MDMA-assisted PTSD and Alcohol Therapy Trial (MPATHY): study protocol for a double-blind, randomised, controlled outpatient trial of MDMA-assisted integrated exposure-based therapy for comorbid post-traumatic stress disorder and alcohol use disorder

Combining MDMA with an integrated exposure-based therapy may improve outcomes for people with both post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD), a comorbidity where standard treatments help only about half of patients. This double-blind trial will randomly assign 100 participants to receive either MDMA (80–160 mg) or an active control (niacin 250 mg) alongside 12 sessions of Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE). The primary PTSD outcome is the clinician-administered PTSD Scale for DSM-5; the primary drinking outcome is heavy drinking days per week, validated by phosphatidylethanol. Secondary measures include depression, sleep disturbances, adverse events, and cost-effectiveness. Results will provide first data on safety, efficacy, and cost-effectiveness of MDMA-augmented therapy for this comorbidity.

Study at a glance

Abstract

INTRODUCTION: The treatment of comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) is significantly more challenging than the treatment of either disorder alone. While gold standard evidence-based treatments exist for this comorbidity, clinically significant improvements are only observed in approximately half of clinical trial participants. The use of adjunctive pharmacotherapies, such as 3,4-methylenedioxymethamphetamine (MDMA), may serve to optimise gold standard interventions. The primary aim of the MDMA-assisted PTSD and Alcohol Therapy Trial study is to examine the therapeutic and cost-effectiveness of combining MDMA with evidence-based integrated care for comorbid PTSD+AUD. Specifically, we will examine MDMA-assisted integrated exposure therapy versus active control-assisted integrated exposure therapy in improving treatment outcomes for PTSD+AUD. METHODS AND ANALYSIS: This world-first double-blind trial will aim to randomise 100 participants with PTSD+AUD to a regimen of Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) (12 sessions)+MDMA (80-160 mg: 2 dosing and 2 integration sessions) or COPE (12 sessions)+active control (niacin 250 mg: 2 dosing sessions and 2 integration sessions). All participants will receive medical management. The primary PTSD outcome will be the clinician-administered PTSD Scale for DSM-5. The primary drinking outcome will be the number of heavy drinking days (HDDs) per week, validated by phosphatidylethanol. Secondary PTSD and alcohol-related outcomes will include PTSD checklist for DSM-5 scores, absence of any HDDs and standard drinks per drinking day. We will also examine change in other clinical conditions and symptoms including depression, sleep disturbances and post-traumatic cognitions; treatment satisfaction and engagement; adverse events; and cost-effectiveness. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and the International Conference on Harmonisation-Good Clinical Practice guidelines. Ethical approval has been granted by the Sydney Local Health District Ethics Review Committee (X22-0121 & 2022/ETH00773). The results of this study will provide world-first data regarding safety, efficacy and cost-effectiveness of MDMA to optimise integrated exposure-based therapy for comorbid AUD and PTSD and will be disseminated to ensure wide accessibility and to support further research and clinical application. TRIAL REGISTRATION NUMBER: NCT05709353.