GLP-1 receptor agonists show promise in treating substance use disorders

A systematic review reveals that GLP-1 receptor agonists may help reduce certain substance use disorders, but findings are inconsistent due to study variability and patient differences.

Review: POTENTIAL ROLE OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS IN SUBSTANCE USE DISORDER: A SYSTEMATIC REVIEW OF RANDOMIZED TRIALS. Image Credit: Designua / Shutterstock

A systematic review published in the journal Drug and Alcohol Dependence provides a detailed analysis of the findings of available clinical trials that investigated the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on substance use disorder.

Background

Substance use disorder is a leading public health concern, affecting approximately 40 million people worldwide. A 23% increase in its prevalence has been observed in 2021 compared to that observed over the past ten years.

Recent estimates indicate that about 5 million and 280 million people are affected by cocaine use disorder and alcohol use disorder, respectively. The mortality rate associated with cocaine overdose is also increasing rapidly worldwide, exceeding opioid overdose-related deaths.

According to the World Health Organization (WHO), alcohol use disorder is associated with 5.3% of deaths and 5.1% of the global burden of disease and injury. Similar to alcohol, tobacco smoking is another leading cause of premature death.

All types of substance addictions are clinically codified as substance use disorder, which is considered a chronic disease characterized by a transition from recreational drug use to compulsive and disordered use. 

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of drugs typically used to maintain glucose homeostasis in type 2 diabetes patients. These agonists also play a vital role in nerve cell differentiation and inhibition of neuroinflammation. Besides neuroprotective effects, GLP-1 receptor agonists have been found to be involved in brain networks associated with reward and addiction.

In this systematic review, the authors conducted a comprehensive analysis of clinical trials to determine the impact of GLP-1 receptor agonists in reducing substance use disorder in patients.

Systematic review design

The authors screened various electronic databases to identify clinical trials that investigated the effect of GLP-1 receptor agonists on different types of substance use disorders (alcohol, nicotine, and cocaine use disorders) in adult patients.

Besides protective effects on substance use disorders, the authors analyzed the impact of GLP-1 receptor agonists on body weight management, body mass index (BMI), and glycated hemoglobin level (a measure of glycemic control). 

After a full-text review of 39 studies, the authors included five randomized controlled clinical trials in the final analysis. These trials included a total of 630 participants and used exenatide or dulaglutide as GLP-1 receptor agonists. The duration of trials ranged from 6 to 26 weeks. Importantly, these trials exhibited a high degree of heterogeneity in terms of the types of substances studied, patient characteristics, and treatment protocols, which posed significant challenges to drawing definitive conclusions. Overall, the selected trials had a low to moderate risk of bias.

Important observations

All five clinical trials that were included in the analysis reported GLP-1 receptor agonist-mediated reduction in substance use disorder, with two trials respectively reporting a significant therapeutic impact of GLP-1 receptor agonist in reducing alcohol use disorder and nicotine use disorder. Importantly, these trials exhibited a high degree of heterogeneity in terms of the types of substances studied, patient characteristics, and treatment protocols, which posed significant challenges to drawing definitive conclusions.

Additionally, in the trial examining alcohol use disorder, a significant reduction in alcohol consumption was observed only in a specific subgroup of patients with obesity, suggesting that patient characteristics, such as BMI, might influence treatment outcomes.

Regarding secondary outcomes, four out of five selected trials reported a significant reduction in body weight, BMI, and glycated hemoglobin levels in GLP-1 receptor agonist-treated participants.

Significance

This systematic review highlights the potential therapeutic impact of GLP-1 receptor agonists in reducing substance use disorders in adult patients. However, the authors urge caution in interpreting these findings due to the limited number of trials, the variations in study designs, and the heterogeneity in patient populations and substance types studied.

The association between obesity and substance use disorder has widely been documented in the literature. It has been observed that exposure to highly palatable foods increases key neuroendocrine signals, which remodel brain reward circuits to reinforce pathological eating behaviors.

This phenomenon is similar to that that happens at the neurobiological level with substance use disorder. Studies using animal models of obesity have found typical neurobiological characteristics of addiction in the brain systems, which result from behaviors similar to addiction to fat and sugar-rich foods.

Considering the widespread expression of GLP-1 receptors in the brain, the authors recommend that future studies should focus on identifying the key neurocircuits involved in mediating the effects of GLP-1 receptor agonists on substance use disorder, as well as determine the specific patient subtypes who are most likely to benefit from these treatments.

They also highlight the need for future clinical trials to more conclusively determine the dose and duration of GLP-1 receptor agonist-based treatments in patients addicted to different types of substances, including amphetamines, opioids, and benzodiazepines.

The clinical trials included in the review had a high degree of heterogeneity in terms of substance types, patients’ characteristics, and types and doses of the administered GLP-1 receptor agonists. This variability restricted the possibility of conducting a meta-analysis and emphasized the need for standardized protocols in future research.

As mentioned by the authors, the findings of this review should be viewed with some caution with respect to the potential therapeutic effect of GLP-1 receptor agonists on substance use disorder.