Grant: Project Grant

During the past decade, there has been a resurgence of interest in psilocybin, the chemical component of "magic mushrooms", as a promising treatment for treatment-resistant depression (TRD). Psilocybin with accompanying psychotherapy, has shown promise as an emerging treatment for TRD in recent clinical trials. All trials have investigated psilocybin with psychotherapy given that its potent psychedelic effects require continuous monitoring, and the notion that the psychotherapy optimizes therapeutic outcomes. The psychotherapy takes at least 12 hours with 2 trained therapists for each psilocybin dosing session. This amount of specialized support adds complexity to the scalability of psilocybin as a pragmatic intervention for TRD given the limited resources and access to trained therapists in most jurisdictions. The benefit of psychotherapy in psilocybin treatment is highly plausible, given that combined treatment of psychotherapy with traditional antidepressants has been established as being superior to medication alone. However, we are unaware of any empirical research that has established the importance of psychotherapy in psilocybin treatment and currently, it is unclear if this component of psilocybin treatment enhances efficacy as opposed to just ensuring psychological and physical safety. In this context, we propose a clinical trial to determine whether psilocybin treatment with accompanying psychotherapy is superior to psilocybin treatment with safety monitoring alone. In a three parallel-arm design, 60 adults with TRD will be randomized to: (1) psilocybin 25 mg plus 12 hours of manualized psychotherapy that has previously been used with psilocybin treatment in MDD; (2) psilocybin 25 mg plus safety monitoring; (3) psilocybin 1 mg plus 12 hours of manualized psychotherapy. The study will address a key unanswered question in the field of psychedelic research and will have major implications for psilocybin's clinical translation.