A sensitization-homeostasis model of nicotine craving, withdrawal, and tolerance: integrating the clinical and basic science literature

UMMS Affiliation

Department of Family Medicine and Community Health

Publication Date


Document Type



Adolescent; Behavior, Addictive; Humans; *Models, Neurological; Nicotine; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Nicotinic; Smoking Cessation; Substance Withdrawal Syndrome; Tobacco Use Disorder


Community Health and Preventive Medicine | Neuroscience and Neurobiology | Preventive Medicine | Psychiatry and Psychology | Psychology | Substance Abuse and Addiction


Recent reports suggest that nicotine withdrawal symptoms are common among adolescents after a few weeks of intermittent tobacco use. No current model of nicotine dependence had predicted the rapid development of symptoms of dependence and withdrawal before the development of tolerance. We present a model that integrates neuroscience with clinical observations regarding how nicotine dependence develops, progresses, and resolves in humans. The central tenet of this sensitization-homeostasis model is that nicotine's dependence liability derives from its ability to stimulate neural pathways responsible for the suppression of craving. As a result of sensitization, the craving suppression produced by nicotine is magnified to superphysiological levels. The overinhibition of neurons responsible for craving initiates compensatory homeostatic measures that stimulate the craving pathways and result in craving when nicotine is absent. Separate homeostatic mechanisms are responsible for craving, withdrawal, and tolerance. The sensitization-homeostasis model is unique in its attribution of dependence to craving suppression, its attention to the temporal relationships among clinical features of nicotine dependence, and its extensive integration of clinical observations and basic science. It provides a framework for theory-based research.

DOI of Published Version



Nicotine Tob Res. 2005 Feb;7(1):9-26. Link to article on publisher's site

Journal/Book/Conference Title

Nicotine and tobacco research : official journal of the Society for Research on Nicotine and Tobacco

Related Resources

Link to Article in PubMed