# The Role of Oxytocin and Oxytocin Gene Receptor Methylation During Withdrawal Therapy in Males With Alcohol Use Disorder

## TL;DR

This study explores how alcohol withdrawal affects methylation of the oxytocin and its receptor gene in males with alcohol use disorder, finding that methylation levels are linked to withdrawal symptoms and craving.

## Contribution

The study is the first to report an association between alcohol use disorder and methylation changes in the oxytocin receptor gene during withdrawal.

## Key findings

- Controls showed significantly higher OXTR gene methylation than patients during withdrawal.
- Craving and withdrawal symptoms were associated with changes in oxytocin gene methylation.
- OXTR gene methylation was reduced in alcohol use disorder patients compared to healthy controls.

## Abstract

Oxytocin is a promising therapeutic target in the treatment of alcohol use disorder (AUD). However, many studies report contradicting evidence regarding its effect on drug craving, relapse risk and withdrawal symptoms. Epigenetic regulation of the oxytocin and oxytocin receptor (OXTR) gene is altered in several mental disorders and influences social behaviour, often depending on the underlying sex. Evidence suggests that altered promoter methylation could result in oxytocin and OXTR expression differences, thereby possibly influencing drug craving and relapse risk. It is unclear whether promoter methylation changes throughout alcohol withdrawal and is linked to craving and withdrawal symptoms. In this exploratory study, we investigated the effect of 2‐week alcohol withdrawal therapy in 99 males on methylation levels (oxytocin and OXTR) compared with 31 healthy controls. We found significantly higher mean methylation values of the OXTR gene in controls than patients across withdrawal (p < 0.001). Regarding oxytocin, we found no differences in mean methylation in healthy controls compared with patients. Across withdrawal, mean methylation decreased in both genes. Fitting a mixed linear model, craving and withdrawal symptoms were associated with changes in methylation levels of the oxytocin gene (p < 0.001), which was also true for the OXTR gene when considering age and smoking as additional covariates. Our study is the first to report an association between AUD, oxytocin and OXTR gene methylation. Methylation of the OXTR gene is reduced in AUD compared with healthy controls, with OT gene methylation linked to craving and withdrawal severity. Our results suggest that investigations of oxytocin as a therapeutic agent need to consider epigenetic regulation of its receptor and gene as a mechanism that could influence oxytocin's effect on craving and withdrawal symptoms.

This study investigates the effect of alcohol withdrawal therapy on promoter methylation of the oxytocin and oxytocin receptor gene. We found significantly higher mean methylation values of the receptor gene in controls compared with patients across withdrawal and no differences in mean methylation of the oxytocin gene. Our results suggest that investigations of oxytocin as a therapeutic agent need to consider epigenetic regulation of its receptor and gene.