Randomized trial of delta-9-tetrahydrocannabinol (THC) versus placebo to augment the effects of prolonged exposure therapy on fear extinction learning in post-traumatic stress disorder: Study rationale and protocol.

Prolonged exposure (PE) therapy is effective for PTSD, but dropout and partial response remain problems. This trial tests whether synthetic THC (dronabinol) can improve PE outcomes. Adults with PTSD are randomly assigned to receive 7.5 mg THC or placebo before PE sessions 3 through 6, when extinction learning occurs. The study measures PTSD symptom severity, brain activation during fear extinction, and physiological responses. If THC enhances extinction learning, this FDA-approved drug could be quickly added to PE therapy to boost its effectiveness.

Study at a glance

Abstract

Prolonged exposure (PE) therapy is effective for PTSD, yet dropout and partial response remain concerning. Preclinical and human studies suggest Δ9-tetrahydrocannabinol (THC) enhances fear extinction and recall through brain cannabinoid receptor activation in fear processing. Examine whether synthetic THC (dronabinol) augments PE effectiveness. Double-blind, placebo-controlled, trial with treatment-seeking PTSD patients (ages 18-60) randomized to 7.5 mg THC (n = 30) or placebo (n = 30). Randomization after sessions 1-2 (psychoeducation) ensures covariate-adaptive balance before the first medicated session. THC/placebo administered before PE sessions 3-6 of 10 total sessions so dosing coincided with extinction-learning sessions. Wayne State University with remote PE delivery via Emory University. Adults with PTSD (CAPS-5 ≥ 25) excluding for severe mental illness, substance use disorders, or contraindications to THC. PE therapy (10 sessions, up to 3 times / week) with THC or placebo administered 120 min before sessions to coincide with peak plasma levels. Primary: PTSD symptom severity (CAPS-5, PCL-5). Secondary: fMRI brain activation during fear extinction paradigms, skin conductance responses, and extinction retention measures pre/post-treatment. Intent-to-treat linear mixed-effects models accounting for therapist clustering. Neuroimaging analyzed via region-of-interest and whole-brain approaches focusing on ventromedial prefrontal cortex, hippocampus, and amygdala. THC dosing and timing is based on prior mechanistic studies that demonstrated THC-related enhancement of extinction recall and frontolimbic circuit engagement. Aligning peak THC levels with exposure sessions maximizes potential for CB1-mediated augmentation of extinction learning. If effective, this FDA-approved augmentation strategy could be rapidly implemented to improve PE outcomes. ClinicalTrials.govNCT04080427.