Design and methodology of the first open-label trial of MDMA-assisted therapy for veterans with post-traumatic stress disorder and alcohol use disorder: Considerations for a randomized controlled trial

Background: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur and are associated with more severe symptomatology than either disorder alone, increased risk of suicide, and poorer response to existing treatments. A promising therapeutic intervention is the integration of 3,4-methylenedioxymethamphetamine (MDMA) and psychotherapy. The Food and Drug Administration (FDA) designated MDMAassisted therapy (MDMA-AT) as a Breakthrough Therapy for PTSD based on results from six Phase 2 clinical trials. Case data from the first study evaluating MDMA-AT study for AUD found the treatment was well tolerated and alcohol use was significantly reduced post treatment. Methods: This manuscript reports the premise, design, and methodology of the first open-label trial of MDMA-AT for military veterans (N = 12) with PTSD and AUD. Neuroimaging and biomarker data are included to evaluate brain changes, and neuroinflammation, pre-post treatment. Conclusions: The clinical component (comorbidity) and the regulatory processes (Schedule I drug) for setting up this clinical trial are long and complex. The research community will benefit from this work to establish common clinical trial outcomes, standardized protocols, and risk assessments for FDA approval. Clinicaltrials.gov: NCT05943665.