Mechanisms of the Nicotine Metabolism Effect on Tobacco Dependence

Study Overview
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Brief Summary
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The purpose of the study is to learn more about tobacco dependence and nicotine metabolism in African-Americans and whites, by studying to see if how fast a person metabolizes nicotine (how the body breaks down nicotine into inactive compounds) affects how dependent they are on smoking cigarettes. The investigators believe that people with a faster rate of metabolism may have more severe nicotine withdrawal symptoms and also may have a harder time trying to quit smoking.

Detailed Description
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Our studies will use the nicotine metabolite ratio (NMR) (the ratio between the nicotine metabolites 3'hydroxycotinine and cotinine)as a simple and clinically feasible biomarker for the rate of nicotine metabolism. The investigators hypothesize that a faster rate of metabolism leads to faster elimination of nicotine from the body and a more rapid dissipation of brain tolerance to nicotine in the interval between cigarettes, leading in turn to (1) more severe nicotine withdrawal symptoms and (2) greater subjective reward from the cigarette smoked following deprivation. These effects would help to explain why smokers with faster rates of nicotine metabolism have a poorer response to smoking cessation therapy when compared to those with slower rates of metabolism. The investigators will explore the relationship of the NMR to the endophenotypes of withdrawal, craving and reward, with the assumption that these factors are likely intermediaries for the mechanism linking nicotine metabolism to tobacco dependence and smoking cessation rates with pharmacotherapy. Our study design uses a brief (6 hour) interval of smoking abstinence followed by a reward cigarette to elicit the subjective responses relating to withdrawal and reward. Because smoking behavior and severity of nicotine dependence vary by race and sex the investigators will also compare the relationship between NMR and withdrawal and reward in African American vs white smokers and in men vs women. Secondary analyses will examine whether nicotine half-life mediates the observed effects of NMR on primary response measures.

Official Title
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Mechanisms of the Nicotine Metabolism Effect on Tobacco Dependence

Conditions
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Cigarette Smoking

Intervention / Treatment
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* Behavioral: Smoking abstinence


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: African-American or Caucasian Age 18-70 years Regular smoker of 5 or more cigarettes per day Saliva cotinine of 100 ng/ml or greater Exclusion Criteria: Obese (BMI > 38) or underweight (BMI < 17) Major systemic or psychiatric condition Medications that are inducers of CYP2A6 History of alcohol abuse Positive drug urine tox test Pregnancy or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Smoking abstinence<br> | Behavioral: Smoking abstinence<br>* 6 hour smoking abstinence<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nicotine withdrawal symptoms | Total withdrawal score as measured by Minnesota Nicotine Withdrawal Scale | 6 hours post nicotine load | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive performance | Cognitive performance will be measured by n-back computerized testing | 6 hours post nicotine load | 
| Smoking behavior: number of cigarettes | Smoking behavior will be measured by number of cigarettes during a monitoring period following the 3rd (reward) cigarette of the protocol | 90 minutes post-abstinence | 
| Smoking behavior: number of puffs per cigarette | Smoking behavior will be measured by number of puffs per cigarette during a monitoring period following the 3rd (reward) cigarette of the protocol | 90 minutes post-abstinence | 
| Smoking behavior: time to first post-reward cigarette | Smoking behavior will be measured by time to first post-reward cigarette during a monitoring period following the 3rd (reward) cigarette of the protocol | 90 minutes post-abstinence |