Clues to psilocybin's epigenetic effects on people with alcohol use disorder - medicalxpress

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Some psychedelics, psychoactive substances that alter people's mood, perceptions and mental processes, were recently found to be promising alternative treatments for some mental health disorders. The substance that has attracted the most interest so far is psilocybin, a naturally occurring hallucinogenic compound found in more than 200 types of mushrooms.

Past studies have found that psilocybin can help reduce the symptoms experienced by some patients with treatment-resistant depression and substance use disorders, including alcohol use disorder (AUD). However, the biological mechanisms underpinning its therapeutic effects are still poorly understood.

Researchers at the University of Heidelberg and the University of Zurich recently carried out a study aimed at exploring how psilocybin influences how the genes of people recovering from AUD are modified. Their findings, published in Translational Psychiatry, offer some hints about how the psychedelic compound might influence these individuals' epigenome, the network of chemical compounds and proteins that are attached to DNA and influence how genes behave.

"The primary goal of our study was to examine epigenetic associations with psilocybin treatment in patients with AUD, as well as potential relationships between such associations and treatment outcomes," Marvin M. Urban, first author of the paper, told Medical Xpress. "Epigenetic mechanisms, including DNA methylation, are involved in psychiatric conditions, such as AUD or depression, and have been proposed to play a role in psychedelic effects as well.

"Despite the potential in this field (e.g., for biomarker identification or mechanistic insights), the epigenetics of psychedelics are still largely unexplored in clinical studies, and we sought to provide a starting point for further research on this topic." 

Study design of the randomized controlled trial: 37 patients participated in this study and were randomly assigned to treatment (psilocybin) or placebo group (mannitol, a sugar without psychoactive effects). Credit: Translational Psychiatry (2026). DOI: 10.1038/s41398-026-03961-3, figure created using biorender.com

Significant genes in our epigenome-wide association study. The genes marked by red circles showed significant longitudinal effects with biologically relevant effect sizes. Credit: Translational Psychiatry (2026). DOI: 10.1038/s41398-026-03961-3

Mapping epigenetic changes after psilocybin treatment

The recent study by Urban and his colleagues specifically explored the effects of psilocybin treatment on a mechanism known as DNA methylation. This mechanism entails the addition of "chemical tags" called methyl groups to DNA, which turn genes on or off by preventing proteins from accessing it.

To investigate how psilocybin influenced DNA methylation in patients recovering from AUD, the team analyzed data collected as part of a clinical trial led by Dr. Nathalie Rieser and her colleagues at the Psychiatric University Clinic in Zurich. The 37 patients who took part in this trial had already completed their detox period and were given either a single 25 mg dose of psilocybin or an inactive placebo as a potential treatment to prevent relapses.

"We received blood samples from before, shortly after, and one month after the treatment, and extracted DNA from them," Urban explained. "The methylation status of roughly 1 million locations in the genome was then assessed in these samples, and a series of statistical approaches was used to identify changes related to the psilocybin treatment and potential correlations with behavioral and psychological outcomes."

The team's analyses led to the identification of a specific DNA methylation-related change that was significantly linked with the intake of psilocybin. This alteration was located in the gene TLE4, which encodes a gene-suppressing protein.

In addition, the researchers observed altered methylation in the gene RASGRP4 and some changes near the genes HTR2A and TNF. RASGRP4 plays a role in the development and function of mast cells, as well as various immune responses. HTR2A encodes a serotonin receptor that plays a role in psilocybin's effects. Finally, TNF is known to be involved in inflammation and immune responses.

"While the findings of this study have to be seen as exploratory and require replication in larger data sets, it was interesting to observe that different lines of analysis pointed to genes related to the immune system," Urban said. "It is known that AUD involves immunological dysregulation, and psilocybin seems to possess immunomodulatory capacities, thus our findings could hint at a potential therapeutic mechanism."

Informing future clinical trials with psilocybin

While the results of this study are still preliminary, they suggest that psilocybin can influence the human epigenome in patients with AUD. Other research groups could build on the team's observations and set out to explore the effects of the psychedelic compound on other epigenetic mechanisms or on DNA methylation in patients with other psychiatric conditions.

Urban and his colleagues hope that their efforts will also inspire more clinical trials involving psychedelics. These trials could lead to the collection of more blood samples that could be used to perform similar analyses, potentially yielding more valuable insights.

"My current plans are just vaguely related to this project and mainly revolve around multimodal neuroimaging in preclinical addiction models, in one study also including intervention with a hallucinogenic compound," Urban added. "However, some of my colleagues are now analyzing epigenetic data collected during a clinical trial on psilocybin against treatment-resistant depression. I am excited to see what they will find out."

by Ingrid Fadelli, Medical Xpress

edited by Lisa Lock, reviewed by Robert Egan 

Source: Clues to psilocybin's epigenetic effects on people with alcohol use disorder