PROJECT SUMMARY This study will provide data and a well-manualized treatment that are critical for the planning and design of a subsequent clinical efficacy trial to elucidate the effects of combining psilocybin with an evidence-based psychotherapy for major depressive disorder. Background. Psilocybin has emerged as a therapeutic agent for a range of mental disorders, including major depressive disorder; however, more recent data suggest its antidepressant effect may not be as powerful as initially reported. While the drug has received the bulk of attention, its use within the scientific literature is always complemented by some amount of psychotherapy. In fact, some psychedelic experts hypothesize that it is the therapy enhanced by the drug (rather than the drug itself) that leads to therapeutic benefits. It is critical we identify the necessary psychotherapeutic components that lead to safe and effective psilocybin treatment. Specifically, there is a significant need for a protocolized psychosocial treatment that can be tested and optimized to adjoin psilocybin treatment for major depression. We have preliminarily protocolized and, for this application, collected initial supporting data for a psilocybin- assisted cognitive behavioral therapy (PA-CBT) for adults with major depressive disorder. PA-CBT includes the core safety elements of standard psilocybin treatment, two psilocybin sessions (10mg & 25mg), and 12 sessions of CBT. Specific Aims. We seek to conduct a feasibility clinical trial of PA-CBT in two phases. Phase I will involve refining and optimizing PA-CBT using participant and clinician feedback through an open trial of PA-CBT. Phase II will be a randomized, two-arm, fixed dose trial that will test the feasibility, acceptability, and adherence to PA-CBT. Both conditions will receive two doses of psilocybin (10mg then 25mg, separated by one month). Participants will be randomized (1:1) to either a 12-session PA-CBT or a 6-session standard psilocybin-assisted therapy (PAT) condition that involves supportive therapy and contains no elements of CBT. Primary outcomes include feasibility (recruitment and retention of participants), quantitative measures of patient and therapist acceptability and treatment adherence (i.e., therapist fidelity to the study’s treatment manuals and, in the PA-CBT condition, participant’s adherence to CBT skill practices). Feasibility. We have received the regulatory approvals for the Phase I portion of this award. Our team consists of experts in psychosocial clinical trials for depression and psychedelic medicine. We have trained our core study personnel and collected supporting data on five initial participants. Impact. In line with NCCIH funding priorities, the proposed research will answer critical questions about the acceptability and feasibility of combining standard psilocybin treatment with one of the gold-standard psychotherapies (CBT) for major depressive disorder and begin to uncover the initial effects by which CBT can influence participants’ depressive severity and psychosocial functioning. This work will lead to the development of a manualized, evidence-based psilocybin- assisted therapy that can be further studied, optimized, and broadly disseminated to clinicians.

PROJECT NARRATIVE Psilocybin-assisted therapy has emerged as a promising therapy for a range of mental disorders, including major depressive disorder; however, recent data suggest its antidepressant effect may not be as powerful as initially reported. While the drug has received the bulk of attention, the psychotherapy component has not been standardized or manualized, does not incorporate evidence-based psychotherapy practices, and most importantly, has not been scientifically tested. This study is the first to focus on the psychotherapy element of psilocybin-assisted therapy to test the feasibility and acceptability of combining an evidence-based psychotherapy (cognitive behavioral therapy; CBT) with psilocybin for the treatment of adults with major depressive disorder, and will lay the groundwork for a larger, full-scale efficacy trial.