Psilocybin-Assisted Cognitive Behavioral Therapy for Adults with Major Depressive Disorder: Rationale and Treatment Development.

Background: Recent studies suggest that one to two administrations of psilocybin have acute antidepressant effects for people with major depressive disorder. These data on psilocybin have generated considerable enthusiasm, but little empirical attention has been paid to the therapy that adjoins psilocybin treatment (psychedelic-assisted therapy, or PAT). Materials and Methods: In this study, we present the initial protocol and plans to empirically test the psychosocial therapy that adjoins psilocybin treatment with the goal of optimizing this therapeutic approach for adults with major depressive disorder. The psychotherapy is based on the principles of cognitive-behavioral therapy (CBT), an evidence-based treatment for major depressive disorder. Participants will be 30 adults with a history of major depressive disorder and current, active depressive symptoms. Following psychiatric and medical safety evaluations, eligible participants will be enrolled in a 12-session CBT that includes classic PAT safety elements (termed psilocybin-assisted CBT; PA-CBT). Following the third and sixth PA-CBT sessions, participants will engage in two psilocybin drug administration sessions (10 and 25 mg, respectively). Participants will provide feedback about the PA-CBT and complete measures of mood symptoms, psychosocial functioning, cognitive schemas, and affective experiences immediately following each drug administration session, at the completion of PA-CBT, and 3 months following treatment completion. Conclusions: The trial will provide preliminary data on the feasibility, safety, acceptability, and psychosocial effects of PA-CBT. Results will inform randomized clinical trials to test the effects of PA-CBT for patients with depression and other mental health conditions, as well as hypotheses concerning mediating mechanisms at the cognitive and affective levels. ClinicalTrials.gov ID: NCT05227612.