Dose-Response Study of MDMA-assisted Psychotherapy in People With PTSD

Posttraumatic stress disorder (PTSD) is a debilitating disorder that can develop after people
experience a traumatic event, such as a rape, car accident or other life threatening event.
PTSD is a worldwide health problem. PTSD is treated with psychotherapy or drugs, but these
treatments do not help everyone. 3,4-methylenedioxymethamphetamine (MDMA)-assisted
psychotherapy might be a potential treatment for PTSD. MDMA is the active ingredient in
ecstasy. Before it was made illegal, some psychotherapists combined MDMA with psychotherapy
to help treat people with psychological problems, including PTSD.

This study is a randomized, double-blind dose-response study comparing comparator-dose MDMA
with full-dose MDMA. The study drug will be given as an initial dose possibly followed 1.5
hours later by a second dose half the size of the first dose. This Phase 2 pilot study will
examine the safety and efficacy of MDMA-assisted psychotherapy in 23 subjects with chronic,
treatment-resistant PTSD of at least 6 months duration who were unable to recover despite
having received prior treatment with either drug or psychotherapy, or who discontinued
treatment due to lack of tolerance for the treatment. Seven subjects will be randomized to
full-dose MDMA and five subjects will be randomized to comparator-dose MDMA.

MDMA will be administered in two experimental sessions lasting up to 8 hours and scheduled
three to five weeks apart.

The study will last up to one and a half years, including approximately three to five months
of psychotherapy, and a long-term follow up visit scheduled a year after the final
experimental session. Study subjects will have a medical and psychiatric examination to make
sure that they can take part in the study. Once in the study, they will see the same male and
female psychotherapist for the entire study. The subject will learn more about MDMA-assisted
psychotherapy and the investigators will learn more about the subject during three
preparatory sessions occurring before the first experimental session. During experimental
sessions, subjects will receive an initial dose of either full or comparator-dose MDMA along
with psychotherapy, and one and a half to two and a half hours later, the subject may have a
supplemental dose half the size of the initial dose of MDMA. Vital signs and psychological
distress will be measured throughout the experimental session. There will be three
integrative psychotherapy sessions after each experimental session, including one occurring
the day after an experimental session. Subjects will express, understand, bring together and
connect any of their thoughts or feelings about your symptoms and their causes, and they will
discuss their experience during experimental sessions with the therapists.

Subjects will learn whether they received the comparator or the full dose of MDMA one month
after their second experimental session. Subjects who received full-dose MDMA will finish
Stage 1 and have a third experimental session, while subjects who received comparator-dose
may go on to Stage 2, an open-label stage that is nearly identical to stage 1, with one
instead of three preparatory sessions, and with experimental sessions with one of two active
doses of MDMA.

Symptoms of PTSD and depression, sleep quality, general psychological well-being,
dissociation and posttraumatic growth (potentially positive effects of experiencing a
traumatic event) will be measured in all subjects at baseline, one month after the second
experimental session and 12 months after their final experimental session. Cognitive function
will be assessed in all subjects at baseline and one month after the second experimental
session. Participant reporting pain or tinnitus will record their symptoms throughout the
study via visual analog scale. Subjects who received either Active Dose 1 or Active Dose 2
and go on to the third experimental session will complete questionnaires and measures of
their symptoms of PTSD and depression, general psychological well-being, dissociation, sleep
quality and posttraumatic growth two months after the third experimental session. Depending
upon condition assignment or continuation to Stage 2, cognitive function will be assessed two
months after the third Stage 1 or Stage 2 session. Subjects assigned to comparator-dose MDMA
will be tested one month after their second Stage 2 experimental session and two months after
the third experimental session. People will also complete measures of their experience of the
experimental session soon after each experimental session.

This study will compare the effects of MDMA-assisted psychotherapy with comparator versus
full-dose MDMA, and it will also assess the duration of any changes in symptoms a year after
MDMA-assisted psychotherapy.

Inclusion Criteria:

- Diagnosed with chronic PTSD for six months or longer

- Have a CAPS score showing moderate to severe PTSD symptoms

- At least one unsuccessful attempt at treatment for PTSD either with talk therapy or
with drugs, or discontinuing treatment because of inability to tolerate psychotherapy
or drug therapy.

- Are at least 18 years old

- Must be generally healthy

- Are willing to refrain from taking any psychiatric medications during the study period

- Willing to follow restrictions and guidelines concerning consumption of food,
beverages or nicotine the night before and just prior to each MDMA session.

- - Willing to remain overnight at the study site;

- Agree to have transportation other than driving themselves home or to where they are
staying after the integrative session on the day after the MDMA session

- Are willing to be contacted via telephone for all necessary telephone contacts

- Must have a negative pregnancy test if able to bear children, and agree to use an
effective form of birth control

- Must provide a contact in the event of a subject becoming suicidal

- Agree to let the investigators know within 48 hours of any planned medical
interventions;

- Are proficient in reading and speaking English

- Agree to have all psychotherapy sessions recorded to audio/video

- Agree not to participant in any other interventional clinical trials during the course
of the study

Exclusion Criteria:

- Are pregnant or nursing, or if a woman who can have children, those who are not
practicing an effective means of birth control

- Weigh less than 48 kg

- Are abusing illegal drugs

- Are unable to give adequate informed consent

- Upon review of past and current drugs/medication must not be on or have taken a
medication that is exclusionary.

- Upon review of medical or psychiatric history must not have any current or past
diagnosis that would be considered a risk to participation in the study