Why addiction researchers are paying closer attention to GLP-1 drugs

Drugs already reshaping diabetes and obesity care are now attracting attention in addiction medicine, as emerging trials reveal how targeting GLP-1 signaling could influence craving, reward, and substance use.

Viewpoint: GLP-1–targeted therapies for alcohol and other substance use disorders: a new era on the horizon? Image Credit: Love Employee / Shutterstock

A recent Viewpoint published in the Journal of Clinical Investigation examined the emerging role of glucagon-like peptide-1 (GLP-1)– targeted therapies in the treatment of alcohol and other substance use disorders, based on the biological rationale, current evidence, and future directions for this promising therapeutic approach.

Impact of Substance Use and Substance Use Disorders

Substances like alcohol, nicotine, and illicit drugs are commonly used worldwide, but their misuse leads to major health risks such as chronic disease, mental health problems, accidents, and premature death. Beyond individual harm, substance use disorders can affect families and communities, contributing to substantial socioeconomic and societal burdens.

A substance use disorder (SUD) can involve loss of control over substance use, persistent cravings, repeated failed attempts to cut down, and ongoing use despite clear negative consequences. SUDs are chronic, relapsing illnesses that can disrupt nearly every aspect of life, from physical health to personal relationships and work stability.

Diagnosing SUDs involves assessing the number and type of symptoms, with DSM-5 criteria requiring at least two of 11 symptoms over the past year and classifying SUD as mild, moderate, or severe. More than 2,000 symptom combinations are possible, resulting in substantial clinical heterogeneity. While counseling and medications can support recovery, many people find it difficult to achieve long-term remission, highlighting the need for more effective treatments.

GLP-1 Pathways and Their Emerging Role in Addiction Treatment

Recent studies support commonalities between SUDs and obesity in biological pathways, particularly within neuroendocrine systems like glucagon-like peptide-1 (GLP-1) signaling. GLP-1 is a hormone involved in regulating appetite, reward, and metabolism. This overlap has opened new possibilities for treating addiction using GLP-1 receptor agonist medications already used for diabetes and, for some agents, obesity, such as semaglutide, liraglutide, and exenatide.

Both animal models and human studies support the possibility that GLP-1 receptor agonists, medications that mimic the action of the GLP-1 hormone, may help reduce cravings for addictive substances and lower actual substance use. In preclinical studies, animals treated with GLP-1 agonists consumed less alcohol, nicotine, and other addictive drugs, and showed less interest in seeking out these substances.

Recent randomized trials in humans have been particularly encouraging for semaglutide in alcohol use disorder (AUD), with three trials providing evidence of reduced alcohol consumption. However, an earlier trial of exenatide did not improve the primary alcohol drinking outcomes in the overall sample. There is also evidence of benefit in tobacco use disorder (TUD), though results across different GLP-1 agonists and studies are more variable. A short pilot trial of liraglutide in people with opioid use disorder (OUD) also reported reduced opioid craving.

While not every trial has shown strong effects, recent randomized studies provide encouraging signals. However, the authors emphasize that enthusiasm has at times outpaced the evidence and that a firm evidence base for GLP-1 therapies in SUDs has not yet been established. If ongoing and future studies confirm their effectiveness, GLP-1–targeted medications could become a widely used and potentially transformative option for people struggling with addiction.

Why GLP-1 Therapies Are Well-Suited for SUD Treatment

GLP-1 receptor agonists have a well-established track record in clinical practice for managing type 2 diabetes (T2D) and obesity. Many individuals with SUDs also suffer from comorbid health issues, including obesity, liver disease, or cardiovascular problems, which GLP-1 therapies may potentially address alongside SUD-related outcomes.

Because these drugs are already widely used in clinical practice and early SUD trials suggest safety profiles comparable to those observed in trials for diabetes and obesity, their repurposing for addiction medicine may meet less resistance and could help ease the stigma that often surrounds SUD treatment.

The exact mechanisms by which GLP-1–targeted therapies benefit people with SUDs remain under investigation. The most widely supported explanation is that GLP-1 receptor agonists reduce the pleasurable (hedonic) value of both food and addictive substances by modulating dopamine transmission in reward-related brain regions, such as the mesolimbic system.

In addition, GLP-1RAs appear to influence neural circuits involved in reward, motivation, and substance desire, which are often implicated in the development and persistence of SUDs. GLP-1 signaling also affects brain regions involved in stress and emotion regulation, which may help explain some of its effects on addictive behaviors.

Challenges and Research Gaps in GLP-1–Based Addiction Treatment

Despite growing interest in GLP-1 therapies for addiction, several critical questions remain. One key area is determining the optimal dosing and duration for GLP-1 receptor agonist therapy. For example, low-dose semaglutide can reduce alcohol consumption in people with AUD who are not seeking treatment, especially in those without obesity. In contrast, a 5-month trial using a higher dose demonstrated efficacy in individuals with both AUD and obesity. However, it is still unclear how long these medications should be used and whether their benefits continue after stopping treatment. The authors also suggest that, if effective, GLP-1RAs might eventually be used during early recovery, as longer-term maintenance therapy, or as a bridge to behavioral and psychosocial treatment.

Not everyone responds to GLP-1 agonists in the same way. Factors such as genetics, metabolism, and other biological or environmental factors can influence both efficacy and safety. Researchers are now developing oral GLP-1 agonists and dual or poly-agonists that also target other hormone pathways, including glucose-dependent insulinotropic polypeptide and glucagon. Dual and poly-agonists could offer stronger effects, but their safety and tolerability for people with substance use disorders need further investigation.

Currently, most studies have focused on alcohol, opioid, and tobacco use disorders, so it remains unknown how well GLP-1 therapies work for other addictions, including stimulant or cannabis use disorders and gambling. More research is also needed to understand how these medications perform in people with polysubstance use disorders, which are more common than isolated SUDs, and how best to combine them with other treatments for optimal real-world outcomes.

Conclusions

GLP-1–based therapies were first developed for diabetes and later became established treatments for obesity, but their potential for treating addiction began attracting scientific attention more than a decade ago. Animal studies first showed that GLP-1 agonists could reduce use of substances like alcohol and nicotine, leading to a growing number of human clinical trials. Although the evidence is still evolving, early results are promising, showing reductions in substance use and cravings in some individuals. With several clinical trials ongoing or recently completed, GLP-1 therapies could eventually provide much-needed additional options for addiction treatment if their efficacy and safety are confirmed.