A phase 2b randomized clinical trial found that psilocybin-assisted psychotherapy did not significantly improve response rates at 6 weeks in patients with treatment-resistant depression, although exploratory secondary outcomes suggested greater reductions in depressive symptoms with high-dose treatment.
The triple-blind study enrolled 144 adults with moderate to severe treatment-resistant depression (TRD), who discontinued antidepressant therapy prior to participation. Patients were randomized to receive psilocybin 25 mg, psilocybin 5 mg, or nicotinamide across two dosing sessions, alongside structured psychotherapy. The primary endpoint—defined as a 50% or greater reduction in Hamilton Depression Rating Scale (HAMD17) score at 6 weeks—was not met, with response rates of 17% for psilocybin 25 mg, 13% for psilocybin 5 mg, and 11% for nicotinamide.
Despite the negative primary outcome, exploratory secondary analyses showed greater reductions in depression severity with psilocybin 25 mg compared with both comparator groups. Improvements were most pronounced early, with response rates at 1 week reaching 34% in the high-dose group vs 6% with nicotinamide. However, the durability and clinical significance of this early effect remain uncertain, with investigators noting it may reflect a transient post-acute “afterglow” rather than a sustained antidepressant response.
Interpretation of these findings is further complicated by methodological challenges highlighted in an accompanying editorial. Psychedelic trials are particularly vulnerable to “functional unblinding,” in which participants can infer treatment assignment based on the subjective effects of the drug. In this study, most participants correctly inferred receipt of high-dose psilocybin, underscoring the difficulty of maintaining blinding. The editorial argues that such unblinding may amplify expectancy effects, which—along with the intensity of the psychedelic experience, therapist involvement, and increased suggestibility—can influence outcomes.
As a result, observed improvements may reflect a combination of pharmacologic effects, psychological experience, and expectancy. The editorial emphasizes that current trial designs cannot disentangle these components and that the magnitude of placebo effects in depression has no clear upper bound, raising the possibility that observed benefits could be explained entirely by expectancy.
Adverse events were common, particularly on dosing days, and consistent with known psilocybin effects such as perceptual disturbances. Suicidal ideation was reported more frequently in the psilocybin 25-mg group (4%) than in comparator groups (1%–2%), and two serious adverse reactions were considered treatment-related, including one case consistent with hallucinogen persisting perception disorder.
Following the second dosing phase—during which all participants received psilocybin 25 mg at least once—depressive symptoms improved across all groups, with no meaningful between-group differences. These findings were exploratory, as the study was not powered for comparisons in this phase.
Taken together, the results reflect the uncertainty of the findings. While secondary outcomes suggest potential antidepressant effects, the failure to meet the primary endpoint and the influence of expectancy complicate interpretation. The authors call for further research, and the accompanying editorial emphasizes the need for improved trial designs.
Disclosures can be found in the study and the accompanying editorial.
Source: JAMA Psychiatry, Editorial
