A single dose of the GLP-1 peptide drug liraglutide reduced cue-induced fentanyl seeking and blocked drug-induced relapse in female rats, with the strongest effects occurring during estrus — the phase when females are most vulnerable to drug seeking.
Blocked drug-induced relapseA single dose of liraglutide (0.3 mg/kg) completely blocked fentanyl-primed reinstatement of drug seeking in female rats, particularly during estrus — the phase of highest addiction vulnerability.
What the researchers found
Female rats readily self-administered fentanyl (1.85 μg/infusion IV) with marked individual differences in consumption patterns. Rats in estrus showed greater fentanyl intake, greater cue-induced fentanyl seeking, and greater drug-induced reinstatement of fentanyl seeking compared to those in non-estrus phases.
Acute liraglutide treatment (0.3 mg/kg subcutaneous) produced two key effects: it reduced cue-induced fentanyl seeking, and it blocked drug-induced reinstatement of fentanyl seeking. These effects were particularly pronounced when rats were tested during estrus — the very phase associated with greatest vulnerability.
This extends previous findings in male rats to females, supporting the broad applicability of GLP-1 receptor agonists as potential non-opioid treatments for opioid use disorder across both sexes.
Why it matters
The opioid overdose crisis, now driven largely by fentanyl, kills over 100,000 Americans annually. Current medications for opioid use disorder (methadone, buprenorphine, naltrexone) are all opioid-based and have limitations. GLP-1 receptor agonists like liraglutide represent a completely different approach — targeting reward and motivation pathways through a non-opioid mechanism. The finding that liraglutide is most effective during the hormonal phase of greatest vulnerability is particularly significant for developing sex-specific treatment strategies.
How the study worked
Female Sprague-Dawley rats were trained to self-administer fentanyl intravenously (1.85 μg/infusion). Estrus cycle phase was tracked to assess hormonal influences on drug-taking behavior. After establishing self-administration, researchers tested cue-induced seeking (exposure to drug-associated cues without drug delivery) and drug-induced reinstatement (a prime dose of fentanyl triggering renewed seeking). Liraglutide (0.3 mg/kg) or vehicle was administered as a single subcutaneous injection before these tests. Individual differences in fentanyl intake patterns were also characterized.
What this study cannot tell us
This is an animal study in rats, and addiction neurobiology differs between rodents and humans. The study used acute (single-dose) liraglutide, so chronic treatment effects are unknown. The fentanyl self-administration model, while well-established, cannot fully replicate the social, psychological, and environmental factors of human opioid use disorder. Sample sizes per group are not specified in the abstract. The 0.3 mg/kg dose in rats does not directly translate to human dosing. Only one GLP-1 agonist (liraglutide) was tested.
How to read the evidence
This is a preclinical animal study with a well-designed behavioral paradigm. The controlled experimental conditions allow strong causal inference within the rat model, but translation to human opioid use disorder remains uncertain. The finding extends previous work in males to females, strengthening the overall evidence base for GLP-1 agonists in addiction.
When this study was published
Published in 2025, this is a very recent study contributing to the rapidly growing body of research on GLP-1 drugs for addiction. Clinical trials in humans may be underway or planned based on this and similar preclinical evidence.
The bigger picture
There is growing interest in repurposing GLP-1 drugs for addiction treatment, with observational studies in humans suggesting that patients on semaglutide or liraglutide for diabetes or obesity show reduced substance use behaviors. This rat study provides controlled experimental evidence supporting that observation, and adds a crucial sex-specific dimension. Women face unique biological risk factors for addiction related to hormonal cycling, and the finding that GLP-1 activation is most effective precisely when vulnerability peaks could inform precision medicine approaches to addiction treatment.
Questions still open
- Would chronic GLP-1 agonist treatment maintain its anti-seeking effects over time, or would tolerance develop?
- Do the anti-addiction effects of GLP-1 drugs extend to other opioids beyond fentanyl, and to other substances of abuse?
- Could menstrual cycle phase in human women predict when GLP-1 treatment would be most effective for preventing opioid relapse?
Common questions
Why would a diabetes drug help with opioid addiction?
Why are hormonal cycles important for understanding addiction in females?
Read the original research
Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats.
Behavioural pharmacology, 36(1), 16-29
Citation
Urbanik, Luke A; Booth, Jennifer L; Acharya, Nikhil K; Evans, Brianna B; Grigson, Patricia S. (2025). Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats.. Behavioural pharmacology, 36(1), 16-29. https://doi.org/10.1097/FBP.0000000000000805