PMID-39937469 — Hendershot: Semaglutide in Alcohol Use Disorder (JAMA Psychiatry 2025)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/JAMA Psychiatry 2026-04-19.]

Citation

Hendershot CS, Bremmer MP, Paladino MB, Kostantinis G, Gilmore TA, Sullivan NR, Tow AC, Dermody SS, Prince MA, Jordan R, McKee SA, Fletcher PJ, Claus ED, Klein KR. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025;82(4):395-405. doi: 10.1001/jamapsychiatry.2024.4789. PMID: 39937469. PMCID: PMC11822619.

External URL: PubMed

Study Design

Design: Phase 2, double-blind, placebo-controlled, parallel-arm, randomized clinical trial
Setting: Single academic medical center in the US, September 2022 – February 2024
Population: Non-treatment-seeking adults with alcohol use disorder (AUD)
N: 48 randomized (of 504 assessed for eligibility)
Intervention: Semaglutide 0.25 mg/wk × 4 wk → 0.5 mg/wk × 4 wk → 1.0 mg × 1 wk (total 9 weeks outpatient treatment)
Primary outcomes: Alcohol self-administration (laboratory task), drinks per drinking day, heavy drinking days, alcohol craving

Key Findings

Grams of alcohol consumed (laboratory task): β = −0.48 (95% CI −0.85 to −0.11), P = 0.01 — medium-to-large effect size reduction
Peak breath alcohol concentration: β = −0.46 (95% CI −0.87 to −0.06), P = 0.03
Drinks per drinking day: β = −0.41 (95% CI −0.73 to −0.09), P = 0.04
Weekly alcohol craving: β = −0.39 (95% CI −0.73 to −0.06), P = 0.01
Heavy drinking over time: Semaglutide predicted greater reductions vs placebo (β = 0.84, P = 0.04)
Average drinks per calendar day: No significant between-group difference
Number of drinking days: No significant between-group difference

Subgroup finding

Semaglutide subgroup with baseline current cigarette use showed greater relative reductions in cigarettes per day — secondary finding relevant to the Wang 2024 Ann Intern Med tobacco-use-disorder real-world analysis.

Clinical Relevance

Hendershot 2025 provides Phase 2 RCT evidence for a signal that had been suggested by preclinical and observational data: GLP-1 receptor agonists may reduce alcohol craving and heavy drinking patterns. Core points:

Reduces alcohol self-administration in a laboratory task — proof-of-concept that sem modulates alcohol-seeking behavior
Reduces heavy-drinking pattern (drinks per drinking day, heavy drinking days) more than frequency of drinking (drinks per calendar day, drinking days) — supports mechanism of reduced consumption-per-occasion rather than reduced occasion frequency
Small n (48); non-treatment-seeking population — should be framed as Phase 2 signal, not definitive AUD efficacy evidence
Aligns with Sa 2026 psychiatric SR which noted "potential therapeutic benefit in disorders of reward regulation" and the FDA null-finding for suicidality
Complements Bezin 2024 eClinicalMedicine nationwide case-time-control which found protective association with suicide/attempt

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (mental-health / emerging indications triangulation)
Lesson 5.4 — Class-level emerging indications

Related Studies

PMID-39945396 – Suicidal Ideation GLP1 Meta-Analysis — Bushi 2025 meta-analysis
PMID-41126551 – Psychiatric Effects GLP1 Systematic Review — Sa 2026 broader psych-effects SR
PMID-39844933 – Bezin GLP1 Suicide Attempt Case-Time-Control eClinicalMedicine — Bezin 2024 suicide/attempt
REG-FDA-Suicidal-Ideation-Review-2024 – FDA GLP1 Suicidal Ideation Null Finding — FDA null finding

PMID-39937469 – Hendershot Semaglutide Alcohol Use Disorder RCT