A new study in the July issue of scientific journal, Psychology & Behavior, examines the evidence of using GLP-1 inhibitors to treat nicotine use disorder. GLP-1 agonists include semaglutide, liraglutide, and exenatide sold under brand names such as Ozempic, Monjouro, and Wegovy. GLP-1 drugs were first prescribed for the treatment of type 2 diabetes and have since been approved by the U.S. Food and Drug Administration (FDA) for obesity.

The original evidence for the use of GLP-1 drugs to treat nicotine use disorder came from firsthand accounts of people taking the drugs for diabetes. Today, there are many clinical trials underway to test the effectiveness of GLP-1 drugs for smoking cessation therapy. One recently completed randomized controlled trial from a team at the University of Texas Health Science Center in Houston used an exenatide GLP-1 patch plus nicotine replacement therapy (NRT) and concluded:

Exenatide in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers.

Exactly how GLP-1 drugs work to reduce cravings and lessen withdrawal symptoms is still a mystery. A team of researchers at the University of Copenhagen in Denmark tried to get to the bottom of the issue in a review for the British Journal of Pharmacology, and concluded, “It is still unclear how GLP-1 receptor stimulation modulates the effects of drugs of abuse and alcohol.”

The researchers note that most studies focus on the effect of GLP-1 drugs on the brain’s reward system, and that other theories have not been reported: “The possibility that GLP-1 receptor stimulation might decrease alcohol intake through additional mechanisms has not been published.” 

The same is true for studies of GLP-1 agonists against opioids. One study found that GLP-1 for problem cocaine use acted through stress hormones:

[C]ocaine taking is associated with elevated plasma corticosterone levels… [T]his effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin.

Returning to the article in the British Journal of Pharmacology, the authors note, “A large literature suggests that activation of stress systems contributes to the addictive effects of various drugs of abuse.” They further speculate on the impact of GLP-1 agonists on stress:

This would suggest that GLP-1 receptor stimulation also modulates mechanisms underlying drug and alcohol “seeking” or “wanting,” and not only intake and satiation.

Finally, the researchers look at another possible source for how GLP-1 agonists reduce cravings, urges, and withdrawal symptoms when used to treat substance use disorder: the gut. Since GLP-1 reduces the appetite for both food and alcohol, the researchers suggest, “These effects may relate to nausea or general malaise, to the regulation of nutrient intake and consummatory behaviours, or both.”

The Danish authors cite studies in mice that show GLP-1 works to reduce alcohol intake independently of its effect on appetite. They cite studies with primates that show “no signs of nausea.” In humans, they review 32 clinical trials involving more than 10,000 humans treated with GLP-1 drugs and show significant gastrointestinal side effects. The authors note a lack of studies for GLP-1 agonists against substance use disorders in subjects who are normal weight. In the battle between the brain and the gut, we are left with this:

In addition to the GLP-1 produced in the small intestines after food intake, GLP-1 is also produced in the nucleus tractus solitarius of the brain and is released as a neurotransmitter in several brain regions.

The authors bring in dopamine signaling as a system modified by GLP-1 agonists, but seem frustrated to explain exactly how the drugs work: “No clear and well-defined circuit-level mechanism has been identified yet.” The researchers note that gender differences and species differences make it difficult to predict the results of human trials.

For now, we are left with a growing body of evidence that GLP-1 agonists have proven effective in reducing cravings and withdrawal symptoms from eating disorders, nicotine use disorder, opioid use disorder, and alcohol use disorder. Exactly how that process works is still being mapped out.

Written by Steve O’Keefe. First published August 21, 2024.

Sources:

“Targeting GLP-1 receptors to reduce nicotine use disorder: Preclinical and clinical evidence,” Psychology & Behavior, July 2024.

“The role of glucagon-like peptide 1 (GLP-1) in addictive disorders,” British Journal of Pharmacology, February 2022.

“Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine,” Neuropsychopharmacology, December 17, 2015.

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