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.

The study, led by Dr. M. Ishrat Husain at the Centre for Addiction and Mental Health, adopts a “double dummy” design to assess risperidone’s anti-psychedelic effects and psilocybin’s antidepressant effects alone and combined with risperidone. The primary outcomes include the feasibility, tolerability, and safety of the administered treatments, with secondary outcomes focusing on subjective psychedelic effects and changes in depression severity measured by the Montgomery-Åsberg Depression Rating Scale. The study, initiated on July 1, 2023, is expected to be completed in February 2026, with an enrollment target of 60 participants.

You can find the protocol for the study here.

Trial Details

Psilocybin, the chemical component of "magic mushrooms", has been administered with psychotherapy in several randomized clinical trials (RCTs) showing large and sustained antidepressant effects. In healthy volunteers, the psychedelic effects of psilocybin have been shown to be blocked by administration of serotonin (5HT)2A receptor antagonists such as risperidone. The purpose of this "double dummy" proof-of-concept trial is to evaluate whether psilocybin's antidepressant effects are dependent on its psychedelic effects. Sixty participants with treatment-resistant depression 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. The investigator's hypothesize that the combination of psilocybin and risperidone will be well tolerated, safe, and will block the psychedelic effects of psilocybin in patients diagnosed with treatment-resistant depression.

Trial Number NCT05710237

Data attribution

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