Navigating the Risks of Psychedelics and MDMA as Therapies Go Mainstream

As interest in psychedelic and MDMA-assisted therapies surges, their potential to revolutionize mental health treatment is becoming increasingly apparent. Clinical studies highlight promising outcomes for conditions such as alcohol use disorder (AUD), major depressive disorder (MDD), and posttraumatic stress disorder (PTSD).¹ However, alongside this optimism, experts urge a more thorough examination of the potential risks associated with these therapies in an article published in JAMA Health Forum, especially as treatment use expands beyond controlled clinical settings.

Data from a pair of phase 3 studies submitted by Lykos Therapeutics demonstrated that midomafetamine capsules (MDMA) in combination with assisted therapy (MDMA-AT) significantly reduced PTSD symptoms among adults who received the treatment compared with those in the placebo group.² The primary outcome was measured by a reduction in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score from baseline to 18 weeks.

Despite these promising results, the FDA rejected Lykos’ application in August, citing that it could not approve the treatment based on the data submitted and suggested that Lykos conduct an additional phase 3 study to expand on the efficacy and safety profile. A widespread conversation surrounding the psychedelic treatment approach had emerged alongside the trials and drug applications, coming to a climax at the FDA Psychopharmacologic Advisory Committee (PDAC) public hearing session. In early June, the committee voted 2 to 9 against supporting the effectiveness of MDMA-AT and 1 to 10 to reject that the benefits of the treatment with the FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD.³

The current article offers insight into how the US approaches these therapies in conjunction with other countries.¹ Australia recently authorized psychiatrists to prescribe psilocybin and MDMA under specific conditions, with the US and other countries considering similar pathways. While these developments mark significant progress, the safety profiles of these substances remain incomplete, particularly outside controlled environments. Naturalistic use—without the stringent oversight of clinical trials—carries heightened risks that demand urgent investigation, the authors stated.

Adverse effects in clinical trials are generally mild and transient, such as acute anxiety or headaches. However, serious concerns remain underexplored. Persisting conditions like hallucinogen persisting perception disorder (HPPD), psychotic episodes, mood disturbances, and existential distress have been reported. The article emphasized that these risks may be amplified in vulnerable populations or under the influence of cultural and digital environments fostering conspiratorial thinking or extremist beliefs.

Historical insights from the 1960s, such as those by Sidney Cohen, MD, caution against the potential for psychedelic use to contribute to quasi-religious authoritarian movements. With the rise of social media and globalized cultural exchanges, such risks may now intersect with broader societal dynamics, necessitating robust, open-ended research.

Clinical trials operate under idealized conditions, with stringent participant screening and therapeutic support, which likely minimizes adverse outcomes, the authors noted. Yet, real-world settings introduce variables that may elevate risks. For example, rare adverse events that occur in one out of 10,000 participants might be undetected in smaller trials but could become evident with broader use.

Epidemiological studies were acknowledged as a critical component of identifying these risks. As programs in Oregon and Colorado expand access and international retreat centers attract global participants, new surveillance systems should be established. Existing data collection platforms, like the National Survey on Drug Use and Health, should also incorporate metrics on adverse effects to provide a clearer picture of the broader implications of psychedelic and MDMA use.

One glaring gap in the current research is the lack of treatments for persistent adverse effects such as HPPD. For individuals who experience debilitating symptoms, the absence of effective interventions can exacerbate suffering. Developing therapeutic options—whether pharmacological or nonpharmacological—is crucial, especially as extramedical use grows.

Additionally, safeguards must address the potential for harm from unethical practitioners, including unregulated therapists and "neoshamans." These individuals may exploit vulnerable populations, necessitating mechanisms for accountability and victim support.

Public education campaigns are equally vital. Health care professionals and the general public need accurate, evidence-based information about the risks of psychedelics and MDMA. These efforts should prioritize harm reduction, promoting informed decision-making and minimizing risk without encouraging use among high-risk groups.

A Public Health Approach to Safeguard MDMA Therapy

As psychedelics and MDMA move toward mainstream medical use and recreational acceptance, the scientific community faces a critical juncture. To ensure safe and ethical practices, researchers and policymakers must prioritize 4 key actions, as highlighted by the authors:

1. Expanding Research on Adverse Effects: Broader studies are needed to capture the full range of potential risks in diverse populations and settings.
2. Leveraging Epidemiology: Understanding real-world outcomes is essential to refining safety protocols and identifying at-risk groups.
3. Developing Interventions: Effective treatments for persistent adverse effects must be a research priority.
4. Enhancing Funding and Education: Increased investment and widespread awareness campaigns can help mitigate risks while supporting responsible use.

By addressing these challenges proactively, the field can advance responsibly, safeguarding both individual well-being and public health.

"It is therefore urgent to better understand the full range of potential risks associated with psychedelic and MDMA use to ensure safe and ethical practice," the authors wrote. "We call for action on 4 key points connected to research on psychedelic and MDMA-related adverse effects."

References

1. Simonsson O, Johnson MW, Hendricks PS. Psychedelic and MDMA-related adverse effects—a call for action. JAMA Health Forum. 2024;5(11):e243630. doi:10.1001/jamahealthforum.2024.3630

2. Grossi G. MDMA-assisted therapy receives a complete response letter from the FDA. AJMC^®. August 9, 2024. Accessed December 5, 2024. https://www.ajmc.com/view/mdma-assisted-therapy-receives-a-complete-response-letter-from-the-fda

3. Antrim A. FDA advisory panel rejects MDMA-assisted therapy for PTSD. Pharmacy Times^®. June 4, 2024. Accessed December 5, 2024. https://www.pharmacytimes.com/view/fda-advisory-panel-rejects-mdma-assisted-therapy-for-ptsd