Psilocybin's Depression Benefit May Be Overestimated

 

• In a comparison of depression treatment trials, control group outcomes in trials of psilocybin were lower than those in trials of SSRIs and esketamine.
• This may suggest that psilocybin's antidepressant efficacy has been overestimated compared with other depression treatment options.
• This could be due to a nocebo effect in the control arms of psilocybin trials, a study author said.

Control group outcomes in randomized trials of psilocybin indicated less improvement in depression scores compared with trials of other antidepressants, according to a meta-analysis, suggesting that psilocybin's efficacy may be lower than previously estimated.

Among 17 trials that tested psilocybin, esketamine (Spravato), or selective serotonin reuptake inhibitors (SSRIs) for depression, standardized mean changes in symptoms measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) from pre- to post-treatment were 1.21 for psilocybin, 1.28 for SSRIs, and 1.43 for esketamine versus 0.50, 1.00, and 1.12 for their respective controls, reported Fredrik Hieronymus, MD, PhD, of the University of Gothenburg in Sweden, and colleagues.

MADRS response rates for control treatments in SSRI and esketamine trials were 14 and 23 percentage points higher, respectively, compared with psilocybin trials, they wrote in JAMA Network Openopens in a new tab or window.

Notably, effect sizes in control treatment arms in psilocybin trials (0.50) were closer to those in waiting-list control (0.37) and care-as-usual (0.64) arms in psychotherapy trials than to those in pill-placebo arms in antidepressant trials (1.05), Hieronymus and team pointed out.

"The poor control treatment outcomes in psilocybin trials suggest that it may not be as broadly effective for depression as estimated," they explained. "The poor performance of control treatments in psilocybin trials is likely caused by 1 of 2 factors: psilocybin trials have recruited patients who are unlikely to respond to control treatment or the psilocybin trialing process applied is less likely to induce control treatment response."

"In other words, assuming that the observed differences are not explained by chance, psilocybin trials must systematically differ from trials of SSRIs and esketamine either in the patient makeup or in some relevant methodologic aspect," they added.

But Hieronymus told MedPage Today that this didn't come as much of a surprise. "There have been reports of poor control group outcomes in psilocybin trials for a while and it's well known that poor control group efficacy can be an issue in depression trials -- for example, in wait-list-controlled psychotherapy trials."

While the meta-analysis confirms the reports of "lower-than-expected control group response rates," it can't explain why this occurs, he noted.

"One intuitive hypothesis is that study participants are able to determine with high certainty when they have not been given a psychoactive dose of psilocybin and that this results in a nocebo effect in the control arms, but the data do not allow us to distinguish that from other possible explanations," he said. "Irrespective of why control group outcomes are worse in psilocybin trials, it's almost certainly a problem. Treatment effects are typically reported and interpreted relative to control groups. For that to be meaningful, the same control treatments, e.g., an inert placebo, needs to work similarly across trials of different compounds."

Psilocybin, found in Psilocybe mushrooms and commonly known as "magic mushrooms," has gained popularity in recent years for psychiatric conditions. However, it's not yet FDA approved for any indications.

For the meta-analysis, the researchers used two prior meta-analyses and an FDA review published between March 2019 and December 2024 to find trials on adult major depressive disorder or treatment-resistant depression. The analysis included four trials on psilocybin (n=373), two on esketamine (n=573), and 11 on SSRIs (n=4,014).

The four psilocybin trials included a phase IIb trial from 2022opens in a new tab or window, a phase II trial from 2023opens in a new tab or window, a phase II trial from 2021opens in a new tab or window, and a phase II trial from 2022opens in a new tab or window.

Time from baseline to evaluation was 6 weeks for nearly all trials, besides two 4-week trials of esketamine and one 2-week evaluation of psilocybin.

During the trials, dropout rates were lower for psilocybin (5% of active arms, 11% of controls) and esketamine (12% of active arms, 8% of controls) trials compared with trials of SSRIs (32% of active arms, 35% of controls).

Study population emerged as a significant moderator of between-group effect sizes (P=0.005) and of pre- to post-control treatment effect sizes (P=0.005), but not of active treatment effect sizes (P=0.55).

"Future studies should strive toward better understanding of which factors moderate control treatment outcomes in psilocybin trials, such as by trialing multiple control treatments and/or by recruiting study participants with positive expectations of the control treatment," the researchers concluded.

isclosures

Hieronymus reported relationships with H. Lundbeck, Janssen Pharmaceuticals, and Flow Neuroscience.

Co-authors reported relationships with the Swedish Research Council, Swedish Cancer Society, Osmond Labs, and Janssen-Cilag AB.

Primary Source

JAMA Network Open

Source Reference: opens in a new tab or windowHieronymus F, et al "Control group outcomes in trials of psilocybin, SSRIs, or esketamine for depression: a meta-analysis" JAMA Netw Open 2025; DOI: 10.1001/jamanetworkopen.2025.24119.

https://www.medpagetoday.com/psychiatry/depression/116748