Studies investigate GLP-1s promise in treating substance use disorders

There have been reports that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may also have the potential to treat alcohol and drug addiction, according to a team of international researchers.

"Early research in both animals and humans suggests that these treatments may help reduce alcohol and other substance use," said lead researcher, Dr Lorenzo Leggio of the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), both part of the National Institutes of Health (NIH) in Bethesda, MD. "Some small clinical trials have also shown encouraging results."

The negative consequences of substance use disorders represent a global problem, affecting individuals, families, communities, and societal health at large. For instance, research indicates that alcohol is the most harmful drug, with consequences that extend beyond individual health to include related car accidents as well as gun and domestic violence, researchers note. Despite the high prevalence and consequences of alcohol and other substance use disorders, less than a quarter of people received treatment in 2023.

Underutilisation is due to a variety of barriers at the patient, clinician and organisational levels, not the least of which is the stigma associated with substance use disorders, according to the study.

"Current treatments for [alcohol and other substance use disorders] fall short of addressing public health needs," the researchers wrote.

GLP-1 therapies have gained widespread renown in recent years for their ability to address obesity and significantly reduce weight. In addition to its inhibitory effects on gastrointestinal systems, GLP-1 has key functions in the central nervous system, the researchers noted. Among them, GLP-1R activation within the central nervous system curbs appetite and encourages individuals to eat when hungry and stop eating when they are full.

Some forms of obesity have been shown to present biochemical characteristics that resemble addiction, including neurocircuitry mechanisms, the study says, acknowledging that such conclusions are controversial.

"Pathways implicated in addiction also contribute to pathological overeating and obesity," the researchers said.

With this pathway in mind, researchers in recent years have looked at GLP-1s as a potential therapy to address substance use disorders. Preclinical and early clinical investigations suggest that GLP-1 therapies modulate neurobiological pathways underlying addictive behaviours, thereby potentially reducing substance craving/use while simultaneously addressing comorbid conditions.

Studies that examine GLP-1 effects on substance use disorders include:

Alcohol use disorder (AUD): A randomised controlled trial with exenatide, the first GLP-1 receptor agonist approved for diabetes, showed no significant effect on alcohol consumption, although a secondary analysis indicated reduced alcohol intake in the subgroup of people with AUD and comorbid obesity. A more recent randomised controlled trial showed that low-dose semaglutide, reduced laboratory alcohol self-administration, as well as drinks per drinking days and craving, in people with AUD.

Opioid use disorder: In rodent models, several GLP-1 receptor agonists have been shown to reduce self-administration of heroin, fentanyl and oxycodone. The studies also found that these medications reduce reinstatement of drug seeking, a rodent model of relapse in drug addiction.

Tobacco use disorder: Preclinical data show that GLP-1 receptor agonists reduce nicotine self-administration, reinstatement of nicotine seeking, and other nicotine-related outcomes in rodents. Initial clinical trials suggest the potential for these medications to reduce cigarettes per day and prevent weight gain that often follows smoking cessation.

Leggio and his colleagues caution that more and larger studies are needed to confirm how well these treatments work. Additional studies will help unveil the mechanisms underlying GLP-1 therapies in relation to addictive behaviours and substance use.

However, that has not dampened the optimism for these therapies to address the serious problems found in substance use disorders.

"This research is very important because alcohol and drug addiction are major causes of illness and death, yet there are still only a few effective treatment options," Leggio said. "Finding new and better treatments is critically important to help people live healthier lives."

The findings were featured in the paper, ‘GLP-1 Therapeutics and Their Emerging Role in Alcohol and Substance Use Disorders: An Endocrinology Primer’, published in the Journal of the Endocrine Society.