Afirst-of-its-kind study published this week in Nature provides a systematic review of the side effects of MDMA therapy and MDMA-assisted psychotherapy (MDMA-AP) across various psychiatric conditions. ⁽¹⁾

‘With MDMA therapy moving towards potential FDA approval (a final decision on the MAPS-sponsored clinical trial is expected later this year) and with the Australian government legalizing MDMA for MDMA-assisted psychotherapy – the future of psychedelics as a legal treatment option is soon upon us. And so, for both the health of the patient and the credibility of the industry, it is imperative to ensure that these medicines are delivered in the safest way possible. ^{(2, 3)}

The new research, originally published in Neuropsychopharmacology (the official publication of the American College of Neuropsychopharmacology) gives a more complete picture of the potential side effects of MDMA therapies.

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A Detailed Review of MDMA Therapy Studies

Research and clinical results conducted so far have shown that MDMA and MDMA therapy are generally safe and well tolerated. But being a relatively new mode of treatment, and with minimal clinical data, there is still a need for a more detailed understanding of potential harm. According to the research authors “a comprehensive understanding of potential safety issues in MDMA-AP is needed to inform both ongoing research and translation to clinical practice.” ⁽¹⁾

Previous research on the adverse effects of MDMA and MDMA therapy didn’t include meta-analyses of side effects or other safety measures, or were focused only on PTSD and depression. These reviews also lacked data from the most recent Phase III study of MDMA therapy. The authors of this new meta-review aimed to fill this gap.

Study Details and Methods

This study gathered research information from databases like PubMed, EMBASE, and others, assessing the quality of side effect reporting in published MDMA therapy trials. The focus was only on Phase II and Phase III trials, as Phase I studies did not incorporate psychotherapy. This comprehensive approach aimed to add to the understanding of the full range of safety outcomes associated with MDMA-AP.

Data was extracted on the following criteria: Design, population, demographics (age, sex, ethnicity). MDMA administration (dosage, number of doses), control conditions, previous MDMA/ecstasy/molly use, health screening, medical comorbidity, concomitant medications, side effects assessment, and types of assessments of side effects or safety.

Thirteen studies met the criteria, which included 333 participants.

Findings from Phase II and Phase III Studies

The meta-analysis reveals that MDMA-assisted psychotherapy is linked with an increased likelihood of side effects both during medication sessions and in the following seven days, particularly in Phase II studies. Phase III studies also showed a higher incidence of various transient and mostly mild to moderate side effects compared to placebo-assisted psychotherapy. Notable among these were anxiety, muscle tightness, decreased appetite, and jaw clenching. 

In summary, MDMA therapy was associated with increased odds of side effects, but were largely transient and mild or moderate in severity. 

The occurrence of serious adverse events related to suicidality or cardiac function was not significantly different between MDMA therapy and control groups, suggesting these are rare.

Phase II Studies

In Phase II studies of MDMA-assisted psychotherapy, participants exhibited a higher likelihood of experiencing side effects during and up to seven days after treatment sessions compared to those receiving placebo. The likelihood differed based on the groups. Specifically, individuals treated with MDMA therapy had 1.7 times greater odds of side effects during medication sessions and 1.6 times in the subsequent week. Notable side effects included anxiety and jaw clenching, with anxiety being particularly pronounced among PTSD patients, who demonstrated 4.1 to 4.8 times higher odds of experiencing anxiety during and after sessions compared to their placebo counterparts.

The differences in treatment-emergent adverse events (TEAEs) between the MDMA therapy and placebo groups were modest and resolved within a week.

Phase III Studies

Phase III studies of MDMA therapy revealed a more pronounced risk profile, with participants experiencing 3.5 times greater odds of any TEAE compared to those in placebo groups. The spectrum of side effects was broad, encompassing muscle tightness, decreased appetite, nausea, excessive perspiration, and more severe reactions like uncontrolled eye movements and non-cardiac chest pain. The increased number of significant adverse events in these studies likely reflects the larger sample sizes used, enhancing the statistical power of the findings. 

Again, the side effects reported were transient and generally of mild to moderate severity.

Implications for Future Research on MDMA-Assisted Psychotherapy

The evidence of this meta-review indicates that relative to placebo, MDMA therapy is associated with greater likelihood of experiencing mild to moderate side effects, but that these effects were temporary and resolved on their own.

This analysis, while adding to the current understanding of safety profiles, highlights the necessity for further research. Anomalies or counter-intuitive results in the research are likely due to the small sample size and future studies are needed to expand the data pool and ensure accurate results. 

Furthermore, according to the authors, this review revealed “a need to improve practices for assessing side effects and adherence to reporting guidelines for harms in MDMA-AP studies” and that future trials “include long-term follow-up and real-world studies to monitor side effects accurately.”

With legal MDMA therapy becoming available in the very near future, these findings advocate for a more detailed view of potential side effects, ensuring informed clinical decisions and patient safety. 

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Sources

Sources

1. Colcott, J., Guerin, A.A., Carter, O. et al. (2024). Side-effects of mdma-assisted psychotherapy: a systematic review and meta-analysis. Neuropsychopharmacol. https://doi.org/10.1038/s41386-024-01865-8

2. Multidisciplinary Association For Psychedelic Studies (2023). Phase 3: MDMA-Assisted Therapy for PTSD. https://maps.org/mdma/ptsd/phase3/

3. Australian Therapeutic Goods Admnistration. (2023). Change to classification of psilocybin and MDMA to enable prescribing by authorised psychiatrists. https://www.tga.gov.au/news/media-releases/change-classification-psilocybin-and-mdma-enable-prescribing-authorised-psychiatrists