Abstract
There is growing interest in novel approaches to treating posttraumatic stress disorder (PTSD), including the use of psychedelic substances combined with psychotherapy, often referred to as psychedelic-assisted therapy, to better meet the needs of patients who do not prefer or respond to traditional evidence-based treatments. Among these treatments, 3,4-methylenedioxymethamphetamine (MDMA)–assisted psychotherapy (MDMA-AT) has shown promising outcomes in recent randomized controlled trials, with high response and remission rates. However, the U.S. Food and Drug Administration declined to approve MDMA-AT for marketable use in August 2024 due to concerns about insufficient evidence. This paper reviews the current state of the scientific literature on MDMA-AT for PTSD, including putative mechanisms of action; key strengths and limitations of methodologies used to date; gaps in the evidence; and clinical, ethical, and regulatory considerations. Key limitations to be addressed in future studies include challenges with blinding, a lack of active comparator conditions, a lack of head-to-head comparisons of different models, inadequate safety monitoring, and limited sample generalizability. We describe emerging research that integrates MDMA with established trauma-focused therapies, such as prolonged exposure therapy and cognitive processing therapy, to leverage MDMA’s effects on known cognitive behavioral mechanisms of action and support future implementation. Future research directions for advancing knowledge and consideration for the dissemination of MDMA-AT are discussed.