Open Label Multi-Site Study of Safety and Effects of MDMA-assisted Psychotherapy for Treatment of 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 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, open-label, Phase 2, lead-in study assesses the safety and effect of
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy 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. The study will be conducted in up to N=60
participants. A flexible dose of MDMA, followed by a supplemental half-dose unless
contraindicated, is administered during the Treatment Period with manualized psychotherapy in
three open-label 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, the 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 open-label manualized Experimental Sessions of
psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session
include 80 mg or 120 mg of MDMA compounded with lactose, followed 1.5 to 2 hours later by a
supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per
Experimental Session range from 80 mg to 180 mg.

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

- Meet DSM-5 Criteria for 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