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Synergistic psychedelic - NMDAR modulator treatment for neuropsychiatric disorders

Molecular Psychiatry volume 29, pages 146–152 (2024)Cite this article

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Abstract

Modern research data suggest a therapeutic role for serotonergic psychedelics in depression and other neuropsychiatric disorders, although psychotomimetic effects may limit their widespread utilization. Serotonergic psychedelics enhance neuroplasticity via serotonin 2 A receptors (5HT2AR) activation and complex serotonergic-glutamatergic interactions involving the ionotropic glutamate receptors, tropomyosin receptor kinase B (TrkB) and the mammalian target of rapamycin (mTOR). N-methyl-d-aspartate receptors (NMDAR) channel antagonists, i.e. ketamine, and glycine modulatory site full and partial agonists, i.e., D-serine (DSR) and D-cycloserine (DCS), share some of these mechanisms of action and have neuroplastic and antidepressant effects. Moreover, procognitive effects have been reported for DSR and DCS and 5HT2AR-NMDAR interactions modulate neuronal excitability in prefrontal cortex and represent a target for new antipsychotics. We hypothesize that the synchronous administration of a psychedelic and a NMDAR modulator may increase the therapeutic impact of each of the treatment components and allow for dose adjustments and improved safety. We propose to initially focus research on the acute concurrent administration of psilocybin and DSR or DCS in depression.

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Fig. 1: Schematic representation of the hypothesized mechanisms of action of combined serotonergic psychedelic—NMDAR modulator treatment.

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Acknowledgements

Hadassah BrainLabs - Center for Psychedelic Research (https://cfpr.brainlabs.org.il/) was established with the support of Negev Labs.

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  1. Department of Psychiatry, Herzog Medical Center; Hebrew University Faculty of Medicine, Jerusalem, Israel

    Uriel Heresco-Levy

  2. Hadassah BrainLabs, Center for Psychedelic Research, Hadassah Medical Center, Hebrew University, Jerusalem, Israel

    Bernard Lerer

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UH and BL have jointly put forward and conceptualized the hypotheses and concepts presented in this paper and prepared the manuscript

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Correspondence to Uriel Heresco-Levy or Bernard Lerer.

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UH is inventor in patents and patent applications for the use of NMDAR modulators in depression, autoimmune encephalopathies, inflammatory disorders and in conjunction with psychedelics in neuropsychiatric disorders. BL is inventor on a patent application for the use of NMDAR modulators in conjunction with psychedelics in neuropsychiatric disorders.

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Heresco-Levy, U., Lerer, B. Synergistic psychedelic - NMDAR modulator treatment for neuropsychiatric disorders. Mol Psychiatry 29, 146–152 (2024). https://doi.org/10.1038/s41380-023-02312-8

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