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In recent years, psychedelics have been investigated not only for their acute psychological effects but also for possible longer-term changes in the body. A relatively new area of research in this regard is epigenetics: processes that can influence which genes are more or less active without changing the DNA code itself. In a recent study in Translational Psychiatry Researchers investigated whether psilocybin in people with alcohol problems was associated with changes in DNA methylation, a commonly used epigenetic “marker”.

This article outlines the findings, with nuance. What does this research say, what does it not say, and why is it particularly interesting as an exploratory step? In doing so, we use “psychedelics” as an umbrella term, but the study discussed specifically concerns psilocybin.

What is epigenetics, and what is DNA methylation?

Epigenetics deals with biological “on-off switches” that help determine how active certain genes are. One of the most studied forms is DNA methylation: small chemical groups (methyl groups) that can attach to specific locations in the DNA. This can be associated with changes in gene activity, although that relationship is not always one-to-one.

Importantly, epigenetic patterns can be influenced by a wide range of factors, such as stress, sleep, diet, age, medication, inflammation, and also by abstinence or recovery processes in addiction. This makes epigenetics interesting, but also complex: a change in methylation is not automatically proof of a mechanism of action, let alone a treatment outcome.

The study in brief: design and context

The researchers analyzed blood samples from 37 participants with alcohol use disorder (alcohol problems) who had previously participated in a randomized, double-blind, placebo-controlled study. The participants had stopped using alcohol beforehand. They received either 25 mg of psilocybin or a placebo (mannitol). There were three measurement points: at baseline, 24 hours after ingestion, and approximately one month later.

In addition to the blood test, participants completed psychological questionnaires and alcohol consumption was monitored. The central question in this specific publication was not “does psilocybin work for alcohol problems?”, but rather: do we see signs of epigenetic changes that might shed light on underlying biological pathways?

What they did not find: no convincing effect on primary alcohol outcomes

A crucial point for interpretation: the original clinical study found no statistically significant difference between the psilocybin group and the placebo group on primary outcomes, such as duration of abstinence and average alcohol consumption. This means that this dataset does not provide strong evidence that psilocybin improved core drinking outcomes in this setting.

That is not the same as “there is no effect”. It could also mean that the study was too small, that the measurement period or design was not optimal, or that there was significant variation among participants. But in fact, this is indeed the state of affairs for this specific study: the primary alcohol outcomes did not differ convincingly.

What they did find: exploratory signals in methylation and mood

Although the primary alcohol outcomes did not differ significantly, the researchers did observe greater improvements in some secondary measures in the psilocybin group, such as depressive symptoms and hopelessness. Such findings are clinically interesting but remain supplementary and hypothesis-generating in this context. Secondary outcomes can provide clues but are less “hard” than predetermined primary endpoints.

At the epigenetic level, a so-called epigenome-wide association study (EWAS) was conducted. This involves scanning a large number of methylation sites (CpG sites) in the genome to see where differences appear. The EWAS found one CpG site that was associated with psilocybin treatment and was linked to the gene. TL4. In addition, the researchers found a differentially methylated region in RASGRP4.

These genes are linked by the authors to broader biological processes such as gene regulation, immune function, and possibly neuroplasticity. The keyword is: possibly. In a small study, this type of linkage is primarily indicative, not decisive.

Serotonin, the immune system, and neuroplasticity: why precisely these themes recur

In the public discussion about psychedelics, neuroplasticity—the brain's ability to adapt—often comes up. Additionally, there is increasing attention being paid to the immune system and inflammatory processes, as chronic stress and addiction are sometimes linked to altered stress biology and immune activity.

In this study, additional analyses (such as network analyses with comethylation modules) revealed a pattern suggesting associations between psilocybin treatment, changes in depressive symptoms, and drinking behavior, with gene functions related to synaptic transfer, cell regulation, immune function, and neuroplasticity.

However, the same applies here: these are statistical correlations in methylation patterns. They do not yet indicate the direction of causality. For example, it is quite possible that abstinence, better sleep, reduced stress, or other recovery processes also influence methylation. The authors acknowledge this themselves: some of the patterns may be related to quitting alcohol or recovery, and are not necessarily caused exclusively by psilocybin.

Candidate genes such as HTR2A and TNF: interesting, but vulnerable

In addition to the broad “scan,” the researchers also looked specifically at candidate genes. Nominal methylation changes were observed there in the promoter region of HTR2A and TNF. HTR2A is relevant because the 5-HT2A receptor is an important target for classic psychedelics. TNF is known within research into immune signaling and inflammatory pathways.

The nuance is that such candidate findings did not all hold up after stricter statistical corrections. This is important because it is easy to find “chance strikes” in many comparisons. Therefore, these results should primarily be viewed as indications for further research, not as confirmed biomarkers.

Why measuring blood is not the same as measuring the brain

A practical limitation of this type of study is that methylation was measured in blood, not in brain tissue. This is logical, because brain tissue cannot simply be sampled from living participants. At the same time, it means that we must be cautious about making statements regarding “what happens in the brain”.

Some systemic processes, such as immune activity or stress-related pathways, can be partially observed in the blood. However, the translation to neural circuits, behavior, and psychological change is complex. Therefore, it is not possible to say, based on this data, that psilocybin “epigenetically reprograms the brain” or make similar definitive claims. The evidence for this is still too limited.

What does this mean for the broader question: psychedelics and epigenetics?

When placed in the broader context, the most important value is that it demonstrates that it is technically and methodologically feasible to investigate epigenetic changes in humans surrounding a psychedelic intervention, and that there are signals consistent with known hypotheses (serotonin signaling, immune pathways, neuroplasticity).

At the same time, it is still early days. The study is small, the effects are subtle, and the primary alcohol outcomes did not improve convincingly. This makes this primarily mechanistic and exploratory research. It helps to ask better questions for larger studies, for example:

1) Are the methylation patterns reproducible in larger groups?

2) Are they specific to psilocybin, or primarily a result of abstinence and recovery?

3) Are they associated with certain subgroups, for example, people with more depressive symptoms, different stress profiles, or a different treatment history?

It is useful for readers to remember that “psychedelics and epigenetics” is currently primarily a field of research, not clinically applicable knowledge. It is interesting because it forms a potential bridge between experience and biology, but it is not yet a basis for conclusions regarding treatment or effectiveness for alcohol problems.

Practical reality: therapy, research and safety

In the Netherlands, sessions with substances such as psilocybin and MDMA are regularly mentioned in the media and in personal accounts in relation to therapy. What remains important in practice is a clear distinction between scientific research, personal experiences, and harm reduction information.

Specifically regarding MDMA, MDMA sessions can currently only be discussed within scientific research or in clinical practice via harm reduction. This means that the focus is on risk mitigation, preparation, setting, integration, and recognizing contraindications, and not on making treatment claims or providing individual medical advice.

Anyone wishing to familiarize themselves with how a guided session in a harm-reduction context is typically described can consult the information page about psilocybin therapy read. View this as general information and not as a substitute for medical or psychological care. For the scientific context and details of the epigenetic study discussed, you can also consult the source summary: Psilocybin, DNA methylation and alcohol use disorder.

Conclusion

This first methylome-wide study in people with alcohol use disorder shows that psilocybin may be associated with small, exploratory changes in DNA methylation, with indications towards serotonin signaling, immune function, and neuroplasticity. At the same time, the underlying clinical study found no convincing effect on primary alcohol outcomes, and the epigenetic signals are still too preliminary to be used as a mechanism or biomarker. The main gain is that this provides the field with a new line of research that needs to be confirmed and refined in larger studies.