In November 2025, Eli Lilly quietly registered two Phase 3 clinical trials that could reshape how the world thinks about peptide therapeutics. The trials weren't for diabetes. They weren't for obesity. They were for alcohol use disorder, and the drug at the center was a synthetic peptide called brenipatide.
The compound, internally designated LY-3537031 and classified as Lilly's "GIP/GLP-1 Coagonist III," represents the pharmaceutical giant's bet that the same class of molecules revolutionizing metabolic medicine can be turned against addiction. It is, in many ways, the moment peptide science crosses a threshold from metabolic therapy into neuroscience.
What Is Brenipatide?
Brenipatide is a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). In simpler terms, it activates two hormonal signaling pathways that regulate insulin secretion, appetite, gastric emptying, and, as researchers are now discovering, the brain's reward circuitry.
It belongs to the same mechanistic family as tirzepatide (marketed as Mounjaro and Zepbound), which Lilly developed for type 2 diabetes and obesity. But brenipatide is a distinct molecule, a new molecular entity with its own pharmacokinetic profile. One notable difference: brenipatide is administered once per month via subcutaneous injection, compared to tirzepatide's weekly dosing. This extended half-life could be significant for adherence in an addiction population where treatment compliance is a persistent challenge.
The amino acid sequence has not been publicly disclosed, which means no research peptide vendors currently offer it. Access is limited to Lilly's clinical trial program.
The Trials: RENEW-ALC-1 and RENEW-ALC-2
Lilly's commitment to this indication is not casual. The two Phase 3 studies, designated RENEW-ALC-1 (NCT07219966) and RENEW-ALC-2 (NCT07219953), are each enrolling approximately 1,100 participants with moderate-to-severe alcohol use disorder. That is 2,200 total subjects across sites in the United States, Argentina, Belgium, China, Germany, Japan, South Korea, Taiwan, and the United Kingdom.
The study design is a 56-week randomized, double-blind, placebo-controlled trial with escalating subcutaneous doses. Primary outcome is change in drinking patterns as measured by the Timeline Followback (TLFB) method, a validated retrospective calendar-based technique for recording daily alcohol consumption. Secondary endpoints include changes in daily alcohol consumption, alcohol craving (Penn Alcohol Craving Scale), AUDIT scores, body weight, and quality of life measures.
Inclusion criteria require participants aged 18-75 who are seeking treatment and motivated to reduce or stop drinking. Key exclusions include advanced liver disease, recent substance use disorders other than alcohol, nicotine, or caffeine, and active suicidal ideation.
Completion is estimated for April 2028.
Lilly has also registered a separate trial (NCT07223840) evaluating brenipatide in 222 participants who recently quit smoking and are motivated to stay quit, signaling that the company sees potential across multiple addiction indications.
Why GLP-1 for Alcoholism? The Neuroscience
The connection between GLP-1 receptor agonists and reduced alcohol consumption was first observed as an unexpected side effect. Patients prescribed semaglutide or tirzepatide for diabetes and obesity began reporting that their desire to drink had diminished. Anecdotal reports accumulated. Researchers took notice.
The biological explanation centers on the brain's reward system. GLP-1 receptors are expressed not only in the pancreas and gut but also in key regions of the central nervous system, including the ventral tegmental area (VTA) and nucleus accumbens, structures that form the core of the mesolimbic dopamine pathway. This is the same circuitry that mediates the reinforcing effects of alcohol, opioids, nicotine, and other addictive substances.
Preclinical studies have shown that GLP-1 receptor agonists reduce voluntary alcohol consumption in rodent models, attenuate alcohol-seeking behavior, and decrease dopamine release in the nucleus accumbens in response to alcohol. The mechanism appears to dampen the reward signal, making alcohol less reinforcing without producing aversive effects.
Multiple large pharmacoepidemiology studies have supported these observations. A study across 136 US healthcare systems found that patients with alcohol use disorder who received GLP-1 receptor agonists for other conditions had significantly lower rates of alcohol intoxication, with a hazard ratio of 0.64. These protective effects were consistent across subgroups with comorbid type 2 diabetes and obesity.
The Clinical Evidence So Far
Before Lilly's Phase 3 program, two completed randomized trials had examined GLP-1 receptor agonists for alcohol use disorder.
The EXALT Trial (2022): A 26-week study of exenatide (the first-generation GLP-1 agonist) in 152 participants with alcohol dependence found no significant reduction in heavy drinking days overall. However, an exploratory analysis revealed that participants with a BMI of 30 or higher showed significantly reduced heavy drinking and total alcohol intake compared to placebo. The study also demonstrated that exenatide attenuated functional MRI alcohol cue reactivity in the ventral striatum and septal areas, brain regions central to drug reward and addiction.
The Semaglutide Trial (2025): Published in JAMA Psychiatry in February 2025, this Phase 2 study randomized 48 participants with AUD to low-dose semaglutide or placebo for 9 weeks. Results were notable. Semaglutide produced medium-to-large effect sizes for reduction in grams of alcohol consumed (β = -0.48) and peak breath alcohol concentration (β = -0.46) during a laboratory self-administration task. The drug significantly reduced drinks per drinking day and weekly alcohol craving, and predicted greater reductions in heavy drinking over time compared to placebo.
What was particularly striking: semaglutide's effects on drinking occurred without participants actively trying to reduce consumption. The study enrolled non-treatment-seeking individuals. The alcohol reduction appeared to be a direct pharmacological effect rather than a behavioral one.
Why a New Molecule Instead of Zepbound?
Lilly's decision to advance brenipatide rather than repurpose tirzepatide for AUD reflects strategic calculation. Several factors are likely at play.
Regulatory independence. A separate molecule allows Lilly to pursue a clean FDA indication for alcohol use disorder without complicating the regulatory or marketing story for Zepbound, which generates billions in annual revenue as an obesity and diabetes treatment.
Pharmacological optimization. The ratio of GIP to GLP-1 receptor agonism can theoretically be tuned for different therapeutic contexts. The balance that produces optimal metabolic outcomes may not be the same balance that produces optimal neurological effects. Brenipatide's once-monthly dosing also suggests engineering for sustained central nervous system exposure.
Market protection. A dedicated AUD molecule establishes a separate franchise with its own patent protection, branding, and clinical data set. This prevents competitors from pointing to Zepbound's label and prescribing it off-label for addiction.
The Competitive Field
Lilly is not alone in pursuing GLP-1-based addiction therapy.
Novo Nordisk has multiple semaglutide trials in progress for AUD. The largest is the CRAVE study, a VA-funded Phase 3 trial of semaglutide 2.4 mg in veterans with moderate-to-severe AUD. The trial includes a dose escalation to the full obesity dose and measures WHO risk drinking level reduction as a primary outcome.
Baseline Therapeutics launched in January 2026 as a startup specifically built to develop GLP-1 agonists for addiction. Their lead asset, BT-001, is a once-weekly GLP-1 analog being advanced into two Phase 3 studies for AUD, with plans to expand into cocaine and methamphetamine use disorders.
Academic investigators are independently studying tirzepatide for AUD at multiple centers, testing whether the dual GIP/GLP-1 mechanism (which showed the largest effect on alcohol-related outcomes in subgroup analyses of observational data) offers advantages over GLP-1-only drugs like semaglutide.
The Scale of the Problem
The potential impact is enormous. Alcohol use disorder affects approximately 29 million Americans. It is the third leading cause of preventable death in the United States and costs the economy an estimated $249 billion annually. Despite this, only three medications have FDA approval for AUD: naltrexone, acamprosate, and disulfiram.
All three were approved decades ago. All three have modest efficacy. Naltrexone, the most widely prescribed, has a number needed to treat (NNT) of 12 to prevent return to heavy drinking. Uptake is dismal: fewer than 10% of people with AUD receive any form of medication treatment. The reasons include stigma, prescriber reluctance, low patient awareness, and the perception that available drugs simply don't work well enough.
A GLP-1-class medication for AUD could bypass many of these barriers. The drugs are already widely prescribed and socially accepted. Primary care physicians are comfortable with them. Patients are actively seeking them. If Lilly succeeds in demonstrating that brenipatide reduces drinking with the same reliability that its cousins reduce weight, it could fundamentally change the treatment field.
What This Means for Peptide Science
Beyond the immediate clinical implications, the brenipatide program represents a conceptual shift for peptide therapeutics. For decades, the public perception of peptides has been shaped by their use in bodybuilding, anti-aging, and performance enhancement. The idea that a peptide could treat alcoholism, one of the most intractable psychiatric conditions, introduces peptide science to an entirely new audience.
If the Phase 3 trials succeed and brenipatide receives FDA approval (potentially in 2029 or later), it would mark one of the first instances of a synthetic peptide being approved specifically for a neuropsychiatric indication. That precedent could accelerate investment and research into peptide-based treatments for other conditions of the central nervous system, including opioid use disorder, cocaine addiction, bipolar disorder (another indication Lilly is exploring with brenipatide), and eating disorders.
The research peptide community has long operated at the frontier of peptide science, identifying and studying compounds years before they enter mainstream medicine. GLP-1 agonists are a case in point: researchers were studying their mechanisms and multi-system effects well before the Ozempic era made them household names. The convergence of incretin biology and addiction neuroscience represents the next chapter of that story.
Key Takeaways
- Brenipatide (LY-3537031) is Lilly's proprietary dual GIP/GLP-1 agonist, dosed once monthly by subcutaneous injection
- Two Phase 3 trials (2,200 total participants) are actively recruiting for moderate-to-severe AUD across 9 countries
- The mechanism involves GLP-1 receptors in brain reward circuits, dampening the reinforcing effects of alcohol
- Prior clinical evidence (semaglutide Phase 2, JAMA Psychiatry 2025) showed medium-to-large effect sizes for reduced alcohol consumption and craving
- Not currently available from any research peptide vendor; the amino acid sequence has not been disclosed
- Completion estimated April 2028, with potential FDA approval in 2029 or beyond
- Also being studied for smoking cessation and bipolar disorder
References
1. ClinicalTrials.gov. A Study of Brenipatide in Participants With Alcohol Use Disorder (RENEW-ALC-2). NCT07219953.
2. Hendershot CS, Bremmer MP, Paladino MB, et al. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025;82(4):395-405.
3. Klausen MK, Thomsen M, Wortwein G, et al. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. British Journal of Pharmacology. 2019;176(14):2396-2409.
4. Qeadan F, et al. GLP-1 receptor agonists and rates of opioid overdose and alcohol intoxication. Journal of Clinical Medicine. 2025.
5. Leggio L, et al. GLP-1 Therapeutics and Their Emerging Role in Alcohol and Substance Use Disorders. Journal of the Endocrine Society. 2025.
6. Wikipedia. Brenipatide. Accessed April 2026.