‘Intriguing and sobering’: Enthusiasm over psilocybin’s effect on depression tempered by questions about durability

The hype around psychedelic therapy has been put to the test, with the publication Wednesday of the largest-ever study of psilocybin to treat depression. The Phase 2 trial found that the drug was effective — it reduced or eliminated symptoms in the short term in more than one-third of patients who took the highest dose — but not as dazzlingly powerful as earlier smaller studies had suggested.

The patients in the study, published in the New England Journal of Medicine, all had treatment-resistant depression, meaning they had tried at least two approved depression therapies that afforded them no relief. So any response in a significant number of patients is promising, though the effects were not as long-lasting as seen in earlier and smaller studies.

“It’s a big step forward for the field of psychedelic research and depression treatment,” said Jimmy Potash, the director of psychiatry at Johns Hopkins who oversees psychedelics research at the university but was not involved in the study. The durability of the response, he added, is “not as good as you’d like, but it’s still quite good.”

The study, sponsored by Compass Pathways, had 233 participants across 10 countries, who were randomly assigned to receive a single dose of 25, 10, or 1 milligram of the company’s synthetic formulation of psilocybin, the key psychedelic compound in magic mushrooms. Patients in the high-dose group saw their scores on a standard depression scale fall by 12 points from an average of 32 before treatment, significantly more than for patients taking the lowest dose. (The 1-milligram dose was used instead of a placebo, to help create a blinded study. Though the tiny dose usually has barely noticeable effects, it can create hallucinogenic-type experiences and make it harder for patients to know they aren’t in the full-dose arms of the trial.)

The researchers found that 29% of participants who received the highest dose were in remission three weeks after the treatment, while 37% saw their depression score fall by at least 50%. This is strong grounds for further research, said Potash: “It very much encourages us to think this is promising and it’s worth doing the next larger study.”

Compass announced the headline results last year, but the data had not yet been published or peer-reviewed. “The results give us a lot of confidence going into Phase 3,” said Steve Levine, the company’s senior vice president of patient access. “We think this is a milestone on the path we’re committed to, which is not just regulatory approval but creating broad and equitable access.”

Compass is the leading private company conducting research on psilocybin, and is seeking to get Food and Drug Administration approval for the drug as a treatment for depression. It has aggressively pursued patents around synthesized psilocybin to help ensure profits, but the company has been criticized by others in the field, who question the value of patenting a drug that occurs naturally in nature.

While the results provide a solid basis for further investigation, Bertha Madras, a psychology professor at Harvard Medical School, noted in an accompanying editorial that the overall response rate of 37% was lower than in antidepressant trials and in a study published last year comparing psilocybin and an SSRI for major depressive disorder. “The findings are both intriguing and sobering,” she wrote.

Three months after treatment, 20% of participants given the highest dose were still in remission. This is less than Compass disclosed in its announcement last year, when it said a quarter of participants were in remission after 12 weeks; Levine said the difference was due to how Compass ultimately decided to define sustained response. The finding is also lower than in an earlier study of 24 participants, conducted by Johns Hopkins researchers and published in 2020, which found that the majority of participants with major depressive disorder were in remission four weeks after treatment.

“That number 20 is not quite as miraculously positive as I and others might have ideally hoped, based on earlier studies that seemed apparently stronger,” said Potash. The finding raises questions about how regularly psilocybin treatments would be needed, or if additional doses would be helpful.

Levine said Compass would evaluate this issue in its forthcoming Phase 3 studies. One study will have a similar protocol to the Phase 2 trial, while another will introduce a second psilocybin dose at three weeks, with evaluation at six weeks for the primary endpoint.

The smaller number of patients with sustained responses likely also reflects the participant population, as it’s harder to achieve full remission in treatment-resistant patients. “That’s no small detail,” said Levine.

Boris Heifets, a neuroscience researcher at Stanford University who studies psychedelics and was not part of the study, said the durability of the psilocybin response was strong compared to ketamine, which is also used to treat depression. “Single ketamine infusion lasts about a week, but for psilocybin you can still see a clear separation in the study at six weeks, after a single dose. It’s impressive, looks real, and is hard to explain as a ‘placebo effect’ given that this population isn’t particularly prone to placebo effects that last weeks and weeks,” he wrote in an email.

Most participants in the new trial also experienced adverse events, though the vast majority of these were fairly minor experiences, such as headaches and nausea. However, 5% of those in both the 25-milligram arm and the 10-milligram arm experienced serious adverse events, such as suicidal ideation and self-injury. Suicidal ideation is fairly common in studies of participants with severe depression, and the numbers are too small to establish whether psilocybin heightened the risk. Participants had also come off antidepressants before the trial, which could well contribute, said Levine: “It looks like this probably was stochastic, and reflective of the population we’ve included.” Any possible risk around suicidal ideation “demands clinical vigilance” in future trials, wrote the authors.

This is one of many questions that psilocybin research has left to answer, as Madras noted in her editorial. Research limitations so far include the difficulty in finding a convincing placebo, as well as an over-representation of participants who are white and college-educated, have prior hallucinogenic experience, and are interested in spirituality. Meanwhile, she added, the movement to legalize recreational psychedelics risks undermining medical protocols.

Because psilocybin is given alongside intensive therapy — study participants have therapy sessions before and after treatment and are in the presence of therapists during the psychedelic experience — it’s difficult to disentangle the impact of therapists versus the drug. It’s also hard to standardize the treatment outside of a carefully supervised trial. ​​”When you scale up and create sites all over the world, it’s hard to have the same quality of therapeutic experience,” said Potash.

Though psilocybin can have a therapeutic benefit, the experience can be challenging. “An online survey of psilocybin mushroom users rated it as among the most challenging experiences of their lifetimes,” wrote Madras. Some survey participants put themselves or others at risk of physical harm, and for a small number — 3 out of 1,993 users — taking psilocybin seemed to be linked with an onset of enduring psychotic symptoms.

Clinical studies on psychedelics currently exclude participants with a first-degree relative with psychotic conditions such as schizophrenia, meaning the link between the drugs and those illnesses is also unknown. “A lot of people seem to think psychedelics can be good for anything and everything,” said Potash. “Like all drugs, it’s not going to be a panacea.”

If you or someone you know may be considering suicide, contact the 988 Suicide & Crisis Lifeline: call or text 988 or chat 988lifeline.org. For TTY users: Use your preferred relay service or dial 711 then 988.