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.
Christine A Rabinak, Paul E Kilgore, Mark A. Lumley, Sheila A. M. Rauch
Contemporary Clinical Trials 2026 DOI: 10.1016/j.cct.2025.108148 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, placebo-controlled, randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 60 |
| Population | Treatment-seeking adults aged 18-60 with PTSD (CAPS-5 ≥ 25) excluding severe mental illness, substance use disorders, or contraindications to THC |
| Interventions | Dronabinol Prolonged exposure therapy |
| Dose | 7.5 mg |
| Duration | 10 sessions of PE therapy (up to 3 times per week); THC/placebo administered before sessions 3-6; pre/post-treatment assessments |
| Measures | CAPS-5, PCL-5, fMRI brain activation, skin conductance responses, extinction retention measures |
| Topics | Cannabis PTSD |
| Keywords | Delta9-Tetrahydrocannabinol THC Exposure therapy Extinction Memory Treatment |
| Key findings | The trial is ongoing; no results are reported in this abstract. |
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.
Comparable studies
Other randomized controlled trials on PTSD, most cited first.
Citations in the library
Cites 4
- Dose-dependent effect of acute THC on extinction memory recall and fear renewal: a randomized, double-blind, placebo-controlled study. Psychopharmacology February 1, 2026
- Cannabinoid Modulation of Frontolimbic Activation and Connectivity During Volitional Regulation of Negative Affect. Neuropsychopharmacology June 2016
- Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiology of Learning and Memory September 2014
- Cannabinoid modulation of subgenual anterior cingulate cortex activation during experience of negative affect. Journal of Neural Transmission June 2012