Suicide is a prevalent cause of mortality, particularly among Veterans with posttraumatic stress disorder (PTSD), with brief opportunities for intervention and limited treatment options. Psilocybin Assisted Therapy (PAT) is a promising rapid-acting intervention for PTSD and other stress- and trauma-related concerns, but its anti-suicidal effects have not yet been studied. Given high stakes associated with treating suicidal thoughts and behaviors (STBs), it is essential to first examine the effectiveness, safety, tolerability, and purported mechanisms of PAT for non-acute STBs before investing resources in costly and potentially risky drug trials. Individuals with STBs have deficits in mentalizing: understanding internal mental states, needed for intimate and gratifying relationships. Hypermentalizing deficits, in which people inaccurately over-interpret the mental states of others, have been specifically observed in STBs. The mentalizing network (MENT) (including the temporoparietal junction, medial prefrontal cortex, and precuneus) overlaps with the default mode network, a network strongly implicated in STBs that has been found to be altered by psilocybin. Importantly, mentalizing is modifiable and improved mentalizing can boost resilience. Psilocybin has been associated with improvements in social cognition, including in mentalizing, correlating with psychiatric improvements. However, the neural mechanisms of PAT in both PTSD and STBs are poorly understood. To address these gaps, I propose a low cost/high yield study that leverages a fully funded clinical trial and related infrastructure. The parent trial (PI: Dr. Lynnette Averill, YIA mentor) examines the safety, tolerability, and feasibility of PAT vs active control in a sample of Veterans with PTSD, a group at risk for STBs. Veterans in an active control group (Niacin+Therapy) will be compared with a treatment group (25mg Psilocybin+Therapy). We will examine safety, tolerability, and effectiveness of PAT as an anti-suicidal intervention (Aim 1). A death implicit association task previously associated with suicide attempts will be administered as a primary STB measure at baseline and 24h after first dose, in addition to secondary explicit STB measures. We hypothesize that, as in Veterans with depression, PAT will be well-tolerated with no increased STBs. Second, we will compare behavioral mentalizing and underlying neurobiology between groups (Aim 2). We will examine effects of treatment group on behavioral changes in mentalizing and neural activation during this social cognitive process. We hypothesize that (a) 25mg PAT will decrease implicit orientation towards death and explicit STBs compared to the niacin control group and (b) PAT treatment group will be associated with improved accuracy on the MASC and will reduce activation in MENT regions during mentalizing, reflecting more accurate mentalizing. This low-risk/high-yield investment by AFSP will allow us to examine a novel therapeutic target with great potential to inform interventions and potentially far-reaching effects for those struggling with stress- and trauma-related concerns and STBs. The proposed study will facilitate future work testing biologically derived models of psychotherapy for PAT and examining PAT in a population with more acute STBs. This project will provide a springboard for a highly promising young investigator to build a career in the translational neuroscience of stress and trauma-related concerns and STBs.
