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

As a result of demonstrating promise in a range of clinical studies, psychedelic and MDMA-based 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 healthcare 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 healthcare 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 to participants in published clinical trials.

The primary acute risks of supervised psychedelic use are psychiatric in nature, driven by profound drug-induced changes in cognitive, affective, and sensory processing^3–5. Transient mood instability, sensory disturbances, and altered salience perception are expected with typical doses of psychedelics^4,5. The associated behavioral risks are generally addressed via preparatory and post-session therapy, along with careful supervision and guidance for the duration of the acute drug effects⁴. In comparison, MDMA provokes a different response with a strong affective component, and guidance is likewise thought to be essential for its therapeutic action^2,6. These acute risks usually resolve within hours of the dosing session. Nevertheless, in some patients, psychedelics or MDMA may provoke worsening symptoms of mood or thought disorder that outlast the acute drug effects^3–5. Older studies have demonstrated that in persons with schizophrenia or schizotypal features, psychedelics may acutely worsen symptoms of psychosis, in rare cases for up to weeks or months^3,5. Worsened mood may occasionally follow psychedelic or MDMA therapy^2,3, with the potential to drive suicidal behavior³. Psychedelics and MDMA have sympathomimetic activity^4–6, which may be an important consideration in select patients. The risk of serotonin syndrome with co-administration of MDMA or psychedelics with other serotonergic agents is unclear¹. Long-term follow-up studies revealed no increases in recreational drug use following MDMA therapy².

Despite their safety record in modern research studies^1,2, more complex risk:benefit assessments may often be required if psychedelic and MDMA therapy are approved for broader clinical use. More data are thus needed on the effects of these drugs in higher-risk groups.^1,7 For example, many patients with intractable post-traumatic stress disorder or major depressive disorder who may benefit from these therapies may have concerning personality features or family histories of schizophrenia or bipolar disorder. Though family or personal history of these conditions may elevate one’s risk of mania or psychosis after using psychedelics, our ability to quantify that risk has been limited by the exclusion of such patients from most modern clinical trials of psilocybin and MDMA-assisted therapy. To what degree is psilocybin or MDMA therapy contraindicated in these individuals? How can practitioners assess the potential for benefit and mitigate the risks of psychedelic therapy in those at elevated risk of psychosis or suicide? Studies in more diverse and representative clinical populations are needed to address these questions.

Government-sponsored efforts will likely play key roles in collecting and reporting the relevant safety data. In the United States, any broadly approved clinical use of psilocybin or MDMA will likely require a risk evaluation and mitigation strategy (REMS). While REMS can provide valuable infrastructure for clinical research, such as the maintenance of patient registries, these systems have also failed and caused occasional access problems⁸. Regulatory requirements also incur significant costs, which may be passed on to the consumer and unethically limit access among certain groups. While the burden of proposing a REMS typically falls on the pharmaceutical company seeking product approval, the chemistries of MDMA and psilocybin have long existed in the public domain, and alternative approaches to REMS implementation for these medicines should be considered.

In the U.S., there is the added complexity of state regulations tentatively permitting psychedelic use, such as in the state of Oregon. As state governments move toward legalization of supported adult use, it is likely that psychedelics will be used to a significant degree outside the purview of a REMS. We thus recommend that governmental and/or non-governmental agencies provide non-coercive incentives and infrastructure for psychedelic practitioners to voluntarily report patient, practice, and outcomes data in a standardized manner that does not overburden the practitioner or their organization. Given the power dynamic inherent to psychedelic and MDMA-assisted therapies, infrastructure should exist for individuals to report concerns about problematic experiences and practitioners to the relevant authorities. A further concern about use under such frameworks is whether higher-risk individuals will be adequately supported. It is paramount that these programs screen for factors associated with increased risk of serious adverse events, provide informed consent, and ensure availability of crisis management and other follow up resources. As part of these efforts, changes in the legal status of psychedelics and MDMA should come with funding for large-scale safety and efficacy studies of these therapies.

We also emphasize the importance of contextual factors in mitigating risk. In particular, the rapport between patient and practitioner is critical to psychedelic- and MDMA-assisted psychotherapy. With higher-risk patients able to form such a rapport, the risks of disordered thought and destabilized mood should be explicitly discussed during preparatory therapy, and contingency plans should be established for severe adverse reactions. Close supervision and a psychologically safe environment are essential for the duration of the acute drug effects⁴. Opportunities for integration should be provided, and the presence of support in the patient’s life should be assessed⁷. Mitigation practices, such as a dose-escalation approach and offering or requiring a brief inpatient stay following psychedelic or MDMA administration, may be appropriate in some especially high-risk cases^3,7. The ethical standard of informed consent should be rigorously followed, and practitioners should exercise cautious clinical judgment in all cases. Currently registered trials for psilocybin in bipolar II depression exemplify a careful approach that might be applied to other higher-risk-scenarios^9,10.

As research and clinical use of psychedelic- and MDMA-aided therapies become more widespread, adverse psychiatric reactions will likely occur even with the most conservative approaches, and these patients may require higher-level psychiatric care. We thus expect that psychiatrists will play key roles in risk:benefit evaluations, specialized technique and protocol development, aftercare, and informed consent standards for higher-risk patients. Moreover, the availability of qualified psychedelic therapy practitioners is likely to be a major access bottleneck. Integration of psychedelic therapy experiences into psychiatry and clinical psychology training programs may help address this problem while improving care for higher-risk individuals. Finally, we emphasize that many psychiatrists, psychologists, and primary care physicians may find themselves responding to patients’ inquiries about psychedelic therapy. As our understanding of these therapies evolves, well-informed safety guidelines will not only help ensure better outcomes, but also allow psychiatrists and their patients considering psychedelic or MDMA therapy to meaningfully weigh the risks and benefits.