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

Introduction

Classical psychedelics, a group of serotonin 2A receptor (5-HT2AR) agonists that includes psilocybin and LSD, have re-emerged in psychiatric research because several recent studies suggest therapeutic potential for major depression, treatment-resistant depression (TRD) and some substance use disorders. Mertens and colleagues note that most published trials to date have important methodological limitations: many are open-label or uncontrolled, sample sizes have generally been small (double digits), and only one available double-blind trial lacked sufficient power and assay sensitivity. The unique subjective effects of psychedelics also create trial-specific problems such as difficulty maintaining blinding and high risk of expectation bias and nocebo effects in control arms. This paper presents the rationale and protocol for the EPIsoDE trial, a Phase IIb, randomized, double-blind, active placebo-controlled parallel-group study designed to examine the efficacy and safety of oral psilocybin in TRD (EudraCT 2019-003984-24; NCT04670081). The investigators frame the trial to address several of the methodological challenges that complicate clinical assessment of psychedelics, and they propose design features (for example the choice of comparators and repeated dosing) that they suggest could serve as prototypes for future trials in this area.