Overview

The study investigators are conducting the first open label pilot trial of MDMA-assisted therapy (MDMA-AT) with a comorbid sample of military veterans with a comorbid diagnosis of Alcohol Use Disorder (AUD) and Post-Traumatic Stress Disorder (PTSD). This novel experimental treatment package consists of two once-monthly Experimental Sessions of therapy combined with a divided-dose of MDMA HCl, along with non-drug preparatory and integrative therapy. The Primary Outcome measure, the Timeline Follow-back (TLFB), will evaluate changes in alcohol use over time. Changes in PTSD symptoms will also be evaluated.

Eligibility

Inclusion Criteria:

1. Are able to provide proof of veteran status.
2. Are fluent in speaking and reading English.
3. At Baseline, meet criteria for Alcohol Use Disorder as measured by the SCID-5.
4. Able to safely abstain from alcohol for at least 48 hours without requiring medical detox.
5. At Baseline meet DSM-5 criteria for current PTSD with a symptom duration of at least 6 months.
6. At Baseline, have a PCL-5 score of 33 or greater.
7. At Baseline, have a confirmed PTSD diagnosis per the CAPS-5 and a Total Severity Score of 28 or greater.
8. Are able to swallow pills.
9. Agree to have study visits recorded, including Experimental Sessions, assessments, and non-drug therapy sessions.
10. Able to 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.
11. Able to identify appropriate support person(s) to stay with the participant on the evenings of the Experimental Sessions, see Section Support Person.

    Weight

12. Body weight of at least 45 kilograms (kg). 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.

    Sex and Contraceptive/ Barrier Requirements

13. For participants assigned female sex at birth:
    • A participant is eligible to participate if not pregnant, not planning to become pregnant, or is not breastfeeding and one of the following conditions applies
    • Is not able to become pregnant
    • Is a person able to be pregnant (PABP) and using a contraceptive method that is highly effective, with a failure rate of <1%. The investigator will evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first does of study intervention. A PABP must have a highly sensitive negative urine pregnancy test at study entry and prior to each Experimental Session, see Schedule of Activities. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy.

Informed Consent

         14. Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the ICF and in this protocol.
             Other Inclusions
         15. Agree to inform the investigators within 48 hours of any medical conditions and
             procedures.
         16. May have asymptomatic Hepatitis C virus (HCV) that has previously undergone evaluation
             and treatment as needed.
         17. Participants must have a plan, agreed upon by investigator, therapy team, and study
             clinician, to reduce use of substances and to manage symptoms without self-medicating.
             Enrollment will require that, in the judgment of the investigator, therapy team, and
             study physician, the plan for decreasing substance use is realistic and has a good
             chance of succeeding to prevent substance use from impacting the safety or efficacy of
             the investigational treatment.
         18. May have a history of or current Diabetes Mellitus (Type 2) if additional screening
             measures rule out underlying cardiovascular disease, if the condition is judged to be
             stable on effective management, and with approval by the study clinician.
         19. May have hypothyroidism if taking adequate and stable thyroid replacement medication.
         20. May have a history of, or current, glaucoma if approval for study participation is
             received from an ophthalmologist.
        Exclusion Criteria:
        Medical Conditions
          1. Have symptomatic liver disease or have significant liver enzyme elevations.
               -  Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 x upper limit of
                  normal (ULN).
               -  Total bilirubin > 1.5 x ULN or direct bilirubin < 35%.
          2. 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.
          3. Have a history of seizures or delirium tremens (DTs).
          4. Significant alcohol withdrawal symptoms, defined as a Clinical Institute Withdrawal
             Assessment of alcohol scale, revised (CIWA-Ar) >10.
          5. Have a recent history of clinically significant hyponatremia or hyperthermia.
          6. Have a marked Baseline QTcF interval >450 ms demonstrated on repeated ECG 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
             enrollment 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.
          7. 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 principal investigators 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 the IMP.
               -  Examples of stable medical conditions that could be allowed include, but are not
                  limited to, Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV)
                  infection, Gastroesophageal Reflux Disease (GERD), hypothyroidism (if taking
                  adequate and stable thyroid replacement medication), glaucoma (if approval for
                  study participation is received from an ophthalmologist). Any medical disorder
                  judged by the investigator to significantly increase the risk of MDMA
                  administration by any mechanism would require exclusion.
          8. Have a diagnosis of controlled or uncontrolled hypertension, defined as repeated blood
             pressure readings of ≥ 140 millimeters of Mercury [mmHg] systolic or ≥ 90 mmHg
             diastolic. The diagnosis may be confirmed by repeated clinic measurements or home
             blood pressure monitoring if clinically indicated.
          9. Have a history of ventricular arrhythmia at any time, other than occasional premature
             ventricular contractions (PVCs) in the absence of ischemic heart disease.
         10. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been
             successfully eliminated by ablation.
         11. 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.
             • Participants with a history of atrial fibrillation, atrial tachycardia, atrial
             flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated
             with a bypass tract may be enrolled only if they have been successfully treated with
             ablation and have not had recurrent arrhythmia for at least one year off all
             antiarrhythmic drugs or are under adequate and stable pharmacologic treatment for
             atrial fibrillation for at least a year, as confirmed by a cardiologist.
         12. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure,
             hypokalemia, family history of Long QT Syndrome).
         13. Exclusion criteria specific to MRI: non-removable ferromagnetic materials;
             claustrophobia; history of head trauma or injury.
             Psychiatric Conditions
         14. Have engaged in a new form of psychiatric or mental health care within 12 weeks of
             enrollment, including Electroconvulsive Therapy (ECT) and ketamine-assisted therapy.
         15. Are currently prescribed antidepressant medications (e.g., selective serotonin
             reuptake inhibitors) requiring a medication taper.
         16. Are currently prescribed antipsychotic medications.
         17. Are likely, in the investigator's opinion and via observation during the Preparatory
             Period, to be re-exposed to their index trauma or other significant trauma or other
             significant trauma during the study.
         18. Have a current moderate (not in early remission in the 3 months prior to enrollment
             and meets at least 5 of 11 diagnostic criteria per DSM-5) or severe cannabis use
             disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic
             criteria per DSM-5).
             • May have current mild cannabis use disorder (meets 3 of 11 diagnostic criteria per
             DSM-5) or moderate cannabis use disorder in early remission for the 3 months prior to
             enrollment (meets 4 or 5 of 11 diagnostic criteria per DSM-5).
         19. Have an active substance use (other than cannabis) disorder at any severity within 12
             months prior to enrollment.
         20. Have used Ecstasy (material represented as containing MDMA) more than 10 times within
             the last 10 years or at least once within 6 months of the first Experimental Session
         21. Any participant presenting current serious suicide risk, as determined through
             psychiatric interview, responses to C-SSRS, and clinical judgment of the investigator
             will be excluded; however, history of suicide attempts is not an exclusion. Any
             participant who is likely to require hospitalization related to suicidal ideation and
             behavior, in the judgment of the investigator, will not be enrolled. Any participant
             presenting with the following on the Baseline C-SSRS will be excluded:
               -  Suicidal ideation score of 4 or greater within the last 6 months of the
                  assessment at a frequency of once a week or more
               -  Suicidal ideation score of 5 within the last 6 months of the assessment
               -  Any suicidal behavior, including suicide attempts or preparatory acts, within the
                  last 6 months of the assessment. Participants with non-suicidal self-injurious
                  behavior may be included if approved by the study clinician.
         22. Would present a serious risk to others as established through clinical interview and
             contact with treating psychiatrist.
             Prior/Concomitant Therapy
         23. Require ongoing concomitant therapy with a psychiatric medication with exceptions
             described in protocol section on Concomitant Medications (refer to Appendix E:
             Permitted and Prohibited Medications).
         24. Current use of pharmacotherapies (i.e., naltrexone or disulfiram) to treat alcohol
             use.
         25. Require use of concomitant medications that could prolong the QT interval during
             Experimental Sessions.
         26. Are currently engaged in trauma-focused psychotherapy or are currently in a treatment
             program for SUD (self-help programs are not an exclusion).
             Prior/Concurrent Clinical Study Experience
         27. Current enrollment in any other clinical study involving an investigational study
             treatment or any other type of medical research, unless approved by the study
             clinician.
             Diagnostic Assessments
         28. Have a history of or a current primary psychotic disorder, bipolar affective disorder
             type I or dissociative identity disorder assessed via the DDIS and clinical interview.
         29. Have a current eating disorder with compensatory behaviors.
         30. Have current major depressive disorder with psychotic features.
         31. Have current Personality Disorders (paranoid, schizoid, schizotypal, antisocial,
             borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive)
             assessed via the SCID-5-PD. Diagnoses will be confirmed by clinical interview.
             Other Exclusions
         32. Are not able to provide adequate informed consent.
         33. Sensitivity to any of the study interventions, or components thereof, or drug or other
             allergy that, in the opinion of the sponsor-investigator or study clinician,
             contraindicates participation in the study.
         34. Are currently engaged in compensation litigation whereby financial gain would be
             achieved from prolonged symptoms of PTSD or any other psychiatric disorders.
         35. Lack of social support or lack a stable living situation since the inclusion of a
             support person to assist the participant following Experimental Sessions is important
             for ensuring participant safety. If a participant is not able to identify a support
             person whom the research team may contact they will not be enrolled.
         36. Previous participation in a MAPS-sponsored MDMA clinical trial.
         37. Employees (and their immediate family members) of MAPS, MAPS Public Benefit
             Corporation, or MAPS Europe B.V; or individuals in a personal relationship with the
             sponsor investigator.
         38. Have any current problem which, in the opinion of the sponsor-investigator or study
             clinician, might interfere with study participation.