The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective at reducing PTSD symptoms in people with at least severe PTSD.

The main question it aims to answer is:

Do three open-label sessions of MDMA-assisted therapy reduce PTSD symptoms?

Participants will receive three non-drug preparatory sessions followed by three sessions of MDMA-assisted therapy. Each MDMA-assisted therapy session is followed by three non-drug integrative therapy sessions.

This multi-site, open-label, Phase 2, lead-in study assesses the safety and effect of MDMA-assisted therapy in participants diagnosed with at least severe posttraumatic stress disorder (PTSD). Therapy teams that have been identified and trained to work on the sponsor's planned Phase 3 studies will treat at least one open-label participant in this study.

This study will compare the effects of three open-label manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session include 100 mg or 125 mg of MDMA compounded with lactose, followed 1.5 to 2 hours later by a supplemental half-dose (50 mg or 62.5 mg). Total amounts of MDMA to be administered per Experimental Session range from 100 mg to 187.5 mg. This ~12-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy.

The primary outcome measure is the change in the Clinician Administered PTSD Scale for DSM 5 (CAPS-5) total severity scores from Baseline to Visit 19. The secondary outcome measure is the change in the customized version of the Sheehan Disability Scale (SDS) for PTSD for the MAPS studies total scores from Baseline to Visit 19.

Inclusion Criteria:

• Are at least 18 years old
• Are fluent in speaking and reading the predominantly used or recognized language of the study site
• Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug psychotherapy sessions
• Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.
• Must agree to inform the investigators within 48 hours of any medical conditions and procedures.
• If of childbearing potential, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session.
• Must not participate in any other interventional clinical trials during the duration of the study,
• Must be willing to remain overnight at the study site after each Experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures

Exclusion Criteria:

• Are not able to give adequate informed consent
• Have uncontrolled hypertension
• Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] corrected by Bazett's formula)
• Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
• Have evidence or history of significant medical disorders
• Have symptomatic liver disease
• Have history of hyponatremia or hyperthermia
• Weigh less than 48 kilograms (kg)
• Are pregnant or nursing, or are of childbearing potential and are not practicing an effective means of birth control.
• Meet DSM-5 criteria for active substance use disorder for any substance other than caffeine or nicotine
• Have used Ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first Experimental Session; or have previously participated in a MAPS or Lykos-sponsored MDMA clinical trial.

We will share outcome data appearing in any published reports upon request.

Data and study-related documents will be available when all participants have completed the study

Interested persons should correspond with the central contact for study.

Safety Set

Treatment-emergent adverse events through study completion (approximately 5 months)

This was an open-label trial with no placebo comparator in a small sample size (n=4).