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

A Randomised, Controlled Trial of MDMA-assisted Prolonged Exposure Therapy for Comorbid Alcohol Use Disorder and Post-traumatic Stress Disorder

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.

Study Overview

• Status: Recruiting
• Conditions: Alcohol Dependence; PTSD; Alcohol Use Disorder; Post-traumatic Stress Disorder; Comorbidities and Coexisting Conditions
• Intervention / Treatment: Behavioral: Prolonged exposure therapy; Drug: MDMA; Drug: Niacin

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 Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kirsten C Morley, PhD; Phone Number: 61295153636; Email: Kirsten.morley@sydney.edu.au
• Study Contact Backup: Name: Ellen Towers; Email: ellen.towers@sydney.edu.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Recruiting
      • Drug Health Services, Royal Prince Alfred Hospital
      • Contact: Paul Haber, MBBS; Email: paul.haber@sydney.edu.au
  • Victoria
    • Richmond, Victoria, Australia, 3121
      • Not yet recruiting
      • Turning Point
      • Contact: Shalini Arunogiri, MBBS; Email: shaliniA@turningpoint.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: COPE + 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	Behavioral: Prolonged exposure therapy; COPE represents an integration of existing evidence-based manualised CBT interventions for PTSD and substance dependence (see manual DOI: 10.1093/med:psych/9780199334513.001.0001). COPE used in the current study will represent an integration of existing evidence-based manualised CBT interventions for PTSD and substance dependence. COPE only begins when the participant in a safe environment and no longer in contact with the traumatic event/exposure. COPE employs imaginal and in vivo exposures to treat PTSD and consists of 12 individual 90-minute sessions (i.e. 19.5 hours) delivered by a clinical psychologist.; Other Names: COPE (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure); Drug: MDMA; Administration of 80 to 160 mg MDMA across two 'dosing' sessions. Supplemental doses (additional 40mg during first session, additional 40- 80mg during second session) will be dependent on clinician and participant consensus during preparatory period of 'dosing session'. These supplemental amounts will be dispensed 60 to 90 minutes after initial 80 mg dose.; Other Names: 3,4-Methyl enedioxy methamphetamine
Other: COPE + Niacin (Control); 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	Behavioral: Prolonged exposure therapy; COPE represents an integration of existing evidence-based manualised CBT interventions for PTSD and substance dependence (see manual DOI: 10.1093/med:psych/9780199334513.001.0001). COPE used in the current study will represent an integration of existing evidence-based manualised CBT interventions for PTSD and substance dependence. COPE only begins when the participant in a safe environment and no longer in contact with the traumatic event/exposure. COPE employs imaginal and in vivo exposures to treat PTSD and consists of 12 individual 90-minute sessions (i.e. 19.5 hours) delivered by a clinical psychologist.; Other Names: COPE (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure); Drug: Niacin; Administration of niacin 250mg or niacin-matched placebo during two 'dosing' sessions.; Other Names: Control, Vitamin B3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	52 weeks
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.	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.	52 weeks

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean alcohol consumption per drinking day	Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels	52 weeks
Change in dependence Severity	Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.	52 weeks
Changes in Anxiety	Measured by cumulative scores on the DASS-21 Anxiety Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more anxiety.	52 weeks
Changes in Depression	Measured by cumulative scores on the DASS-21 Depression Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates greater depression.	52 weeks
Changes in Stress	Measured by cumulative scores on the DASS-21 Stress Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more stress.	52 weeks
Sleep Disturbances	As measured by the ISI (Insomnia Severity Index). This Index has a minimum score of 0 and a maximum score of 28. The higher the score indicates more severe insomnia.	52 weeks
Changes in Suicidal Ideation	Changes in suicidal ideation & behaviours across the treatment period. This will be measured on the C-SRSS (Columbia Suicide Severity Rating Scale). At baseline this will be measured by the baseline version. At each visit following this, this will be recorded on the since last visit version. Higher scores indicate more severe suicidality.	52 weeks
Changes PTSD cognitions	As measured by the PTCI. This is a 33 question inventory measures negative cognitions about the self & world, as well as self-blame. Higher scores indicate more negative cognitions.	52 weeks
Drinking Diary	Daily texts will be sent out to participants querying the amount of alcohol they have consumed. Participant responses to this will be recorded. This will be managed through SEMA software.	16 weeks
Mood states	Daily texts will be sent out to participants querying their moods. This will be in line with the POMS instrument (Profile of Mood States).	16 weeks
Mood following dosing session	The week following each dosing session will involve calls with participants to complete POMS (profile of mood states)	week 5, week 10
Changes in Quality of Life	To assess whether treatment can change quality of life as measured by the short form Health Survey (SF-36). This survey has 36 items that measure 8 domains of health, including: physical functioning, physical role limitations, bodily pain, general health perceptions, energy/vitality, social functioning, emotional role limitations and mental health. The scores are transformed to range from 0 (worst possible health) to 100 (best possible health).	16 weeks
Changes in use of Health Services	As measured by the Brief Health Services Use Questionnaire. This questionnaire assesses Health Service Use across the last 3 months. It is a qualitative questionnaire.	16 weeks
Therapeutic Alliance between therapist	As measured by the Helping Alliance Questionnaire (HAQ-II). This instrument will be completed by the patient (patient version) and the clinician (clinician version). This outlines how a person may feel or behave in relation to their therapist. Higher scores indicates a better therapeutic alliance.	16 weeks
COPE Session Rating Scale	As measured by the session rating scale (SRS). Following each COPE session, both the therapist and participant will complete a brief post-session rating. This scale measures; relationship, goals & topics, approach or method and overall psychotherapy session. Higher scores on each of these indicate a more positive experience.	16 weeks
Treatment Satisfaction as measured by the YES (your experience of service).	This instrument is designed to gather information from consumers about their experiences of care.	16 weeks
Treatment Satisfaction ss measured by the CSQ-8 (client satisfaction questionnaire).	This instrument measures clients satisfaction with treatment. Total scores range from 8 to 32, with the higher number indicating greater satisfaction.	16 weeks
Measurement of Distress ss measured by a Likert Scale	This instrument will be administered hourly within the dosing sessions. It aims to measure the participant's mood on a scale of 1 (worst) -10 (best)	week 5, week 12
Measurement of Drug Effect as measured by the Revised Mystical Experience Questionnaire 30 (MEQ-30)	MEQ-30 Measures mystical, positive mood, transcendence, ineffability experienced in dosing sessions. MEQ-30 will be compelted at the end of each dosing session. participants will be asked to rate rate the degree to which at any time during that session they experienced certain phenomena on a scale of 0 (not at all) to 5 (more than any other time in their life)	week 5, week 12

Collaborators and Investigators

• Sponsor: University of Sydney
• Collaborators: Monash University; Sydney Local Health District
• Investigators: Principal Investigator: Kirsten C Morley, PhD, University of Sydney

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: January 20, 2023
• First Posted (Actual): February 2, 2023

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MDMA; MDMA-assisted therapy; Randomised-Controlled Trial; Comorbid PTSD and AUD; COPE; Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; Psychedelic-Assisted Therapy
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Trauma and Stressor Related Disorders; Alcohol Drinking; Alcoholism; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Vitamins; Dopamine Uptake Inhibitors; Vitamin B Complex; Central Nervous System Stimulants; Sympathomimetics; Adrenergic Uptake Inhibitors; Methamphetamine; Niacin
• Other Study ID Numbers: X22-0121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No