Epigenome-wide association study of psilocybin-induced methylome changes in alcohol use disorder

Does psilocybin treatment produces lasting changes in DNA methylation (the blood methylome) ?

The aim of this study was to determine whether psilocybin treatment produces lasting changes in DNA methylation (the blood methylome) in people with Alcohol Use Disorder, and whether these epigenetic changes are associated with improvements in depression symptoms, hopelessness, and drinking outcomes. The authors hypothesized that DNA methylation might be one mechanism underlying the long-lasting therapeutic effects reported after psilocybin.

Key points

• Psilocybin altered DNA methylation at specific genomic sites

• Methylation changes were linked to neuroplasticity and immune function

• Changes occurred in biologically relevant candidate genes

• Evidence pointed toward immunomodulatory effects

• Clinical improvements were seen mainly in depression—not alcohol outcomes

The underlying randomised clinical trial found no significant differences between the psilocybin and placebo groups in the primary alcohol-related outcomes (abstinence duration and mean alcohol consumption). However, psilocybin was associated with improvements in secondary psychological outcomes, including depressive symptoms and hopelessness, which were explored in relation to DNA methylation changes in this epigenome-wide association study

Abstract

The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 37 patients with blood sampling and acquisition of psychometrics – at baseline, 24 h after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment.

As the primary endpoints (duration of abstinence and mean alcohol use) in this trial were not reached, our investigation included secondary psychometrics that differed significantly between groups: Beck’s Depression Inventory and Beck’s Hopelessness Scale. The epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior.

Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Interestingly, several of the reported analyses point to immunomodulatory actions of psilocybin.

While the findings of this pilot study are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.

Urban, M.M., Zillich, L., Rieser, N.M. et al. Epigenome-wide association study of psilocybin-induced methylome changes in alcohol use disorder. Transl Psychiatry 16, 283 (2026). Read Paper

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