Project 461579

One third of patients with major depressive disorder (MDD) do not respond to conventional treatments and experience treatment-resistant depression (TRD). There has been a resurgence of interest on the use of psychedelics as novel treatments for mental disorders, including TRD. Psilocybin, the chemical component of "magic mushrooms", has been administered with psychotherapy in several randomized clinical trials (RCTs) showing large and sustained antidepressant effects. The results of these trials have led to increasing public attention with growing calls for transition to clinical use. As the use of psilocybin expands, it is becoming more important to understand whether psilocybin's psychedelic effects are needed for its antidepressant effects. It is presumed that psilocybin's therapeutic effects are induced by the psychedelic "trip", which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. Given the safety concerns associated with psilocybin's psychedelic effects, all studies have used it in conjunction with intensive psychotherapy involving two therapists present during full-day dosing sessions. This makes psilocybin-assisted psychotherapy (PAP) highly resource intensive and impedes scalability given the limited resources and access to trained therapists in most jurisdictions. Some studies in healthy volunteers have shown that psilocybin's psychedelic effects are blocked by 5-HT2AR antagonists like the antipsychotic risperidone or antihypertensive ketanserin. In a recent pre-clinical study using a mouse model of depression, administration of ketanserin followed by psilocybin had the same antidepressant effects as psilocybin alone. Using a "double dummy" RCT in 60 adults with TRD, we propose to conduct the first study to test in humans whether psilocybin's antidepressant effects are dependent on psilocybin's psychedelic effects. The study has direct implications for the clinical adoption of psilocybin as a treatment for MDD and TRD.