned human research at all. The mushrooms did not disappear. The science did.

The field reopened at Johns Hopkins in 2006. Roland Griffiths and colleagues ran a double-blind study in which adults who had never taken hallucinogens, all active in religious or spiritual life, received in separate sessions a high dose of psilocybin and an active stimulant comparator chosen to obscure the design, under carefully supportive conditions. The drug produced acute perceptual and mood upheaval, including transient anxiety in some; it also sharply raised measures of mystical experience, and two months on the volunteers rated the session among the most personally meaningful and spiritually significant experiences of their lives. At fourteen months the ratings held, fifty-eight percent had met formal criteria for a “complete” mystical experience, and it was the mystical experience itself, statistically, that carried the durable change. That is the empirical keystone of the revival: what lasts tracks the quality of the experience, not merely the fact of the dose.

Two institutions became the field’s centers of gravity. Johns Hopkins formally launched its Center for Psychedelic and Consciousness Research in September 2019, reported at the time as the first dedicated center in the United States. At Imperial College London, Robin Carhart-Harris — who had joined David Nutt there in 2008, and in 2016 published the first modern trial of psilocybin for treatment-resistant depression — founded the Centre for Psychedelic Research, described as the first of its kind in the world. Around the two centers a clinical literature accumulated, and it is best read with both of its columns showing.

The strongest early signal came in 2016, in two trials published simultaneously: fifty-one patients at Hopkins and twenty-nine at NYU, all with life-threatening cancer and clinical depression or anxiety, in randomized double-blind crossovers pitting a high dose against placebo-like comparators. Both found large, rapid, and sustained reductions in depression, anxiety, and the fear of death, with most patients still markedly improved half a year later — and in both, the mystical experience mediated the effect. An open-label Hopkins pilot in smoking cessation reported six-month abstinence in twelve of fifteen smokers, far beyond what standard treatments achieve, though a design without controls permits no conclusion about efficacy. In depression the record is more instructive for its complications. A small Hopkins randomized trial published in 2021 found large, rapid antidepressant effects in twenty-seven adults. The same year, Imperial’s double-blind comparison of psilocybin against the antidepressant escitalopram became a landmark for the opposite reason: on its primary outcome, the difference between the two was not statistically significant. And the largest trial to date — 233 participants with treatment-resistant depression, given a single dose of synthetic psilocybin in one of three arms — found the high-dose arm clearly better than the control arm at three weeks, could not demonstrate sustained response at twelve, and recorded adverse events in roughly three-quarters of participants, including instances of suicidal ideation and behavior. Regulators had already moved: the FDA granted breakthrough-therapy designations to psilocybin programs in 2018 and 2019; Oregon voted in 2020 to become the first state to permit supervised use in licensed settings, and Colorado followed in 2022 with a framework of its own — while the compound remains, federally and internationally, in Schedule I.

The criticisms deserve the same weight as the findings. A psychedelic trial is nearly impossible to blind — participants and staff can usually tell within the hour who received the drug — and the volunteers are a self-selected, hopeful population, conditions under which expectancy alone can move a depression scale. A 2021 methodological review found that trials largely failed even to measure their own blinding or their participants’ expectations, and concluded that the field’s effect sizes are likely overestimated. A 2024 meta-analysis in the BMJ, pooling seven trials and 436 participants, found a statistically significant but moderate benefit, and found it largest exactly where bias would predict — on self-report scales, in depression secondary to other illness, among participants who had taken psychedelics before; every pooled trial carried at least moderate risk of bias. Samples remain small; durability beyond a few months remains undemonstrated in the largest study; the adverse events are real. None of this erases the signal. It shrinks it to the size the evidence can actually carry.

What gives the field its claim on this site’s attention — and this is the site’s reading, offered as such — is the instrument at its center. The Mystical Experience Questionnaire is a self-report scale built to quantify mystical-type experience in the laboratory. A 2012 factor analysis of more than sixteen hundred psilocybin accounts reduced it to thirty items in four dimensions: a mystical core of unity, noetic quality, and sacredness; positive mood; transcendence of time and space; ineffability. That list was not invented by pharmacologists. It is the classical vocabulary of mysticism — the terms in which contemplative traditions have described their summit states — operationalized as a clinical measure, complete with a threshold score, the “complete mystical experience,” for sessions that register high on every dimension at once. And the operationalization does real empirical work: a 2015 validation in controlled psilocybin sessions found that questionnaire scores predicted persisting change in attitudes, behavior, and well-being even after controlling for the sheer intensity of the drug effect, and the construct sits behind the repeated finding, in trial after trial, that the mystical experience mediates the clinical outcome. A laboratory has built a gauge out of the language of the mystics and found that it measures something with consequences. What that shows is exact, and limited. It shows that experiences answering the old descriptions occur, can be occasioned with some reliability under clinical conditions, and matter to what follows. It does not show that the traditions’ metaphysics are true. The questionnaire records the conviction of having encountered something ultimate; no questionnaire can establish whether the conviction is correct. The resemblances between the trial reports and the contemplative literature are real, and worth every hour the field has spent on them. They are evidence of a shared experience, not of a shared object.

María Sabina’s complaint — cure the sick, not find God — was precise. Seven decades of chemistry, scandal, prohibition, and trial later, the laboratories have arrived at a careful version of her position — that under clinical conditions the mushrooms may help the sick, and that the help appears to run through the kind of experience her tradition would not have needed a questionnaire to name. The instruments are new. The finding is not.

→ Related: Mysticism · Aldous Huxley