Substance use disorders (SUDs) may become the next therapeutic target for GLP-1 receptor agonists (GLP-1s). Although the evidence remains preliminary, growing preclinical, observational, and early clinical data suggest these drugs may reduce the cravings that drive addiction.

Interest has accelerated over the past few years, fueled by reports that patients taking semaglutide or tirzepatide for diabetes or obesity drink less alcohol, smoke fewer cigarettes, or experience fewer cravings. Those observations have prompted a wave of studies exploring whether these drugs could have a role in treating alcohol, nicotine, opioid, and other SUDs.

More recently, large retrospective analyses have suggested that GLP-1s may be associated with lower rates of overdose, SUD-related mortality, and new-onset SUDs.

At this point, however, much of the evidence comes from animal studies, observational research, and patient reports. Definitive answers will require randomized clinical trials. More than 30 studies are now investigating GLP-1s for alcohol, nicotine, opioid, cocaine, and methamphetamine use disorders, making addiction one of the fastest-growing areas of GLP-1 research.

One possible explanation comes from the phenomenon patients describe as “food noise.” If GLP-1s dampen the intrusive reward-driven thoughts associated with eating, researchers are asking whether they might also quiet the compulsive cravings that characterize addiction.

“The leading theory involves the brain’s reward circuitry,” Alvaro Teixeira Filho, MD, addiction psychiatrist at Yale School of Medicine in New Haven, Connecticut, told Medscape Medical News.

Animal studies suggest GLP-1s blunt the dopamine surge normally triggered by alcohol, nicotine, opioids, and cocaine, reducing both substance use and relapse-like behavior, he noted.

The Biological Rationale

Nancy Shenoi, MD, addiction psychiatrist and assistant professor of psychiatry at Baylor College of Medicine in Houston, said the drugs may influence addiction through several pathways.

GLP-1s may influence addiction through multiple mechanisms. In addition to modulating mesolimbic dopamine signaling, potentially reducing cravings and reinforcement, they may alter hypothalamic pathways involved in satiety and impulse control and regulate gamma-aminobutyric acid release, potentially dampening the excitatory signaling that can trigger addictive behaviors, Shenoi said.

She also noted that chronic substance use has been linked to neuroinflammation and oxidative stress, both of which may be mitigated by the anti-inflammatory and neuroprotective effects of GLP-1 medications.

The strongest clinical evidence to date comes from studies of alcohol use disorder (AUD), where several randomized trials have reported reductions in alcohol craving and heavy drinking with GLP-1s.

Two randomized clinical trials have reported encouraging findings. In one, published in JAMA Psychiatry, semaglutide significantly reduced alcohol consumption, drinks per drinking day, and alcohol craving among adults with AUD.

Similarly, another study showed significant reductions in alcohol craving and heavy drinking with semaglutide in adults with AUD.

However, the evidence has been mixed. In a separate randomized trial, exenatide did not significantly reduce heavy drinking compared with placebo among adults with AUD, although exploratory analyses suggested greater benefit in participants with obesity.

Observational studies, meanwhile, have linked GLP-1s to lower hospitalization rates and reduced return-to-drinking rates among patients with AUD and metabolic comorbidities.

What the Evidence Shows

The evidence is less robust for other SUDs. Small clinical studies and preclinical research suggest potential benefit for cocaine, opioid, and nicotine use disorders, but human data remain limited. Several trials in opioid and cocaine use disorders are underway, while findings in nicotine use disorder have been mixed.

Shenoi characterized the evidence beyond AUD as “preliminary.” Filho noted that research on opioid and cocaine use disorders remains largely preclinical, although early clinical findings are beginning to emerge.

“I’d call this the beginning of a paradigm shift,” Filho said. “What’s genuinely new here is the idea itself: that a drug class designed for metabolism could treat addiction by working through the shared neurobiology of reward.”

Shenoi was less definitive, noting that the evidence is “strongest at the mechanistic level and in animal studies, but still early in human studies — so not quite a paradigm shift.”

Michael Weaver, MD, professor of psychiatry and medical director of the Center for Neurobehavioral Research on Addiction at UTHealth Houston, said the current evidence provides “intriguing signals,” but many questions remain about the role of GLP-1s in treating SUDs. “The research is just beginning, and definitive answers are still a few years away,” he told Medscape Medical News.

One of the biggest unanswered questions is whether GLP-1s act on addiction itself or more broadly dampen reward-seeking behavior.

“This is still up for debate, but the evidence leans more toward a broad effect on the reward pathway rather than anything addiction-specific,” Filho said.

Consistent with that hypothesis, animal studies show that GLP-1s reduce not only drug-seeking behavior but also consumption of highly palatable foods and other rewarding stimuli. Brain imaging studies also suggest reduced activation in reward-related brain regions in response to both food and drug cues, he noted. 

Shenoi said reports of reduced cravings for food, alcohol, drugs, and even gambling behaviors support the idea that GLP-1s act on shared reward pathways. However, she cautioned that “specific targeted anti-addiction pharmacology studies are still emerging.” 

What Questions Remain

Weaver said another important unanswered question is how selective those effects ultimately prove to be.

“Reward-seeking behavior is very broad,” he told Medscape Medical News. It remains unclear whether GLP-1s selectively reduce cravings for addictive substances while preserving motivation for other rewarding activities, such as pursuing personal goals or enjoying everyday experiences.

The distinction has important clinical implications. Researchers are trying to determine whether GLP-1s can reduce pathological reward-seeking without diminishing normal pleasure and motivation.

“Case reports of anhedonia and emotional blunting do exist, but population-level data have been reassuring, as GLP-1s use hasn’t been linked to increased depression or suicidality, and some studies even suggest mental health benefits,” said Filho. 

Despite growing optimism about GLP-1s for addiction treatment, important questions remain. Researchers still need to determine which patients are most likely to benefit, the optimal dose and duration of therapy, whether benefits persist after treatment stops, how GLP-1s interact with psychiatric comorbidities, whether they should be used alone or alongside existing addiction medications, and whether benefits extend beyond individuals with obesity.

“The honest answer is that the literature is not there yet, and it probably depends on the substance, among other factors,” Filho told Medscape Medical News.

The likely role of GLP-1s may differ by SUD. For opioid use disorder (OUD), add-on therapy may be the most plausible approach, he added. “Methadone and buprenorphine cut mortality by roughly half or more, so any new drug would most likely be added on top, not used in their place.”

That approach already has some support. A retrospective study of methadone patients with OUD and comorbid type 2 diabetes showed that GLP-1 use was associated with higher remission rates and lower overdose risk, Filho noted.

The outlook may be different for AUD. Although three FDA-approved medications — naltrexone, acamprosate, and disulfiram — are available, their efficacy is modest and they remain underutilized, Filho said.

He noted that in a trial of semaglutide, the number needed to treat (NNT) was 4.3 for a clinically meaningful reduction in World Health Organization drinking risk level, a standard measure of alcohol consumption, comparing favorably with NNTs of 7 or higher reported for the approved AUD medications.

Where Do GLP-1s Fit?

For cocaine and other stimulant use disorders, the picture may be different. No FDA-approved medications are currently available, meaning a GLP-1, if approved, could become the first pharmacologic treatment option.

Filho noted that addiction varies by substance, disease severity, comorbidities, genetics, and social and environmental factors. Current medications are limited, often have only modest efficacy or are difficult to sustain, and remain underused.

“That’s the treatment gap GLP-1s are stepping into. So, before we even know where they’ll land — first-line, add-on, or reserved for certain patients — just having more tools and mechanisms to choose from is very important for individualized and comprehensive care.” 

Where GLP-1s ultimately fit into addiction care — and when that role becomes clear — remains uncertain.

Several randomized trials are expected to report results over the next 1-2 years, but larger and longer studies will be needed to answer questions about durability, safety, and relapse prevention.

“That said, the data have been strong enough that some doctors are already using these drugs off-label for alcohol use disorder,” Filho said, particularly among patients who also have obesity or another approved indication.

If GLP-1s ultimately become part of routine SUD treatment, equitable access will be another challenge.

Shenoi noted that studies show there is lower GLP-1 use among Asian, Black, and Hispanic individuals and those with lower incomes and that Medicaid does not cover the medications for obesity. She said evidence-based prescribing guidelines would be needed to help ensure equitable and appropriate use if GLP-1s are adopted for SUDs.

However, even as interest in GLP-1s grows, experts emphasized that the drugs are not ready to replace established addiction treatments.

“Failing to offer FDA-approved medications for addiction is a missed opportunity,” Shenoi said, noting that most people with SUDs still do not receive evidence-based treatment.

Filho, Weaver, and Shenoi reported having no relevant disclosures.