In November 2021, when psychedelic drug company Compass Pathways released top-line results from a trial looking at psilocybin in patients with treatment-resistant depression, the company’s stock plunged nearly 30% . The dive was reportedly due to the somewhat modest results of the study, but also because of the dispersion of serious adverse events that occurred during the trial.
Injuries are already taboo. After all, the field was vilified for decades and only recently re-entered the mainstream. But as clinical trials get bigger — and drugs become more commercialized — more negative results are likely to emerge. As the Compass trial results hint at, it’s arguably time to start a conversation about the potential side effects of psychedelics—even if it means tempering the hype that’s already built up.
These results, now published in full in the New England Journal of Medicine , represent the largest A randomized, controlled, double-blind psilocybin treatment study has been done. The participants – 233 of them at 22 sites in 10 countries – were divided into three roughly equal groups. One group received 1 milligram (mg) of COMP360, Compass’ synthetic psilocybin, at a very low dose that could be used as a placebo. The next group received 10 mg and the last group received 25 mg. Psychological support was also provided along with the treatment.
The results are promising, if not painting a picture of a miracle cure. In the 25-mg group, 29 percent experienced remission after three weeks, compared with 8 percent in the placebo group. The positive effects waned over time: after 12 weeks, only 20% of those on the high dose still responded—an improvement over placebo, but not statistically significant.
Meanwhile, 179 of the 233 people involved in the trial reported at least one side effect, such as headache, nausea, fatigue or insomnia—uncomfortable, sure, but not a huge problem . However, 12 individuals experienced serious
adverse events. These were defined as exhibiting suicidal ideation, including self-harm. Suicidal behavior was reported in 5 people in the highest dose group and 6 in the 10 mg group. This was compared with only one in the placebo group.
“Is this expected in a trial like this? In a way, yes,” said Assistant Professor and Medical Director of the Johns Hopkins Center for the Study of Psychedelic and Consciousness Natalie Gukasyan told WIRED. Working with a patient population as vulnerable as those with treatment-resistant depression is expected to have higher rates of suicidal ideation. But notably, she said, these events occurred more frequently in the high-dose group, raising the question of whether the drug was working. One thing she thinks will help to be included in the study is the participants’ lifetime history of previous suicide attempts, which are important predictors of future suicidal behavior.
But given the general reluctance to dwell on the downsides of psychedelics, the fact that Compass is candid about adverse events is a good thing, says PhD candidate who studies psychedelics patient experience Joost Breeksema at the University Medical Center Groningen in the Netherlands, Breeksema told WIRED. In August 2022, Breeksema published a review that looked at how adverse events were flagged in psychedelic studies and found that they were inconsistent and likely underestimated. Many of the trials Breeksema studied reported no adverse effects—an unlikely reality. The Compass Pathways study “reported adverse effects more rigorously than many of the other trials in our systematic review,” he said.
