Combining GLP-1 and Amylin Receptor Drugs Reduces Alcohol Drinking in Both Male and Female Rats | Research

The takeaway

Adding an amylin receptor agonist (salmon calcitonin) to ongoing GLP-1 treatment (dulaglutide) reduced alcohol intake in both male and female rats, though simultaneous initiation led to tolerance — suggesting treatment sequencing matters.

Reduced alcohol intake in both sexes with sequential treatment
Adding an amylin receptor agonist to ongoing GLP-1 treatment reduced alcohol drinking in both male and female rats — but starting both drugs simultaneously led to tolerance, highlighting the importance of treatment sequencing.

What the researchers found

Adding salmon calcitonin (sCT, amylin receptor agonist) to ongoing dulaglutide (GLP-1R agonist) treatment reduced alcohol intake in both male and female rats without tolerance development. When sCT and dulaglutide were started simultaneously, an initial reduction in alcohol intake was observed in both sexes, but tolerance developed over time. Both treatment combinations consistently decreased food consumption and body weight in males and females. The treatment combination did not affect inflammatory mediators or receptor gene expression but did change fat tissue morphology.

Why it matters

Alcohol use disorder (AUD) is a leading cause of preventable death with limited treatment options. The growing anecdotal and clinical evidence that GLP-1 drugs reduce alcohol cravings has generated enormous interest. This study takes the logical next step — combining two gut-brain peptide pathways (GLP-1 and amylin) to potentially enhance the anti-alcohol effect. The finding that treatment sequencing matters is practically important for clinical trial design.

How the study worked

Two separate alcohol-drinking experiments in rats of both sexes. Experiment 1: sCT was added to ongoing dulaglutide treatment (sequential approach). Experiment 2: sCT and dulaglutide were initiated simultaneously (concurrent approach). Outcomes measured included alcohol intake, food consumption, body weight, inflammatory mediators, amylin and GLP-1 receptor gene expression, and fat tissue morphology.

What this study cannot tell us

Rat alcohol-drinking models may not fully replicate human AUD patterns and motivations. Tolerance development with simultaneous treatment is concerning and would need to be addressed before clinical use. The study did not include a mechanistic analysis of why sequential addition worked better than simultaneous treatment. Specific dose-response relationships were not explored. The alcohol reduction effect was not compared to either drug alone as a single agent. Fat tissue morphology changes were observed but their significance is unclear.

How to read the evidence

This is a preclinical rat study using established alcohol-drinking paradigms with both sexes tested — an important design consideration often overlooked. The comparison of sequential vs. simultaneous treatment is informative. However, findings are limited to a rat model and the alcohol reduction effects were not compared to single-agent controls.

When this study was published

Published in 2024, this study arrives at the height of interest in GLP-1 drugs for addiction and represents an innovative approach to combining gut-brain peptide pathways for AUD treatment.

The bigger picture

The discovery that gut-brain peptides can modulate alcohol consumption connects the metabolic and addiction fields in unexpected ways. GLP-1 drugs are already in clinical trials for AUD, and amylin-based treatments are being developed for obesity. This study suggests that the combination could be more effective — but only with the right treatment sequence. As multi-receptor peptide drugs (like tirzepatide combining GIP/GLP-1) become available, adding amylin pathway activation could create a three-pronged approach to both obesity and addiction.

Questions still open

Why does sequential addition of amylin to GLP-1 treatment avoid the tolerance seen with simultaneous initiation?
Would combining GLP-1 and amylin receptor agonists reduce alcohol consumption in human clinical trials?
Could triple agonists targeting GLP-1, GIP, and amylin receptors provide enhanced anti-alcohol effects?

Common questions

Could GLP-1 drugs combined with amylin help people stop drinking?

This rat study suggests combining these two gut-brain peptide drugs can reduce alcohol consumption — but the timing matters. When amylin was added to ongoing GLP-1 treatment, rats drank less alcohol sustainably. When both were started at once, the effect wore off. If confirmed in humans, this sequential approach could offer a new treatment strategy for alcohol use disorder.

Why would gut hormones affect alcohol drinking?

GLP-1 and amylin are peptide hormones that signal between the gut and brain to regulate appetite and reward. Alcohol activates some of the same brain reward circuits as food. By modulating these circuits through two different peptide pathways simultaneously, the combination may reduce the rewarding effects of alcohol — essentially making it less appealing.

Read the original research

The combination of a glucagon-like peptide-1 and amylin receptor agonists reduces alcohol consumption in both male and female rats.

Acta neuropsychiatrica, 37, e42

View on PubMed ↗Publisher’s paper ↗

Citation

Aranäs, Cajsa; Edvardsson, Christian E; Zentveld, Lindsay; Vallöf, Daniel; Witley, Sarah; Tufvesson-Alm, Maximilian; Shevchouk, Olesya T; Vestlund, Jesper; Jerlhag, Elisabet. (2024). The combination of a glucagon-like peptide-1 and amylin receptor agonists reduces alcohol consumption in both male and female rats.. Acta neuropsychiatrica, 37, e42. https://doi.org/10.1017/neu.2024.58