Examining 3,4-methylenedioxymethamphetamine (MDMA) Effects on Psychological, Relational and Hyperarousal-Related Neural Reactivity Mechanisms in Veterans With PTSD and Moral Injury

NCT06394284 | Recruiting Phase 3 FDA Drug

• 1 other identifier: MOH_2023-07-02_012787
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Despite being exposed to a high level of potentially traumatic experiences due to exposure to combat, military veterans have poor response rates to traditional PTSD treatments, in some reports, just 1/3 of veterans recover using traditional treatments. In recent years 3,4-methylenedioxymethamphetamine (MDMA), a psychedelic drug has demonstrated a significant treatment potential for severe and treatment resistant PTSD though not specifically in a veteran population. Additionally, even in groups where participants receive a placebo, the effect of the psychedelic treatment formulation, intensive, focused and respectful structure, appears to have promising effects. Indeed, in the current psychedelic literature, the setting and mind with which participant approach psychedelic therapy, significantly contributes to the treatment effect. The current study proposes to address the major gaps in the theoretical literature by examining the proposed mechanisms by which MDMA enhances the "window of tolerance" for PTSD therapy, specifically in those with comorbid symptoms of moral injury; namely by reducing hyperarousal and enhancing connection (to self and others) and whether MDMA assisted therapy is more successful in reducing PTSD in veterans compared to a matched somatic experiential PTSD treatment, Somatic Experiental Acceptance Intensive Trauma-based therapy, (SEA-IT) which builds upon the promising placebo results, enhancing them with somatic and acceptance based treatment protocols.

Conditions

PTSD, Post Traumatic Stress Disorder; Moral Injury

Keywords

MDMA; PTSD; Moral Injury; Oxytocin; veterans; Hyperarousal

Outcome Measures

Primary Outcomes (2)

• PTSD

  Clinician-Administered PTSD Scale-5 (CAPS-5) will be performed during the intake interview. The CAPS-5 is a structured clinical interview used to assess the presence of a PTSD diagnosis and PTSD symptom levels over the past month.

  Enrollment and visit 16, two weeks to one month after the final therapy session, approximately 4 months after first visit.

• Oxytocin

  As this study is designated as a mechanisms of change study, the primary outcome is that of exploring the role of oxytocin in the therapeutic process. The primary outcome measure is thus the hormone assessment of increased oxytocin (primary) as mediating the change in PTSD (and MI-exploratory) symptoms. Saliva collection will be the same for both MDMA-assisted and Somatic-based therapy groups and the collection relevant for the measurement of both oxytocin (primary) and cortisol (exploratory). Four saliva samples will be collected at four time points during each of the experimental (or intense) sessions: prior to commencing the session, +90 minutes +210, +320 minutes following the administration of MDMA or commencement of the Somatic-based arm. To assess oxytocin concentrations, saliva samples will be thawed and then dried using a SpeedVac concentrator. The evaporated samples are then reconstituted with an assay diluent. Oxytocin concentrations will be measured using an ELISA kit

  At 4 time points during the 3 long sessions (visit 4, one month after enrollment, visit 8, two months after enrollment and visit 12, three months after enrollment)

Secondary Outcomes (9)

• Hyperarrousal- EEG

  EEG- during visits 3 (three weeks after enrollment), 7 (three weeks after the first long session) and visit 16 (two weeks to a month after the final therapy session) (pre, post 1st long session, post study)

• Hyperarrousal- cortisol

  Cortisol, as outlined in oxytocin collection

• Moral Injury

  visit 1 and visit 16 (two weeks to a month after the final therapy session) (pre-post)

• Functional Impairment

  Visits 1,7 (three weeks after first long session),11 (three weeks after second long session) and 16 (two weeks to a month after final therapy session)

• Self Compassion

  Visits 1,7 (three weeks after first long session),11 (three weeks after second long session) and 16 (two weeks to a month after final therapy session)

Study Arms (2)

MDMA Assisted Therapy

EXPERIMENTAL

This intensive therapy is comprised of 16 sessions of therapy with two therapists including three long sessions of MDMA assisted therapy followed by an overnight stay and then 3 weekly integration sessions.

Drug: MDMA-AT

SEA-IT

EXPERIMENTAL

This intensive trauma focused therapy is comprised of 16 sessions of therapy with two therapists including three long sessions of between 6 to 8 hours followed by an overnight stay and then 3 weekly integration sessions. The therapy is modeled on components of Somatic Experiencing, Acceptance and Commitment Therapy and the psychedelic assisted therapy protocols.

Behavioral: SEA-IT

Interventions

MDMA-AT DRUG

As described above in arm description

MDMA Assisted Therapy

SEA-IT BEHAVIORAL

As described in arm description

SEA-IT

Eligibility Criteria

• Gender Eligibility Details: Identify as male and not taking hormone therapy to transition to female identity
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Were assigned male sex at birth and currently identify as a male (e.g. are not transgender nor taking hormone replacement therapy) 2. Are veterans of the Israeli military 3. Are at least 18 years old. 4. Are fluent in speaking and reading Hebrew 5. Are able to swallow pills. 6. Agree to have EEG (three times) and salivary monitoring (during experimental sessions) at multiple occasions throughout the study.
• \. Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug therapy sessions.
• \. Must provide a contact (relative, spouse, close friend or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming unwell or unreachable.
• \. Must agree to inform the investigators within 48 hours of any medical conditions and procedures.
• \. Agree to the following lifestyle modifications: comply with requirements for fasting and refraining from certain medications prior to experimental sessions, not enroll in any other interventional clinical trials during the duration of the study, remain overnight at the study site after each experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures.
• Medical History
• \. At Screening, meet diagnostic criteria (Diagnostic Statisticians Manual, 5th version, DSM-5) for current military-based PTSD with a symptom duration of 6 months or longer with a history of at least one attempt at psychiatric or psychological treatment.
• \. At Screening, have a PCL-5 total score of 33 or greater and at Screening/Baseline a confirmed diagnosis of PTSD per CAPS-5 and a total severity score of 28 or greater.
• \. Have a body weight of at least 45 kilograms. Participants with a body weight of 45 to 48 kg must also have a body mass index (BMI) within the range of 18 to 30 kg/m2.
• \. Capable of giving signed informed consent.

You may not qualify if:

• \- Medical Conditions
• Alanine transaminase (ALT) \[or aspartate transaminase (AST)\]higher than 2 x upper limit of normal (ULN).
• Total bilirubin higher than 1.5 x ULN (isolated bilirubin higher than; 1.5 x ULN is acceptable if total bilirubin is fractionated and direct bilirubin less than; 35%).
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Note: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B (e.g., the presence of hepatitis B surface antigen or positive hepatitis C antibody test result without evidence of active infection at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria.
• Have a recent history of clinically significant hyponatremia or hyperthermia.
• Have a marked baseline QTcF (QT interval corrected for heart rate ) interval higher than 450 ms demonstrated on repeated ECG (electrocardiogram) assessments. Participants whose QTcF exceeds this value during screening may be initially enrolled if a pre-study concomitant medication is suspected to be prolonging the QT-interval. ECGs should be repeated after initial enrollment and tapering off the pre-study concomitant medication to ensure the participant meets eligibility criteria prior to enrolment confirmation and to IMP dosing.
• Note: The QTcF is the QT interval corrected for heart rate according to Fridericia's formula. It is either machine-read or manually over-read.
• Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure and heart rate. This includes, but is not limited to, a history of myocardial infarction, cerebrovascular accident, heart failure, severe coronary artery disease, or aneurysm.
• Participants with other mild, stable chronic medical problems may be enrolled if the study clinician and Sponsor Investigator (S-I) agree the condition would not significantly increase the risk of MDMA administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of MDMA.
• Have a diagnosis of uncontrolled hypertension, defined as repeated blood pressure readings of ≥140 mmHg systolic or ≥90 mmHg diastolic. The diagnosis may be confirmed by repeated clinic measurements or home blood pressure monitoring if clinically indicated.
• Participants with well-controlled hypertension that has been successfully treated with anti-hypertensive medicines may be enrolled if they pass a risk assessment and potentially additional screening to rule out underlying cardiovascular disease.
• Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease.
• Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation.
• Have a history of arrhythmia, other than premature atrial contractions (PACs) or occasional PVCs in the absence of ischemic heart disease, within 12 months of screening.

Sponsors & Collaborators

• Herzog Hospital: lead
• Metiv Israel Psychotrauma Center: collaborator

Study Sites (1)

METIV Israel Psychotrauma Center, Herzog Medical Center

Jerusalem, 3090844, Israel

RECRUITING

Related Links

• Study recruitment page

MeSH Terms

Conditions

Combat Disorders; Stress Disorders, Post-Traumatic

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Study Officials

• Anna Harwood-Gross, PhD

  Metiv Israel Psychotrauma Center

  STUDY DIRECTOR

• Pinhas Danon, Prof

  Herzog Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Moriya Rahmani, PhD

CONTACT

0097226264889; moriya@metiv.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2024
• First Posted: May 1, 2024
• Study Start: February 18, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: May 1, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Available currently
• Access Criteria: Protocol is available to researchers on request

Locations

IL (1)