This study protocol outlines a 4-week, three-arm, double-blind, proof-of-concept randomized controlled trial (RCT) investigating the feasibility, tolerability, and antidepressant effect of combining psilocybin with risperidone in adults with treatment-resistant depression (TRD). The hypothesis is that risperidone, a 5-HT2A receptor antagonist, will block psilocybin's psychedelic effects while preserving its antidepressant properties. Sixty participants will be randomized to one of three groups: psilocybin 25mg + risperidone 1mg, psilocybin 25mg + placebo, or placebo + risperidone 1mg. All participants will receive 12 hours of manualized psychotherapy. Primary outcomes assess feasibility and tolerability. Secondary outcomes measure psychedelic effects (5D-ASC) and antidepressant effects (MADRS). This trial will advance understanding of psilocybin's mechanism of action and could increase access to psilocybin treatment for TRD.

Muhammad Ishrat Husain, Daniel M Blumberger, David J Castle, Nicole Ledwos, Elise Fellows, Brett D M Jones, Abigail Ortiz, Stefan Kloiber, Wei Wang, Joshua D Rosenblat, Benoit H Mulsant