Tirzepatide vs. Semaglutide for Addiction: Does the Dual Agonist Work Better?
Key Findings
- Tirzepatide reduced voluntary alcohol intake by over 50% in rats
- Prevented relapse-like drinking behavior after a period of abstinence
- Attenuated alcohol-induced dopamine release, particularly via the lateral septum
- Effects were sustained across repeated dosing (no tolerance observed)
- Altered histone-related proteins linked to addiction epigenetics
The Study
Researchers at the University of Gothenburg, in collaboration with the Medical University of South Carolina, published a comprehensive preclinical study in eBioMedicine (a Lancet journal) in January 2026. Led by Professor Elisabet Jerlhag Holm, the team tested tirzepatide — the active ingredient in Mounjaro and Zepbound — across multiple alcohol-related behavioral paradigms in mice and rats.
The results were robust across every measure tested. Tirzepatide attenuated alcohol-induced locomotor stimulation (a proxy for the stimulating, rewarding effects of alcohol), reduced the expression of alcohol-induced conditioned place preference (meaning the animals were less drawn to environments associated with alcohol), and cut voluntary alcohol intake by more than 50% in an intermittent access model that mimics binge drinking patterns.
Crucially, tirzepatide also prevented relapse-like behavior. After a period of forced abstinence, animals treated with tirzepatide showed significantly less alcohol-seeking behavior than controls — a finding directly relevant to the clinical reality of addiction, where relapse is the most common and dangerous outcome.
Why Dual Agonism Might Matter
Semaglutide (Ozempic, Wegovy) activates only GLP-1 receptors. Tirzepatide (Mounjaro, Zepbound) activates both GLP-1 receptors and GIP (glucose-dependent insulinotropic polypeptide) receptors — actually with higher binding affinity for GIPR than GLP-1R.
GIP receptors are expressed in several brain regions involved in reward processing, and emerging evidence suggests that GIP signaling may independently modulate dopamine transmission. The dual mechanism could theoretically provide stronger or more sustained modulation of reward circuitry than GLP-1 agonism alone.
The Gothenburg study found that tirzepatide attenuated alcohol-induced dopamine effects specifically in the lateral septum — a brain region linked to motivation, reward, and relapse that is distinct from the VTA and nucleus accumbens regions most studied in semaglutide research. This suggests tirzepatide may engage additional neural pathways relevant to addiction.
Head-to-Head: What We Know
| Factor | Semaglutide | Tirzepatide |
|---|---|---|
| Receptor targets | GLP-1R only | GLP-1R + GIPR (dual) |
| Human addiction RCTs | Yes (Lancet 2026, JAMA Psych 2025) | None yet |
| Rodent alcohol data | Reduces intake, modulates GABA in amygdala | Reduces intake >50%, prevents relapse, affects lateral septum dopamine |
| Epigenetic effects | Not yet studied in addiction context | Altered histone-related proteins (Gothenburg study) |
| Key brain regions | VTA, NAc, central amygdala | VTA, NAc, lateral septum |
| Tolerance with repeated dosing | Not observed in trials | Not observed (sustained effects over 2 weeks) |
The Missing Piece: Human Data
The critical gap is that tirzepatide has no human addiction data at all. Every published clinical trial and observational study examining GLP-1 medications and addiction has focused on semaglutide, liraglutide, or dulaglutide — all pure GLP-1 agonists. No randomized controlled trial has tested tirzepatide in people with any substance use disorder.
Until that data exists, comparing the two drugs' anti-addiction potential remains speculative. The rodent data is encouraging, but rodent models of addiction, while valuable, don't always translate directly to human clinical outcomes.
"This is not yet a new treatment for alcohol use disorder. But the findings reinforce the view that drugs targeting these neural systems may be relevant to investigate further as potential treatment options." — Professor Elisabet Jerlhag Holm, University of Gothenburg
The Bottom Line
Tirzepatide's dual GLP-1/GIP mechanism is scientifically compelling and the preclinical data is strong. But semaglutide is currently years ahead in human evidence for addiction. Anyone interested in GLP-1 medications for substance use should discuss the options with their healthcare provider and consider enrolling in clinical trials.
Sources
- Edvardsson CE, Adermark L, Gottlieb S, et al. Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents. eBioMedicine. 2026;124:106119. doi:10.1016/j.ebiom.2025.106119.
- Klausen MK, et al. Once-weekly semaglutide versus placebo in patients with AUD and comorbid obesity. The Lancet. 2026;407(10540):1687-1698.
- Chuong V, et al. The GLP-1 analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI Insight. 2023;8(12):e170671.