Psilocybinthe hallucinogen in “magic mushrooms”, may help treat severe depression, according to the largest ever trial of therapeutic emission.
First trial data were published in November 2021, but these results were not peer-reviewed at the time. The new peer-reviewed report, published Wednesday, November 2 in the New England Journal of Medicine (opens in a new tab)comes out as trial organizers prepare to launch 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 developed in consultation with the FDA,” the lead author said. Dr Guy Goodwin (opens in a new tab), the chief medical officer of Compass Pathways, the pharmaceutical company that conducted the latest trial. “It will give us immense experience to take into the approval process,” Goodwin told Live Science.
The recently published trial included 233 participants from 10 countries in North America and Europe. All participants had treatment resistance the 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 dose of 25 milligrams of psilocybin; 75 received 10 milligrams; and 79 received 1 milligram. The trial was double-blind, which means that neither the organizers nor the participants knew what dose each person was given.
The 1 milligram dose served as a benchmark for higher doses, but unlike a true placebo, even one milligram of psilocybin can have psychoactive effects, Goodwin said. That fact actually helped keep the trial double-blind, he told Live Science.
“These patients were naïve to the psychedelic experience in 94% of cases” and therefore could not guess what dose they had received, Goodwin said. In comparison, a recent trial that tested psilocybin as treatment of alcohol use disorders gave participants either psilocybin or the drug diphenhydramine (Benadryl). In this trial, participants and supervising therapists correctly guessed which drug was administered 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. The therapists also arranged follow-up sessions with the participants – one session the day after administration and one week later.
Organizers used the Montgomery-Asberg Depression Rating 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 points more, 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 their MADRS scores fell by at least 50% and 29% had gone into remission by week three.
During this time, the scores of the 10 milligram group fell slightly but were not significantly different from those of the 1 milligram group. In this mid-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: FDA calls psychedelic psilocybin ‘breakthrough therapy’ for severe depression
Three months after treatment, 20% of the 25 milligram group still showed a “sustained response,” meaning their scores dropped and remained low, compared with 10% of the 1 milligram group. However, this conclusion is not considered “definitive” and will need to be confirmed, the report notes.
Three-quarters of participants experienced an 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 those aren’t things we’re concerned about,” Goodwin said.
However, some participants experienced serious adverse events. During the three weeks following treatment, several patients in the mid- and high-dose groups had suicidal ideation and non-suicidal self-harm. These events also occurred in the mid-dose group between weeks three and 12, and three participants in the high-dose group showed suicidal behavior during this time. These three participants had a history of suicidal behavior or nonsuicidal self-harm and had not responded to psilocybin treatment.
Since 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 that without just 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 next phase 3 trial will include two large groups, according to the Compass Pathways website (opens in a new tab). In a group of 378 people, the organizers will compare the effects of a 25 milligram dose of psilocybin to a real 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 three weeks apart; they will receive either two doses of 25, 10, or 1 milligram. This will reveal whether multiple doses can boost participants’ response to therapy and help effects last for months. The first results from the trial are expected in 2024, Goodwin said.