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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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PTSD, Alcohol Use Disorder, Alcohol Dependence, Post-traumatic Stress Disorder, Comorbidities and Coexisting Conditions

Intervention / Treatment
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* Behavioral: Prolonged exposure therapy
* Drug: MDMA
* Drug: Niacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Aged ≥18 years old Adequate cognition and English language skills to give valid consent and complete research interviews assessments Willing to give written informed consent Received prior treatment for PTSD or AUD (not including study interventions) Stable housing 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: 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 Pregnant or lactating (contraception must be used and a sensitive pregnancy test will be performed at baseline and prior to dosing) Significant alcohol withdrawal (current Clinical Institute Withdrawal Assessment for Alcohol [CIWA-Ar] score ≥10, including history of delirium tremens or alcohol withdrawal seizures). 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) 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) Substance use disorder other than tobacco (e.g. benzodiazepines, cannabis) 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) 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 Clinically unstable systemic medical (e.g., cancer) or psychiatric disorder or condition that might require hospitalisation that precludes trial participation Regular use of ecstasy (e.g. at least twice in last 6 months, or >10 times within the last 5 years) Enrolled in any other interventional clinical trials in the previous two months or over the duration of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, double-blind between group comparison of change in PTSD symptoms and alcohol consumption
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COPE + MDMA<br>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<br>* 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.<br>* Other names: COPE (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure);Drug: MDMA<br>* 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.<br>* Other names: 3,4-Methyl enedioxy methamphetamine;|
| Other: COPE + Niacin (Control)<br>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<br>* 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.<br>* Other names: COPE (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure);Drug: Niacin<br>* Administration of niacin 250mg or niacin-matched placebo during two 'dosing' sessions.<br>* Other names: Control, Vitamin B3;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure, MDMA-assisted therapy, Randomised-Controlled Trial, Comorbid PTSD and AUD, MDMA, COPE, Psychedelic-Assisted Therapy