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Clin Pharmacol Ther. 2019 Mar;105(3):641-651. doi: 10.1002/cpt.1238. Epub 2018 Oct 25.

Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence.

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Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Westat, Rockville, Maryland, USA.
Center for Tobacco Control Research and Education, University of California, San Francisco, San Francisco, California, USA.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Toronto, ON, Canada.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.


This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms.


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