Does Psilocybin Require Psychedelic Effects to Treat Depression? (PSI-RIS)
This double-blind, placebo-controlled proof-of-concept trial (n=60) aims to investigate whether the antidepressant effects of psilocybin are dependent on its psychedelic effects. Participants with treatment-resistant depression (TRD) will be randomly assigned to one of three groups: 1) psilocybin 25 mg plus risperidone 1 mg; 2) psilocybin 25 mg plus placebo; and 3) placebo plus risperidone 1 mg.
Details
Randomised, quadruple-blind, parallel-group proof-of-concept RCT (n=60) in treatment-resistant depression comparing psilocybin 25 mg with and without risperidone 1 mg using a double-dummy design.
Single dosing session (5–6 hours) with preparatory therapy (up to 4 hours) and two 1-hour integration sessions; participants receive 10 hours of manualised supportive psychotherapy overall.
Primary aim is to test whether blockade of 5-HT2A receptor-mediated psychedelic effects by risperidone alters psilocybin’s antidepressant efficacy; safety and tolerability are closely monitored with psychiatric and medical oversight.