GLP-1 Medications Reduce Risk of Substance Use Disorders and Overdose Deaths, Study Finds

GLP-1 receptor agonists such as semaglutide and tirzepatide are associated with reduced risk of developing substance use disorders across all major addictive substances and reduced risk of severe harm, including overdose and death, in people who already have such disorders, according to a study published March 4 in The BMJ.

Researchers at Washington University School of Medicine in St. Louis analyzed electronic health records of 606,434 U.S. veterans with type 2 diabetes. The participants were split into two groups: those without a pre-existing substance use disorder and those who already had a substance use disorder. The study looked back on their health records for up to three years, beginning when they started taking either a GLP-1 receptor agonist — most commonly semaglutide, liraglutide or dulaglutide — or another type of medication, called an SGLT2 inhibitor, to treat their diabetes.

Compared to patients treated for diabetes with a non-GLP-1 medication, GLP-1 use was associated with 14% reduced risk of developing any substance use disorder. Risk of developing each substance use disorder also declined significantly — by 18% for alcohol, 14% for cannabis, 20% for cocaine and nicotine, and 25% for opioids. This translated into seven fewer new substance use disorder diagnoses per 1,000 GLP-1 users.

Among patients with pre-existing substance use disorder, GLP-1s were tied to fewer hospitalizations, overdoses and deaths related to substance use. After three years, there was a 30% reduction in emergency department visits, 25% reduction in hospitalizations, 40% reduction in overdose and 50% reduction in drug-related deaths. This translated into 12 fewer serious harm events per 1,000 GLP-1 users.

Patients have reported decreased interest in alcohol and nicotine when taking GLP-1s, and observational studies have shown an association between treatment with GLP-1 medication and lower risk of alcohol and cannabis use disorders, opioid overdose, and alcohol-related hospitalization. But these studies examined substances one at a time.

There are GLP-1 receptors in the brain in regions that modulate reward processing. A recent study published in eBioMedicine found that the drug tirzepatide reduces alcohol consumption and prevents relapse behaviors in rodents.

The research team tested how tirzepatide affects the brain's reward system using male mice. When the mice received alcohol, their dopamine levels spiked. However, when the researchers gave the mice tirzepatide before the alcohol, this dopamine surge was mostly blocked. The drug prevented the chemical reward usually associated with alcohol consumption.

To see if this effect was direct, the researchers delivered alcohol directly into the nucleus accumbens of some mice, rather than injecting it into their bodies. Tirzepatide still blocked the dopamine release. This suggests the medication interacts directly with the brain's reward circuitry.

The team also examined voluntary drinking habits in both male and female rats. They used an intermittent access model, which provides the animals with alcohol every other day to encourage heavier drinking. A single dose of tirzepatide cut the animals' alcohol consumption by more than half, and it also decreased their overall preference for alcohol compared to plain water.

To study relapse, the researchers temporarily took alcohol away from rats that had grown accustomed to drinking it. Normally, this forced abstinence causes animals to drink much more than usual once the alcohol is returned. When the researchers administered tirzepatide before returning the alcohol, the rats did not show this spike in drinking. Instead of drinking more, their alcohol intake dropped below their original baseline levels. The drug successfully prevented the relapse-like behavior.

Baseline Therapeutics and Eli Lilly are both advancing phase 3 programmes with GLP-1RAs for alcohol use disorder. Nearly 29 million Americans are living with alcohol use disorder. Tirzepatide is a newer medication that mimics two different gut hormones at the same time. It targets the glucagon-like peptide-1 receptor alongside another receptor for a hormone called glucose-dependent insulinotropic polypeptide. The medication is already approved and widely used for the treatment of diabetes and obesity.