by Psilocybinhallucinogen in “magic mushrooms,” may help treat severe depression, according to results of the largest trial of the treatment ever.
Early data from the trial were released in November 2021, but these results were not peer-reviewed at that time. The new peer-reviewed report, published Wednesday (November 2) in the New England Journal of Medicine (opens in new tab)It comes as trial organizers prepare to begin an even larger trial, called a Phase 3 trial, which will provide the data needed for Food and Drug Administration (FDA) approval.
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“Phase 3 was designed in consultation with the FDA,” said the lead author Dr. Guy Goodwin (opens in new tab), the chief medical officer of Compass Pathways, the pharmaceutical company that conducted the latest trial. “This will give us a tremendous amount of experience to use in the approval process,” Goodwin told Live Science.
The newly published trial included 233 participants from 10 countries in North America and Europe. All participants were resistant to treatment depression, meaning they had 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-blind, meaning that neither the organizers nor the participants knew what dose each person was given.
The 1-milligram dose served as a benchmark for the higher doses, but unlike an actual placebo, even one milligram of psilocybin can have some psychoactive effects, Goodwin said. That fact actually helped keep the trial double-blind, he told Live Science.
“These patients were naive to the psychedelic experience 94 percent of the time,” and therefore could not guess what dose they had been given, Goodwin said. In comparison, a recent trial that examined psilocybin as a treatment for alcohol use disorder gave participants either psilocybin or the drug diphenhydramine (Benadryl). In that trial, participants and supervising therapists correctly guessed which medication had been given 90% of the time.
For the new trial, participants met with a therapist at least three times before receiving psilocybin, and then the same therapist supervised their dosing sessions, along with an assistant. Therapists also conducted follow-up sessions with the participants — one session the day after administration and one one week later.
The organizers used the Montgomery-Asberg Depression Scale (MADRS), a common measure of clinical depression, to assess participants before and after treatment. Three weeks after treatment, the scores of people in the 25-milligram group had dropped 6.6 more points, on average, than the scores of people in the 1-milligram group. More than a third of the high-dose group responded to treatment, meaning MADRS scores fell by at least 50%, and 29% had entered remission by week three.
Meanwhile, the 10-milligram group’s scores decreased slightly but were not significantly different from those of the 1-milligram group. In this medium-dose group, 19% responded to treatment, as did 18% of the low-dose group. 9% and 8% of each group went into remission, respectively.
Related: The FDA calls the psychedelic psilocybin a “breakthrough treatment” for major depression
Three months after treatment, 20 percent of the 25-milligram group still had a “sustained response,” meaning their scores had fallen and remained low, compared with 10 percent of the 1-milligram group. However, this finding is not considered “definitive” and should be confirmed, the report notes.
Three-quarters of participants experienced an adverse event during the trial, such as headache, fatigue, nausea, or dizziness on the day of the dosing session. “Most of these impacts were mild and not things we’re concerned about,” Goodwin said.
However, some participants experienced serious side effects. At three weeks post-treatment, several patients in the mid- and high-dose groups experienced suicidal ideation and non-suicidal self-injury. These events also occurred in the mid-dose group between weeks three and twelve, and three participants in the high-dose group experienced suicidal behavior during this time. These three participants had a history of suicidal behavior or non-self-injury and had not responded to psilocybin treatment.
Because only a small number of people experienced these serious events, it is unclear whether there is a statistically significant difference in risk between the groups. “It’s very difficult to interpret this without simply saying we need more information,” Goodwin said of the suicidal behavior seen only in the high-dose group. “We will continue to be vigilant about this imbalance, but expect it to even out as we see more patients.”
The upcoming Phase 3 trial will include two major groups, according to the Compass Pathways website (opens in new tab). In a group of 378 people, organizers will compare the effects of a 25-milligram dose of psilocybin with an actual placebo, such as 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 three weeks apart. they will either receive two doses of 25, 10 or 1 milligram. This will reveal whether giving multiple doses can boost participants’ response to treatment and help the results last for months. Initial results from the trial are expected in 2024, Goodwin said.
