A review of psychedelics trials completed in depression, informed by European regulatory perspectives.

There is a growing body of clinical research on the therapeutic potential of psychedelics for the treatment of mental health disorders, notably depression. Accordingly, the new revision of the European Medicines Agency guideline on the clinical investigation of products for depression will incorporate a section covering specific regulatory recommendations for the design of studies with psychedelics. The present review investigated the methodological approaches adopted in completed controlled trials of psychedelics for depression in light of initial considerations included in the draft guideline revision. A systematic search conducted on scientific databases (Embase and Medline) and clinical trial registries (clinicaltrials.gov and WHO ICTPR) identified 8 completed trials as of February 2024. The trials tested psilocybin, LSD, Ayahuasca, and DMT, for major depressive disorder or treatment-resistant depression, and were all pahse 2 or 1/2. Patterns in pre-defined methodological variables pertaining to trial design, population, interventions, outcome measures and safety assessments were analysed and collated against considerations on unblinding and expectancy, choice of comparator, the definition of treatment frameworks, the characterisation of the subjective psychedelic experience and the specification of adverse events in relation to subjective psychedelic effects. Areas for future research, including long-term efficacy and safety and the influence of inter-individual differences, can be investigated in larger studies, necessary for marketing authorisation applications. Ultimately, balancing the intricacies of conducting trials with psychedelics with ensuring adherence to regulatory requirements can be facilitated by early dialogue with medicines regulators, and will be essential for the medical development of psychedelics to address unmet patient needs.