Weight loss drugs can also be leveraged to curb nicotine use
Rae Herman was the lead author on this study. Rae is a 5th year PhD Candidate in the lab of Dr. Heath Schmidt. Her research investigates the potential of repurposing current medications for obesity/type II diabetes as novel treatments for substance use disorders. She also explores neural basis of drug seeking with a focus on nicotine and fentanyl use disorder.
or technically,
Liraglutide attenuates nicotine self-administration as well as nicotine seeking and hyperphagia during withdrawal in male and female rats
[See Original Abstract on Pubmed]
Authors of the study: R J Herman, M R Hayes, J Audrain-McGovern, R L Ashare, & H D Schmidt
Nicotine use has long plagued humanity, despite how it negatively impacts our health. Indeed, numerous studies have shown that daily smoking leads to increased risk of cancers, lung disease, and heart disease1. However, despite this knowledge, most nicotine users are unable to stop smoking over the long-term. Only 10% of smokers are successful when they try to quit smoking2, and individuals who do manage to quit often develop strong cravings for highly palatable foods (i.e., foods that taste sweet or savory with high fat and/or sugar content)3. Weight gain during nicotine abstinence is a major concern for people trying to quit smoking and is one of the most significant barriers to quitting for good4. Current approved treatments for nicotine use, like varenicline and bupropion, are only modestly effective and do not prevent weight gain after quitting5.
However, there might be a pharmacological therapy that provides some hope for nicotine addiction. A class of drugs known as glucagon-like peptide-1 receptor (GLP-1R) agonists have recently been approved by the FDA to treat obesity. These drugs have been tremendously successful, with individuals suffering from obesity losing approximately 20% of their weight after long-term use6. The success of the drug has captured the attention of many people. For example, there are numerous ads on TV or social media posts relaying stories of people using the GLP-1R-based drugs for weight loss. Science magazine even named the development of this drug class as the “Breakthrough of the Year” in 20237. With the success of these drug treatments, users noticed that they had reduced cravings for both palatable foods and drugs such as nicotine and alcohol8.
This report was intriguing to Dr. Heath Schmidt, a professor at the University of Pennsylvania (Penn). His team was led by Rae Herman, a graduate student in the Neuroscience Graduate Group at Penn. They hypothesized that this class of miracle weight loss drugs might reduce nicotine use, and simultaneously prevent the cravings for highly palatable foods that arise after quitting smoking. Effectively, using one drug to treat two conditions, or essentially using one stone to kill two birds.
To test their hypothesis, the researchers used a rodent model of drug taking. Specifically, they inserted an intravenous catheter into the jugular vein of rats. By doing this, they could train the rats to press a lever and receive an infusion of nicotine into the bloodstream. The rats repeatedly self-administer nicotine, which mimics nicotine use throughout the day in humans. Once the rats became addicted to nicotine, the experimenters treated half of the mice with the GLP-1R agonist liraglutide, and the other half of the mice received no treatment. Strikingly, after mice were treated with liraglutide, they had a reduced number of self-administered infusions for nicotine. They also demonstrated less nicotine seeking lever presses in reinstatement tests, an animal model of relapse to drug taking. These results provide evidence that GLP-1R drugs can be repurposed from their current use as weight loss drugs to reduce nicotine use and relapse.
Next, the researchers evaluated how nicotine withdrawal affects food intake and body weight. First, rats self-administered nicotine every day for 21 days. Then, the rats went through nicotine withdrawal, where they no longer had access to nicotine. During withdrawal, the rats were given a highly palatable food source, which was high in fat and sugar. During nicotine withdrawal, rats ate more of the highly palatable food and gained more weight than a control group of rats that had no nicotine experience. This experiment confirmed that rats, like humans, eat more of highly palatable foods and gain weight during nicotine withdrawal. In parallel with this experiment, a separate group of nicotine-addicted rats received daily treatment with GLP-1R agonist liraglutide during the nicotine withdrawal period. Strikingly, although these rats were also given the highly palatable food, they consumed less food and did not gain weight compared to control rats that had no nicotine experience. Therefore, liraglutide was able to stop nicotine withdrawal from causing increased palatable food intake and body weight gain.
This exciting research suggests a novel role for GLP-1R-based drugs to curb nicotine use and prevent nicotine withdrawal-induced weight gain. Future studies can now determine the effectiveness of GLP-1R drugs at reducing nicotine use in humans, and if other drugs can be leveraged, in combination with GLP-1R drugs, to further help nicotine users achieve long-term abstinence.
About the brief writer: Aaron McKnight
Aaron is a PhD Candidate in Amber Alhadeff’s lab. The Alhadeff Lab is focused on understanding how different macronutrients are detected within the gastrointestinal tract and how this information is relayed to hypothalamic agouti-related protein (AgRP)-expressing neurons (a group of neurons that drive feeding behavior!).
Citations:
1. CDC (2020) Smoking Cessation: A Report of the Surgeon General. CDC Center for Disease Control and Prevention.
2. Babb S, Malarcher A, Schauer G, Asman K, Jamal A (2017) Quitting Smoking Among Adults - United States, 2000-2015. MMWR Morb Mortal Wkly Rep 65:1457–1464
3. Chao AM, Wadden TA, Ashare RL, Loughead J, Schmidt HD (2019) Tobacco Smoking, Eating Behaviors, and Body Weight: A Review. Curr Addict Rep 6:191–199
4. Benowitz NL (2009) Pharmacology of nicotine: addiction, smokinginduced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49:57–71
5. Mills EJ, Wu P, Lockhart I, Thorlund K, Puhan M, Ebbert JO (2012) Comparisons of high-dose and combination nicotine replacement therapy, varenicline, and bupropion for smoking cessation: a systematic review and multiple treatment meta-analysis. Ann Med 44:588–597
6. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, MTD T, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF, Group SS (2021) Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 384:989
7. Couzin-Frankel, J. Obesity Meets Its Match. Science (2023). Vol 382, Issue 6676.
8. Blum, D. People on Drugs Like Ozempic Say Their “Food Noise” Has Disappeared. (2023) New York Times.