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

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Phileas J Proskynitopoulos1, Alissa F Haarmeyer1, Stefan Bleich1

  • 1Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.

Addiction Biology
|July 14, 2025
PubMed

Insights

This study reveals that alcohol use disorder (AUD) is linked to altered oxytocin receptor (OXTR) gene methylation. Methylation changes in the oxytocin gene correlate with craving and withdrawal severity in AUD patients.

Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Oxytocin shows potential for treating alcohol use disorder (AUD), but its effects on craving and withdrawal are debated.
  • Epigenetic regulation, specifically DNA methylation of oxytocin and oxytocin receptor (OXTR) genes, influences social behavior and may be altered in mental disorders.
  • The role of epigenetic changes in oxytocin and OXTR during alcohol withdrawal and their association with AUD symptoms remains largely unexplored.

Purpose of the Study:

  • To investigate the impact of alcohol withdrawal therapy on the methylation levels of the oxytocin and OXTR genes.
  • To explore the association between these methylation changes and symptoms of craving and withdrawal in individuals with AUD.
  • To determine if OXTR gene methylation differs between individuals with AUD and healthy controls.

Main Methods:

  • An exploratory study involving 99 males undergoing 2-week alcohol withdrawal therapy and 31 healthy male controls.
  • Analysis of methylation levels in the promoter regions of the oxytocin and OXTR genes.
  • Statistical modeling (mixed linear models) to assess the relationship between gene methylation, withdrawal duration, craving, and withdrawal symptoms, considering covariates like age and smoking status.

Main Results:

  • Significantly lower mean methylation values of the OXTR gene were observed in patients with AUD compared to healthy controls (p < 0.001).
  • No significant differences in oxytocin gene methylation were found between the AUD group and controls.
  • Mean methylation levels for both oxytocin and OXTR genes decreased during the 2-week withdrawal period.
  • Craving and withdrawal symptoms were significantly associated with changes in oxytocin gene methylation (p < 0.001).
  • OXTR gene methylation changes were also linked to craving and withdrawal severity when age and smoking were included as covariates.

Conclusions:

  • This is the first study to demonstrate a direct association between alcohol use disorder, oxytocin, and OXTR gene methylation.
  • Reduced OXTR gene methylation in AUD patients compared to controls suggests a potential epigenetic mechanism.
  • Oxytocin gene methylation is significantly linked to the severity of craving and withdrawal symptoms in AUD.
  • Future research on oxytocin as an AUD therapeutic should consider the epigenetic regulation of oxytocin and its receptor as a key factor influencing treatment efficacy.
Keywords:
DNA methylationalcohol use disorderepigeneticsoxytocinsubstance use disorder

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