Toward Risk-Benefit Assessments in Psychedelic- and MDMA-Assisted Therapies

Mazdak M. Bradberry; Natalie Gukasyan; Charles L. Raison

doi:10.1001/jamapsychiatry.2022.0665

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Viewpoint

April 27, 2022

Toward Risk-Benefit Assessments in Psychedelic- and MDMA-Assisted Therapies

Mazdak M.聽Bradberry,聽PhD^1,2; 狈补迟补濒颈别听骋耻办补蝉测补苍,听惭顿^3,4; Charles L.聽Raison,聽MD⁵

Author Affiliations Article Information

¹Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison
²Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison
³Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland
⁴Center for Psychedelic and Consciousness Research, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
⁵School of Human Ecology, University of Wisconsin-Madison, Madison

JAMA Psychiatry. 2022;79(6):525-527. doi:10.1001/jamapsychiatry.2022.0665

As a result of demonstrating promise in a range of clinical studies, psychedelic and 3,4-methylenedioxymethamphetamine (MDMA)鈥揵ased treatments have generated a tsunami of optimistic public interest and commercial investment.¹^,2 Despite this enthusiasm, substantial challenges exist to the integration of these therapies into modern health care systems, which will be critical for equitable access among patients. In particular, these therapies have thus far been performed in small, carefully selected research populations, making interpretation of their risks in broader populations more challenging.¹^,2 If psychedelic- and MDMA-assisted treatments become broadly available, practitioners and health care organizations will face new challenges in determining which individuals are good, or poor, candidates for these therapies. Meeting these challenges will require improved risk-benefit assessments, which will, in turn, rely on the study of these therapies in broader and higher-risk populations. In this Viewpoint, we briefly review the primary risks of supervised psychedelic and MDMA use, highlight situations that may present complex risk-benefit assessments for these therapies, and offer recommendations for the study of these therapies in individuals at higher risk of adverse outcomes as compared with participants in published clinical trials.

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May 13, 2022

Undertheorized sources of risk in psychedelic-assisted therapy's limited research evidence

Emma Tumilty, PhD | Deakin University

Psychedelic- and MDMA-assisted therapies (P-AT; MDMA-AT) are the object of a 鈥渢sunami of optimistic public interest and commercial investment鈥� (Bradberry et al., 2022, p. E1) despite only being in the early stages of investigation. They rightly call for careful consideration of the risk-benefit assessment but with some faulty assumptions.

The authors have financial and personal interests suggesting their presentation of evolving results should be considered in light of their conflicts. The evidence for these interventions is nascent and rife with methodological concerns (Aday et al., 2022). Furthermore, recent media reports and a Health Canada review of MDMA-AT trials call into question some of the published data (Lindsay, 2022). Bradberry et al. (2022) imply that P-AT works, but that further research is required to understand safety for complex and high-risk patient populations in the translation to clinical settings.

A concern, which has been absent from critiques of P-AT and necessitates urgent attention is the assumption that psychotherapy is a harmless adjunct to the drug treatment. It is theorized that in P-AT and MDMA-AT, the drugs and psychotherapy work synergistically to enhance outcomes; however, due to the focus of regulatory approval process, the psychotherapy component of these interventions remains unexamined (Mitchell et al., 2021). Psychotherapy is not an intervention without risk (Lilienfeld, 2007). Bradberry et al.鈥檚 (2022) focus on participant/patient responses to the drug follows a concerning trend of locating the source of all risk in the individual receiving treatment, rather than also carefully examining the interaction between the psychedelic drugs and psychotherapy and the role of therapists.

Psychedelic research suffers from several significant gaps in the literature, especially in the areas of clinical practice and ethical norms. For example, one of the first pieces to grapple with touch in this context was published in 2020 (Smith & Sisti, 2020)鈥攊n eight paragraphs there is one source cited specific to touch in P-AT, which is the MAPS code of ethics, developed in response to participant abuse in their MDMA clinical trials. The safety of conducting research, let alone administering psychedelics in clinical settings, is brought into question until the field has sufficiently developed normative frameworks for ethical practice.

The Complainers - A multidisciplinary psychedelic ethics research group:
Sarah McNamee, MSW; Lily Kay Ross, PhD; Ne艧e Devenot, PhD; Meaghan Buisson, BSc; David Nickles & Emma Tumilty, PhD

Aday JS, Heifets BD, Pratscher SD, Bradley E, Rosen R, & Woolley JD. Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. J. Psychopharmacol. 2022; doi:10.1007/s00213-022-06123-7

Bradberry MM, Gukasyan N, & Raison CL. Toward Risk-Benefit Assessments in Psychedelic- and MDMA-Assisted Therapies. JAMA psychiatry. 2020; doi:10.1001/jamapsychiatry.2022.0665

Lilienfeld SO. Psychological Treatments That Cause Harm. Perspect Psychol Sci. 2007; 2(1):53-70.

Lindsay, B. (2022) 鈥淗ealth Canada announces review of all MDMA trials, as complaint alleges major flaws and safety issues鈥� CBC; Retrieved 9th May 2022 from: https://www.cbc.ca/news/canada/british-columbia/health-canada-mdma-trial-complaints-flaws-safety-issues-1.6409849

Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, (...). Doblin, R. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat. Med. 2021; 27(6), 1025-1033.

CONFLICT OF INTEREST: Ne艧e Devenot is an unpaid board member and David Nickles is Managing Editor of Psymposia, a 501c3 nonprofit research organization that operates as a watchdog and think tank, engaging with critical issues at the intersection of drugs, politics, and culture. Ms. Buisson and Ms. McNamee have both participated in previous MAPS trials.

July 7, 2022

Psychedelics: A need for considering potential placebo effects

Luana Colloca, MD, PhD, MS, Power Professor | University of Maryland School of Nursing and Medicine, Baltimore, USA

The prospect of introducing psychedelics and 3,4-methylenedioxymethamphetmine (MDMA) into the medical arsenal for mental (and other) disorders is highly valuable [1]. Scientifically, there is a renewed enthusiasm in the potential benefits induced by psychedelics and MDMA treatments [2]. While there is awareness about the risk-benefit assessments as well as the need for providing access to these treatments in terms of diversity, equity and justice, it remains necessary to take into account contextual effects namely the impact of the rituality and placebo effects around these treatments. Placebo effects might play a critical role in amplifying or at least modifying, the action of psychedelics and MDMA treatments via learning and conditioned effects [3].

1. Bradberry MM, Gukasyan N, Raison CL. Toward Risk-Benefit Assessments in Psychedelic- and MDMA-Assisted Therapies. JAMA Psychiatry. 2022;79(6):525-527.
2. Szuster RR. Asclepius Revisited-Ancient Myth and 21st-Century Psychedelic Medicine. JAMA. 2022;327(19):1851-1852.
3. Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med. 2020;382(6):554-561.

CONFLICT OF INTEREST: None Reported

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