# Research Project 3 : Nicotine Delivery Rate and Its Abuse Potential: Impact of Menthol

> **NIH NIH U54** · YALE UNIVERSITY · 2020 · $497,205

## Abstract

Abstract: Project #3
 Rapid delivery to the brain enhances the abuse potential of drugs of abuse, including nicotine. As proposed
by Shihadeh and Eissenberg, “nicotine flux”, or the rate at which a given electronic cigarette (e-cigarette)
delivers nicotine, is the most critical factor for evaluating its abuse potential. In this model, when an e-cigarette
delivers nicotine at rates above a certain, yet undetermined, threshold it can have high abuse potential and
may initiate or maintain tobacco addiction. In contrast, when the nicotine flux is optimal, that e-cigarette may
have low addiction potential while providing sufficient nicotine delivery to help smokers quit smoking by
alleviating urges to smoke. This proposed “optimal nicotine flux” concept has yet to be empirically assessed in
controlled human studies. In addition, flavors and other e-cigarettes ingredients may also affect the impact of
delivery rate on the addictive effects of nicotine. Most notably, menthol may have such an effect through
inhibition of nicotinic receptors and slowing of nicotine metabolism. Systematic studies from our group and
others have shown that intravenous (IV) nicotine infusion is an optimal approach for quantifying the influence of
delivery rate on nicotine's behavioral and physiological effects. The primary aim of this project is to examine
the impact of nicotine delivery rate on nicotine's abuse potential (assessed by positive subjective effects and
reinforcement), and its potentially beneficial effects of alleviating smoking urges and withdrawal. We also seek
to determine if switching from menthol to non-menthol cigarettes, modeling a ban on menthol cigarettes,
changes the impact of nicotine delivery rate on the study outcomes. To reach these goals, we propose 2
placebo-controlled studies that will recruit male and female nicotine dependent smokers. Study 1 will recruit
equal numbers of menthol (n=35) and non-menthol (n=35) preferring smokers for 5 experimental sessions,
which will be at least 24 hours apart. Each session will include 1 randomly assigned infusion that will be either
saline or a single dose of nicotine (1 mg per 70 kg body weight) delivered at 4 different infusion rates: 0.24,
0.096, 0.048 or 0.024 µg per kg body weight per second). The rates are within the range of nicotine delivery
rates achieved by combustible and e-cigarettes and have been piloted in our recent study. In Study 2, menthol-
preferring smokers (n=38) will be randomized to a sequence of menthol or non-menthol cigarette smoking
conditions, each lasting for 2 weeks, using a crossover design. During week 2 of each period, 3 experimental
sessions will be held on 3 separate days. The results from our application will help the FDA in establishing
standards for nicotine delivery rates that minimize the addictive risks of e-cigarettes and other electronic
nicotine delivery systems (ENDS).

## Key facts

- **NIH application ID:** 9999555
- **Project number:** 5U54DA036151-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mehmet Sofuoglu
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,205
- **Award type:** 5
- **Project period:** 2013-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999555

## Citation

> US National Institutes of Health, RePORTER application 9999555, Research Project 3 : Nicotine Delivery Rate and Its Abuse Potential: Impact of Menthol (5U54DA036151-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999555. Licensed CC0.

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