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Glucagon-like peptide-1 (GLP-1) receptor agonists, FDA-approved for type 2 diabetes and obesity, are emerging as a potential treatment avenue for substance use disorder. While medications like semaglutide and liraglutide have proven effective for metabolic conditions, preclinical research suggests they may also influence brain reward pathways involved in addiction. GLP-1 receptors are present in regions that mediate addictive behaviors, raising questions about whether these agents could reduce cravings for alcohol, opioids, or stimulants. However, this application remains investigational with no FDA approval for substance use disorder treatment. Patients and clinicians should understand that current evidence is preliminary, and any use for addiction represents off-label prescribing requiring careful consideration alongside established addiction therapies.
Summary: GLP-1 receptor agonists are being investigated for substance use disorder based on preclinical evidence suggesting they may reduce cravings and consumption, but they have no FDA approval for addiction treatment and remain investigational.
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of medications originally developed and FDA-approved for the treatment of type 2 diabetes mellitus and, more recently, obesity. These agents—including semaglutide (Ozempic, Wegovy), dulaglutide (Trulicity), liraglutide (Victoza, Saxenda)—work by mimicking the incretin hormone GLP-1, which is naturally released from the intestine in response to food intake. Tirzepatide (Mounjaro, Zepbound) is a dual GIP/GLP-1 receptor agonist that acts on both pathways.
The primary mechanisms of action include enhancement of glucose-dependent insulin secretion, suppression of glucagon release, slowing of gastric emptying, and reduction of appetite through central nervous system pathways. These effects have proven highly effective for glycemic control and weight management, leading to widespread clinical adoption. However, emerging preclinical and observational data suggest that GLP-1 receptor agonists may have effects beyond metabolic regulation, particularly in modulating reward pathways in the brain that are implicated in addictive behaviors.
While there is no FDA indication for GLP-1 medications in the treatment of substance use disorder (SUD), growing interest from researchers and clinicians has sparked investigation into whether these agents might reduce cravings and consumption of alcohol, opioids, stimulants, and other substances. This represents a novel and potentially transformative area of research, though it remains investigational and should not be considered standard care at this time. The American Society of Addiction Medicine (ASAM) has not issued guidelines endorsing this use. Patients and providers should understand that any use for addiction treatment is currently off-label and requires careful consideration of the existing evidence base.
The potential role of GLP-1 receptor agonists in substance use disorder stems from the presence of GLP-1 receptors in key brain regions involved in reward processing and addictive behavior. These receptors are found in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, and other components of the mesolimbic dopamine system—the same neural circuitry that mediates the reinforcing effects of drugs of abuse, alcohol, and other addictive substances.
Preclinical studies in rodent models have demonstrated that GLP-1 receptor activation can reduce voluntary consumption of alcohol, decrease self-administration of cocaine and amphetamines, and diminish opioid-seeking behavior. The proposed mechanisms include modulation of dopamine signaling and reduction in the rewarding properties of substances. Some preclinical research suggests GLP-1 receptor agonists may influence stress-related pathways, though these findings require confirmation in human studies.
It is important to note that the neurobiological effects observed in animal models do not always translate directly to human clinical outcomes. The brain reward system is complex, and addiction involves psychological, social, and environmental factors beyond neurotransmitter activity alone. Furthermore, the doses and formulations used in preclinical research may differ substantially from those used clinically for diabetes or obesity. While the mechanistic rationale is compelling, robust human clinical trial data are needed to confirm whether GLP-1 receptor agonists can meaningfully reduce substance use or support recovery in patients with diagnosed substance use disorders.
The evidence base for GLP-1 receptor agonists in substance use disorder is in its early stages, consisting primarily of animal studies, case reports, and retrospective observational analyses. Some epidemiological studies using electronic health records have suggested associations between GLP-1 receptor agonist use and alcohol-related outcomes. For example, a 2024 study published in Nature Medicine found associations between semaglutide use and reduced incidence of alcohol-related diagnoses, though such observational data cannot establish causation and are subject to confounding.
Small pilot studies and case series have reported anecdotal reductions in alcohol consumption and cravings among individuals treated with semaglutide or liraglutide, but these reports lack the rigor of randomized controlled trials. As of early 2025, several clinical trials are underway to evaluate GLP-1 receptor agonists specifically for alcohol use disorder, opioid use disorder, and stimulant use disorder. These studies will be critical in determining efficacy, optimal dosing, treatment duration, and patient selection criteria.
Clinicians should be aware that the current evidence does not support routine prescribing of GLP-1 receptor agonists for substance use disorder outside of research settings. Standard evidence-based treatments remain the foundation of addiction care, including:
Behavioral therapies (cognitive-behavioral therapy, motivational interviewing)
FDA-approved medications for alcohol use disorder (naltrexone, acamprosate) and opioid use disorder (buprenorphine, methadone, naltrexone)
Contingency management for stimulant use disorder
Comprehensive psychosocial support
Patients seeking GLP-1 medications for addiction treatment should be counseled about the investigational nature of this application and encouraged to participate in formal clinical trials when available. Importantly, patients should not discontinue FDA-approved medications for opioid or alcohol use disorders to trial GLP-1 agents.
GLP-1 receptor agonists are generally well-tolerated, but they are associated with a range of adverse effects that require clinical awareness and monitoring, particularly if considered off-label for substance use disorder. The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, constipation, and abdominal discomfort. These symptoms are typically dose-dependent and may diminish over time with gradual dose titration. However, in patients with active substance use or in early recovery, gastrointestinal distress could complicate adherence to treatment or exacerbate nutritional deficiencies.
More serious adverse effects include:
Pancreatitis: Rare but potentially severe; patients should be counseled to report persistent abdominal pain.
Gallbladder disease: Increased risk of cholelithiasis and cholecystitis, particularly with rapid weight loss.
Hypoglycemia: Risk is low when used as monotherapy but increases when combined with insulin or sulfonylureas.
Thyroid C-cell tumors: A boxed warning exists based on rodent data; GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.
Renal impairment: Dehydration from gastrointestinal side effects can precipitate acute kidney injury, especially in patients with preexisting renal disease.
Diabetic retinopathy complications: Semaglutide has been associated with worsening of diabetic retinopathy in patients with pre-existing retinopathy, particularly with rapid improvement in blood glucose.
Delayed gastric emptying: May affect absorption of oral medications, particularly those with a narrow therapeutic index.
Additional considerations include:
Perioperative management: GLP-1 agents may need to be temporarily discontinued before procedures due to aspiration risk.
Pregnancy/lactation: These medications are not recommended during pregnancy and should be discontinued at least 2 months before a planned pregnancy (for semaglutide).
Gastroparesis: Use with caution in patients with severe gastrointestinal disease.
The FDA is evaluating reports of suicidal ideation and depression but has not established a causal relationship. This is particularly relevant in populations with substance use disorders, who may already have elevated psychiatric comorbidity.
Clinicians considering off-label use should conduct thorough baseline assessments, including renal and hepatic function, and establish a monitoring plan. Patients should be educated about warning signs and instructed to seek immediate care for severe abdominal pain, persistent vomiting, or mood changes. Coordination with addiction specialists, mental health providers, and primary care teams is essential to ensure comprehensive and safe care.
Patients interested in GLP-1 receptor agonists for substance use disorder should have an open and informed conversation with their healthcare provider. It is essential to clarify that these medications are not currently FDA-approved for addiction treatment, and their use in this context is investigational. Patients should ask about the strength of the evidence, potential benefits and risks, and whether participation in a clinical trial might be appropriate.
Key discussion points include:
Current substance use and treatment history: Full disclosure of substances used, frequency, and prior treatment attempts helps the provider assess appropriateness and safety.
Coexisting medical conditions: Diabetes, obesity, cardiovascular disease, kidney disease, thyroid disorders, diabetic retinopathy, and psychiatric conditions all influence the risk-benefit profile.
Current medications: Drug interactions and the potential for hypoglycemia or other adverse effects must be reviewed.
Treatment goals and expectations: Patients should understand that GLP-1 receptor agonists, if used, would be adjunctive to—not a replacement for—evidence-based addiction treatments such as counseling, peer support, and FDA-approved pharmacotherapies.
Monitoring and follow-up: Regular appointments, laboratory testing, and symptom tracking are necessary to ensure safety and assess response.
Cost and insurance coverage: GLP-1 receptor agonists are expensive, and insurance typically will not cover off-label use for substance use disorder. Prior authorization appeals may require substantial documentation.
Patients should be encouraged to continue or initiate standard addiction treatment modalities, including behavioral therapies, mutual support groups (such as Alcoholics Anonymous or SMART Recovery), and medications with established efficacy for their specific substance use disorder. Patients should not discontinue FDA-approved medications for opioid or alcohol use disorders to trial GLP-1 agents.
Referral to an addiction medicine specialist or psychiatrist with expertise in substance use disorders is advisable for comprehensive evaluation and management. Shared decision-making, realistic expectations, and a multidisciplinary approach are essential to optimize outcomes and ensure patient safety.
For immediate support with substance use concerns, contact the SAMHSA National Helpline at 1-800-662-HELP (4357) or the 988 Suicide & Crisis Lifeline for mental health crises.
No, GLP-1 receptor agonists are not FDA-approved for substance use disorder treatment. They are approved only for type 2 diabetes and obesity, and any use for addiction is considered off-label and investigational.
GLP-1 receptors are found in brain reward regions involved in addictive behavior. Preclinical studies suggest these medications may modulate dopamine signaling and reduce the rewarding properties of substances, though human clinical trial data are still needed to confirm these effects.
No, patients should not discontinue FDA-approved medications for opioid or alcohol use disorders to trial GLP-1 agents. Evidence-based treatments like buprenorphine, naltrexone, and behavioral therapies remain the standard of care and should be continued.
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