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Therapeutic mechanisms of psychedelics and entactogens

Neuropsychopharmacology volume 49, pages 104–118 (2024)Cite this article

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Abstract

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration—factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity—outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

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Fig. 1: Potential circuits mediating the effects of psychedelics and entactogens.
Fig. 2: Candidate processes mediating therapeutic outcomes.

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Funding

Funding

BDH acknowledges support from the National Institute of Mental Health under award R01MH130591. DEO acknowledges support from the National Institute of General Medical Sciences and the National Institute on Drug Abuse under awards R01GM128997 and R01DA056365, respectively.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Boris D. Heifets

  2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA

    Boris D. Heifets

  3. Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, 95616, USA

    David E. Olson

  4. Department of Chemistry, University of California, Davis, Davis, CA, 95616, USA

    David E. Olson

  5. Center for Neuroscience, University of California, Davis, Davis, CA, 95618, USA

    David E. Olson

  6. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA

    David E. Olson

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BDH: Writing—original draft, Writing—review & editing. DEO: Writing—original draft, Writing—review & editing.

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Correspondence to Boris D. Heifets or David E. Olson.

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Competing interests

BDH is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant for Clairvoyant Therapeutics and Vine Ventures, all unrelated to the present work. DEO is a co-founder of Delix Therapeutics, Inc., serves as the Chief Innovation Officer and Head of the Scientific Advisory Board, and has sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed technology from the University of California, Davis.

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Heifets, B.D., Olson, D.E. Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacol. 49, 104–118 (2024). https://doi.org/10.1038/s41386-023-01666-5

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