New Territory: Ethical Challenges Associated With MDMA-Assisted Psychotherapy for PTSD
Publication: American Journal of Psychiatry Residents' Journal
Abstract
The present article explores ethical considerations related to 3,4-methylenedioxymethamphetamine (MDMA)–assisted therapy (MDMA-AT) as a potential treatment for posttraumatic stress disorder. The authors focus on U.S. Food and Drug Administration regulatory challenges associated with evaluating MDMA and psychotherapy in conjunction and the role that a risk evaluation in management mitigation program may play in assessing risks and benefits of MDMA-AT. Also discussed are workforce considerations, including foreseeable training requirements, and concerns related to off-label use. The authors emphasize the need for continued research, careful regulation, and thorough clinician education to realize the therapeutic potential of MDMA while ensuring patient safety.
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as “Ecstasy” in recreational contexts, has been considered by the U.S. Food and Drug Administration (FDA) as a treatment for posttraumatic stress disorder (PTSD). Treatment options for PTSD are limited, with only two medications approved by the FDA. Psychotherapy, although effective for some, is often challenging to access, and some patients do not achieve satisfactory outcomes. MDMA, known as an “entactogen” for its ability to increase feelings of empathy and emotional closeness, can decrease amygdala activation in response to fear-inducing stimuli, potentially aiding in the psychotherapeutic processing of traumatic memories (1). A major phase III randomized double-blind placebo-controlled study demonstrated a significant reduction in PTSD symptoms and clinician-assessed functional impairment among patients receiving MDMA-assisted therapy (MDMA-AT) compared with those undergoing placebo plus therapy (2). These findings, along with those from another successful phase III trial, supported the new drug application (NDA) from Lykos Therapeutics, previously known as the Public Benefit Corporation of the Multidisciplinary Association for Psychedelic Studies (MAPS) (3). MDMA-AT represents a potential paradigm shift in psychiatric care, challenging conventional approaches to psychopharmacology and psychotherapy. Here, we explore critical ethical questions around regulation, safety, and access and important considerations for clinicians and policy makers if MDMA-AT is approved.
FDA’s Regulatory Challenge
The FDA faces a unique regulatory challenge with MDMA-AT, which combines pharmacology and psychotherapy. Although the FDA has regulated several cognitive-behavioral therapy–based mobile applications, those products are evaluated as low- to moderate-risk medical devices through specific pathways (e.g., de novo, 510[k]) (4). For pharmaceuticals, labeling regulations can suggest concurrent use of medications with other therapies (5). Initially, the labeling for naltrexone and buprenorphine recommended their use within comprehensive substance use treatment programs offering psychosocial support. However, the FDA later revised its perspective, acknowledging that the service scarcity should not restrict medication access (6). This change highlights the FDA’s ethical dilemma of ensuring comprehensive care while maintaining treatment accessibility, which is a challenge relevant to MDMA-AT and other psychedelic-assisted therapies.
The precise role of psychotherapy in the effectiveness of MDMA-AT is uncertain. Psychotherapy was a cornerstone of the clinical trials supporting the NDA. Simultaneously, the FDA recently issued a draft guidance for psychedelic trials, emphasizing concerns that psychotherapy may increase expectancy and performance biases (7). Skeptics have questioned whether psychedelic treatments require psychotherapy (8), prompting swift criticism from experts who cite decades of evidence defining common elements of psychedelic-assisted therapy, including the stages of preparation, treatment, and integration (9). Proponents argue that psychedelic-assisted therapy “creates a therapeutic container to prevent unassisted or poorly assisted drug administration” (10). While ongoing research aims to clarify the effectiveness of psychotherapy in MDMA-AT, regulatory bodies face the challenge of making policy decisions based on currently available evidence. These decisions significantly affect treatment accessibility and patient safety, setting a precedent for future psychedelic treatments.
Risk Evaluation and Mitigation Strategy
The FDA may shape the psychotherapy component of MDMA-AT through a risk evaluation and mitigation strategies (REMS) program (11). Required for medications with notable safety concerns, REMS programs aim to balance a drug’s benefits against its risks. A component of REMS, elements to assure safe use (ETASU), can mandate specialized training for health care providers administering a medication. The potential requirement of psychotherapy training under ETASU is a key consideration for MDMA-AT and similar therapies. Advocates for less stringent FDA regulation suggest that REMS programs are designed to ensure medication safety, not to enhance efficacy. However, in the realm of psychedelic-assisted therapy, differentiating between safety and efficacy becomes more complex. MDMA and classic psychedelics, such as psilocybin and lysergic acid diethylamide, are recognized for inducing states of heightened openness and suggestibility, which many consider central to their therapeutic effects (12). The psychotherapy protocol for MDMA-AT includes the potential use of therapeutic touch, which contributes both to its profound therapeutic potential and its risk of misuse (13). Sexual misconduct and boundary violations have troubled the field of psychedelic therapy, even in the strictly regulated MAPS-sponsored trials (14, 15). In developing a REMS, the FDA is tasked with the critical goal of safeguarding patient safety without hindering the therapeutic potential of psychotherapy.
The REMS framework may also address the unique dynamics between the physical environment and patient outcomes in psychedelic therapy. The concept of “set and setting” emphasizes the important role the patient’s psychological state (“set”) and the surrounding environment (“setting”) play in the patient’s experience (16). Implementing guidelines to document “set and setting” could enhance the rigor of research, improve treatment outcomes, and reduce patient risks (17). Requirements for REMS certification could include criteria for the treatment environment, such as appropriate lighting, music, and decor, ensuring a setting conducive to positive therapeutic outcomes.
Psychotherapy Training and Certification
The possibility of psychotherapy training requirements for REMS participation prompts a crucial question: Who will qualify to provide MDMA-AT? The training protocol developed by MAPS is comprehensive, consisting of a 14-week 100-hour course (13). Therapy sessions are videotaped and reviewed by trained adherence raters for quality assurance. Training and certification could be facilitated exclusively through MAPS, which could promote consistency and quality. However, the intensive nature of training may limit scalability and impede widespread clinical use. An alternative could involve independent certifying bodies to increase therapist numbers. Several states have taken steps to regulate psychedelic-assisted psychotherapy. For example, Oregon’s Psilocybin Services Act and Colorado’s Natural Medicine Health Act establish regulatory frameworks that mandate licensing for facilitators of psilocybin-assisted therapy (18, 19). These models could expand access but may lead to variability in quality. Regardless, it is crucial to train therapists from diverse backgrounds to create a workforce that reflects the diversity of patients seeking MDMA-AT.
Psychiatrists may not comprise the majority of therapists administering MDMA-AT, suggesting a distinction between the certification processes for prescribing MDMA and conducting therapy. Akin to the X-waiver for buprenorphine, prescribers of MDMA may need to complete specialized training that focuses on its pharmacology, associated risks, and safe prescribing practices. Psychiatrists who prescribe MDMA but do not provide psychotherapy should still understand the theory of psychedelic-assisted therapy. This understanding helps inform discussions with patients about the potential risks and benefits of treatment. For example, the FDA’s recent draft guidance on psychedelics has been criticized for classifying hallucinations and other subjective phenomena as “abuse-related adverse events” (20). Considering the potential therapeutic value of these experiences, there is a call for the FDA to revise its terminology (20). The MAPS protocol trains therapists to prepare patients for both positive and negative experiences, enhancing their ability to integrate these experiences into the healing process. Psychiatrists must be aware of these unique elements of MDMA-AT, balancing positive expectancy with transparency about the current state of research. Current psychiatry residency training programs do not systematically include training in psychedelic medicine, but ongoing initiatives aim to close this gap (21).
Postapproval Considerations: Diagnostic Pressure and Off-Label Use
The NDA for MDMA specifically targets PTSD treatment. Psychiatrists may face increasing pressure to diagnose PTSD from patient expectations or their own compassionate instinct to relieve hardship and distress. Psychiatrists should uphold their clinical judgment and base diagnoses on clinical evidence, rather than modifying diagnoses to align with desired or available treatments. At the same time, REMS programs do not specify clinical indications for medications. This may be particularly relevant in psychiatry, where medications are frequently used off-label. As emerging evidence explores the utility of MDMA and other psychedelics for indications beyond PTSD, psychiatrists must balance doing good (beneficence) with avoiding harm (nonmaleficence). It is unethical to withhold potentially beneficial treatments, but it is equally important not to expose patients to medications without a thorough understanding of the potential risks and benefits. As psychedelic research expands, psychiatrists must stay informed about the latest evidence to make responsible off-label use decisions and ensure patients are fully aware of the treatments’ evidence base, indications, and risks.
Public Health and Risk of Abuse
FDA approval of MDMA-AT could significantly influence public perception and contribute to increased recreational MDMA use. Ketamine, whose expanded use in treating depression may have contributed to its rise in recreational consumption, provides a useful comparison (22). Experts recommend the creation of a clinical registry to monitor off-label therapeutic use of ketamine, with a focus on tracking misuse and adverse effects (23). A comprehensive system for reporting adverse events would be similarly beneficial for MDMA. MedWatch, the FDA’s program for reporting medication safety information and adverse events, could be adapted for this purpose, or new reporting infrastructure may be necessary. Given unresolved questions surrounding psychotherapy in MDMA-AT, collecting data on the care setting and the level of psychotherapy support will be crucial. This information will assist in categorizing adverse events and evaluating the effectiveness and safety of concurrent psychotherapy.
Conclusions
MDMA-AT and similar psychedelic-assisted therapies represent a potential paradigm shift in PTSD treatment, posing a significant regulatory challenge for the FDA. Although the FDA does not directly regulate psychotherapy, it may play a vital role in shaping treatment protocols through its REMS program and possible collaboration with MAPS or other organizations involved in psychotherapy training and certification. Clinicians, irrespective of their involvement in psychotherapy, should understand the fundamental principles of MDMA-AT. Policy and clinical decisions regarding MDMA-AT must be made with careful consideration to safeguard patient safety and ensure the accessibility of effective treatments. Further research will be necessary to elucidate the role of psychotherapy and to refine regulatory strategies appropriately.
Key Points/Clinical Pearls
•
MDMA-assisted therapy (MDMA-AT) poses a challenge for the Food and Drug Administration, which has not historically regulated psychotherapy.
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Risk evaluation in management mitigation programs may clarify psychotherapy’s role in MDMA-AT and enhance awareness of risks and benefits.
•
U.S. Food and Drug Administration policy must balance patient access and safety.
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Psychiatrists may face pressure for off-label MDMA-AT use, and therefore they should be informed about its benefits, risks, and indications.
Acknowledgments
The authors thank Michael D. Alpert, M.D., for reviewing this article and sharing his expertise related to MDMA-assisted psychotherapy.
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American Journal of Psychiatry Residents' Journal
Pages: 19 - 22
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Published online: 6 September 2024
Published in print: September 6, 2024
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