Once-Weekly Semaglutide in Adults With Daily Cigarette Use: A Randomized Clinical Trial.
Level 2 - randomized trial
Phase 2a randomized placebo-controlled clinical trial
PubMed 42189538 · doi:10.1001/jamanetworkopen.2026.14898
What was done
This phase 2a parallel-arm randomized clinical trial with embedded laboratory sessions evaluated subcutaneous semaglutide versus placebo over 9 weeks (dose escalation: 0.25 mg for 4 weeks, 0.5 mg for 4 weeks, 1.0 mg for 1 week) in non-treatment-seeking adults smoking at least 5 cigarettes per day. Out of 45 enrolled participants, 24 were randomized (12 semaglutide, 12 placebo; mean age 44 years; 20 [83%] female; mean BMI 33.5; mean 15.4 cigarettes per day). Co-primary outcomes were laboratory measures of smoking resistance and self-administration before and after treatment. Weekly cigarette use, craving, and weight were also tracked.
What was found
Primary treatment-by-time interactions were not statistically significant for laboratory smoking resistance (beta = 0.16 [95% CI, -0.07 to 0.40]; P = .16; 23 participants) or number of cigarettes (beta = -0.08 [95% CI, -0.25 to 0.08]; P = .30; 22 participants). Supplementary change score analyses showed significantly greater reductions in laboratory smoking in the semaglutide group versus placebo after treatment (beta = -0.69 [95% CI, -1.26 to -0.13]; P = .02; d = 0.67). Semaglutide significantly reduced cigarette craving (treatment-by-time interaction: beta = -0.11 [95% CI, -0.20 to -0.03]; P = .01) and body weight (beta = -0.04 [95% CI, -0.05 to -0.03]; P < .001) over treatment weeks.
Why it matters
This pilot trial indicates that while semaglutide did not meet primary efficacy endpoints for smoking reduction in non-treatment-seeking adults, it suppressed nicotine cravings and reduced weight.
Limits
The study had a very small sample size (24 randomized, 21 completing primary assessments), limiting statistical power. Participants were non-treatment-seeking and predominantly female (83%). Treatment duration was short (9 weeks total, with only 1 week at the 1.0 mg dose), and both co-primary endpoints failed to reach statistical significance.
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