Human Laboratory Study Of Varenicline in Smokers

The purpose of this study is to understand the therapeutic mechanisms of varenicline, a novel
nicotinic analogue, through focused measures of potential psychological and physiological
mediators. Varenicline is an FDA-approved pharmacotherapy for smoking cessation that is
believed to provide relief from craving and withdrawal through agonism and antagonism of some
central nervous system nicotinic acetylcholinergic receptors. However, no controlled studies
have established the physiological and psychological processes that mediate the efficacy of
varenicline in humans. The main goal of the proposed pilot study is to evaluate and compare
the effects of varenicline on subjective, cognitive, and physiological outcomes, using a
randomized, placebo-controlled, double-blind between-groups design. The study will combine
both brief clinical trial methodology with human laboratory approaches. A secondary goal is
to validate the utility of the laboratory paradigms for the identification of future smoking
cessation agents.

Inclusion Criteria:

1.1. Who. Subjects will be women and men between the ages of 18 and 40 who have smoked at
least 10 cigarettes per day for at least 1 year. They will respond to requests in the
public media for individuals who are interested in quitting smoking.

1.2. Total sample/Number per group. The total randomized sample size will equal 20
subjects, equally distributed across the two medication groups.

1.3. Inclusion Criteria.

1. 18 years to 60 years.

2. Smoke Marlboro Lights (This criterion was selected to reduce inter-subject variation
in response variables as has been done in many human laboratory studies of smoking
behavior. Over 40% of all smokers smoke some type of the Marlboro brand of cigarette
(Substance Abuse and Mental Health Services Administration, 2005). Based on telephone
screen data for 767 subjects collected at TURC, Marlboro Light cigarettes are the most
common type of Marlboro smoked in our sampling population (158/252 Marlboro users
[63%]). Therefore, we have decided to only enroll those smoking Marlboro Light
cigarettes, non-menthol).

3. Smoked at least 10 cigarettes/day for at least 1 year.

4. English speaking and reading.

5. Females who are of childbearing potential must practice effective contraception and
meet the following criteria:

1. Are instructed to avoid pregnancy through 30 days after the last dose of study
medication.

2. Have a negative urine pregnancy test at baseline.

3. Agree to use of the birth control methods listed: an oral contraceptive agent, an
intrauterine device (IUD), an implantable contraceptive (e.g., Norplant), or an
injectable contraceptive (e.g., Depo-Provera) for at least one month prior to
entering the study and will continue its use through at least 30 days after the
last dose of the study medication. A barrier method of contraception (e.g.,
condom or diaphragm with spermicide) while participating in the study and 30 days
after the last dose of study medication.

6. Willingness to not use illicit drugs during study period including marijuana.

Exclusion Criteria:

1. Concurrent use of tobacco products (other than cigarettes) or nicotine products.

2. Medications that might affect the outcome measures of nicotine reward, cognition,
anxiety, and stress will also be a basis for exclusion. These medications include
psychotropic drugs (i.e., anti-psychotic, anti-depressant, anti-anxiety, or
stimulant), anti- hypertensive agents (e.g., beta-blockers), and other drugs that can
influence the outcome domains.

3. History of kidney disease or renal impairment since varenicline is primarily excreted
by the kidney and thus such patients are vulnerable to increased and potentially toxic
levels of varenicline.

4. Treatment for drug or alcohol dependence during the last year, or evidence of alcohol
abuse so severe that the patient is judged potentially unable to comply with the
protocol.

5. Suicidal or homicidal ideation.

6. History of bipolar disorder, schizophrenia, schizoaffective disorder, attention
deficit disorder, or attention deficit hyperactivity disorder.

7. Current major depression or anxiety disorder.

8. Pregnant or lactating or planning pregnancy during treatment period.

9. Having plans to leave the immediate geographical area within 2 months.

10. Unwillingness or inability to give written informed consent.