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.

Psychedelic compounds are being studied as potential treatments for psychiatric conditions, but their mechanism of action is not well understood. This review proposes that changes in DNA methylation, a form of epigenetic regulation, may underlie the therapeutic effects of psychedelics. The authors focus on the N-methyl D-aspartate receptor (NMDAR), which is important for synaptic plasticity and is known to be dysfunctional in schizophrenia and major depressive disorder. They review evidence linking abnormal DNA methylation to NMDAR dysfunction in these disorders and present a model suggesting that psychedelics may act through epigenetic mechanisms to provide therapeutic benefits.

Study at a glance

Abstract

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.