# Effects of Semaglutide on Nicotine Intake and Smoking Lapse

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $235,155

## Abstract

PROJECT SUMMARY
Tobacco use remains the foremost cause of preventable deaths in the U.S. and worldwide. Advancing new
smoking cessation therapies, including those with novel pharmacological targets, is a critical public health
priority. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in the regulation of reward-
related behavior, including drug seeking, in part reflecting its modulatory role in dopamine (DA) function.
Historically, efforts to advance 5-HT drugs as addiction treatments have been complicated by the diversity of 5-
HT receptor subtypes and their divergent influences on behavior, as well as unwanted side effects
characteristic of non-selective 5-HT agents. However, the subsequent development of highly selective 5-HT
receptor ligands has allowed for targeted investigations of 5-HT receptor subtypes in preclinical models of
addiction. These studies show that targeted manipulation of the serotonin 5-HT2C receptor alters drug-related
behavior; in particular, 5-HT2C receptor agonists are shown to reduce nicotine intake and reinstatement. Of the
selective 5-HT2C receptor agonists, lorcaserin has the best near-term potential for repurposing as a smoking
cessation therapy, having been approved by the U.S. Food and Drug Administration for weight management.
Preclinical findings implicate several potential behavioral mechanisms by which 5-HT2C receptor agonists might
reduce drug intake, including drug-specific processes (e.g., incentive salience of drug cues, self-administration,
reinstatement) and drug-nonspecific behaviors (e.g., reductions in impulsivity). To date, potential mechanisms
of 5-HT2C receptor agonists have not been characterized in human studies of addiction. Given emerging
interest in lorcaserin as a novel smoking cessation therapy, further studies are needed to evaluate its efficacy
profile, including studies to evaluate candidate treatment mechanisms. Human laboratory studies play a pivotal
role in drug development by providing a time- and cost-efficient means of validating preclinical findings, also
providing an ideal platform for studying mechanisms of pharmacotherapy effects. This application proposes the
first targeted human laboratory investigation of lorcaserin in smokers. The effects of lorcaserin vs. placebo on
smoking-related outcomes will be evaluated in a double-blind, within-subjects, crossover study with human
laboratory endpoints. We also propose the first human investigation of impulsivity subdomains as candidate
mechanisms for 5-HT2C receptor agonists. By evaluating an approved 5-HT2C agonist with emergent efficacy
for smoking cessation, this project has near-term potential to inform clinical applications of 5-HT2C agonists for
addiction.

## Key facts

- **NIH application ID:** 9928923
- **Project number:** 7R21DA047663-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Christian S Hendershot
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,155
- **Award type:** 7
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928923

## Citation

> US National Institutes of Health, RePORTER application 9928923, Effects of Semaglutide on Nicotine Intake and Smoking Lapse (7R21DA047663-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9928923. Licensed CC0.

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