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.
Molecular Psychiatry November 1, 2023 DOI: 10.1038/s41380-023-02235-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression |
| Citations | 14 |
| Key findings | Alterations to DNA methylation are proposed as a converging model for the therapeutic effects of psychedelic compounds, with NMDAR dysfunction as an anchoring point in schizophrenia and major depressive disorder. |
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.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 5
- Epigenetic drugs and psychedelics as emerging therapies for alcohol use disorder: insights from preclinical studies. Journal of Neural Transmission May 1, 2024
- Epigenetic landscapes of classical psychedelics and ketamine: molecular mechanisms of long-lasting neuromodulation Molecular Psychiatry July 10, 2026
- LSD Restores Synaptic Plasticity in VTA of Morphine-Treated Mice and Disrupts Morphine-Conditioned Place Preference. bioRxiv : the preprint server for biology June 15, 2025
- Serotonergic psychedelics as epigenetic modulators: A paradigm shift in Alzheimer's disease therapeutics. Neuroscience & Biobehavioral Reviews May 1, 2026
- The epigenetic mechanisms of ketamine in the treatment of depression: a systematic review. Epigenomics November 7, 2025
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- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
and 30 more in the library