Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE) - Rationale and study design.

Psychedelics such as psilocybin have recently gained remarkable interest in both the specialist literature and the lay press because studies suggest that these substances may have great therapeutic potential in various psychiatric disorders, including major depression. However, clinical trials with psychedelic drugs pose particular methodological challenges to researchers, some of which differ considerably from those with other psychotropic drugs. These include the problem of successful blinding, which can hardly be guaranteed in clinical trials with psychedelic substances and - directly related - the high risk of expectation bias and nocebo effects. Some of these challenges are being addressed in the given clinical trial on the efficacy and safety of psilocybin in treatment-resistant major depression. It is a phase II randomized, double-blind, active placebo-controlled parallel group trial with 144 patients. The rationale, the study design, and the core features of the study are presented here. The trial (EPIsoDE trial; EudraCT number: 2019-003984-24; NCT04670081) is funded by the German Federal Ministry of Education and Research (BMBF 01EN2006 ​A/B).