Epigenome-wide Association Study of Psilocybin-Induced Methylome Changes in Alcohol Use Disorder

A single dose of psilocybin (25 mg) was associated with changes in DNA methylation in patients with alcohol use disorder. One methylation site in the TLE4 gene and a region in the RASGRP4 gene showed significant alterations. Co-methylation networks linked to psilocybin treatment were also associated with reduced depressive symptoms and drinking behavior, and involved genes related to neuroplasticity and immune function. Baseline methylation differences between treatment responders and non-responders appeared in genes related to synaptic plasticity and neurotransmitter systems. The findings are preliminary due to the small sample size but align with prior research and suggest possible biological pathways for psilocybin's therapeutic effects.

Study at a glance

Abstract

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 40 patients with blood sampling and acquisition of psychometrics – at baseline, 24 hours after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. Our 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 . Furthermore, at p < 0.05, we found baseline differences between treatment responders (< 1 standard unit alcohol in 4-week follow-up) and non-responders in genes related to synaptic plasticity and different neurotransmitter systems. While these findings 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.