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

A systematic review of 44 clinical studies (34 quantitative, 10 qualitative) involving 598 patients treated with MDMA or serotonergic psychedelics (psilocybin, LSD, ayahuasca) found that treatments were generally well tolerated, though adverse events were often not systematically assessed. Common acute adverse events across diagnoses and compounds included nausea, headaches, and anxiety. Late adverse events included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious adverse event occurred during MDMA administration (increased premature ventricular contractions requiring brief hospitalization); no other events required medical intervention. Qualitative studies suggested that psychologically challenging experiences may be therapeutically beneficial. The authors conclude that adverse events are poorly defined and likely underreported due to study design and sample selection.

Study at a glance

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 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.