A new study from the laboratory of Cody Siciliano, assistant professor of pharmacology, suggests that two widely used medications for alcohol use disorder—commonly called alcoholism—may be equally effective overall but individuals only respond to one of the two medications.
The findings, published in Nature Communications Medicine, could help explain why clinical trials of naltrexone and nalmefene, the two drugs in question, have produced conflicting results and may point toward a precision-medicine strategy for treating AUD, which affects millions of people worldwide and accounts for more than 5 percent of the global disease burden.
“Naltrexone and nalmefene are two clinically available medications for treating AUD, yet intense and ongoing debate surrounds their relative effectiveness,” Siciliano said. “They’ve never been directly compared within the same clinical trial, and regulatory agencies have taken opposing stances on their approval.”
Both drugs target the brain’s opioid system, the same system involved in motivation and reward. To directly compare them, Siciliano’s team used a mouse model in which animals learn to press a lever to receive alcohol. Uniquely, each mouse received both medications on different days, allowing researchers to assess not just average effects, but individual responses.
“When each mouse was tested with naltrexone on one day or nalmefene on a different day, it revealed that the beneficial effects of each compound were actually driven by completely separate subjects: Those that responded well to naltrexone showed no response to nalmefene, and vice versa,” Siciliano said.
When results were averaged across all animals, both drugs reduced alcohol consumption equally well. But individual analysis revealed two distinct subgroups:
- About 60 percent of mice responded to naltrexone but showed no benefit from nalmefene.
- The remaining 40 percent responded to nalmefene but not to naltrexone.
In other words, the apparent similarity between the drugs masked biologically meaningful differences.
“If these findings translate to humans, they could explain why clinical trials, which have tested one of the two compounds in isolation, have produced such conflicting results,” Siciliano said.
His lab is working to understand the biological mechanisms underlying the differences in the subgroups and is exploring whether sex differences potentially account for drug response.
In conjunction with their work on the underlying biology of the drugs’ actions, the authors trained a machine learning algorithm to predict treatment response based on behavioral and blood-based markers. The model predicted which medication would work for a given mouse with about 80 percent accuracy.
“The behavioral and blood-based predictors we identified could potentially be assessed in patients to guide treatment selection,” Siciliano said. “That offers a precision medicine approach to AUD that could be implemented relatively quickly since both drugs are already available on the market.”
Current medications help some patients with AUD but not others, and clinicians have had no reliable way to determine which drug will be most effective for a given individual.
“This work provides a roadmap for improving AUD treatment outcomes using medications that already exist,” Siciliano said. In the short term, he hopes the findings will encourage clinical researchers to conduct human trials that focus on individual-level responses rather than group averages.
If validated in patients, clinicians could one day use behavioral assessments or blood-based screening to match their patients with the medication most likely to help them.
“This personalized approach could substantially improve treatment success rates, reduce healthcare costs associated with ineffective treatments, and ultimately help more people achieve lasting recovery,” he said.
Go deeper
The paper “Nalmefene and naltrexone reduce alcohol intake via selective efficacy in subpopulations distinguished by behavioral and blood-based biomarkers” was published in Nature Communications Medicine in January 2026.
Funding
This research used funds from the National Institutes of Health, the Whitehall Foundation, and the Brain & Behavior Research Foundation.
School of Medicine Basic Sciences shared resources
The researchers made use of Vanderbilt’s Neurochemistry Core.
Open access
The study was published open access through a transformative agreement negotiated by Vanderbilt University’s Jean and Alexander Heard Libraries. Transformative agreements eliminate traditional paywalls and remove the obstacle of article processing charges, ensuring immediate and unrestricted access to research worldwide. Vanderbilt authors can learn more about the Heard Libraries’ agreements supporting open access publishing in this research guide.