GLP-1 Drugs Show Promise in Alcohol, Opioid Use Disorders

03 Aug 2023
www.biospace.com
Phase 2
Pictured: Man with head in hands and a bottle of whiskey/iStock, Vahe Aramyan The powerhouse of weight loss and type 2 diabetes drugs, glucagon-like peptide-1 receptor agonistsglucagon-like peptide-1 receptor agonists, have also shown the potential to treat nonalcoholic fatty liver disease, cardiovascular disease and Alzheimer’s disease—and early research suggests they could treat addiction too. Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion after eating, enabling a feeling of fullness and regulating blood sugar. GLP-1 agonists mimic the effects of this hormone, making them an effective treatment for diabetes and obesity. Now, anecdotal reports suggest the mechanism may work in addictive disorders as well. Michael Glickman, an obesity medicine specialist at Revolution Medicine, Health & Fitness, told BioSpace he has had many patients report less desire to drink or smoke after starting such treatments. Negating the Reward Drug consumption is partly driven by the pharmacological effects that trigger reward circuits in the brain, according to a review published in 2019 in Physiological Reviews. These effects mostly depend on dopamine signaling in the nucleus accumbens, the authors write. Preclinical studies have shown that GLP-1 agonists can circumvent the release of dopamine in this primary reward center, Patricia “Sue” Grigson, an addiction researcher at Pennsylvania State University, told BioSpace. Glickman agreed, saying the patient reports suggest that GLP-1 is “blunting that pleasure response across the board. I think there are so many interplays in the brain that are involved with the dopamine pleasure response, and addiction falls into that.” The other way targeting the GLP-1 receptor may work, Grigson said, is by reducing someone’s responsiveness to “cues” for a drug. There are three roads to relapse, she said. “One is being re-exposed to cues in contexts that are associated with the drug. The second is being re-exposed to the drug after a period of abstinence, and the other is stress.” GLP-1 and its receptor are particularly engaged in people who both drink and eat a lot, Lorenzo Leggio, a physician-scientist at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA), told BioSpace. Lorenzo Leggio “There is an important overlap in the body between the mechanism that regulates pathological overeating and the mechanism that regulates pathological overdrinking,” he said. “The idea is that in order for [a drug targeting GLP-1 to work], you need to have an imbalance in the pathological GLP-1 system, and by giving GLP-1 . . . you are fixing that impairment.” Leggio’s team is exploring this hypothesis in a number of studies, including one where they measured GLP-1 levels in the blood of alcohol use disorder (AUD) patients. “What we saw was that . . . after drinking alcohol, GLP-1 was going down,” Leggio told BioSpace. While GLP-1 levels rise with food consumption to regulate glucose, Leggio said that alcohol may work along the same pathway but have the opposite effect. Leggio recently published another paper in JCI Insight showing that semaglutide, the key ingredient in Novo Nordisk’s GLP-1 receptor agonistsGLP-1 receptor agonists Wegovy, Ozempic and Rybelsus, reduces alcohol consumption and binge-like drinking in rodents. Leggio said this preclinical evidence shows semaglutide “may be a promising new medication for [AUD].” He said that from a pure, neurobiological standpoint, there is a strong consensus that GLP-1 plays an important role in AUD. What is not known, he cautioned, is whether the preclinical findings will translate to humans. In the Clinic Recent evidence suggests it might. In 2022, Mette Kruse Klausen of the Psychiatric Centre Copenhagen and colleagues published a study of 127 people with AUD randomized to receive either AstraZenecaAstraZeneca’s GLP-1 receptor agonistGLP-1 receptor agonist exenatide or a placebo once a week for 26 weeks, in addition to standard cognitive-behavioral therapy. While exenatide did not significantly reduce the number of heavy drinking days compared with placebo, the authors reported that it did reduce alcohol cue reactivity in the ventral striatum and septal area—also key reward centers in the brain. Interestingly, exploratory analyses showed that exenatide did significantly reduce heavy drinking days and total alcohol intake in a subgroup of obese patients. Leggio is also pursuing this question, with plans to study semaglutide in people with AUD. The study is currently under review by the Institutional Review Boards (IRB), and Leggio said he expects the outcome “very soon.” NIAAA is also collaborating with the University of North Carolina at Chapel Hill on a Phase II trial studying the use of semaglutide in smokers with AUD. Preclinical evidence indicates that GLP-1 “impacts both alcohol and nicotine motivation and intake,” according to the study outline, published on ClinicalTrials.gov. Patricia “Sue” Grigson And at Penn State, Grigson’s team is conducting a study assessing another GLP-1 analog, liraglutide, as a treatment for opioid use disorder in patients at the Caron Treatment Centers. She expects initial data this October. Grigson’s lab takes the position that addiction involves having a “real physiological need for the drug.” So, her team is also exploring whether GLP-1 drugs might reduce the experience of withdrawal when someone abruptly stops using a substance to which their system is accustomed. In a soon-to-be-published preclinical study, the researchers were able to block evidence of conditioned withdrawal using a GLP-1 agonist. “GLP-1 agonists might be working there in order to reduce that heavy physiological need,” Grigson said. Leggio called it a “very, very exciting time” for the space because “several clinical investigators are jumping to this very promising target and running studies.” Still Early Days Not all research on GLP-1 agonists for addiction has been positive, however. A study published in 2021 found that low-dose exenatide did not alter cocaine self-administration in people with cocaine use disorder (CUD). However, the authors stated that they were unable to draw firm conclusions as to exenatide’s efficacy in CUD as the drug was only given once rather than as chronic pre-treatment. Grigson agreed that the single dose could have contributed to the result and added that the study participants didn’t have a desire to quit taking cocaine. In Grigson’s experience, there is also a notable difference in the effect of GLP-1 drugs on people seeking out a drug and taking it when it is placed in front of them. “The effects on taking are smaller than the effects on seeking,” she said. “The seeking is where you get the big effect.” Grigson cautioned that GLP-1 drugs will not work for everyone. “No drug is going to be a panacea,” she said. “But it’s one more tool in our toolbox; one more opportunity to provide treatment for some people.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.
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