A Multi-site Randomized Controlled Trial of Psilocybin for Treatment-Resistant Depression (TRD) in Veterans

About This Grant

Significance to VA: Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Also, TRD in Veterans is associated with a high risk of suicide, addiction, unemployment and medical morbidity. Innovation and Impact: Clinical studies have revealed antidepressant effects of psilocybin for depression and TRD in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of comorbid PTSD and when used in combination with serotonin reuptake inhibitor antidepressants. This state-of-art clinical trial will evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD to advance knowledge in psychedelic therapy in Veterans. Methodology: This multi-site, double-blind, randomized controlled trial will evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will be randomized (N=240) and undergo two psilocybin dosing sessions along with preparation, administration, and integration psychological support. For the 1st psilocybin administration, participants will receive either a 1mg dose (control condition) or a 25mg dose (active) under blinded conditions. At their 2nd psilocybin dosing visit 4 weeks later, all participants will receive a 25mg dose. Outcomes will be measured by a centralized independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session and over 6 months follow-up. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug after each dosing session and at follow-up. Assessments of subjective experiences of psilocybin, expectancy and blinding are included in the protocol. Specific Aim 1 (Efficacy): Evaluate the short-term antidepressant effects of 25mg psilocybin compared to 1mg psilocybin for TRD under blinded conditions by centralized evaluator. Primary Hypothesis: Participants treated with the 25mg psilocybin dose (n=120) will show a significantly greater decrease on the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week-4 post-dose compared to the 1mg psilocybin dose control group (n=120). The Hamilton Depression scale is also collected as a common data element. Specific Aim 2 (Safety): Evaluate risks in participants who took ≥ one psilocybin dose with the Swiss Psychedelic Side Effects Inventory and other reported adverse events. Exploratory Aims (E): E1 PTSD: For the subgroup with TRD+PTSD (~50% of the sample), estimate the change from baseline to week 4 on Clinician-Administered PTSD Scale-Revised (CAPS- 5-R) by group. E2 2nd Dose: Examine the antidepressant effects of one vs two 25mg dosing sessions by comparing change in MADRS from baseline to week 8 (i.e., ~4 weeks after the 2nd dose) between the group receiving the 1mg dose followed by the 25mg dose versus the group treated with two 25mg doses. E3 Response & Remission: Explore rates of response (ΔMADRS ≥50% reduction) and remission (MADRS score ≤10) at week 4, week 8 and month 6, within group and between groups. E4 Other Relevant Outcomes: Explore potential effects of treatment on patient-reported and other outcomes over time, including expectancy, depression, PTSD, suicidality, psychological flexibility, and functional outcomes. Measure altered experience during psilocybin dosing sessions and explore impact on outcomes and functional unblinding. Qualitative Aim: Participants (~10 per site; n=50) will be interviewed on topics of acceptance, satisfaction, and facilitators/barriers of treatment with psilocybin to gain a better understanding of Veteran preferences on the treatment itself, the composition/structure of the psychological support model and future implementation of clinical psychedelic treatment programs in VA. Path to Translation/Implementation: Industry-sponsored studies seeking FDA approval are already underway. The timing of FDA-approval of psilocybin should align with the conclusion of this study. VA can use these results to make decisions on offering psilocybin treatment and to guide implementation within VA mental health systems.