Psychedelics for treatment resistant depression: are they game changers?

ABSTRACT

Introduction

A new era of treatment for adults with treatment-resistant depression (TRD), which involves psychedelic substances, is dawning. Emerging evidence indicates that psychedelics can exert antidepressant effects through multiple neurobiological and psychological mechanisms. However, it remains to be seen if these new treatments will revolutionize the treatment of TRD.

Areas covered

The present review focuses on the efficacy of serotoninergic psychedelics psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ayahuasca, 5‐methoxy‐N,N‐dimethyltryptamine (5-MeO-DMT) and mescaline (3,4,5-trimethoxyphenethylamine), as well as 3,4-methylenedioxymethamphetamine (MDMA), for TRD. A systematic search was conducted for psilocybin in TRD as emerging trials had not yet been subject to review. A narrative review summarized findings on other psychedelics.

Expert opinion

Psychedelic therapy has created a paradigm shift in the treatment of TRD, as it can maximize therapeutic benefits and minimize potential risks. Psilocybin holds promise as a potential game-changer in the treatment of TRD, with initial evidence suggesting a rapid antidepressant effect sustained for some responders for at least 3 months. Nevertheless, further adequately powered, double-blind, comparator-controlled trials are required to explore and clarify the mechanisms of action and long-term effects of psychedelics in TRD. Psychedelics also hold promise for other psychiatric conditions, such as bipolar depression and post-traumatic stress disorder.

KEYWORDS:

• Psychedelics
• psilocybin
• major depressive disorder
• treatment resistant depression
• systematic review

Article highlights

• Psychedelics may represent a new era of treatment in psychiatric disorders.

• Treatment-resistant depression (TRD) is prevalent and associated with a significant burden, highlighting a demand for novel treatments.

• Preliminary evidence suggests that psilocybin is effective and safe in TRD.

• Evidence on the efficacy of LSD, DMT, 5-MeO-DMT, ayahuasca, mescaline, and MDMA in TRD is limited.

• Psychological support is an important component of treatment with psychedelics which serves to maximize benefits and mitigate potential adverse reactions.

• Further research is needed to confirm efficacy and to understand the mechanisms and long-term effects of psychedelics in TRD.

Declaration of interest

M Kalfas, R H Taylor, and D Tsapekos were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed in the research are those of the authors.

A H Young reports paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZeneca (AZ), Compass Pathways, Eli Lilly, Lundbeck, Sunovion, Servier, LivaNova, and Janssen. No shareholdings in pharmaceutical companies. Lead Investigator for Embolden Study (AZ), BCI Neuroplasticity study and Aripiprazole Mania Study. Investigator initiated studies from AZ, Eli Lilly, Lundbeck, Wyeth, Janssen.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

For the purposes of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Accepted Author Manuscript version arising from this submission.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2023.2281582

Additional information

Funding

This paper was not funded.