MDMA for AUD/PTSD Comorbidity

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 medicaldetox.

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 SeverityScore 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 aparticipant becoming unwell or unreachable.

11. Able to identify appropriate support person(s) to stay with the participant on theevenings 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 tobecome pregnant, or is not breastfeeding and one of the following conditionsapplies

• Is not able to become pregnant

• Is a person able to be pregnant (PABP) and using a contraceptive method that ishighly effective, with a failure rate of <1%. The investigator will evaluatethe potential for contraceptive method failure (e.g., noncompliance, recentlyinitiated) in relationship to the first does of study intervention. A PABP musthave a highly sensitive negative urine pregnancy test at study entry and priorto each Experimental Session, see Schedule of Activities. The investigator isresponsible for review of medical history, menstrual history, and recent sexualactivity to decrease the risk for inclusion of a participant with an earlyundetected pregnancy. Informed Consent

14. Capable of giving signed informed consent, which includes compliance with therequirements 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 andprocedures.

16. May have asymptomatic Hepatitis C virus (HCV) that has previously undergoneevaluation and treatment as needed.

17. Participants must have a plan, agreed upon by investigator, therapy team, and studyclinician, to reduce use of substances and to manage symptoms withoutself-medicating. Enrollment will require that, in the judgment of the investigator,therapy team, and study physician, the plan for decreasing substance use isrealistic and has a good chance of succeeding to prevent substance use fromimpacting the safety or efficacy of the investigational treatment.

18. May have a history of or current Diabetes Mellitus (Type 2) if additional screeningmeasures rule out underlying cardiovascular disease, if the condition is judged tobe stable on effective management, and with approval by the study clinician.

19. May have hypothyroidism if taking adequate and stable thyroid replacementmedication.

20. May have a history of, or current, glaucoma if approval for study participation isreceived 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 ofnormal (ULN).

• Total bilirubin > 1.5 x ULN or direct bilirubin < 35%.

2. Current unstable liver or biliary disease per investigator assessment defined by thepresence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal orgastric varices, persistent jaundice, or cirrhosis.

• Note: Stable chronic liver disease (including Gilbert's syndrome, asymptomaticgallstones, and chronic stable hepatitis B (e.g., the presence of hepatitis Bsurface antigen or positive hepatitis C antibody test result without evidence ofactive infection at screening or within 3 months prior to starting studyintervention) 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 WithdrawalAssessment 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 ECGassessments. Participants whose QTcF exceeds this value during screening may beinitially enrolled if a pre-study concomitant medication is suspected to beprolonging the QT-interval. ECGs should be repeated after initial enrollment andtapering off the pre-study concomitant medication to ensure the participant meetseligibility criteria prior to enrollment confirmation and to IMP dosing.

• Note: The QTcF is the QT interval corrected for heart rate according toFridericia's formula. It is either machine-read or manually over-read.

7. Have a history of any medical condition that could make receiving a sympathomimeticdrug 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 enrolledif the study clinician and principal investigators agree the condition wouldnot significantly increase the risk of MDMA administration or be likely toproduce significant symptoms during the study that could interfere with studyparticipation or be confused with side effects of the IMP.

• Examples of stable medical conditions that could be allowed include, but arenot limited to, Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV)infection, Gastroesophageal Reflux Disease (GERD), hypothyroidism (if takingadequate and stable thyroid replacement medication), glaucoma (if approval forstudy participation is received from an ophthalmologist). Any medical disorderjudged by the investigator to significantly increase the risk of MDMAadministration by any mechanism would require exclusion.

8. Have a diagnosis of controlled or uncontrolled hypertension, defined as repeatedblood pressure readings of ≥ 140 millimeters of Mercury [mmHg] systolic or ≥ 90 mmHgdiastolic. The diagnosis may be confirmed by repeated clinic measurements or homeblood pressure monitoring if clinically indicated.

9. Have a history of ventricular arrhythmia at any time, other than occasionalpremature ventricular contractions (PVCs) in the absence of ischemic heart disease.

10. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not beensuccessfully eliminated by ablation.

11. Have a history of arrhythmia, other than premature atrial contractions (PACs) oroccasional PVCs in the absence of ischemic heart disease, within 12 months ofscreening.

• Participants with a history of atrial fibrillation, atrial tachycardia, atrialflutter or paroxysmal supraventricular tachycardia or any other arrhythmiaassociated with a bypass tract may be enrolled only if they have been successfullytreated with ablation and have not had recurrent arrhythmia for at least one yearoff all antiarrhythmic drugs or are under adequate and stable pharmacologictreatment for atrial fibrillation for at least a year, as confirmed by acardiologist.

12. Have a history of additional risk factors for Torsade de pointes (e.g., heartfailure, 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 ofenrollment, including Electroconvulsive Therapy (ECT) and ketamine-assisted therapy.

15. Are currently prescribed antidepressant medications (e.g., selective serotoninreuptake inhibitors) requiring a medication taper.

16. Are currently prescribed antipsychotic medications.

17. Are likely, in the investigator's opinion and via observation during the PreparatoryPeriod, to be re-exposed to their index trauma or other significant trauma or othersignificant trauma during the study.

18. Have a current moderate (not in early remission in the 3 months prior to enrollmentand meets at least 5 of 11 diagnostic criteria per DSM-5) or severe cannabis usedisorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnosticcriteria per DSM-5).

• May have current mild cannabis use disorder (meets 3 of 11 diagnostic criteria perDSM-5) or moderate cannabis use disorder in early remission for the 3 months priorto 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 timeswithin the last 10 years or at least once within 6 months of the first ExperimentalSession

21. Any participant presenting current serious suicide risk, as determined throughpsychiatric interview, responses to C-SSRS, and clinical judgment of theinvestigator will be excluded; however, history of suicide attempts is not anexclusion. Any participant who is likely to require hospitalization related tosuicidal ideation and behavior, in the judgment of the investigator, will not beenrolled. Any participant presenting with the following on the Baseline C-SSRS willbe excluded:

• Suicidal ideation score of 4 or greater within the last 6 months of theassessment 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, withinthe last 6 months of the assessment. Participants with non-suicidalself-injurious behavior may be included if approved by the study clinician.

22. Would present a serious risk to others as established through clinical interview andcontact with treating psychiatrist. Prior/Concomitant Therapy

23. Require ongoing concomitant therapy with a psychiatric medication with exceptionsdescribed in protocol section on Concomitant Medications (refer to Appendix E:Permitted and Prohibited Medications). Therapy with SSRIs at baseline is allowed aslong as approved by a physician to taper off before initiating the study procedures.

24. Current use of pharmacotherapies (i.e., naltrexone or disulfiram) to treat alcoholuse.

25. Require use of concomitant medications that could prolong the QT interval duringExperimental Sessions.

26. Are currently engaged in trauma-focused psychotherapy or are currently in atreatment 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 studytreatment or any other type of medical research, unless approved by the studyclinician. Diagnostic Assessments

28. Have a history of or a current primary psychotic disorder, bipolar affectivedisorder type I or dissociative identity disorder assessed via the DDIS and clinicalinterview.

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 orother 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 beachieved 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 asupport person to assist the participant following Experimental Sessions isimportant for ensuring participant safety. If a participant is not able to identifya 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 BenefitCorporation, or MAPS Europe B.V; or individuals in a personal relationship with thesponsor investigator.

38. Have any current problem which, in the opinion of the sponsor-investigator or studyclinician, might interfere with study participation.