Adapted Massed Exposure Therapy Enhanced with MDMA for PTSD (aMETEMP): A randomized, double-masked protocol adapted for Veterans Affairs healthcare system

Posttraumatic stress disorder (PTSD) remains prevalent and disabling, especially among veterans, with a substantial proportion failing to achieve remission following first-line evidence-based trauma-focused psychotherapies. 3,4-Methylenedioxymethamphetamine (MDMA) is hypothesized to enhance psychotherapy outcomes through effects on fear extinction, cognitive flexibility, and emotional engagement, and is being studied as a promising augmentation strategy for PTSD psychotherapy. There is limited research combining MDMA with evidence-based PTSD treatment. MDMA-assisted psychotherapy trials to date have also been limited by lack of an active comparator and functional unmasking. We describe the methodology of an ongoing randomized, double-masked, pilot trial evaluating massed prolonged exposure (PE) therapy enhanced with MDMA for PTSD (aMETEMP), adapted for a U.S. Veterans Affairs outpatient setting. Up to 20 veterans with PTSD in the VA will receive a 6-8hr in-person MDMA dosing session (randomized dose 35mg - 125mg) integrated with a 3-week massed exposure protocol. The remaining visits are virtual and include PE sessions and sessions to prepare for and process the MDMA session (28-30hrs total over 11 visits), with the use of telehealth intended to improve access and ease patient burden. After treating the first 4 participants, who were fully informed of the trial design, we switched to using an incomplete disclosure strategy (not disclosing the number of treatment arms or specific possible doses) to further improve masking. Primary outcomes include PTSD severity using the Clinician-Administered PTSD Scale for DSM-5, safety, feasibility, and masking success. Findings are intended to provide preliminary descriptive information regarding feasibility, safety/tolerability, masking integrity, and symptom-change signals for aMETEMP with incomplete disclosure in a large outpatient healthcare system.ClinicalTrials.gov Identifier: NCT06117306