Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review

This review (2022) assesses the presence of adverse events (AEs) during and after the administration of psychedelics including MDMA, psilocybin, LSD and ayahuasca. Across all compounds, commonly reported AEs included nausea, headaches and anxiety, while only one serious AE occurred in a study involving MDMA administration. Results from qualitative studies suggest that psychologically challenging experiences could have therapeutic benefits. Overall, AEs in psychedelic research require more detailed reporting.

Abstract

“Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions.

Objective: To systematically review the presence of AEs during and after the administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies.

Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies.

Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies.

Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

Authors: Joost A. Breeksema, Bouwe W. Kuin, Jeanine Kamphuis, Wim van den Brink, Eric Vermetten & Robert A. Schoevers