# Animal models to inform FDA tobacco regulation: Assessing the relative abuse liability of different classes of tobacco products

> **NIH NIH R01** · HENNEPIN HEALTHCARE RESEARCH INSTITUTE · 2020 · $411,165

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this study is to use preclinical models to understand whether non-nicotine constituents unique to
cigarette smoke (CS) contribute to differences in abuse liability between conventional cigarettes and non-
combusted, alternative nicotine delivery systems (ANDs) in order to inform FDA CTP tobacco regulation.
Conventional tobacco cigarettes have greater abuse liability than ANDs, such as electronic cigarettes (ECs),
smokeless tobacco (ST), and nicotine replacement therapy (NRT). Non-nicotine constituents associated with
CS may contribute to the greater abuse liability of cigarettes because some of these constituents (e.g.,
monoamine oxidase (MAO) inhibitors, volatile organic compounds (VOCs)) can mimic or enhance the effects
of nicotine, or exhibit abuse liability themselves. Evaluating this hypothesis could lead to identification of new
Harmful or Potentially Harmful Constituents (HPHCs) and development of addiction-related product standards
that extend beyond the FDA's current focus on nicotine. Animal models are needed for this purpose, as they
avoid limitations associated with human studies. Animal studies involving exposure to extracts of commercial
tobacco products have been consistent with the differential abuse liability between products observed in
humans. We have found that the relative abuse liability of ST extract and EC refill liquid is similar to that of
nicotine alone, whereas others have found that CS extracts can produce greater addiction-related effects than
nicotine alone under certain conditions. This may reflect the higher levels of addiction-relevant non-nicotine
constituents in CS extracts. The proposed studies will evaluate this possibility by directly comparing the relative
abuse liability of CS, ST, and EC aerosol extracts and nicotine alone (NRT analog) in state-of-the-art, FDA-
recommended models for assessing abuse liability. Levels of a range of behaviorally relevant non-nicotine
constituents (e.g., MAO inhibitors, acetaldehyde) will be measured and effects of isolated MAO inhibitors and
VOCs will be studied to identify the specific constituents that may be responsible for observed differences in
abuse liability. In Aim 1, demand for CS extract will be compared to nicotine dose-equivalent concentrations of
ST extract, EC extract, and nicotine alone when each is available in isolation or under novel concurrent-choice
procedures to determine relative reinforcing efficacy and substitutability of formulations. Aim 2 will compare
reinforcement-enhancing and aversive effects between formulations. Aim 3 will evaluate the reinforcement-
enhancing and aversive effects of isolated MAO inhibitors and VOCs when administered alone or in
combination with nicotine. It is hypothesized that CS extract will have greater addiction-related effects than the
other formulations due to its higher levels of behaviorally active non-nicotine constituents (e.g., MAO inhibitors,
VOCs). These studies will charact...

## Key facts

- **NIH application ID:** 9996665
- **Project number:** 5R01DA046318-03
- **Recipient organization:** HENNEPIN HEALTHCARE RESEARCH INSTITUTE
- **Principal Investigator:** ANDREW Charles HARRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,165
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996665

## Citation

> US National Institutes of Health, RePORTER application 9996665, Animal models to inform FDA tobacco regulation: Assessing the relative abuse liability of different classes of tobacco products (5R01DA046318-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996665. Licensed CC0.

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