Serotonergic psychedelics as epigenetic modulators: A paradigm shift in Alzheimer's disease therapeutics

This review highlights that epigenetic alterations - rather than genetic mutations alone play a major role in Alzheimer’s pathology. It argues that psychedelics may represent a new class of Alzheimer’s therapeutics because their 5-HT2A–mediated epigenetic remodeling could restore neuroplastic gene programs disrupted in the disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuroinflammation, which collectively drive progressive memory loss, cognitive decline, and behavioral changes.

Increasing evidence implicates epigenetic dysregulation as a key contributor to these pathological processes by altering gene expression programs. Serotonergic psychedelics, which primarily act as agonists of the serotonin 2 A receptor (5-HT₂AR), have recently attracted attention for their ability to robustly promote neuroplasticity and induce sustained transcriptional changes in the brain. Preclinical studies indicate that these compounds can modulate epigenetic mechanisms, including histone modifications and DNA methylation (DNAm).

This review examines the emerging intersection between psychedelic-induced epigenetic modulation and AD pathology, and proposes that targeted engagement of 5-HT₂Ars may help counteract epigenetic abnormalities that contribute to AD pathogenesis.

Gojani et al Serotonergic psychedelics as epigenetic modulators: A paradigm shift in Alzheimer's disease therapeutics. Neuroscience & Biobehavioral Reviews Volume 184, May 2026, 106619 Read Paper

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