Clinical Trial of MDMA-Assisted Therapy for Military Service Members With Posttraumatic Stress Disorder

A Randomized, Double-Blind, Active-Controlled, Clinical Trial of the Safety, Efficacy, and Durability of MDMA-Assisted Therapy for Military Service Members With Posttraumatic Stress Disorder

This study is a Phase 2, randomized, double-blind, active-controlled, two-arm, single-site clinical trial designed to evaluate the safety, tolerability, and feasibility of MDMA-Assisted Therapy (MDMA-AT) for Service Members (Active Duty, Guard, or Reserve) diagnosed with moderate-to-severe Post-Traumatic Stress Disorder (PTSD) within a Military Health System (MHS) setting.

The trial incorporates Acceptance and Commitment Therapy (ACT) as a core therapeutic modality. Participants will receive MDMA-AT utilizing either full-dose or active-control low-dose MDMA. The trial will also assess a regional referral center model by recruiting participants locally from the National Capital Region and non-locally across the MHS.

This Phase 2, randomized, double-blind, active-controlled, single-site clinical trial evaluates the safety, tolerability, and efficacy of MDMA-Assisted Therapy (MDMA-AT) for Service Members with moderate-to-severe Post-Traumatic Stress Disorder (PTSD) within a Military Health System (MHS) setting. The study integrates Acceptance and Commitment Therapy (ACT) as the core therapeutic modality, comparing full-dose MDMA against an active-control low-dose MDMA among 86 randomized participants. To test the feasibility of a regional referral center model, participants are recruited both locally from the National Capital Region and non-locally throughout the MHS. Additionally, the trial begins with an open-label lead-in training cohort of five participants receiving full-dose MDMA-AT to establish protocol fidelity and train therapists prior to the randomized phase.

The primary goal of this trial is to evaluate the therapeutic efficacy, safety, and tolerability of MDMA-AT for Service Members with PTSD, with the primary endpoint assessed one month after the final dosing session. The secondary goal is to evaluate the feasibility, tolerability, and acceptability of the regional referral center model for non-local recruitment and treatment, which will be measured at the secondary endpoint three months after the final dosing session. Additionally, the trial's preparatory goal is to ensure therapist adherence to the treatment protocol through the initial open-label training cohort.

For each participant, the trial progresses sequentially through five clinical phases, beginning with a Screening Phase to confirm eligibility and obtain informed consent. This is followed by a Preparation Phase, which includes medication tapering and three 90-minute preparatory sessions to confirm enrollment. The 12-week Intervention Phase consists of three month-long cycles, with each cycle containing a single 6-to-8-hour dosing session followed by three 90-minute non-drug integration sessions. Finally, participants enter the Follow-up Phase, which involves primary endpoint assessments at one month, monthly safety follow-up calls, and secondary endpoint assessments leading to Study Completion three months after the final dosing session.

Inclusion Criteria:

1. Positive endorsement of at least 1 index trauma on the LEC-5.
2. Have a PCL-5 total score of 38 or greater at screening.
3. Meet DSM-5-TR criteria for current PTSD per Mini International Neuropsychiatric Interview (MINI) at screening with a symptom duration of 6 months or longer.
4. Meet criteria for PTSD diagnosis per CAPS-5-R with a score of 26 or greater.
5. Are at least 18 years old at the time of enrollment.
6. Weigh greater than 48 kilograms.
7. Are able to swallow pills.
8. Are fluent in speaking, reading, and comprehending English.
9. Must agree to inform the investigators within 48 hours of any new medications, medical conditions, and procedures.
10. Females of childbearing potential must have a negative pregnancy test at study entry and prior to each Dosing Session and must agree to use adequate birth control for the duration of the study until at least 30 days after the final dosing session. Adequate birth control methods include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal hormonal methods, abstinence, oral hormones plus a barrier contraception, vasectomized sole partner, or double barrier contraception. Two forms of contraception are required with any barrier method or oral hormones (i.e. condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom). Non-childbearing potential is defined as permanent sterilization, postmenopausal, or assigned male at birth.
11. Males must agree to use adequate birth control for the duration of the study until at least 30 days after the final dosing session. Adequate birth control methods for males include double barrier contraception (condom with spermicidal gel or foam), surgical sterility (defined as a vasectomy at least 3 months prior to the screening visit), or abstinence.
12. Must agree to refrain from sperm, egg, blood, and bone marrow donations for at least 30 days after the final dosing session.
13. Must have a 12-lead electrocardiogram (EKG) with QTc < 450 ms and no clinically significant abnormalities, as determined by a cardiologist.
14. Are able to demonstrate comprehension of consent form and study instructions, and provide informed consent.
15. Agree to have study visits recorded, including Dosing Sessions, Independent Rater assessments, and non-drug therapy sessions.
16. Must provide an emergency contact (relative, spouse, close friend, or other support person) who is willing and able to be reached by the investigators in the event a participant is imminently unsafe or unreachable.
17. Agree to the following lifestyle modifications (described in more detail in the Informed Consent Form): comply with requirements for fasting and refraining from certain medications prior to Dosing Sessions; not participate in any other interventional clinical trials during the duration of this study without prior approval of the Independent Safety Monitor; remain overnight at the study site or have an identified support person that can remain with the participant and escort them to the therapy session the day after each dosing; and commit to medication dosing, therapy, and study procedures.
18. Must be Active Duty, National Guard, or Reserve in the United States military.
19. Must receive approval from their command to participate in the study.
20. Must be DEERS eligible.

Exclusion Criteria:

1. History of or current primary psychotic disorder to include Schizophrenia, Schizoaffective Disorder, or Bipolar Disorder 1 assessed via MINI or clinical evaluation.

2. Current Major Depressive Disorder with Psychotic Features assessed via MINI or clinical evaluation.

3. Current eating disorder with active purging assessed via MINI or clinical evaluation.

4. Current Borderline Personality Disorder assessed via SCID-5-PD or clinical evaluation.

5. Any of the following findings on Screening C-SSRS:

   1. Suicidal ideation score of 5 within the last month
   2. Suicidal ideation score of 4 or greater in the last month at a frequency of once per week or more
   3. Any suicidal behaviors within the last 3 months. The exception is that non suicidal self-injurious behavior is not exclusionary if approved by the PI.

6. Current high suicide risk or is likely to require psychiatric hospitalization, as determined through C-SSRS, clinical interview, or clinical judgment of the investigator. Distant history of suicide attempts without current high suicide risk factors is not exclusionary.

7. Current severe substance use disorder (6 or more criteria per MINI) not in sustained remission (criteria not met for past 12 months) at time of enrollment. I.e., severe substance use disorders may only be included if in sustained remission. Tobacco/nicotine use disorders may be included regardless of severity.

8. Current moderate substance use disorder (4-5 criteria per MINI) not in early remission (criteria not met for past 3-12 months) or sustained remission (criteria not met for past 12 months) at time of enrollment. I.e., moderate substance use disorders may only be included if in early or sustained remission (criteria not met for 3 or more months). Tobacco/nicotine use disorders may be included.

9. For any illicit or prescribed substance: current substance use disorder of any severity, not in sustained remission (criteria not met for past 12 months). I.e., substance use disorders of any severity with illicit or prescribed substances may only be included if in sustained remission.

10. Any urine drug testing during screening or enrollment that is confirmed positive for a non-prescribed substance, and the result cannot be better explained as a false positive due to another concomitant prescribed medication or proven dietary practice.

11. Have current or history of psychiatric diagnoses or symptoms that may negatively affect study participation.

12. Clinically significant abnormalities on screening 12-lead EKG or 1 minute 12-lead rhythm strip that precludes administration of MDMA, stimulants, or sympathomimetics, as determined by a cardiologist.

13. Two or more premature ventricular contractions (PVCs) on 1-minute rhythm strip. 1 minute 12-lead rhythm strip will be obtained when there are one or more PVCs on screening EKG or when indicated by a cardiologist.

14. Resting QTc ≥ 450 ms.

15. History of drug-induced QTc prolongation.

16. Inability to hold or discontinue concomitant medications that significantly prolong the QTc interval.

17. Clinically significant cardiac or cardiovascular abnormalities, including history of myocardial infarction, unexplained exertional syncope, Torsade de Pointes, congenital long QT syndrome, hypertrophic cardiomyopathy, congestive heart failure, family history of Long QT Syndrome, persistent atrial fibrillation, symptomatic valvular heart disease, asymptomatic severe aortic stenosis, asymptomatic severe mitral stenosis, history of diagnosis of aortic dissection or asymptomatic aortic aneurysm > 4.5 cm at the sinus of Valsalva, or history of untreated angina pectoris or unrevascularized coronary stenosis > 70%.

18. Current clinically significant electrolyte abnormalities, to include hyponatremia and hypokalemia.

19. Has clinically significant abnormal laboratory results during screening that indicate impaired liver function, to include ALT or AST >2x ULN or Total bilirubin >1.5 mg/dL unless history of Gilbert's Syndrome

20. Renal disease defined as eGFR <45 mL/min/1.73m² or creatinine >2.0 mg/dL, end-stage kidney disease, dialysis, history of renal transplant, clinically significant or progressive renal disease deemed to increase risk, or recent/unstable renal function consistent with acute kidney injury at screening. Participants with eGFR 45-59 mL/min/1.73m² may be eligible only if renal function is stable and cleared by the study physician.

21. Uncontrolled essential hypertension defined as blood pressures of greater than 140/90 mmHg assessed on three separate occasions. May have well-controlled hypertension that has been successfully treated with anti-hypertensive medicines, if additional screening is passed to rule out underlying cardiovascular disease.

22. Uncontrolled hypothyroidism. May have hypothyroidism if taking adequate and stable thyroid replacement medication.

23. Type 2 Diabetes Mellitus with comorbid cardiovascular disease. May have a history of or current Type 2 Diabetes Mellitus 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 Independent Safety Monitor.

24. Glaucoma without approval from an ophthalmologist. May have a history of, or current, glaucoma if approval for study participation is received from an ophthalmologist.

25. 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 cerebrovascular disorders (cerebrovascular accident, aneurysm, arteriovenous malformations, or carotid stenosis). Participants with other mild, stable chronic medical conditions may be enrolled if the study physician and Independent Safety Monitor agree the condition is unlikely to confer a significant additional health risk with administration of MDMA. This includes conditions such as gastroesophageal reflux disease and chronic low back pain.

26. Current medical diagnoses or physical health symptoms that may negatively affect study participation.

27. Report any prescribed or non-prescribed lifetime personal use history of MDMA, 3,4 methylenedioxymethamphetamine, midomafetamine, "Ecstasy," "Molly," "Mandy," or "Adam."

28. Lack adequate social support, in the judgement of the PI.

29. Unable to safely taper off prohibited concomitant medications.

30. Are pregnant or nursing, or are able to become pregnant and are not practicing an effective means of birth control.

31. Have any current or anticipated problem which, in the opinion of the PI or Independent Safety Monitor, may interfere with study participation.