Epigenome-wide association study of psilocybin-induced methylome changes in alcohol use disorder.
Marvin M. Urban, Lea Zillich, Nathalie M. Rieser, Marcus Herdener, Rainer Spanagel, Franz X. Vollenweider, Katrin H. Preller, Marcus W. Meinhardt
Translational Psychiatry May 26, 2026 DOI: 10.1038/s41398-026-03961-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Longitudinal, placebo-controlled pilot study with epigenome-wide association study Peer reviewed |
|---|---|
| Sample size | 37 |
| Population | Detoxified patients with alcohol use disorder |
| Interventions | Psilocybin Placebo (mannitol) |
| Dose | 25 mg |
| Duration | 24 hours and one month after treatment |
| Topics | Addiction Psilocybin |
| Citations | 1 |
| Key findings | Psilocybin treatment was associated with methylation changes in TLE4 and RASGRP4, and co-methylation networks linked to neuroplasticity and immune functions were related to reductions in depressive symptoms and drinking behavior. |
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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Primary endpoints of abstinence duration and mean alcohol use were not reached, but psilocybin was associated with methylation changes in TLE4 and RASGRP4 and co-methylation networks linked to reductions in depressive symptoms and drinking behavior.
Synthesized
Comparable studies
Other randomized controlled trials on psilocybin for addiction, most cited first.