Exploring Mechanisms of Action in MDMA-assisted Psychotherapy for PTSD

PTSD is a complex psychiatric disease characterized by a deficit in fear extinction,
hyperarousal, emotional numbing, and intrusive symptoms that cause the patient to
persistently re-experience a traumatic event over a period longer than a month. PTSD is
considered chronic when symptoms are present for at least six months. MDMA-assisted
psychotherapy is an innovative experimental mode of treatment that combines
psychotherapeutic techniques with the administration of MDMA. It may amplify certain aspects
of psychotherapy, as the pharmacological action of MDMA is thought to act as an adjunct to
psychotherapy. With positive results in two studies and ongoing Phase 2 clinical studies it
is important to further characterize the psychotherapeutic processes that occur during
treatment sessions conducted according to the manualized method of MDMA-assisted
psychotherapy. Changes in physiological status or brain activity that are associated with
improvement or recovery in people with chronic PTSD may offer a means of assessing treatment
response that relies less on self-report. This may be particularly important in studies with
MDMA-assisted psychotherapy where blinding is difficult due to the psychoactive nature of
the investigational product. This study is also interested in identifying and categorizing
psychotherapeutic processes taking place during MDMA-assisted psychotherapy. The sub-study
will also examine elements of the experience with a self-report measure of self-compassion.

This exploratory sub-study will identify psychotherapeutic processes occurring during MDMA-
assisted psychotherapy in people with chronic PTSD and assess the feasibility of exploring
physiological correlates of clinical outcomes in subjects enrolled in the ongoing clinical
trial of MDMA-assisted psychotherapy, NCT #: NCT01211405. The sub-study will be conducted in
collaboration with researchers at the Medical University of South Carolina (MUSC), Smith
College and the New School for Social Research.

To support the clinical outcomes measured by CAPS from the MP-8 study, the sponsor is
interested in correlations of outcomes with treatment-related changes in potential
biological markers of PTSD, measured by HRV and fMRI. Brain activity while listening to
neutral and personalized trauma-related scripts will take place at baseline and after
experimental MDMA-assisted psychotherapy with low or medium or full dose MDMA. The fMRI scan
will be followed by a Diffusion Tensor Imaging (DTI) scan. After each scanning session,
pulse measurements will be extracted as a digital data file from which HRV will be
calculated. FMRI scans and HRV measurements will occur at baseline for participants in all
conditions, one month after the second experimental session and again after a final
experimental session for participants in the low or medium dose condition, and two months
after the final experimental session for participants in the full dose condition.
Participants will complete the Self-Compassion Scale, a self-report measure of
self-compassion at Baseline and after the final MDMA-assisted psychotherapy session.
Psychotherapeutic processes will be assessed via observing psychotherapy and sorting a set
of 100 therapy-related items as a means of describing the interactions. Trained coders will
observe at least one pre-drug psychotherapy session, one experimental (drug-assisted
psychotherapy) session and one post-drug psychotherapy session.

Inclusion Criteria:

- Enrolled in the parent study, "A Randomized, Triple-Blind, Phase 2 Pilot Study
Comparing 3 Different Doses of MDMA in Conjunction with Manualized Psychotherapy in
24 Veterans, Firefighters, and Police Officers with Chronic, Treatment-Resistant
Posttraumatic Stress Disorder (PTSD)." NCT #: NCT01211405

Exclusion Criteria:

- Mass brain lesion

- Have metal in their skulls,

- Having brain or heart pacemakers

- History of major head trauma

- Have past or present panic or extreme discomfort with being in small enclosed spaces
(claustrophobia)