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Epigenetic moderators of naltrexone efficacy in reducing heavy drinking in Alcohol Use Disorder: a randomized trial

The Pharmacogenomics Journal volume 22, pages 1–8 (2022)Cite this article

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Abstract

Polymorphisms in genes associated with opioid signaling and dopamine reuptake and inactivation may moderate naltrexone efficacy in Alcohol Use Disorder (AUD), but the effects of epigenetic modification of these genes on naltrexone response are largely unexplored. This study tested interactions between methylation in the μ-opioid receptor (OPRM1), dopamine transporter (SLC6A3), and catechol-O-methyltransferase (COMT) genes as predictors of naltrexone effects on heavy drinking in a 16-week randomized, placebo-controlled trial among 145 treatment-seeking AUD patients. OPRM1 methylation interacted with both SLC6A3 and COMT methylation to moderate naltrexone efficacy, such that naltrexone-treated individuals with lower methylation of the OPRM1 promoter and the SLC6A3 promoter (p = 0.006), COMT promoter (p = 0.005), or SLC6A3 3’ untranslated region (p = 0.004), relative to placebo and to those with higher OPRM1 and SLC6A3 or COMT methylation, had significantly fewer heavy drinking days. Epigenetic modification of opioid- and dopamine-related genes may represent a novel pharmacoepigenetic predictor of naltrexone efficacy in AUD.

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Fig. 1: Effect of naltrexone (open symbols), relative to placebo (closed symbols), on percent heavy drinking days (PHDD) during the 16-week trial as a function of SLC6A3 promoter and OPRM1 promoter methylation.
Fig. 2: Effect of naltrexone (open symbols), relative to placebo (closed symbols), on percent heavy drinking days (PHDD) during the 16-week trial as a function of COMT promoter and OPRM1 promoter methylation.
Fig. 3: Effect of naltrexone (open symbols), relative to placebo (closed symbols), on percent heavy drinking days (PHDD) during the 16-week trial as a function of SLC6A3 VNTR and OPRM1 promoter methylation.

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Acknowledgements

We gratefully acknowledge Robert Wilson, Ph.D., W. Bailey Glen, Ph.D., and E. Starr Hazard, Ph.D. for their assistance with conducting the methylation assays; Patricia Latham, Ph.D., R.N., Sarah Book, M.D., and Scott Stewart, M. D., for medical management of participants; Konstantin Voronin, M.D., Ph.D., Mark Ghent, B. A., and Melissa Michel, M. A., for assistance with participant recruitment and assessment; Patrick K. Randall, Ph.D., for study data management and initial statistical support; and Yeong-bin Im, M. S., for performing the DNA extraction and genotyping assays.

Author contributions

JPS conceived the study, conducted the data analysis and interpretation, and drafted the paper. MH and BHC assisted with data analysis and interpretation. RFA conceived and designed the study and assisted with data interpretation. All authors revised the paper critically for important intellectual content, approved of the final version, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01 AA017633, PI: RFA) and the Medical University of South Carolina Center for Genomic Medicine (PI: JPS). Additional funding was provided by a generous gift from Robert and Karen Sywolski.

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Authors and Affiliations

  1. Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Joseph P. Schacht

  2. Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

    Joseph P. Schacht, Michaela Hoffman & Raymond F. Anton

  3. FOXO Technologies Inc., Minneapolis, MN, USA

    Brian H. Chen

  4. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Brian H. Chen

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Correspondence to Joseph P. Schacht.

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Competing interests

JPS reports that, in the past 3 years, he has consulted for and received grant funding from Laboratorio Farmaceutico CT. BHC is an employee of FOXO BioScience. RFA reports that, in the past three years, he has received grant funding from Laboratorio Farmaceutico CT and consulted for Allergan, Alkermes, Dicerna, Insys, and Life Epigenetics (FOXO BioScience). He is the Chair of the Alcohol Clinical Trials Initiative (ACTIVE), which is conducted under the auspices of the American Society for Clinical Psychopharmacology and funded (in the past 3 years) in part by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. MH reports no biomedical financial interests or potential conflicts of interest.

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Schacht, J.P., Hoffman, M., Chen, B.H. et al. Epigenetic moderators of naltrexone efficacy in reducing heavy drinking in Alcohol Use Disorder: a randomized trial. Pharmacogenomics J 22, 1–8 (2022). https://doi.org/10.1038/s41397-021-00250-8

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  • DOI: https://doi.org/10.1038/s41397-021-00250-8

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