The first randomized controlled trial to compare the illicit psychedelic psilocybin with a conventional selective serotonin reuptake inhibitor (SSRI) antidepressant found that the former improved symptoms of depression just as well on an established metric—and had fewer side effects. The study was fairly small, however, and was not explicitly intended to show how well the drugs stacked up on other measures of well-being.

In a study published on Thursday in the New England Journal of Medicine, psychiatrist David Nutt, psychologist Robin Carhart-Harris and other researchers, all then at Imperial College London, conducted a six-week trial of 59 participants split into two groups. One group was given a full dose of psilocybin (the active ingredient in “magic mushrooms”) in combination with psychotherapy. The other received daily amounts of the SSRI escitalopram plus two minuscule amounts of psilocybin with psychotherapy. All of the participants suffered from major depressive disorder (MDD), which affects roughly 10 percent of the U.S. population in a given year.

Researchers had previously conducted an open-label trial (in which subjects and practitioners know which treatment they are getting) and four randomized controlled trials of psilocybin for depression and anxiety. But until now, no randomized controlled trials had directly compared psilocybin with an SSRI.

“Conventional antidepressants have dominated psychiatry for so long, so it is noteworthy to compare psilocybin—still an illegal drug—with a standard first-line treatment,” says Carhart-Harris, now at the University of California, San Francisco’s Neuroscape center. Psilocybin is designated as a Schedule I substance, defined as having “no currently accepted medical use and a high potential for abuse.” “This study clearly suggests we need to change the legal status of psilocybin because it is starkly at odds with the data,” Carhart-Harris says.

The researchers used a variety of measures to score study subjects for depressive symptoms and employed the 16-point Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16)—a self-assessment questionnaire—as the study’s primary outcome. The QIDS-SR-16 mean scores did not show a statistically significant difference between the group given psilocybin alone and the one given the SSRI after six weeks.

But the psilocybin group showed significantly larger reductions in suicidality, anhedonia (a lack of the ability to feel pleasure), and standard psychological scores for depression known as the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D). In particular, Carhart-Harris notes, within the 16 items in the QIDS-sR-16 questionnaire, many of the differences were highly significant: 70 percent of subjects in the psilocybin group responded to the treatment, compared with 48 percent of those in the SSRI group. The difference in remission rates was also statistically significant: the rate in the psilocybin group was 57 percent, and it was 28 percent in the escitalopram group.

“Looking at their data, it’s very clear to me that there is a substantial difference between those two groups in precisely the direction we would have predicted,” says Roland Griffiths, director of the Johns Hopkins Center for Psychedelic and Consciousness Research, who was not involved in this study but published his own “landmark” paper in JAMA Psychiatry last year: the first randomized controlled trial to examine psilocybin therapy for MDD.

“One of the most notable aspects of this new paper from Imperial [College London] is where it is being published, the NEJM, which is a marker for where mainstream medicine is situated,” says psychiatrist Charles Grob of the University of California, Los Angeles, who was also not involved in this study and has studied psilocybin and other psychedelics for decades. His most cited papers examined the psilocybin’s ability to reduce anxiety and improve quality of life in patients with terminal cancer. “This also indicates where we are as a society,” Grob says. “In 2006, when we began recruiting for our studies on cancer, it was very challenging.” By comparison, the scientists conducting the new trial were overwhelmed with volunteers: they ultimately screened 1,000 people, of whom they selected only 59.

The team anticipated that this high number of “self-referrals,” most of whom experienced a strong preference for psilocybin over an SSRI, would likely influence the study’s outcomes, Carhart-Harris says. Those who received escitalopram would probably express disappointment, and those receiving the psilocybin could improve even more than they would if the study had been conducted 10 years ago. Many factors make careful statistical scrutiny of psychedelic therapies difficult—and raise the question of whether “blinding” subjects to the treatment they receive is even possible with such strong psychoactive drugs.

The researchers attempted to minimize this effect by telling people in both groups they would receive psilocybin to set up equivalent expectations. They gave both groups the standard experience of a psychedelic dosing: an extended, four-to-six-hour session in which each subject was instructed to lie still while blindfolded and listening to music, with one or two therapists in the room for support. The participants assigned to the psilocybin group were given a 25-milligram dose of psilocybin for the full effect. Those in the escitalopram group were given a one-milligram subperceptual “microdose” with no obvious psychedelic effects. Finally, after the first dosing, the team gave every subject a bottle of pills and instructed them to take one per day: the escitalopram group received the SSRI, whereas those in the psilocybin group simply took a placebo.

“This is an incredibly exciting topic, but it does require very rigorous scientific methodology to really understand the safety and efficacy of these treatments,” says psychiatrist Gerard Sanacora, an associate professor at the Yale School of Medicine and director of the Yale Depression Research Program, who was not involved in the study. This is a relatively small number of people with no placebo group, so we are limited in what conclusions we can draw from this data,” he says. “I look at this data as promising and warranting this study. But sometimes the excitement does get ahead of the science, so we need to be honest in saying what the limitations are.”

Sanacora also notes that the psychotherapeutic component of the study—which gave equal amounts of preparation, counseling and follow-up to both  the escitalopram and psilocybin groups—is unusual and noteworthy. Every participant received between 38 and 40 hours of psychotherapy in total—roughly double the normal amount subjects in most psychedelic studies receive. “That kind of psychosocial intervention is really quite powerful,” he says.

“It’s really important for us to recognize that, in the study, both groups did well, and the reason they both did well is because there was so much care and attention in this study,” says psychologist Rosalind Watts, a co-author of the paper and lead of the clinical portion of the research. She is now a member of the advisory board at Synthesis, a center that offers psychedelic therapy retreats in the Netherlands. That nation is one of the few jurisdictions where psilocybin (in the form of truffles) is legal. In Oregon, citizens voted in November 2020 to legalize psilocybin therapy for medical purposes.

The psychological component of psychedelic therapy tends to be underemphasized by both scientists and the media, yet it is thought to be integral to the therapy’s efficacy, Watts says—in particular because these experiences can be unsettling, powerful, confusing and even scary. The feeling of “safety” and an “alliance” with a therapist is often crucial for any psychological breakthrough. This is especially true for many patients with depression, who often lack confidence to try new treatments after many have failed.

“I thought the drug might work for some people but probably would not work for me. I was quite terrified because I didn’t really trust my brain; I felt like it was always working against me,” says Ali Thorne, a 32-year-old registered nurse in the U.K., who took part in the trial after suffering from depression for two decades. “I think the trial—both the psilocybin and the psychological support—really saved my life.” (Following the study, participants were informed which treatment they had received.)

Yet while some of the subjects experienced enduring benefits after the trial concluded, others relapsed into depression. Leonie Schneider, a 44-year-old Greek woman living in England, was one of the participants who became depressed again, following a particularly challenging period of unfortunate events that included severe financial difficulties as a result of COVID and family members with a terminal illness. “I became more depressed than I’d been in my entire life, and it was even more difficult because I had come off the medication I had previously relied on prior to the trial. Plus, COVID was kicking off, and I didn’t have the stabilizing crutches I normally had to cope,” she says.

Schneider notes, however, that two decades of trying a multitude of SSRI antidepressants in addition to talk therapy did not give her the resilience she needed. “Antidepressants often just felt like a palliative care approach to mental health,” she says. In comparison, “the [psilocybin] trial gave me the tools to begin that work and build that emotional resilience.”

“While studies for somebody who is facing death and depressed due to terminal illness may show a lasting change from one session with psilocybin, if someone has been depressed for decades for no discernible reason, it is less likely to be alleviated with just one or two doses,” Watts notes.

When the trial ended in March 2020, as the COVID-19 pandemic was exploding, Watts and other members of the team set up online therapy sessions for trial participants who felt they needed extra support. Schneider was quick to sign up, as was Thorne, along with 16 other participants who have met regularly with the study psychologists and one another online for a year. This has extended the period known as “integration,” when individuals make sense of the visions and insights they felt under the influence of psilocybin.

“People describe psychedelic therapy as 25 years of therapy in one afternoon. And it can absolutely feel like that, but it’s not a silver bullet—and it’s just an afternoon,” Schneider says. “The real magic in this is not in the dosing day, it’s in the work that you do afterward.”