Paola Cubillos draws attention to the ethical and methodological concerns from MDMA- Assisted Therapy research and argues that these issues merit a stringent research ethics oversight framework for psychedelic clinical studies.

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Interest in psychedelics, including 3,4-methylenedioxymethamphetamine (MDMA) for mental health treatments has surged. Leading this effort, the Multidisciplinary Association for Psychedelic Studies has conducted clinical trials on MDMA-assisted psychotherapy (MDMA-AT) for post-traumatic stress disorder. In December 2023, the Association’s for-profit arm, Lykos Therapeutics, submitted a New Drug Application for MDMA-AT to the US Food and Drug Administration. This application was rejected in August 2024, after the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) raised significant concerns about methodology, safety, and efficacy. To protect future trial participants and uphold the integrity of the research, psychedelic trials must undergo stringent ethical and scientific review standards. The lessons for Research Ethics Boards (REBs) are pressing.

Central to the PDAC deliberations were MDMA-AT risk-benefit analysis, translating into beneficence and non-maleficence considerations. The PDAC voted that the benefits of MDMA-AT did not outweigh the risks and identified safety data gaps such as drug-drug interactions and hepatotoxicity. The lack of data on the drug’s abuse liability potential, a key consideration for psychoactive substances, was troubling. Adding to these concerns was the dearth of information on the length and characteristics of post MDMA administration impairment, identified as a risk for boundary transgressions. While not presented in the data, Committee members expressed concern about MDMA induced vulnerability, citing the instance of sexual abuse reported by a Canadian phase 2 clinical trial participant.

Photo credit: deviantart.com. Image Description: A textured abstract psychedelic dream.

Questions about the bespoke psychotherapy used with MDMA also arose. In these trials there is a lack of empirical validation, susceptibility to variability, and the use of non-standardized, potentially harmful practices. These problems presented challenges in ascertaining the effects of MDMA. Moreover, concerns about the inherent flexibility of the MDMA psychotherapy and its possible contribution to the ethical transgression reported in earlier clinical trials have been raised in the published literature.

The PDAC also voted negatively on the efficacy of MDMA-AT, citing difficulties in the interpretation of the efficacy results from functional unblinding, a generalized issue across psychedelic research. The drug’s psychoactive symptoms pose obstacles to maintain participants’ and therapists’ blinding, and this may artificially inflate positive drug responses, and potentially affect the treatment provided by therapists. Lack of expectancy effects measurements, selection bias (many participants had a prior history of MDMA use) and uncertainty about the durability of effects further compromise the validity of the results.

Considering the significant limitations in the safety and efficacy data from the MDMA-AT trials, concerns for autonomy and informed consent arise for future clinical trial participants, and potentially for future users of this therapeutic modality. Reports of inadequate adverse event reporting and potential encouragement of favorable patient reports, as reported by the Institute of Clinical and Economic Review, further put into question the transparency required for informed consent. Misconduct allegations and instances of ethical violations, such as failure to disclose conflicts of interest, may erode trust in the research process.

In addition, the lack of diversity in the MDMA-AT participant pool raises concerns for justice, which entails the equitable distribution of risks and benefits from the research. Most participants were white males, limiting the generalizability of results to broader populations. Furthermore, the proprietary nature of the psychotherapy and the elaborate risk management strategies proposed by the FDA in the event of approval, may favor commercial interests, undermining equitable access to future treatments.

In psychedelics research, the ethical and methodological issues related to trial design, expectancy bias, adverse events evaluation, comprehensiveness of informed consent, conflicts of interest, abuse liability and impairment, psychotherapy validity, and transparent reporting of adverse events are of utmost ethical importance.  The issues highlighted by the review of MDMA-AT clinical trial data raise important questions about the current level of research ethics oversight for psychedelic studies and should prompt reflection on the suitability of existing research ethics frameworks for the evaluation of these trials, particularly in an environment of enthusiastic public support, hype, and instances of harm in psychedelic studies.

The 2024 version of the Declaration of Helsinki states that research must be scientifically sound and rigorously designed and executed, to ensure that results are reliable, valid, and valuable, and to avoid research waste.  Ethical research is scientifically rigorous research. REBs must be prepared to implement more stringent standards of ethical and scientific oversight for psychedelic studies. They must question study designs that do not adequately address the issues discussed above in order fulfil their duty to protect research participants, and the integrity of the research process. Comprehensive ethical assessment by REBs will improve the welfare of research participants, and the quality of future psychedelic treatment policies.

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Paola Cubillos is an internationally-trained physician, a member of the Research Ethics Board administration of the William Osler Health System’s REB, and is pursuing a MHSc in Bioethics from the University of Toronto – Dalla Lana School of Public Health. BlueSky: @paolacubillosr.bsky.social