Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct;36(10):1100-1117.
doi: 10.1177/02698811221116926. Epub 2022 Aug 26.

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

Joost J Breeksema  1   2   3 , Bouwe W Kuin  1 , Jeanine Kamphuis  1 , Wim van den Brink  4 , Eric Vermetten  2 , Robert A Schoevers  1
Affiliations

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

Joost J Breeksema et al. J Psychopharmacol. 2022 Oct.

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.

Keywords: LSD; MDMA; Psychedelics; adverse effects; adverse events; ayahuasca; psilocybin.

PubMed Disclaimer

Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RS received a research grant from the Netherlands Organization Health Research and Development for a clinical study on oral esketamine, and is the co-investigator of a clinical study on psilocybin funded by Compass Pathways. He has also received an educational grant from Janssen, Pharmaceutical Companies of Johnson and Johnson, and honorarium from Clexio Biosciences. EV is the principal investigator of a clinical trial on MDMA funded by the Multidisciplinary Association for Psychedelic Studies. WvdB has been a consultant for Janssen Netherlands and is a member of the Scientific Advisory Board of Clearmind. JJB, BK and JK declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Flowchart.
See this image and copyright information in PMC

References

    1. Aday JS, Davis AK, Mitzkovitz CM, et al.. (2021) Predicting reactions to psychedelic drugs: A systematic review of states and traits related to acute drug effects. ACS Pharmacol Transl Sci 4: 424–435. - PMC - PubMed
    1. Aday JS, Heifets BD, Pratscher SD, et al.. (2022) Great expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology 239: 1989–2010. - PMC - PubMed
    1. Andersen KAA, Carhart-Harris R, Nutt DJ, et al.. (2020) Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta Psychiatr Scand 2021 143: 101–118. - PubMed
    1. Anderson BT, Danforth A, Daroff PR, et al.. (2020) Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. eClinicalMedicine 27: 100538. - PMC - PubMed
    1. Andersson HW, Lilleeng SE, Ruud T, et al.. (2022) Suicidal ideation in patients with mental illness and concurrent substance use: Analyses of national census data in Norway. BMC Psychiatry 22: 1–9. - PMC - PubMed

Publication types

MeSH terms