Exploring Mechanisms of Action in MDMA-assisted Psychotherapy for PTSD

Study Overview
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Brief Summary
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This study measures biological and psychological processes that might help researchers to better understand what is taking place during low or medium dose and full dose MDMA-assisted psychotherapy treatment in people with PTSD. Heart rate variability (HRV) will be measured up to three times; before and once or twice after receiving MDMA-assisted psychotherapy. Brain activity will be measured before and after MDMA-assisted psychotherapy in response to personalized trauma-related scripts. Participants will complete a measure of self-compassion at baseline and two months after a final experimental treatment session. Therapy techniques observed during recorded treatment sessions will be classified using a standardized clinical measure.

Detailed Description
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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.

Official Title
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Exploring Mechanisms of Action of ±3,4-methylenedioxymethamphetamine (MDMA)- Assisted Psychotherapy for Posttraumatic Stress Disorder (PTSD)

Conditions
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Posttraumatic Stress Disorder

Intervention / Treatment
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* Drug: Midomafetamine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Full dose MDMA<br>Participants will receive 125 mg MDMA possibly followed 1.5 to 2 h later by 62.5 mg MDMA | Drug: Midomafetamine<br>* 125 mg MDMA<br>* Other names: MDMA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brain activity measured via fMRI while listening to trauma scripts | Brain activity measured via functional magnetic resonance imaging (fMRI) after listening to trauma-related scripts. | Baseline, two months after final experimental session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heart rate variability in response to trauma script | Assessment of Heart rate variability (HRV) in response to trauma-related scripts; a potential physiological correlate of response to treatment for PTSD | Baseline, one month post-drug | 
| Change in Self Compassion Scale Score | Self-report measure of self-compassion | Baseline, one month post-drug | 
| Change in heart rate variability in response to trauma script | Assessment of Heart rate variability (HRV) in response to trauma-related scripts; a potential physiological correlate of response to treatment for PTSD | Baseline, two months post final drug administration | 
| Change in Self Compassion Scale Score | Self-report measure of self-compassion | Baseline, two months post final drug administration | 
| Change in brain activity measured via fMRI while listening to trauma scripts | Brain activity measured via functional magnetic resonance imaging (fMRI) after listening to trauma-related scripts | Baseline, one month post-drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, MDMA, Brain activity, fMRI, Heart rate variability, Physiological correlate