Hype Or Hope? Latest Research On GLP-1 Receptor Agonists And Addiction
The talk of the town at this year's American Society of Addiction Medicine (ASAM) Annual Conference was GLP-1 receptor agonists (GLP-1 RAs), generally known as medications to treat obesity. Mainstream media appears to mirror this trend as nearly every other radio and television ad seemingly involves a weight loss medication. In addition to treating obesity and type 2 diabetes, GLP-1s have also shown promise with substance use disorders (SUD). Because so many questions exist about safety, efficacy, long-term effects and more, ASAM appropriately invited several scientists and clinicians to present the latest data on the role of GLP-1 RAs in addiction.
As a physician, even I'm having trouble keeping track of the assembly-line of anti-obesity medicines. The common ones include semaglutide (Ozempic, Wegovy), liraglutide (Victoza), tirzepatide (Mounjaro, Zepbound), dulaglutide (Trulicity) and exenatide (Byetta). They vary in their duration, formulation and other features. What they share, however, is a common lizard origin—the Gila monster.
Origin Story Starts With A Venomous Lizard
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Exendin-4, a peptide hormone discovered in 1991 in the venom of the Gila Monster, was structurally similar to the human hormone, glucagon-like peptide-1 (GLP-1), explained Joji Suzuki, MD, FACLP, director of the Division of Addiction Psychiatry at Brigham and Women's Hospital. GLP-1s increased the release of insulin but had an extremely short half-life (1-2 minutes), making them highly unfavorable as a treatment for diabetes. The lizard hormone half-life was nearly 100 times longer (~2.5 hours) which led to more research focusing on increasing half-life, resisting degradation and enhancing binding to the GLP-1 receptor.
Since that initial discovery nearly four decades ago, the pace of research and publications on GLP-1 RAs has been nothing short of rapid and robust, according to data shown by Dr. Suzuki. Liraglutide began clinical trial in 2000. Exenatide became the first FDA-approved GLP-1 analog in 2005. Semaglutide was approved by the FDA in 2017 as an injectable treatment for type 2 diabetes under the brand name, Ozempic. Tirzepatide was approved in 2022. That same year, GLP-1 drug sales reached $22 billion.
Role In Addiction
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GLP-1 receptors are widely located in the brain, notably in the reward centers. Addictive substances such as nicotine, alcohol and opioids hijack the brain's reward pathway to trigger excess release of dopamine, the 'feel-good' neurotransmitter. Studies show that activation of the GLP-1 receptor in the brain reduces dopamine release from addictive substances such as nicotine and alcohol, leading to less cravings and reinforcement. Researchers who are studying the impact of GLP-1 agonists in addiction are hopeful.
'For the first time in a long time, we actually have the possibility for a whole new class of medications our patients [with addiction] might benefit from,' shared Dr. Suzuki. He continued: 'The exciting part is that GLP-1 RAs might benefit a broad range of addictive behaviors including disordered eating or behavioral addictions.'
Nicotine Addiction
While randomized control trials (RCT) are few, we do have promising preclinical data showing reduced nicotine withdrawal-induced hyperphagia (excessive hunger) and weight gain with liraglutide. In addition, epidemiological studies have demonstrated that patients with type 2 diabetes (T2D) who used GLP-1 RAs were less likely to be diagnosed with nicotine misuse compared to those who used other medicines for T2D. Less healthcare utilization for tobacco use disorder was also associated with this patient group.
Like all medicines, GLP-1 RAs are not benign. Luba Yammine, PhD, associate professor of psychiatry at UTHealth Houston, reminded the packed ballroom that common side effects include gastrointestinal symptoms like nausea, vomiting and diarrhea, as well as acute kidney injury. There's also a higher risk of pancreatitis and medullary thyroid cancer.
But Dr. Yammine is optimistic, particularly for people who are addicted to several substances: 'A substantial proportion of people with SUD uses multiple substances. Pending positive outcomes from ongoing and forthcoming RCTs, GLP-1 RA medications may become a pharmacotherapeutic approach for treating polysubstance use.'
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Alcohol Addiction
Among all substances, alcohol is by far the most investigated when it comes to GLP-1 RAs. Michael Weaver, MD, professor of psychiatry at UTHealth Houston, highlighted research showing that GLP-1 RAs reduced alcohol consumption in vervet monkeys which are alcohol-preferring primates. Stephanie Weiss, MD, PhD, Assistant Director for Clinical Research, Medication Development Program at NIDA, shared data from the first published clinical trial of GLP-1 RAs in alcohol use disorder: in patients with obesity with a BMI over 30, exenatide reduced heavy drinking days by 23.6% and lowered total alcohol intake. She also shared multiple, ongoing NIDA-funded clinical trials including Semaglutide Therapy for Alcohol Reduction or STAR which is currently recruiting patients.
What About Other Drug Addictions?
We have limited research on cocaine, according to Dr. Weaver. So far, an experimental (not FDA-approved) GLP-1 agonist compound has been shown to lower cocaine self-administration in rats. We don't have much data for opioids, either. One study revealed that repeated doses of liraglutide ('Victoza') decreased heroin self-administration in rats. Experts are cautious but optimistic. 'Clinical research is necessary. Watch this space,' Dr. Weaver advised the captive audience.
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Ethical Issues Regarding GLP-1 Medications
The eruption of GLP-1 RAs has several societal implications including equitable access. Nancy Shenoi, MD, assistant professor of psychiatry at Baylor College of Medicine, pointed out gaps in obesity treatment in low- and middle-income countries and rural areas. She also shared that only four countries offer insurance coverage for obesity treatment: Brazil, Canada, Chile and the U.S. Canada's universal healthcare system and lower prices for diabetes medications enhance accessibility. In addition, the Inflation Reduction Act of 2022 allowed Medicare to negotiate the price of 10 costly medications without a generic; no GLP-1 RA is on this list. Mental health must also be a consideration, stated Dr. Shenois, as some studies suggest that liraglutide and semaglutide may trigger suicidal thoughts, self-injury and depression.
Bottom Line
Current data on GLP-1 receptor agonists and addiction is certainly promising. Decreased mortality, anti-inflammatory properties and neuroprotective effects can be beneficial in chronic substance use which is associated with neuroinflammation and oxidative stress. But there was a clear consensus among experts at the ASAM conference: more research is needed. 'What we urgently need now are rigorous studies to establish both safety and efficacy of GLP-1 agonists,' reminded Dr. Suzuki. We also need patience. 'Let's not all just jump on the band wagon. Results from clinical trials are years away,' emphasized Dr. Weaver.
Lipi Roy, MD, MPH
Every presenter also agreed that while we're waiting for the science, let's not forget that we already have anti-addiction medications that work but they're grossly underutilized. Only 1 in 5 people with opioid use disorder and less than 8% of those with alcohol use disorder receive treatment. As an addiction medicine doctor, I cannot underscore this point enough: methadone, buprenorphine, naltrexone and nicotine replacement therapy are safe and effective but unacceptably under-prescribed. Let's maximize existing, lifesaving and transformative medicines for people with addiction while also exploring innovative therapeutic options like GLP-1 receptor agonists.
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