GLP-1s & Opioid Addiction: Penn State's Breakthrough Research

Why Would Weight-Loss Drugs Help Opioid Addiction?

For decades, addiction has been understood as hijacking the brain's "reward pathway." But Penn State researchers Patricia Sue Grigson and Scott Bunce theorized something different: what if addiction also involves the "need pathway"—the same circuitry that drives us to eat when hungry?

The Research Timeline

Penn State has been investigating GLP-1 drugs for opioid addiction since 2017. Here's how the research has progressed:

The First Human Trial: Liraglutide Results

In February 2024, Grigson presented data from the first randomized controlled trial testing a GLP-1 drug against opioid addiction. The study was conducted at Caron Treatment Centers in Pennsylvania.

Key Observations

• Rapid onset: Effects were evident at the very first dose, at the lowest dose level—important for treatment since patients can't wait days or weeks for medication to work
• Timing: Craving reduction was effective "in the afternoon and evening—times of high risk and high relapse"
• Combination approach: Patients on both liraglutide AND buprenorphine had lower GI distress and dropout rates than those on liraglutide alone
• Safety: No notable differences in side effects between liraglutide and placebo groups, except GI distress (twice as common with liraglutide)

Limitations

The trial had significant limitations that researchers acknowledged:

• Small sample: Only 20 participants enrolled
• High dropout: Only 9 patients completed the 3-week trial, largely due to GI distress
• Residential setting: Controlled environment may not reflect real-world outcomes
• Short duration: 3 weeks insufficient to assess long-term relapse prevention

The Ongoing Phase II Trial: Semaglutide

Based on the promising early results, Penn State is now conducting a larger trial using semaglutide (the active ingredient in Ozempic and Wegovy) rather than liraglutide.

Why Semaglutide Instead of Liraglutide?

• Convenience: Once-weekly injection vs. daily—may improve adherence
• Tolerability: Previous studies suggest semaglutide has fewer GI side effects
• Potency: Semaglutide generally shows stronger effects in weight loss and other outcomes

Safety Considerations in This Population

Researchers have identified unique challenges with using GLP-1 drugs in patients with opioid use disorder:

• Weight loss in non-obese patients: Many people with OUD are not overweight. Researchers have built in weight monitoring with cutoffs to remove participants losing weight at dangerous levels.
• GI side effects: Nausea and vomiting could be problematic in a vulnerable population already dealing with physical symptoms.
• Compliance: Weekly injections require consistent follow-up, though this may actually help maintain clinical contact.

The Broader Addiction Research Landscape

Penn State is pioneering opioid research, but GLP-1 drugs are now being studied for multiple addictions:

• Alcohol: A landmark JAMA study (April 2025) showed semaglutide reduced alcohol consumption in a randomized trial. Read our analysis →
• Nicotine: Multiple trials underway testing GLP-1 drugs for smoking cessation
• Cocaine: Animal studies show reduced self-administration with GLP-1 agonists
• Gambling: Early speculation (not yet tested in trials)

Eli Lilly CEO Dave Ricks indicated at the 2025 JP Morgan healthcare conference that the company plans to study tirzepatide (Mounjaro/Zepbound) for "a number of dependencies—alcohol, tobacco seems pretty straightforward."

What This Means for Patients

GLP-1 drugs are not approved for opioid use disorder. The research is promising but preliminary:

• Current FDA-approved treatments for OUD (buprenorphine, methadone, naltrexone) remain the standard of care
• Off-label use for addiction is not recommended outside of clinical trials
• If Phase II results are positive, Phase III trials would be needed before FDA approval
• A new indication for OUD could potentially take 3-5+ years even with positive results

The Bottom Line

The first randomized controlled trial of GLP-1 drugs for opioid addiction showed a 40% reduction in cravings—a promising signal that these medications may help through the same brain mechanisms that reduce food cravings and overeating.

However, the trial was small and short. Larger studies are now underway, and results from the 200-patient Phase II trial at Penn State, NYU, and University of Maryland should provide much clearer answers about whether semaglutide can meaningfully reduce opioid relapse in real-world outpatient settings.

With opioid overdoses killing tens of thousands annually, any new tool that reduces cravings and prevents relapse would be significant—even if used alongside, rather than replacing, existing medications.