GLP-1s: A New Frontier in Substance Use Disorder Management

Substance use disorder (SUD) impacts more than 48 million individuals and is characterized by an inability to control the use of alcohol, nicotine, illicit drugs, or prescriptions.¹ With high relapse rates and limited pharmacological interventions, a need remains for additional therapeutic options. Since the rise of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the management of type 2 diabetes and obesity, emerging evidence has indicated their potential benefits in the management of SUD.²

Research findings have shown an association between lower SUD rates and concurrent GLP-1 RA use, sparking interest in the use of GLP-1 RA as a therapy for SUD.³ Studies have already started looking into various SUDs, such as nicotine use disorder (NUD), alcohol use disorder (AUD), and opioid use disorder (OUD).^2,4

Because NUD is one of the most prevalent and burdensome forms of SUD, there is growing interest in evaluating alternative therapies for NUD treatment. For example, early studies are looking into using GLP-1 RAs as monotherapy or adjunct therapy in NUD because the drugs can mitigate weight gain associated with traditional therapy and present new options for individuals who have contraindications to standard therapy.⁴ Although the mechanism is not fully understood, data from preclinical studies have demonstrated that activation of central GLP-1 receptors can modulate dopaminergic signaling in the mesolimbic reward pathway. These changes can potentially reduce cravings and reward-seeking behaviors that are typically observed in SUD.^2,4

Current first-line pharmacotherapy for NUD includes nicotine replacement therapies (NRTs). However, the efficacy of smoking cessation is low, with an average of 30 attempts at quitting per successful outcome.⁵ Additionally, weight gain and withdrawal symptoms are adverse effects that may discourage patients from quitting, and study data have shown that GLP-1 RA use has mitigated post-cessation weight gain and reduced withdrawal symptoms, showing further promise in SUD management.²

Modulating Dopaminergic Signaling in Addiction

Dopamine, often called the “reward” neurotransmitter, plays major roles in motivation, mood, memory, and learning, and lies at the center of drug reward pathways.^6,7 The ventral tegmental area (VTA) and nucleus accumbens (NAc) play a major role in the reward system of the mesolimbic pathway. The VTA activates dopaminergic neurons in response to completing a rewarding task, releasing dopamine that is then received by the NAc, which determines the level of reward based on the amount of dopamine received. Substances such as nicotine, opioids, or alcohol can cause rapid increases in dopamine, triggering the reward system. This feeling, sometimes described as a “high,” leads to intense cravings and substance-seeking behavior in SUD.^4,8,9

Centrally acting GLP-1 RAs can modulate activity in the VTA.⁸ These modulations in turn reduce the amount of dopamine released and therefore decrease the reward sensed by NAc. Because the sense of reward from the substance is reduced, preventing the same “high” from occurring, it may lead to reduced cravings and diminished reward from the substances.^4,8,9

Current NUD Therapies and Possible Role of GLP-1s

NUD treatment typically includes NRTs available OTC and by prescription, as well as other prescription oral medications.¹⁰ Pharmacological therapies include varenicline (Chantix; Pfizer), which acts as a partial agonist at the α4β2 nicotinic receptor and induces a slow, steady release of dopamine to reduce cravings. Transdermal NRT patches work by slowly absorbing nicotine into the bloodstream to reduce cravings and slowly taper off nicotine. These 2 options are the standard therapy for NUD. Varenicline has 26.1% effectiveness after 52 weeks, and NRT has 20.3% effectiveness.¹⁰

GLP-1 RAs have been shown to significantly suppress nicotine self-administration in both male and female rats, which is significant because females have a harder time quitting and have poorer outcomes with NRT.^4,11 Clinical trials are currently underway to evaluate the drug repurposing potential of GLP-1 RAs in SUD.

The Emerging Clinical Trials Landscape

Given the increased interest in this area, there are at least 8 ongoing clinical trials evaluating the safety and efficacy of GLP-1 RAs in SUD, as shown in the Table.^12-19 One such trial is comparing GLP-1 RAs and Dipeptidyl Peptidase-4 inhibitors in patients with diabetes and NUD, notably without requiring an intention to quit.¹² The trial is evaluating cessation rates at 12 and 24 weeks compared to the placebo vs the GLP-1 RA. Given the limited robust evidence on GLP-1 RA use in SUD management, results from these emerging trials can inform SUD guidelines and help pharmacists make evidence-based recommendations.

The Role of the Pharmacist

Pharmacists play a key role in medication adherence and improving patient outcomes. Although GLP-1 RAs are not currently approved for the treatment of SUD and there is no clinical guidance on their off-label use, early research findings show potential benefits in modulating reward pathways. Pharmacists contribute by monitoring and critically appraising emerging evidence, ensuring safe and appropriate use, and educating health care providers and patients on comprehensive, appropriate SUD care and symptom management. Due to their close patient interactions and frequent medication counseling sessions, pharmacists are uniquely positioned to reduce the stigma surrounding SUD, provide support, and encourage patient medication adherence.

Understanding possible new uses of medications and key counseling points about common adverse effects vs withdrawal are imperative. For example, gastrointestinal issues can be an adverse effect of GLP-1 RA usage as well as a hallmark sign of withdrawal from alcohol or opioids.^20,21 Understanding how to differentiate these symptoms is an important counseling point that can help patients maintain adherence, prevent premature discontinuation of treatment, and avoid substance-seeking behavior.

If approved, there may still be barriers to prescribing and dispensing GLP-1 RAs for patients with SUD. For example, GLP-1 RA supply shortages have severely impacted patients with diabetes.²² Therefore, supply shortage may be a recurring issue with expanding indications. These shortages can lead patients to purchase from unsafe websites, putting patients at risk of adulterated and possibly counterfeit products. Pharmacists must be able to counsel patients on how to navigate these shortages and appropriate alternatives as guidelines are updated.

Conclusion

Although GLP-1 RAs are not currently FDA approved for SUD, they are an emerging area of treatment for various SUDs. Given their role in the mesolimbic reward pathway, GLP-1 RAs may mitigate withdrawal and craving symptoms associated with these disorders. Much of the data are preliminary, and clinical trials may further establish the role of GLP-1 RAs in SUD management. As evidence for GLP-1 RA use evolves, so may the role of pharmacists regarding medication adherence, patient education, and reducing the stigma behind SUD.

About the Authors

Brittany Grammas, MMS, is a second-year doctor of pharmacy candidate at the South College School of Pharmacy in Knoxville, Tennessee, and serves as president of the Student Society of Health-System Pharmacists.

Abraham Padilla is a second-year doctor of pharmacy candidate at the South College School of Pharmacy in Knoxville, Tennessee, and serves as the treasurer of the Student National Pharmaceutical Association.

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