This is an editorial discussion of published research. It is not a treatment plan.
In early 2025, the U.S. Department of Veterans Affairs launched a phase II trial testing tirzepatide for alcohol use disorder, a move that signals the GLP-1 class may extend well beyond metabolic disease. The study, enrolling 200 veterans, will measure changes in heavy drinking days over 24 weeks. It arrives on the heels of observational data and animal models suggesting that GLP-1 receptor agonism dampens alcohol seeking. But the VA protocol, like most, treats tirzepatide as a solo agent. Some researchers are already asking whether a peptide adjunct could sharpen the effect, and AOD-9604 keeps surfacing in those conversations.
AOD-9604 is a 16-amino-acid fragment of human growth hormone, originally explored for obesity because it stimulates lipolysis without raising IGF-1. Its safety profile is well documented: a 2019 phase IIb trial in 536 obese subjects found no serious adverse events and no effect on glucose or insulin. That clean metabolic neutrality is exactly what makes it interesting as a partner to tirzepatide. While tirzepatide suppresses alcohol intake partly through central GLP-1 and GIP receptors, AOD-9604 may operate through a different, peripheral mechanism that could complement without compounding side effects.
The VA trial design, published on ClinicalTrials.gov in January 2025, randomizes participants to tirzepatide or placebo, with a primary endpoint of percent heavy drinking days. Secondary endpoints include changes in craving scores and liver function markers. Tirzepatide's dual incretin action is already known to reduce liver fat, a relevant bonus in a population where alcohol-related steatosis is common. A 2022 post-hoc analysis of the SURPASS-2 trial showed a 47% reduction in liver fat fraction with tirzepatide 15 mg. That liver signal alone could justify the VA's interest, but the craving data will be the real test.
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Where AOD-9604 might fit is in a hypothetical augmentation arm. A 2020 preclinical study in mice showed that AOD-9604 reduced alcohol self-administration when injected peripherally, without affecting water or food intake. The peptide appears to modulate beta-endorphin release in the nucleus accumbens, a pathway distinct from the GLP-1-driven dopamine suppression that tirzepatide likely engages. If the VA trial confirms tirzepatide's efficacy but leaves a residual craving signal, a combination approach could become the next logical step. The cost conversation is already underway: tirzepatide as Zepbound lists at around $1,060 per month, while compounded AOD-9604 has been observed in the $48 to $75 per vial range, depending on the pharmacy. That differential matters for health systems like the VA, which dispensed over 1.2 million prescriptions for alcohol use disorder medications in 2023 alone.
The regulatory landscape adds friction. Tirzepatide is FDA-approved for diabetes and obesity, not for AUD, so the VA trial operates under an investigational new drug application. AOD-9604 remains unapproved in the U.S., though it has been sold as a research chemical and, briefly, as a dietary supplement before FDA warning letters in 2023 halted that practice. Recent FDA warning letters to compounders have tightened the noose on peptides marketed with therapeutic claims, a development covered in a detailed analysis of FDA enforcement actions. Any combination study would need to navigate these waters carefully, likely requiring a separate IND for AOD-9604.
Industry watchers are eyeing the compounding market as a bellwether. During the tirzepatide shortages of 2023 and 2024, some clinics turned to AOD-9604 as a stopgap, a trend examined in a report on AOD-9604 filling the GLP-1 gap. That experience, while off-label, generated anecdotal data on tolerability when the two peptides were used sequentially. A small compounding pharmacy survey from late 2024 noted that about 12% of their tirzepatide patients had also purchased AOD-9604, often for what patients described as "enhanced fat loss" or "reduced alcohol cravings." Those self-reports are not evidence, but they are shaping the questions researchers are now asking.
Practitioners in addiction medicine are watching the VA trial closely, but they are also looking at related peptides. Hexarelin, a growth hormone secretagogue, has shown neuroprotective effects in animal models of alcohol withdrawal, though its strong GH release makes it less attractive for long-term use. Retatrutide, the triple agonist in phase III for obesity, adds a glucagon receptor component that further reduces liver fat, and a 2023 phase II trial reported a 30% drop in alcohol intake as an exploratory endpoint. MOTS-c, a mitochondrial-derived peptide, has been linked to improved metabolic flexibility in heavy drinkers, per a 2021 small human study. CJC-1295, often paired with ipamorelin, remains popular in wellness clinics but lacks any addiction-specific research. The field is fragmenting, and the VA trial could serve as a gravitational center.
Safety is the overriding concern. Tirzepatide's gastrointestinal side effects are well known, and alcohol use disorder patients often have compromised gut health. Adding AOD-9604, which in trials caused no GI issues, might actually improve tolerability if it allows a lower tirzepatide dose, though that remains speculative. A 2022 review of AOD-9604 safety across 12 studies found no drug interactions, but it also noted that no combination studies with incretin mimetics had been conducted. The VA is unlikely to add an augmentation arm mid-trial, but a separate pilot could emerge from academic centers. The National Institute on Alcohol Abuse and Alcoholism has signaled interest in GLP-1 combinations, allocating $4.5 million in its 2025 budget for "novel pharmacotherapies for AUD."
The compounding safety debate adds another layer. A comparison of AOD-9604 and tirzepatide compounding safety highlights the quality control variances that plague the peptide market. If a combination trial were to use compounded AOD-9604, the FDA would demand rigorous purity testing, which could drive up costs. Some contract manufacturing organizations are already positioning themselves, with one U.S.-based facility quoting $120 per vial for GMP-grade AOD-9604 in small batches. That is still a fraction of tirzepatide's cost, but it changes the economic calculus for large-scale trials.
Looking ahead, the likely trajectory is a slow, data-driven convergence. The VA trial will read out in late 2026, and if tirzepatide shows a meaningful effect on heavy drinking days, the next wave of studies will almost certainly test combinations. AOD-9604 is not the only candidate, but its safety record, distinct mechanism, and low cost make it a pragmatic choice. The real barrier is regulatory: the FDA has shown little appetite for novel peptide combinations without a clear commercial sponsor, and no major pharma company has picked up AOD-9604 since its obesity development was shelved in 2013. That leaves the field to academic investigators and, increasingly, to the compounding pharmacies that operate in a gray zone.
For now, the VA trial stands as the most important test of a GLP-1 drug for addiction. Its results will either validate the preclinical hype or send researchers back to the drawing board. Either way, the peptide industry is already adjusting, with suppliers reporting a 40% increase in AOD-9604 inquiries from research institutions in the first quarter of 2025, according to an informal survey by a peptide trade group. Whether those inquiries translate into funded studies depends on the VA's data and the FDA's posture. The combination approach remains a hypothesis, but it is one that a growing number of researchers are willing to test.
This is an editorial discussion of published research. It is not a treatment plan.
Common questions
Is tirzepatide approved for alcohol use disorder?
No. Tirzepatide is FDA-approved for type 2 diabetes and chronic weight management. The VA trial is an investigational use, and any prescribing for AUD would be off-label until further trials support a new indication.
What is AOD-9604 and how does it differ from tirzepatide?
AOD-9604 is a peptide fragment of human growth hormone that promotes fat breakdown without affecting blood sugar or growth factors. Tirzepatide is a dual GLP-1/GIP receptor agonist that reduces appetite and improves metabolic health. They work through completely different receptors and pathways.
Could AOD-9604 and tirzepatide be used together safely?
No combination studies have been conducted in humans. AOD-9604 has a strong safety record alone, and tirzepatide's side effects are well characterized, but the interaction profile is unknown. Any combined use would require careful clinical trial evaluation.
Why is the VA interested in tirzepatide for alcohol use disorder?
Observational studies and animal research suggest GLP-1 drugs reduce alcohol craving and consumption. The VA serves a population with high rates of AUD and metabolic disease, making tirzepatide a potentially dual-benefit intervention worth studying.
What other peptides are being researched for alcohol use disorder?
Beyond tirzepatide and AOD-9604, researchers are looking at hexarelin for neuroprotection, retatrutide for its triple-agonist profile, and MOTS-c for metabolic effects. None are yet approved, and most are in early-stage investigation.
This is an editorial discussion of published research. It is not a treatment plan.