Cigarette smoking is more prevalent among Veterans (27%) than the general U.S. population (21%). Smoking is common among people who use marijuana or caffeine heavily, and the use of menthol cigarettes is becoming increasingly common, affecting approximately 9% of the Veteran population. Recent research by the group and others indicates that heavy marijuana or caffeine use, or the use of predominantly menthol cigarettes, can alter brain nicotinic acetylcholine receptor (nAChR) densities. For the proposed study, brain imaging with PET scanning will be used to determine nicotine receptor densities in Veteran cigarette smokers with and without heavy marijuana or caffeine use, and in menthol and non-menthol Veteran smokers. Results of the proposed research may have implications for improving treatments for Veterans who smoke cigarettes and who have specific drug use co-morbidities or who use menthol cigarettes.

Despite improvements in tobacco control, the prevalence of Tobacco Dependence (TD) remains high at 27% among Veterans and 21% among the general U.S. population (~46 million U.S. adults). Both co-morbid substance use and menthol cigarette preference are important issues contributing to greater severity of TD. Among smokers, a lifetime history of substance use/dependence is common and approximately 33% of all smokers use primarily menthol cigarettes, meaning that roughly 9% of Veterans smoke menthol. In addition to menthol cigarette usage being prevalent among Veterans, this problem is likely to worsen over time, because recent military deployments increase the chances of smoking initiation and marketing of menthol cigarettes is aimed at roughly the age group that comprises the active military.

For substance use/dependence, marijuana (MJ) users are five times more likely than non-MJ users to smoke tobacco cigarettes, and regular caffeine users are twice as likely as non-caffeine users to smoke cigarettes. Cigarette smoking contributes greatly to morbidity and mortality among patients with drug (and alcohol) dependencies, making it vital to understand better the complex relationship between drug/alcohol dependence and brain nicotine receptor densities in cigarette smokers.

Based on prior literature and pilot data collected during the previous Merit Review period, the primary hypotheses for the proposed research are that: 1) Participants who are heavy MJ users will have higher 4 2* nAChR densities in the thalami (and other brain regions) than participants who are not heavy MJ users, 2) Participants who are daily heavy caffeine users will have lower 4 2* nAChR densities in the thalami (and other regions) than participants who are not heavy daily caffeine users, 3) Densities of 4 2* nAChRs in the thalami (and other brain regions of interest) will be higher in menthol than non-menthol cigarette smokers, and 4) lesser severity of 4 2* nAChR up-regulation at baseline (along with clinical factors such as lesser severity of nicotine dependence) will be associated with better treatment outcomes in a standard smoking cessation program, including an improved likelihood of quitting and/or decreasing smoking.

To test these hypotheses, cigarette smokers will be recruited through flyers posted at the VA Greater Los Angeles Healthcare System in areas where smokers are likely to be present. Participants will undergo the following sequence of procedures: (1) telephone/in-person screening, (2) a bolus-plus-continuous-infusion 2-FA positron emission tomography (PET) scanning session, (3) a structural magnetic resonance imaging scan within one week of the initial PET session, and (4) referral to a standard 12-week smoking cessation program. Rating scales for the determination of smoking-related symptoms will be collected before and during the PET scanning procedure. Smoking status and measures of nicotine exposure and metabolism will be collected during the study using participant reports, exhaled carbon monoxide (CO) levels, urine cotinine levels, and plasma nicotine, cotinine, and 3'-hydroxycotinine levels.

Inclusion Criteria:

• Must be a Veteran cigarette smoker, living within commuting distance of the VA San Diego Healthcare System
• Healthy adult Veterans (18 to 65 years old) who are tobacco dependent cigarette smokers (10 to 40 cigarettes per day) meeting criteria for Nicotine Dependence as defined by DSM-IV criteria109 and who want to quit smoking.
• Heavy marijuana or caffeine use (defined as using the equivalent of > 2 marijuana cigarettes per week or the use of at least 3 coffee cup equivalents per day) for at least the past 6 months or no heavy drug/alcohol use.
• Ability to read, write, and give voluntary informed consent.
• An exhaled CO > 8 ppm during the study screening visit to verify smoking status.

Exclusion Criteria:

• Any Axis I diagnosis (including mood, anxiety, and psychotic disorders) other than Nicotine, Marijuana, or Caffeine Dependence within the past 1 year.
• A current diagnosis (within the past month) of other substance abuse/dependence diagnoses (such as cocaine, amphetamine, or opiates). (Length of abstinence will be verified through participant interview and a chart review at the initial study visit, which typically includes information about substance abuse treatment history and objective verification with breathalyzer and/or urine toxicology screens). Occasional drug/alcohol use not meeting criteria for abuse/dependence will not be exclusionary.
• Any current medication or any history of a medical condition that might affect the central nervous system at the time of scanning (e.g., current treatment with a psychotropic medication, or history of severe head trauma with loss of consciousness, epilepsy, or other neurological diseases).
• The combination of both heavy marijuana and caffeine use.
• Unstable cardiovascular disease, severe liver disease, or renal insufficiency, which might make tolerating study procedures difficult. Routine history and physical examination will be performed at the initial screening visit to insure that participants meet study criteria (Section D4).
• Pregnancy (urine pregnancy tests will be obtained on all women of childbearing potential) due to the theoretical risk of radiation exposure to the fetus.

Veterans who are cigarette smokers (10 to 40 cigarettes per day) who either use significant amounts of caffeine or marijuana (or who have little or no such use).

3 weeks