Mechanisms of the Nicotine Metabolism Effect on Tobacco Dependence (NMR)

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.

Study Overview

• Status: Completed
• Conditions: Cigarette Smoking
• Intervention / Treatment: Behavioral: Smoking abstinence

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Smoking abstinence	Behavioral: Smoking abstinence; 6 hour smoking abstinence

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco

Publications and helpful links

General Publications

• Nardone N, Shahid M, Strasser AA, Dempsey DA, Benowitz NL. The influence of nicotine metabolic rate on working memory over 6 hours of abstinence from nicotine. Pharmacol Biochem Behav. 2020 Jan;188:172836. doi: 10.1016/j.pbb.2019.172836. Epub 2019 Dec 5.
• Liakoni E, Edwards KC, St Helen G, Nardone N, Dempsey DA, Tyndale RF, Benowitz NL. Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence. Clin Pharmacol Ther. 2019 Mar;105(3):641-651. doi: 10.1002/cpt.1238. Epub 2018 Oct 25.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: June 14, 2012
• First Submitted That Met QC Criteria: June 22, 2012
• First Posted (Estimate): June 25, 2012

Study Record Updates

• Last Update Posted (Estimate): December 3, 2015
• Last Update Submitted That Met QC Criteria: December 1, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder
• Other Study ID Numbers: 12-08635