Psychedelic compounds are being increasingly explored as a potential therapeutic option for treating several psychiatric conditions, despite relatively little being known about their mechanism of action. One such possible mechanism, DNA methylation, is a process of epigenetic regulation that changes gene expression via chemical modification of nitrogenous bases. DNA methylation has been implicated in the pathophysiology of several psychiatric conditions, including schizophrenia (SZ) and major depressive disorder (MDD). In this review, we propose alterations to DNA methylation as a converging model for the therapeutic effects of psychedelic compounds, highlighting the N-methyl D-aspartate receptor (NMDAR), a crucial mediator of synaptic plasticity with known dysfunction in both diseases, as an example and anchoring point. We review the established evidence relating aberrant DNA methylation to NMDAR dysfunction in SZ and MDD and provide a model asserting that psychedelic substances may act through an epigenetic mechanism to provide therapeutic effects in the context of these disorders.
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We thank Mr. Jake D. Clarin for his comments on the manuscript. The images were created with BioRender.com. This study was supported by NIH R21MH121836, R21MH129989, R01MH131053, and Pennsylvania Commonwealth 4100085747 (CURE 2016) to WJG.
The authors declare no competing interests.
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Flynn, L.T., Gao, WJ. DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02235-4