A new meta-analysis found that participants receiving control treatments in psilocybin trials had smaller reductions in depressive symptoms compared with those in control groups of trials evaluating selective serotonin reuptake inhibitors or esketamine. Researchers said this may indicate that psilocybin’s antidepressant effects may be overestimated relative to standard treatments.

The analysis included 17 randomized clinical trials in adults with major depressive disorder (MDD) or treatment-resistant depression (TRD). Four trials assessed psilocybin (n = 373), two examined esketamine (n = 573), and eleven evaluated selective serotonin reuptake inhibitors (SSRIs) (n = 4,014). All studies used the Montgomery-Åsberg Depression Rating Scale (MADRS) to measure changes in symptom severity and followed a double-blind design.

Researchers calculated standardized mean changes (SMCs) from baseline to posttreatment for both active and control groups, as well as standardized mean differences (SMDs) between groups.

• Control group SMCs: 0.50 for psilocybin, 1.12 for esketamine, and 1.00 for SSRIs

• Active treatment SMCs: 1.21 for psilocybin, 1.43 for esketamine, and 1.28 for SSRIs

• Between-group SMDs: 0.70 for psilocybin, 0.30 for esketamine, and 0.27 for SSRIs

Statistical analysis showed that the type of drug trial influencedboth between-group differences (P = .005) and control group responses (P = .005), but not active treatment effects (P = .55).

Control group response rates also differed:

• Psilocybin: 19% achieved at least a 50% reduction in MADRS score

• SSRIs: 33%

• Esketamine: 42%

Active treatment response rates were more consistent:

• Psilocybin: 48%

• SSRIs: 46%

• Esketamine: 52%

Dropout rates varied:

• Psilocybin: 11% control vs 5% active

• Esketamine: 8% control vs 12% active

• SSRIs: 35% control vs 32% active

The researchers noted that lower control response in psilocybin trials may reflect functional unblinding, as the noticeable psychoactive effects of psilocybin can reveal treatment allocation to participants. Other potential factors include differences in patient expectations, trial supervision, or design features such as study duration and population characteristics.

“The sample average treatment effects (ATEs) differed between psilocybin control treatment and esketamine and SSRI control treatments. However, the data did not allow us to determine the specific factors that explained the observed sample ATE differences or the extent to which the sample ATEs generalized to the population ATE for the respective treatments,” said Fredrik Hieronymus, MD, PhD, of the Institute of Neuroscience and Physiology at the University of Gothenburg, Sweden, and colleagues.

While the analysis confirmed significant differences in control group outcomes across treatment types, it could not determine the specific reasons behind them. The authors suggest that future studies include multiple types of control treatments and assess participant expectations to more accurately evaluate psilocybin’s effects.

These findings indicate that the lower control response observed in psilocybin trials may lead to inflated effect size estimates, underscoring the importance of rigorous trial design in evaluating emerging depression treatments.

Full disclosures can be found in the study.

Source: JAMA Network Open