A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD

PTSD is a serious debilitating disorder that negatively impacts a person's daily life. PTSD
is a stress-related psychiatric condition that may occur following a traumatic event such as
war, disaster, sexual abuse, violence, terrorism, and accidents. PTSD negatively impacts a
person's daily life, resulting in relationship difficulties, difficulty in finding and
maintaining a job, reduced cognitive and psychosocial functioning, substance abuse, high-cost
healthcare use, and increased depression and suicide risk. Available PTSD treatments,
including medications and therapy, effectively treat only a fraction of people who try them
for adequate dose and duration. People with PTSD can be treated with psychotherapies and
pharmacotherapies. In the past decade, there has been a growing amount of research into
medications and other methods that may augment the effectiveness of psychotherapy for PTSD

3,4-methylenedioxymethamphetamine (MDMA) is a drug that releases serotonin, norepinephrine
and dopamine in the brain and indirectly increases levels of the neurohormones oxytocin,
arginine vasopressin and cortisol. The combined neurobiological effects of MDMA increase
compassion, reduce defenses and fear of emotional injury, and enhance communication and
introspection. MDMA produces anxiolytic and prosocial effects, which counteract avoidance and
hyperarousal in the context of therapy. A combined treatment of MDMA and psychotherapy may be
especially useful for treating PTSD.

This multi-site, double-blind, randomized Phase 3 study assesses the efficacy and safety of
MDMA-assisted psychotherapy versus psychotherapy with placebo control in participants
diagnosed with at least severe posttraumatic stress disorder (PTSD). The study will be
conducted in N ≈ 100 participants. Participants will be enrolled in one of two groups at a
1:1 ratio. A flexible dose of MDMA or placebo, followed by a supplemental half-dose unless
contraindicated, is administered during the Treatment Period with manualized psychotherapy in
three monthly Experimental Sessions. 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 change
in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline. Exploratory measures
will address specific symptoms, or behavior that is sometimes related to PTSD. Drug safety
will be assessed by measuring blood pressure, heart rate and body temperature during
experimental sessions, collecting adverse events and measuring suicidal thoughts or behaviors
with the Columbia Suicide Severity Rating Scale (CSSRS). This study will compare the effects
of three manualized Experimental Sessions of psychotherapy supported by assisted by flexible
doses of MDMA versus placebo. Initial doses per Experimental Session include 80 mg or 120 mg
of MDMA compounded with mannitol and magnesium stearate or placebo alone (mannitol and
magnesium stearate), followed 1.5 to 2 hours later by a supplemental half-dose (40 or 60 mg).
Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180

Inclusion Criteria:

- Are at least 18 years old

- Are fluent in speaking and reading the predominantly used or recognized language of
the study site

- Are able to swallow pills

- 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

- At baseline, meet DSM-5 criteria for current severe PTSD

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

- Are abusing illegal drugs