Abstract
Background
The relative efficacies of nalmefene versus naltrexone for alcohol use disorder is the subject of intense and ongoing debate. The two pan-opioid receptor ligands differ primarily in actions at the kappa opioid receptor, where naltrexone acts as an antagonist and nalmefene acts as a partial agonist. Parallel clinical trials for nalmefene or naltrexone have produced widely disparate outcomes and a marked lack of consensus regarding which of the compounds should be used for the treatment of alcohol use disorder.
Methods
Here we leveraged a mouse model (n = 56 male C57BL/6 J) to directly compare the efficacy of nalmefene and naltrexone within-subject. After acquiring operant responding for ethanol, each subject underwent four treatment block conditions: nalmefene (0.1 mg/kg i.p.), naltrexone (1.0 mg/kg i.p.), the selective kappa opioid receptor agonist U50,488 (1.0 mg/kg i.p.) and placebo (saline 10 ml/kg i.p.). Each treatment block consisted of an ethanol self-administration session followed by two subsequent sessions of punished (quinine adulterated) ethanol self-administration sessions with treatment given 30 min prior to each session.
Results
We show that nalmefene and naltrexone have similar efficacy in reducing ethanol consumption, whereas U50,488 increases ethanol consumption. Despite similar effects in aggregate analyses, nalmefene- and naltrexone-induced reductions in drinking are driven by fully separate subpopulations which do not show any beneficial response to the non-preferred compound and display markedly different behavioral phenotypes prior to treatment. A predictive model based on circulating biogenic amines allows for high accuracy classification of nalmefene- versus naltrexone-responders.
Conclusion
Together, these results provide a roadmap for improving alcohol use disorder treatment outcomes via precision application of existing compounds.
Plain Language Summary
Nalmefene and naltrexone are two drug treatments for alcohol use disorder, but disagreement exists on which is more effective. Despite ongoing controversy, treatment outcomes have only been compared across separate studies, rather than head-to-head. Using a preclinical model where mice learn to press a lever for alcohol, we treated each mouse with nalmefene, naltrexone, and placebo control. While both drugs equally reduced alcohol consumption on average, individual-level analysis revealed two distinct subpopulations: one responding to nalmefene but not naltrexone, and vice versa. Using machine learning on a single blood sample, we could predict which treatment would be more effective for each individual. This work suggests treatment outcomes for alcohol use disorder could be improved by using predictive models to deliver the right treatment to the right person at the right time.
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Acknowledgements
This work was supported by NIH grants R00 DA04510 (C.A.S), R01 AA030115 (C.A.S.), U01 AA029971 (C.A.S.), P60 AA031124 (C.A.S.), and the Whitehall Foundation (C.A.S). Z.Z.F. was supported by NIH fellowships T32 MH064913 and F31 DA056196. S.O.N. was supported by an NIH fellowship (F32 DA051136). S.M. was supported by a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.
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Z.Z.F., A.R.B., & C.A.S. conceived of the project. Z.Z.F. & C.A.S. designed experiments. Z.Z.F. & A.R.B. collected and analyzed data. Z.Z.F., A.R.B., S.O.N., & S.M. contributed to the execution of experiments. Z.Z.F., A.R.B., & C.A.S. wrote the manuscript. All authors read and edited the manuscript.
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Farahbakhsh, Z.Z., Brown, A.R., Nolan, S.O. et al. Nalmefene and naltrexone reduce alcohol intake via selective efficacy in subpopulations distinguished by behavioral and blood-based biomarkers. Commun Med (2026). https://doi.org/10.1038/s43856-025-01369-6
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DOI: https://doi.org/10.1038/s43856-025-01369-6
