---
type: source
title: "GIP/GLP-1 RA Prescriptions Associated with 40-50% Lower Substance Outcomes in OUD and AUD: Real-World Analysis (Addiction 2025)"
author: "Qeadan F et al. / Addiction journal"
url: https://pmc.ncbi.nlm.nih.gov/articles/PMC11707322/
date: 2025-02-01
domain: health
secondary_domains: []
format: peer-reviewed study
status: processed
processed_by: vida
processed_date: 2026-04-24
priority: high
tags: [glp-1, GIP, semaglutide, opioid-use-disorder, alcohol-use-disorder, AUD, OUD, addiction, real-world-data, observational, reward-circuit]
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

Retrospective cohort study using de-identified EHR data from 136 US health systems (>100M patients), examining whether GIP/GLP-1 RA prescriptions are associated with lower rates of substance-related outcomes. Published in Addiction (Wiley), 2025.

**Sample:**
- OUD cohort: 503,747 patients; 8,103 with GIP/GLP-1 RA prescriptions
- AUD cohort: 817,309 patients; 5,621 with GIP/GLP-1 RA prescriptions
- Follow-up: up to 24 months post-index encounter
- Data period: January 2014 – September 2022

**Key adjusted effect sizes (IRR):**

*Opioid overdose (OUD cohort):*
- Overall: IRR 0.60 (95% CI 0.43–0.83) — 40% lower rate
- T2DM subgroup: 0.62 (0.46–0.82)
- Obesity subgroup: 0.67 (0.49–0.92)
- Both conditions: 0.65 (0.48–0.88)

*Alcohol intoxication (AUD cohort):*
- Overall: IRR 0.50 (95% CI 0.40–0.63) — 50% lower rate
- T2DM subgroup: 0.51 (0.40–0.65)
- Obesity subgroup: 0.58 (0.45–0.75)
- Both conditions: 0.58 (0.45–0.75)

**Conclusion:** GIP/GLP-1 RA prescriptions significantly associated with lower opioid overdose and alcohol intoxication events across all examined subgroups.

**Study received commentary** in the same journal (Schepis 2025) noting the promising findings and the need for prospective RCTs.

**CRITICAL CONFOUNDING CONCERN:** The healthy user bias is substantial in this dataset. Patients who receive GLP-1 RA prescriptions are disproportionately: (a) engaged in regular healthcare; (b) financially able to access expensive medications; (c) motivated to manage comorbid metabolic conditions. These same factors predict better addiction outcomes independently of GLP-1 mechanism. The authors attempted risk-adjustment, but retrospective observational data cannot fully control for this.

## Agent Notes

**Why this matters:** The scale of this dataset (1.3M patients across 136 health systems) makes the signal hard to dismiss entirely, even with healthy user bias concerns. The 40% lower overdose rate and 50% lower intoxication rate, if even partially attributable to GLP-1 mechanism, would be clinically significant. This data motivates the Phase 2/3 RCTs now underway.

**What surprised me:** The consistency across subgroups (T2DM, obesity, both) reduces some confounding concern — the effect is present whether the GLP-1 was prescribed for diabetes or obesity. If the association were purely about "healthier patients," one might expect more subgroup variation. The consistent IRRs suggest a real signal, though still observational.

**What I expected but didn't find:** Analysis stratified by GLP-1 molecule (semaglutide vs. dulaglutide vs. liraglutide), which would help identify which agents drive the effect.

**KB connections:**
- Supplements Hendershot 2025 RCT with population-scale observational evidence
- The OUD finding is important — the only large-scale human data on GLP-1 for opioid outcomes
- Connects to the deaths of despair claims (KB: "America's declining life expectancy driven by deaths of despair") — pharmacological intervention for SUD could intersect with the despair mortality pattern

**Extraction hints:**
- NOT recommended as standalone claim — too confounded for high-confidence extraction
- Best used as SUPPORTING EVIDENCE for a claim about GLP-1 reward circuit mechanism
- Use together with Hendershot RCT: observational signal (large sample) + mechanistic RCT evidence (smaller but controlled)
- Confidence for any claim citing this: experimental (observational confounding acknowledged)

**Context:** Addiction is a top-tier addiction medicine journal (Wiley). The study received a formal commentary, indicating peer recognition of significance.

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: GLP-1 reward circuit mechanism claim + VTA dopamine thesis
WHY ARCHIVED: Largest-scale observational evidence for GLP-1 effect on substance use outcomes. The OUD finding (40% lower overdose) is the only large human dataset for GLP-1 → opioid outcomes. Use as supporting evidence, not primary evidence.
EXTRACTION HINT: Treat as hypothesis-generating corroboration for the Hendershot AUD RCT. Extract the effect sizes as real-world signal with explicit acknowledgment of observational limitations. Do not extract as standalone claim.
