Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin
Abate, A., Ali, S., Bawks, J., Blainey, M. G., Brietzke, E., Brudner, R. M., Cronin, V., Danielewitz, J., Dhawan, S., Di Fonzo, M., Doyle, Z., Drzadzewski, P., Dunlop, W., Fiszter, H., Gomes, F. A., Grewal, S., Kaczmarek, E., Kratiuk, K., Leon-Carlyle, M., Mansur, R. B., Marlborough, M., McCallum, M., McIntyre, R. S., Meshkat, S., Mofidi, N., Offman, H., Quinn, J. M., Riva-Cambrin, J., Schmidt, J., Schulz-Quach, C., Sethi, R., Smolkin, M., Zumrova, A.
This open-label waitlist trial (n=30) assessed the feasibility of psilocybin-assisted psychotherapy (PAP/PAT) in a complex population with treatment-resistant depression (TRD), including major depressive and bipolar II disorders, baseline suicidality, and significant comorbidity. Participants received one, two, or three sessions of PAP with psilocybin (25mg), accompanied by preparation and integration psychotherapy sessions. Immediate treatment showed greater reductions in depression severity (MADRS) compared to the waitlist period, with a large effect size (g = 1.07, p < 0.01). Repeated doses were associated with further reductions in depression severity. Adverse events were transient, and the study demonstrated feasibility, preliminary antidepressant efficacy, safety, and tolerability in this population.
Abstract
Background: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period.Methods: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466).Findings: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge’s g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline.Conclusions: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity.Funding: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.