Glucagon-like peptide 1 (GLP-1) receptor agonists were initially approved for the treatment of diabetes in 2005, but over the last several years, use of these agents for myriad health problems has proliferated rapidly.
GLP-1 is an amino acid peptide hormone secreted by enteroendocrine L cells in the intestine and alpha cells in the pancreas that binds to GLP-1 receptors, resulting in the regulation of glucose homeostasis.1 GLP-1 receptor agonists, such as semaglutide, tirzepatide, exenatide, and liraglutide, mimic the actions of endogenous GLP-1, stimulating insulin secretion and suppressing glucagon secretion, thus aiding in glucose regulation and effectively treating diabetes. These effects on insulin and glucagon, as well as delayed gastric emptying and central nervous system (CNS) effects such as appetite suppression, make these agents effective for weight loss.2,3 These agents can also be used for binge eating disorders and/or “food addiction.”4,5
GLP-1 is produced in the nucleus tractus solitarius (NTS) of the brain stem by preproglucagon (PPG) neurons, and GLP-1 receptors are found in abundance within the frontal lobes, hippocampus, hypothalamus, cerebellum, and spinal cord1,3,6,7 Multiple studies have demonstrated that GLP-1 receptor agonists readily cross the blood-brain barrier, underscoring their potential CNS effects.3,7,8 Beneficial effects of GLP-1 receptor agonists on the CNS, including reduced neuroinflammation, increased signal transduction, and enhanced synaptic transmission, have been identified.9
Emerging research has examined the use of GLP-1 receptor agonists in the treatment of a variety of substance use disorders (SUDs), including alcohol use disorder, tobacco use disorder, opioid use disorder (OUD), and stimulant use disorder. Given the chronic, remitting-relapsing nature of SUDs, novel evidence-based treatment options are needed.10 Although GLP-1 receptor agonists have demonstrated promise in this area, they are not yet Food and Drug Administration (FDA)-approved for SUDs and, thus, are not widely used in this setting.
This 3-part series provides a clinical update on the use of GLP-1 receptor agonists for the treatment of SUDs, reviewing the neurobiological basis for GLP-1 receptor agonist use for the treatment of SUDs and providing an overview of GLP-1 receptor agonists used in this setting. Additional articles in the series will examine GLP-1 receptor agonists for the treatment of alcohol use disorder and tobacco use disorder, specifically.
Neurobiological Basis of GLP-1 Receptor Agonists in the Treatment of SUD
GLP-1 receptors are expressed in multiple brain regions involved in reward and addiction, specifically the ventral tegmental area (VTA) and the nucleus accumbens (NAc).3,11,12 GLP-1 directly impacts mesolimbic neurons in the VTA and NAc, which are instrumental in facilitating goal-oriented behavior and reward processing.3 GLP-1 affects VTA and striatal dopamine levels, regulating hunger, satiety, and body weight.13,14 Furthermore, GLP-1 receptor agonists have been shown to modulate dopaminergic neurotransmission, a key mediator of reward processing,15 with GLP-1 receptor activity in the mesolimbic dopaminergic reward system influencing intrinsic control of eating, altering food satiety signals, and modulating satiety.15
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Multiple preclinical studies have supported the use of GLP-1 receptor agonists for the treatment of OUD and have demonstrated that GLP-1 receptor agonist exposure reduces opioid-seeking behavior in animal models.
GLP-1 receptor agonists have also been found to reduce SUD and addiction-related symptoms, including escalation of substance use, tolerance, and drug-seeking behavior.12 It has been suggested that GLP-1 modulates “satiety” in substances of misuse (ie, alcohol, opioids, tobacco/nicotine), ultimately altering or mitigating reward-related neuropsychiatric changes in response to multiple substances of misuse.13
The exact mechanism of these effects has not been elucidated completely, but recent research on the effect of GLP-1 on dopaminergic activity showed that GLP-1 increased dopamine uptake, clearance, and dopamine transporter surface expression in animal models.11
Despite ambiguity surrounding their exact mechanism of action in modulating the dopaminergic reward system, GLP-1 receptor agonists are being investigated for use in the treatment of SUDs. Given the promise of these agents for SUD treatment, healthcare providers should be familiar with emerging evidence supporting their use in the treatment of individuals with SUDs and related problems.
GLP-1 Receptor Agonists in the Treatment of SUDs
Despite the availability of 3 FDA-approved medications for the treatment of OUD (methadone, buprenorphine, and naltrexone), many individuals with this disorder who need treatment do not receive it, and many cases are refractory to treatment.16 Thus, novel interventions are needed for OUD, and GLP-1 receptor agonists have shown promise in this regard. Multiple preclinical studies have supported the use of GLP-1 receptor agonists for the treatment of OUD17 and have demonstrated that GLP-1 receptor agonist exposure reduces opioid-seeking behavior in animal models.18-20
There is limited but emerging clinical data to support the use of GLP-1 receptor agonists for OUD. To date, there has only been 1 randomized controlled trial examining the use of a GLP-1 receptor agonist (liraglutide) for the treatment of OUD.21 Although data from this trial have yet to be published, preliminary results presented at the 2024 American Association for the Advancement of Science demonstrated that those with OUD who received liraglutide reported a 40% reduction in opioid cravings relative to those who received placebo.22
In a retrospective cohort study, investigators analyzed electronic health record data on 503,747 adults with a history of OUD from 136 US health systems and found that patients prescribed a GLP-1 receptor agonist demonstrated significantly lower rates of opioid overdose, even when stratified by comorbidities, than those without a GLP-1 receptor agonist prescription (adjusted incidence rate ratio, 0.60; 95% CI, 0.43-0.83).23 Additional high-quality data are needed to support the widespread use of GLP-1 receptor agonists in the treatment of OUD, but these early clinical data are promising.
Psychostimulant use, including cocaine and methamphetamine, is also on the rise and is associated with morbidity and mortality.24 Emerging preclinical data suggest that GLP-1 receptor agonists might be effective in treating stimulant use disorder, with animal studies showing a reduction in cocaine- or stimulant-seeking behavior after GLP-1 receptor agonist exposure.22,25 However, there are limited clinical data available on GLP-1 receptor agonists for the treatment of stimulant use disorders,12 with only 1 ongoing clinical trial for which data have yet to be reported.22 (Bruns et al, 2024).
Despite increasingly prevalent cannabis use, there are no preclinical or clinical studies examining the association between GLP-1 receptor agonists and cannabis use.
Conclusions
SUDs and their associated consequences remain a public health problem for which novel treatment intervention options are needed. GLP-1 receptor agonists have gained popularity for various indications, including diabetes and weight loss. Thought to be generally safe and well tolerated, these agents might prove to be an efficacious treatment to reduce substance use and improve quality of life among those with SUDs. Emerging data suggest that GLP-1 receptor agonists might be effective in treating opioid and stimulant use disorders.
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This article originally appeared on Clinical Advisor
