GLP-1 Drugs and Substance Use Disorders: A Systematic Review

Key Finding Across 11 studies, GLP-1 receptor agonists were consistently associated with reduced substance-related outcomes in alcohol, tobacco, and opioid use disorders, with the largest effect signals seen in opioid overdose risk reduction (HR 0.32–0.58).

GLP-1 receptor agonists are among the most studied drug classes in modern metabolic medicine, but a growing body of evidence suggests their effects may extend well beyond glycemic control and weight management. A systematic review published in October in Disease-a-Month examines whether these drugs reduce outcomes in substance use disorders — a potential application that, if confirmed, would represent a significant expansion of their therapeutic footprint.

What the review examined

The review, conducted according to PRISMA guidelines, searched PubMed, Scopus, Web of Science, CENTRAL, and PsycINFO through March 2026, identifying 1,641 records. Eleven studies met inclusion criteria — a mix of randomized controlled trials and observational cohort studies covering alcohol use disorder, tobacco use disorder, opioid use disorder, and composite substance use outcomes.

The authors assessed study quality independently, finding the RCTs to be low risk of bias and the observational studies to be moderate risk.

The key findings across substance categories

Alcohol use disorder. GLP-1RA use was associated with a reduction in alcohol-related hospitalization (adjusted hazard ratio range 0.64–0.72) and reduced incidence of new alcohol use disorder (odds ratio range 0.26–0.71). However, the randomized controlled trial data in this category were contradictory: one trial showed a 29% reduction that was not statistically significant (p = 0.37), while another found a statistically significant 29% reduction (p = 0.04). This inconsistency is the central tension in the evidence base — the observational data look promising, but the randomized data have not yet confirmed them.

Tobacco use disorder. Semaglutide was associated with a reduced risk of incident tobacco use disorder (HR 0.68; 95% CI 0.63–0.74). This finding came from large-scale observational data and represents a moderate but consistent signal.

Opioid use disorder. The association here was the strongest across all categories. GLP-1RA use was associated with a greatly decreased risk of opioid overdose (HR 0.32–0.58). The magnitude of this association — a 42–68% reduction in overdose risk — warrants attention, though the confidence intervals are wide and the number of studies limited.

Composite outcomes. Across all substance use disorder categories combined, GLP-1RA use was associated with reduced incidence (HR 0.86), mortality (HR 0.50), and suicidal ideation (HR 0.75). Weight reduction was consistent across studies (−2.9 kg on average, with 37.5% of patients losing ≥16 kg), and HbA1c improved by −0.25%.

The safety signal

No patterns of increasing serious adverse events emerged across the studies. Safety profiles were described as positive, which is consistent with the well-documented tolerability profile of GLP-1RAs in metabolic indications. This is relevant because any new indication for an existing drug class would benefit from an already-characterized safety profile.

What is still unknown

The review’s conclusion is measured and important: GLP-1RAs have “good potential protective properties against SUD especially in observational research with good safety.” But the authors are explicit that “robust randomized trials are needed to confirm causality and clinical applicability.”

This is the pattern that matters. The observational data are consistent across multiple substance categories and multiple study populations — that consistency is what makes the signal worth pursuing. But inconsistency in the RCT data for alcohol use disorder, and the complete absence of dedicated SUD trials for other substances, means the question is genuinely open. The association may be causal, or it may reflect that people who are prescribed GLP-1RAs also receive more healthcare contact overall — the healthy-user effect that observational studies cannot fully eliminate.

The existing GLP-1 receptor agonist reference protocols — for tirzepatide and semaglutide — are maintained on ResearchProtocols for those seeking the compound-level background. The question of whether these drugs will one day carry an SUD indication depends on the trials that, as of this review, have not yet been designed.