Psilocybin, the hallucinogen in "magic mushrooms," may help treat severe depression, results from the largest-ever trial of the therapy show.
Early data from the trial were released in November 2021, but those results had not been peer-reviewed at the time. The new peer-reviewed report, published Wednesday (Nov. 2) in the New England Journal of Medicine, comes out as the trial's organizers are preparing to launch an even larger trial, called a Phase 3 trial, that will supply the needed data for Food and Drug Administration (FDA) approval.
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"The Phase 3 was worked out in consultation with the FDA," said lead author Dr. Guy Goodwin, the chief medical officer of Compass Pathways, the pharmaceutical company that ran the latest trial. "That'll give us an immense amount of experience to take into the approval process," Goodwin told Live Science.
The newly published trial included 233 participants from 10 countries in North America and Europe. All the participants had treatment-resistant depression, meaning they'd been prescribed at least two standard antidepressants in the past. Some participants had tried three or four treatments, to no avail.
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Seventy-nine of the participants received a single 25-milligram dose of psilocybin; 75 received 10 milligrams; and 79 received 1 milligram. The trial was double-blinded, meaning neither the organizers or the participants knew which dose was given to each person.
The 1-milligram dose served as a point of comparison for the higher doses, but unlike a true placebo, even one milligram of psilocybin can have some psychoactive effects, Goodwin said. This fact actually helped to keep the trial double-blinded, he told Live Science.
"These patients were naive to the psychedelic experience in 94% of cases" and therefore couldn't guess what dose they'd been given, Goodwin said. By comparison, a recent trial that tested psilocybin as a treatment for alcohol use disorder gave participants either psilocybin or the drug diphenhydramine (Benadryl). In that trial, the participants and supervising therapists correctly guessed which medication had been given in 90% of cases.
For the new trial, participants met with a therapist at least three times before receiving psilocybin and then the same therapist oversaw their dosing sessions, along with an assistant. Therapists also conducted follow-up sessions with the participants — one session on the day after dosing and one a week later.
The organizers used the Montgomery-Asberg Depression Rating Scale (MADRS), a common measure of clinical depression, to evaluate participants before and after treatment. Three weeks post-treatment, the scores of the people in the 25-milligram group had fallen 6.6 more points, on average, than the scores of the people in the 1-milligram group. More than a third of the high-dose group responded to the treatment, meaning their MADRS scores fell by at least 50%, and 29% had entered remission by the third week.
Meanwhile, the scores of the 10-milligram group dipped slightly but were not significantly different from those in the 1-milligram group. In that middle-dose group, 19% responded to treatment, as did 18% of the low-dose group; 9% and 8% of each group entered remission, respectively.
Related: FDA calls psychedelic psilocybin a 'breakthrough therapy' for severe depression
Three months post-treatment, 20% of the 25-milligram group still showed a "sustained response," meaning their scores had fallen and remained low, compared to 10% of the 1-milligram group. However, this finding is not considered "definitive" and will need to be confirmed, the report notes.
Three-quarters of the participants experienced some adverse event during the trial, including headache, fatigue, nausea or dizziness on the day of the dosing session. "Most of those effects were mild, and they were not things that we're concerned about," Goodwin said.
However, some participants experienced serious adverse events. In the three weeks post-treatment, several patients in the middle- and high-dose groups experienced suicidal ideation and nonsuicidal self-injury. These events also occurred in the middle-dose group between the third and twelfth week, and three participants in the high-dose group showed suicidal behavior in that timeframe. These three participants had histories of suicidal behavior or nonsuicidal self-injury and had not responded to the psilocybin treatment.
Because only a small number of people experienced these serious events, it's not clear if there's a statistically significant difference in risk between the groups. "It's very difficult to interpret that without simply saying we need more information," Goodwin said of the suicidal behavior only seen in the high-dose group. "We will continue to be vigilant about that imbalance, but we expect it to equalize itself out when we see more patients."
The upcoming Phase 3 trial will include two large groups, according to the Compass Pathways website. In one group of 378 people, the organizers will compare the effects of one 25-milligram dose of psilocybin to a true placebo, like a sugar pill. This will allow the team to confirm the safety profile of psilocybin, Goodwin said.
In a second group of 568 people, participants will receive two doses of psilocybin spaced three weeks apart; they'll either get two 25-, 10- or 1-milligram doses. This will reveal whether providing multiple doses can boost participants' response to the therapy and help the effects last for months on end. Initial results from the trial are expected in 2024, Goodwin said.
