Psilocybin Produces Mixed Outcomes in Phase 2b MDD Study
Key Clinical Summary
- In a phase 2b randomized clinical trial of 144 adults with treatment-resistant depression (TRD) in Germany, oral psilocybin 25 mg did not significantly improve the primary endpoint of Hamilton Depression Rating Scale (HAMD17) response at 6 weeks versus nicotinamide or psilocybin 5 mg.
- Secondary outcomes favored psilocybin 25 mg, including greater reductions in HAMD17 scores at week 6 compared with nicotinamide and psilocybin 5 mg.
- The treatment was generally tolerated, but investigators reported safety signals, including 4 serious adverse events overall, 2 of which were considered related to psilocybin 25 mg.
A Phase 2b randomized clinical trial published in JAMA Psychiatry found nonsignificant differences in response rate between psilocybin 25 mg, psilocybin 5 mg, and placebo with supporting psychotherapy in treatment-resistant major depressive disorder (MDD). Secondary outcomes, however, demonstrated clinically meaningful reductions in depressive symptoms for psilocybin 25 mg versus other treatment arms.
The EPISODE trial was conducted at 2 outpatient centers in Germany by investigators affiliated with Heidelberg University, the Central Institute of Mental Health, and Charité-Universitätsmedizin Berlin.
Study Findings
The triple-blinded, placebo-controlled trial enrolled 144 adults aged 25 to 65 years with treatment-resistant depression (TRD) who had been withdrawn from antidepressant medication. Participants were randomized in a 2:2:1:1 scheme to receive 2 study doses 6 weeks apart: placebo (nicotinamide 100 mg) followed by psilocybin 25 mg, psilocybin 5 mg followed by psilocybin 25 mg, or psilocybin 25 mg followed by psilocybin 5 mg or by a second 25 mg dose, all embedded in psychotherapeutic sessions.
The primary endpoint was treatment response, defined as a 50% or more reduction on the Hamilton Rating Scale for Depression (HAMD17), at week 6 before receiving the second dose. Results showed that response at week 6 on HAMD17 was 17.0% with psilocybin 25 mg, 12.5% with psilocybin 5 mg, and 10.6% with placebo. The difference between psilocybin 25 mg and nicotinamide was not statistically significant (adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03).
Secondary outcomes (mean changes from baseline on HAMD17 and Beck Depression Inventory II [BDI-II]) were more favorable. At week 6, the estimated mean difference in Hamilton score change from baseline was -4.60 points for psilocybin 25 mg versus nicotinamide and -3.09 points versus psilocybin 5 mg. On the BDI-II, response at week 6 was 23.4% with psilocybin 25 mg, compared with 10.6% with nicotinamide and 6.3% with psilocybin 5 mg.
Safety findings were more complex. Severe adverse events occurred in 28% of cases after psilocybin 25 mg on day 0, compared with 4% after psilocybin 5 mg and 8% after nicotinamide. Investigators also reported 4 serious adverse events, including 2 considered related to psilocybin 25 mg.
Clinical Implications
Many questions remain after this trial returned results that are not unequivocally positive. The prespecified primary outcome was negative, which limits claims of efficacy and argues against overinterpreting the study as confirmatory evidence for psilocybin in treatment-resistant depression.
At the same time, the secondary efficacy signals were clinically notable. Investigators observed greater symptom reductions with psilocybin 25 mg on both clinician-rated and self-reported depression scales, and effects were evident as early as week 1 on several measures. That pattern suggests a potential antidepressant effect that may justify further confirmatory trials, but it does not settle questions about clinical use, durability, or patient selection.
The safety profile also matters. Although most participants tolerated treatment, the report noted safety signals and serious adverse events, which reinforces the need for careful monitoring, structured psychotherapy support, and cautious interpretation in real-world psychiatric practice.
Expert Commentary
“These findings highlight the potential of psilocybin with adjunct psychotherapy for depression, including TRD, while emphasizing the need for larger, adequately powered confirmatory trials with long-term follow-up to clarify durability and mechanisms of action,” concluded Lea J. Mertens, MSc, Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, and study co-authors.
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