MDMA-assisted Prolonged Exposure Therapy for Comorbid Alcohol Use Disorder and Post-traumatic Stress Disorder

Phase 2

Recruiting

• Conditions: Post-traumatic Stress Disorder; PTSD; Alcohol Use Disorder; Alcohol Dependence; Comorbidities and Coexisting Conditions
• Interventions: Behavioral: Prolonged exposure therapy; Drug: MDMA; Drug: Niacin

• Registration Number: NCT05709353
• Lead Sponsor: University of Sydney

Brief Summary

To explore the effectiveness of of MDMA-assisted prolonged exposure therapy in improving treatment outcomes for individuals with comorbid PTSD and alcohol use disorder in a double-blind randomised placebo-controlled trial.

Detailed Description

New strategies for the treatment of comorbid PTSD and alcohol dependence are urgently required. Recent evidence has shown strong support for trauma-focused integrated treatments (namely COPE), however, only 49% demonstrate clinically significant improvements. MDMA may be a promising approach to improve response to COPE for this population. Emerging evidence suggests that MDMA-assisted therapy may be of promise for PTSD, and has demonstrated a good safety profile and potential efficacy in alcohol dependence.

This project will evaluate the clinical efficacy and tolerability of MDMA-assisted COPE relative to a control-assisted COPE. Active control used in this study is niacin. The investigators hypothesise that MDMA treated participants will be have a reduction in PTSD symptom severity as well as heavy drinking.

The trial will utilise a double blind, randomised, controlled design. A sample of 120 individuals will receive 14 weeks of treatment including 12 COPE sessions and 2 dosing sessions with MDMA (80-160mg) or control (niacin 250mg).

Study Timeline

• Study First Submitted: 2023-01-20
• Study First Submitted QC: 2023-01-20
• Study First Posted: 2023-02-02
• Study Start: 2023-09-19
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-02
• Last Update Posted: 2023-11-07
• Primary Completion: 2026-05
• Study Completion: 2026-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

1. Both AUD and current PTSD according to the DSM-5 criteria, for 6 months or longer with at least moderate severity, according to investigator judgement and CAPS-5
2. Aged ≥18 years old
3. Adequate cognition and English language skills to give valid consent and complete research interviews assessments
4. Willing to give written informed consent
5. Received prior treatment for PTSD or AUD (not including study interventions)
6. Stable housing
7. Able to identify a significant other (such as a family/friend/partner) who could accompany them from clinic/provide transport and/or be contacted by the study team if required

Exclusion Criteria

1. History of, or currently meeting, DSM-5 criteria for:

   • current or lifetime psychotic or bipolar disorders, or
   • major depression with psychotic features Assessed via Structured Clinical Interview for DSM-5 - Research Version (SCID-5-RV). Potential participants will be screened for personality disorders but suitability will then be confirmed by clinical interview given the prevalence of high scores in this comorbid population

2. Pregnant or lactating (contraception must be used and a sensitive pregnancy test will be performed at baseline and prior to dosing)

3. Significant alcohol withdrawal (current Clinical Institute Withdrawal Assessment for Alcohol [CIWA-Ar] score ≥10, including history of delirium tremens or alcohol withdrawal seizures).

4. Concurrent use of psychotropic medication (antidepressants and alcohol pharmacotherapy use considered if assessed by physician and titrated down with 5 half-lives + 1 week washout)

5. Use of, and unable or unwilling to cease, any medications likely to interact with MDMA in the opinion of the physicians and investigators during the trial (low dose opiates are permitted for pain management but not the night before or after MDMA sessions)

6. Substance use disorder other than tobacco (e.g. benzodiazepines, cannabis)

7. Abnormal clinical findings including a history of, or current: cardiac disease and/or dysrhythmia, uncontrolled hypertension or severe hypotension, abnormal electrocardiogram findings, stroke, liver disease, a history of epilepsy, hyponatraemia, or malignant hyperthermia (controlled hypertension and diabetes type II may be permitted)

8. Suicide risk according to clinician judgement and responses to Columbia Suicide Severity Rating Scale-Lifetime (C-SSRS-L) and SCID-5-RV.

   • Details surrounding any previous attempts >6 months ago will be gathered whereby attempts related to their trauma/PTSD and/or associated with the use of psychostimulants will contribute to risk assessment and guide trial safety measures if enrolled

9. Clinically unstable systemic medical (e.g., cancer) or psychiatric disorder or condition that might require hospitalisation that precludes trial participation

10. Regular use of ecstasy (e.g. at least twice in last 6 months, or >10 times within the last 5 years)

11. Enrolled in any other interventional clinical trials in the previous two months or over the duration of the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
COPE + MDMA	MDMA	4x COPE sessions Dose 1: 2x MDMA capsules (80mg) + 1x niacin-matched placebo capsule Optional supplementary dispense: 1x MDMA capsule (40mg) 4x COPE sessions Dose 2: 2x MDMA capsules (80mg) + 1x niacin-matched placebo capsule Optional supplementary dispense: 1x OR 2x white MDMA capsule (40 or 80mg) 4x COPE sessions
COPE + MDMA	Prolonged exposure therapy	4x COPE sessions Dose 1: 2x MDMA capsules (80mg) + 1x niacin-matched placebo capsule Optional supplementary dispense: 1x MDMA capsule (40mg) 4x COPE sessions Dose 2: 2x MDMA capsules (80mg) + 1x niacin-matched placebo capsule Optional supplementary dispense: 1x OR 2x white MDMA capsule (40 or 80mg) 4x COPE sessions
COPE + Niacin (Control)	Prolonged exposure therapy	4x COPE sessions Dose 1: 2x MDMA-matched placebo capsules + 1x niacin capsule (250mg) Optional supplementary dispense: 1x MDMA-matched placebo capsule 4x COPE sessions Dose 2: 2x MDMA-matched placebo capsules + 1x niacin capsule (250mg) Optional supplementary dispense: 1x OR 2x MDMA-matched placebo capsule 4x COPE sessions
COPE + Niacin (Control)	Niacin	4x COPE sessions Dose 1: 2x MDMA-matched placebo capsules + 1x niacin capsule (250mg) Optional supplementary dispense: 1x MDMA-matched placebo capsule 4x COPE sessions Dose 2: 2x MDMA-matched placebo capsules + 1x niacin capsule (250mg) Optional supplementary dispense: 1x OR 2x MDMA-matched placebo capsule 4x COPE sessions

Primary Outcome Measures

Name	Time	Method
change in self-reported PTSD symptom severity via Post-Traumatic Stress Disorder Checklist for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) (PCL-5) from baseline to visit 16.	52 weeks	PCL-5 has excellent psychometric characteristics for a secondary indicator of PTSD symptom severity.; Items are summed to provide a total severity score (range = 0-80). The PCL-5 can determine a provisional diagnosis in two ways: Summing all 20 items (range 0-80) and using a cut-point score of 31-33 appears to be reasonable based upon current psychometric work.
change in clinician-rated PTSD severity via Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) (CAPS-5) from baseline to visit 16.	52 weeks	CAPS-5 is a structured diagnostic interview with excellent psychometric properties and diagnostic efficiency and used widely in MDMA-assisted PTSD studies. The CAPS-5 will be administered by independent evaluators blind to treatment condition.; CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms.; CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, Criterion E (items 15-20).

Secondary Outcome Measures

Name	Time	Method
Number of Heavy Drinking Days per week (HDDs) (>5 standard drinks/day for men; >4 for women)	52 weeks	This will be measured by the Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels
Absence of any HDD	52 weeks	Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels

Trial Locations

Locations (2)

Turning Point; 🇦🇺 Richmond, Victoria, Australia

Drug Health Services, Royal Prince Alfred Hospital; 🇦🇺 Sydney, New South Wales, Australia