Glucagon-like peptide-1 receptor agonists, often called GLP-1 RAs, are a class of peptide-based therapies that researchers have studied extensively for obesity, type 2 diabetes, heart failure, and cardiovascular risk reduction. Over the past several years, however, a separate and somewhat unexpected body of literature has started to accumulate around a different question: can these same molecules influence how people consume alcohol and tobacco?
A recent review published in the Journal of Cardiovascular Pharmacology examined this emerging area carefully. The authors noted that the signal is real but uneven across different molecules and different substances, meaning not every GLP-1 RA behaves the same way, and not every addictive substance has the same quality of evidence behind it. The paper frames the findings specifically for cardiologists, asking whether metabolic therapies might also quietly reduce cardiovascular risk by changing certain behavioral patterns.
This article walks through what the review found, why the mechanism might exist, and what the current limits of the evidence are.
The incretin system in brief
Incretin hormones are released by the gut after eating and help regulate insulin secretion, appetite, and food intake. GLP-1 is one such hormone, and researchers have developed synthetic peptide analogs that mimic or amplify its effects. These analogs bind to GLP-1 receptors found not only in the pancreas and gut but also in areas of the brain involved in reward, motivation, and behavior.
The presence of GLP-1 receptors in the brain is part of why researchers became curious about substance use in the first place. Reward circuitry in the brain, including pathways tied to dopamine signaling, is implicated in both appetite regulation and the reinforcing effects of substances like alcohol and nicotine. The hypothesis is that if a peptide dampens the reward signal associated with food, it might also blunt the reward signal from other substances.
Alcohol: the strongest signal so far
According to the review, alcohol currently has the most robust body of evidence among substances studied in relation to incretin therapies. Small randomized studies have examined whether semaglutide, a GLP-1 RA, can reduce laboratory measures of alcohol self-administration and self-reported craving. Those studies found reductions in both measures, suggesting the effect is not purely observational.
An earlier randomized trial using exenatide, another GLP-1 RA, was neutral overall in its primary outcome. However, the review notes that within that trial, participants with obesity appeared to show a benefit, which may point to a subgroup effect worth investigating further.
Beyond controlled trials, large registry studies and analyses of electronic health records have associated GLP-1 RA use with lower rates of alcohol-related hospitalization, lower rates of incident alcohol use disorder, and lower rates of recurring alcohol-related events. The review characterizes this as a consistent directional signal across multiple data sources, though the authors are careful to note that observational data carries its own limitations around confounding.
Tobacco use and early findings
The evidence around tobacco is described in the review as more limited but growing. A pilot smoking-cessation trial using exenatide has been published, and a separate analysis described as a target-trial emulation linked semaglutide use to fewer healthcare encounters related to tobacco use disorder.
The authors treat these findings cautiously. Pilot trials are by design small and are not powered to confirm effects. Target-trial emulations use real-world data structured to approximate what a randomized trial might look like, which is a legitimate and increasingly used methodology, but one that still relies on assumptions about confounding. Taken together, the tobacco literature suggests a plausible signal that warrants larger prospective investigation.
Other substances and tirzepatide
The review briefly addresses evidence beyond alcohol and tobacco. Observational analyses have reported lower rates of opioid overdose, alcohol intoxication as a discrete event, and cannabis use disorder among people exposed to GLP-1 RAs. The authors characterize this evidence as preliminary.
Tirzepatide is a dual incretin agonist that targets both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor. The review notes that tirzepatide-specific evidence in this area remains sparse. Given that tirzepatide activates a second receptor with its own distribution across brain and peripheral tissues, whether its behavioral effects will mirror, exceed, or differ from those of GLP-1-selective peptides is an open question in the literature.
Molecule specificity matters
One of the more important points the review makes is that not all incretin-based peptides appear to behave identically with respect to substance-related outcomes. The clearest human evidence is concentrated around semaglutide, with a more mixed picture for exenatide and little molecule-specific data for others in the class.
This matters because it pushes back against treating GLP-1 RAs as a uniform pharmacological category when it comes to behavioral outcomes. Differences in receptor binding affinity, receptor selectivity, pharmacokinetics, and brain penetration could all contribute to differences in behavioral effects. Researchers studying this area will likely need to characterize effects molecule by molecule rather than assuming class-wide equivalence.
Cardiovascular relevance of behavioral change
The review is addressed specifically to cardiovascular practitioners, and the framing reflects that context. Alcohol misuse and tobacco use are both well-established contributors to cardiovascular risk, including through pathways involving blood pressure, cardiac arrhythmia, atherosclerosis, and direct myocardial toxicity. If an already-prescribed cardiometabolic therapy also reduces the frequency of these behaviors, the downstream cardiovascular benefit could be meaningful.
The authors are clear that they are not proposing incretin therapies should be reclassified or repositioned as addiction treatments. The clinical question they raise is narrower: whether prescribers who are already using these peptides for metabolic indications should be aware that substance-related behaviors may also shift, and whether that possibility should factor into research design and patient monitoring.
For researchers and clinicians following this literature, the emerging picture suggests that the behavioral effects of incretin peptides are not a side observation to be dismissed but a phenomenon that warrants systematic study in prospective trials designed with those outcomes in mind.
