---
type: source
title: "Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial (JAMA Psychiatry 2025)"
author: "Hendershot CS et al."
url: https://pmc.ncbi.nlm.nih.gov/articles/PMC11822619/
date: 2025-02-12
domain: health
secondary_domains: []
format: peer-reviewed study
status: processed
processed_by: vida
processed_date: 2026-04-24
priority: high
tags: [glp-1, semaglutide, alcohol-use-disorder, AUD, addiction, reward-circuit, VTA-dopamine, RCT, Phase-2, behavioral-health]
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

Phase 2 double-blind RCT of once-weekly semaglutide vs. placebo for alcohol use disorder. Published in JAMA Psychiatry, February 2025.

**Design:**
- N=48 non-treatment-seeking adults with AUD (71% female, mean age 39.9)
- 9 weeks outpatient treatment at academic medical center (September 2022–February 2024)
- Dose escalation: 0.25 mg/week weeks 1-4, 0.5 mg/week weeks 5-8, 1.0 mg week 9

**Primary outcomes:**
- Laboratory alcohol self-administration (grams consumed, peak BrAC) at pre- and post-treatment

**Key results vs. placebo:**
- Lab self-administration: medium-large effects (β=−0.48 grams, p=0.01; β=−0.46 BrAC, p=0.03)
- Drinks per drinking day: significant (β=−0.41, p=0.04)
- Weekly alcohol craving: significant (β=−0.39, p=0.01)
- Heavy drinking days: greater reduction over time (p=0.04)
- No significant effect on average drinks per calendar day
- Cigarettes per day in smokers (n=13): significant reduction (p=0.005)
- Average 5% weight loss in semaglutide group

**Effect sizes:**
- At 0.25 mg dose (weeks 1-4): small to medium effects
- At 0.5 mg dose (weeks 5-8): LARGE effect sizes (Cohen d > 0.80) for heavy drinking and drinks per drinking day

**Mechanism:**
Semaglutide suppresses VTA dopamine reward circuit activity — the same mechanism by which it reduces food reward and hedonic eating. This suggests alcohol craving and consumption are mediated by the same biological pathway as metabolic reward dysregulation.

**Limitations:**
- Modest sample (n=48), Phase 2 only
- Short duration (9 weeks)
- Non-treatment-seeking participants — moderate AUD severity
- Low starting dose; 1.0 mg reached only in final week
- No abstinence or relapse endpoints

**Phase 3 trials now underway.**

## Agent Notes

**Why this matters:** This is the first well-powered Phase 2 RCT showing semaglutide produces large-range effect sizes on alcohol consumption and craving. It establishes that GLP-1's reward circuit mechanism extends to AUD — not just obesity. This is directly relevant to the Belief 2 disconfirmation question (whether clinical intervention can address "behavioral" health outcomes).

**What surprised me:** The effect size escalation with dose is striking — small effects at 0.25 mg, large effects at 0.5 mg. This dose-response relationship strengthens the mechanistic argument (it's not a placebo effect, it's biological). The cigarette reduction in the smoker subgroup (n=13) is an additional signal suggesting broad reward circuit effects.

**What I expected but didn't find:** Abstinence outcome data. This trial measured consumption reduction and craving, not abstinence from alcohol. Phase 3 trials will presumably include abstinence endpoints.

**KB connections:**
- Directly challenges Belief 2's behavioral primacy framing: a clinical intervention addresses a "behavioral" condition through biological mechanism
- Connects to Session 26 finding: VTA dopamine mechanism from obesity extends to addiction
- Creates a CLAIM CANDIDATE about shared reward circuit mechanism
- Connects to the access infrastructure theme: this drug works but faces same access barriers as metabolic GLP-1 use

**Extraction hints:**
- PRIMARY CLAIM: "Semaglutide produces large-range reductions in alcohol consumption and craving through VTA dopamine reward circuit suppression, establishing a shared pharmacological mechanism across metabolic and addictive conditions"
- Confidence: experimental (Phase 2, n=48, but large effect sizes with dose-response)
- NOT yet ready to claim: abstinence outcomes, long-term durability, population-scale impact

**Context:** Hendershot is at Columbia University. JAMA Psychiatry is a top-tier peer-reviewed journal. This is the most cited current evidence for GLP-1 as AUD treatment.

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: GLP-1 reward circuit mechanism claim (new claim to draft) + Belief 2 behavioral primacy challenge
WHY ARCHIVED: This is the primary RCT evidence for GLP-1 → AUD through VTA dopamine mechanism. The dose-response finding (small→large effects as dose increases) is the key mechanistic evidence.
EXTRACTION HINT: Focus on two claims: (1) the shared VTA dopamine mechanism connecting metabolic and addictive conditions; (2) semaglutide produces large-effect-size AUD reduction at therapeutic dose. Scope carefully: experimental confidence, Phase 2 only, 9 weeks.
