A proof-of concept randomized controlled trial to show that the antidepressant effect of psilocybin does not require a psychedelic experience: study protocol
European Psychiatry November 17, 2023 M. I. Husain, D. M. Blumberger, D. J. Castle et al.
The antidepressant effects of psilocybin, the active compound in magic mushrooms, may not require its psychedelic effects. Psilocybin's psychedelic effects depend on activation of the serotonin 2A receptor, and blocking that receptor with drugs like risperidone or ketanserin eliminates the psychedelic experience in healthy volunteers. A mouse study showed that ketanserin did not reduce psilocybin's antidepressant effect. This proposed three-arm, double-blind, proof-of-concept randomized controlled trial in adults with treatment-resistant depression will test whether giving psilocybin with risperidone blocks psychedelic effects without reducing antidepressant effects. If so, psilocybin-assisted psychotherapy, which currently requires intensive therapist support, could become more scalable and accessible.