Preliminary Effectiveness of Hybrid Individual and Group MDMA-assisted Therapy for War-related PTSD

This is a single-site, two-arm, open-label, nonrandomized study evaluating the safety and preliminary effectiveness of MDMA-assisted therapy (MDMA-AT) in participants diagnosed with posttraumatic stress disorder (PTSD). The study will enroll at least 30 participants in the MDMA-AT arm. A treatment-as-usual (TAU) comparison arm of approximately 30 participants will be recruited separately. Therapy teams delivering MDMA-AT have been trained in the MAPS therapeutic approach. The MDMA-AT intervention lasts approximately 18 weeks and includes an initial individual phase followed by a group phase. Participants receive three MDMA experimental sessions: two individual experimental sessions and one group experimental session. MDMA hydrochloride is administered during each experimental session, with a planned supplemental half-dose unless tolerability concerns arise or the participant declines. Experimental sessions last approximately 8 hours and are followed by an overnight stay. Following screening, informed consent, eligibility assessment, baseline assessment, and enrollment, participants begin a preparatory period. This includes three 90-minute individual non-drug preparatory sessions (V1-V3), during which participants are prepared for the therapeutic process and experimental sessions. Medication tapering, when required, is completed according to the study protocol. The individual treatment phase includes two individual MDMA experimental sessions (V4 and V8). Each experimental session is followed by three individual non-drug integration sessions. The first integration session takes place on the morning after the experimental session, with subsequent integration sessions occurring over the following weeks. Thus, V4 is followed by V5-V7, and V8 is followed by V9-V11. The PCL-5 is also administered during the treatment period as specified in the assessment schedule. After completion of the individual phase, participants transition to the group phase. Because participants complete their individual treatment schedules on different dates, an interval is permitted before initiation of the group phase to allow members of each treatment group to begin group treatment together. To minimize variability in this interval, participants intended for the same group are scheduled to begin the individual treatment phase within approximately the same time period. Scheduling may nevertheless be adjusted because of recruitment, screening, staff availability, medication tapering, and other operational considerations. The group phase begins with two non-drug group preparatory sessions (V12-V13), intended to introduce participants to the group format, facilitate acquaintance among group members, and discuss individual goals and expectations. Participants then complete one group MDMA experimental session (V14). During the main drug-effect period, participants engage primarily in inward-focused therapeutic work, with therapist support available as needed. The group experimental session is followed by three group integration sessions (V15-V17), with V15 occurring on the morning after V14 and subsequent sessions occurring over the following weeks. The primary clinical outcome is change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score from baseline to the post-treatment assessment at V18. V18 also serves as the final study visit for the active treatment period. Additional CAPS-5 follow-up assessments are conducted at 3, 6, and 12 months following completion of the treatment protocol. Safety is monitored throughout treatment and follow-up according to study procedures. The TAU comparison arm includes approximately 30 participants with PTSD receiving routine care through the psychiatric clinic of the Israeli Ministry of Defense at Emek Medical Center. Participants in this arm continue their usual psychiatric and psychotherapeutic care and do not receive MDMA as part of the study. Outcomes from this cohort will be used as an exploratory longitudinal comparator for the MDMA-AT cohort.