# Addictive Threshold of Nicotine and the Impact of Sweeteners

> **NIH NIH U54** · YALE UNIVERSITY · 2023 · $348,221

## Abstract

Project Summary
Nicotine is the key addictive ingredient of tobacco. The FDA is considering a regulatory strategy aiming to
reduce the nicotine content of tobacco products to “non-addictive” levels to prevent the development of
addiction among youth experimenting with tobacco products. The implementation of such a strategy would
require strong scientific support from a range of preclinical and clinical studies. However, there are gaps in our
current knowledge about the actual threshold for nicotine's addictive effects and whether this threshold varies
across individuals or with flavors that are commonly added to inhaled tobacco products. Studies aiming to
address these gaps are hampered by difficulty in delivering accurate doses of nicotine through cigarette
smoking or e-cigarettes. Further, separating nicotine's effects from multiple other chemicals that are inhaled
with nicotine remains a challenge. Among pure nicotine options, the intravenous (IV) route is the gold standard
for preclinical research and is increasingly used in clinical studies as well. IV route approximates the inhaled
delivery for nicotine pharmacokinetics, and it also produces reinforcing and subjective-rewarding effects. In a
series of pilot studies, we refined our IV nicotine procedure to better model puff-sized nicotine delivered by
smoking cigarettes or e-cigarettes and to allow assessment of nicotine's dose-dependent effect on multiple
addiction-related outcomes, including reinforcement, drug discrimination, and subjective-rewarding effects.
Using this method, we propose to determine benchmarks regarding the addictive threshold of nicotine and the
impact of sweeteners on this threshold. Specifically, we will 1) determine the nicotine threshold dose(s) for
reinforcement, discrimination, and subjective-rewarding effects in smokers (Aim 1) and 2) evaluate whether
these threshold doses change with inhaled sweetener (sucralose), administered by e-cigarettes concurrent
with IV nicotine infusions (Aim 2). For both Aims, we will use a placebo-controlled study that will recruit male
and female cigarette smokers. For Aim 1, in each of the 4 test sessions, a different nicotine dose (0.1, 0.05,
0.025, and 0.0125 mg nicotine/pulse) will be compared to saline for reinforcement, nicotine discrimination, and
subjective effects. Concurrently with the pulsed infusions, participants will inhale unflavored e-cigarettes, which
will allow a closer matching of the sensory aspects of inhaled tobacco use. To assess the effect of sweeteners
in Aim 2, participants in a placebo-controlled study will have 6 test sessions. Each Test Session will include
one of the 3 nicotine doses (selected from Aim 1) vs. saline, all combined with or without the sweetener
sucralose. Sweetener and control solution will be administered by e-cigarettes concurrent with IV infusions. By
providing novel information on the addictive threshold of nicotine and the impact of sweeteners on this
threshold, the results of this s...

## Key facts

- **NIH application ID:** 10666236
- **Project number:** 2U54DA036151-11
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mehmet Sofuoglu
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $348,221
- **Award type:** 2
- **Project period:** 2013-09-30 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666236

## Citation

> US National Institutes of Health, RePORTER application 10666236, Addictive Threshold of Nicotine and the Impact of Sweeteners (2U54DA036151-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10666236. Licensed CC0.

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