Monitoring the Misuse Potential of MDMA and Other Substances in Clinical Trials: A Systematic Review of Methodological Approaches

Abstract

The empathogen 3,4-methylenedioxymethamphetamine (MDMA) is a psychoactive compound increasingly studied in combination with assisted therapy (AT) for the treatment of psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and substance use disorders (SUDs). MDMA acts primarily by increasing the synaptic availability of serotonin, dopamine, and norepinephrine, thereby influencing neural circuits involved in reward, emotion regulation, and social processing. Given its reinforcing properties and Schedule I classification, MDMA warrants systematic evaluation of its potential for misuse in clinical contexts. Standardized and transparent methodologies for monitoring the abuse potential of MDMA administration are essential to ensure participant safety in human clinical trials. As such, the present systematic review examines human clinical trials involving MDMA administration to evaluate methodological approaches used to monitor the potential misuse of MDMA and other substances both during and outside the clinical trial setting. We conducted a systematic review of PubMed, Embase, CINAHL, Cochrane Central Register of Controlled Trials, PsycINFO, Web of Science Core Collection, and WHO's International Clinical Trials Registry Platform to examine: (1) how MDMA’s misuse potential has been operationalized and assessed in clinical trials, (2) what monitoring and risk mitigation strategies have been implemented, and (3) how these methodologies align with regulatory standards for misuse liability evaluation.

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