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Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics

Molecular Psychiatry volume 28, pages 3595–3612 (2023)Cite this article

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Abstract

Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.

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Fig. 1: Chemical structures of psychedelic and non-psychedelic 5-HT2A receptor agonists.
Fig. 2: Orientation of LSD (top) and Lisuride (bottom) in the binding pocket of the 5-HT2A receptor.
Fig. 3: 5-HT2A receptor signaling pathways and their downstream effects.
Fig. 4: Summary schematic of the ongoing research fields in psychedelics.

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Acknowledgements

We thank J. Rolquin for his assistance with computational ligand docking analysis.

Funding

This work was supported by NIH grants R01MH084894, P30DA033934, and F31DA057818. Figures were created using biorender.com

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Alaina M. Jaster & Javier González-Maeso

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Alaina M. Jaster

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Conceptualization (AMJ, JGM), Writing – original draft (AMJ), Writing – review and editing (JGM), Funding acquisition (AMJ, JGM), Supervision (JGM).

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Correspondence to Javier González-Maeso.

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JGM has or has had sponsored research contracts with Terran Biosciences, Gonogo Solutions, and Noetic Fund, and serves on scientific advisory boards for Adelia Therapeutics, Cognesy Therapeutics, and Psylo. AMJ has a consulting contract with Terran Biosciences.

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Jaster, A.M., González-Maeso, J. Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Mol Psychiatry 28, 3595–3612 (2023). https://doi.org/10.1038/s41380-023-02274-x

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