Adjunctive delta-9-tetrahydrocannabinol during prolonged exposure therapy for PTSD: A randomized, double-blind feasibility pilot trial with mechanistic assessment of extinction recall

Abstract Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition. Delta-9-tetrahydrocannabinol (THC) has been shown to influence fear extinction learning and recall, providing a mechanistic rationale for its use as an adjunct to exposure-based therapy. We conducted a randomized, double-blind, placebo-controlled pilot feasibility trial evaluating low-dose oral THC administered during Prolonged Exposure (PE) therapy for PTSD. Twenty-three adults with PTSD completed massed PE delivered via telehealth and were randomized to receive either 7.5 mg oral dronabinol (THC) or placebo prior to PE sessions 3–6. Primary outcomes included clinician-rated PTSD severity assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and self-reported symptoms assessed with the PTSD Checklist for DSM-5 (PCL-5). Mechanistic assessments examined extinction recall using behavioral, psychophysiological, and neuroimaging measures. Across both drug conditions, clinician-rated and self-reported PTSD symptoms decreased substantially, and improvements were maintained through 3-month follow-up, at which point 91% of participants no longer met diagnostic criteria for PTSD. Significant improvements were also observed for anxiety, depression, sleep quality, and dissociative symptoms. The study was not powered to detect between-group differences; however, descriptive contrasts yielded numerically lower PTSD severity and reduced persistence of dissociative symptoms among THC-treated participants. THC was well tolerated, with no serious adverse events. During extinction recall, THC was associated with greater hippocampal differentiation between extinguished and unextinguished threat cues, whereas behavioral and psychophysiological measures did not differ between groups. These findings demonstrate the feasibility and tolerability of pairing low-dose THC with PE therapy and support evaluation in adequately powered randomized trials.