The purpose of this study is to determine if varenicline is effective in treating tobacco dependence in adults who smoke 5-10 cigarettes per day.

Nearly 50% of U.S. cigarette smokers smoke ≤ 10 cigarettes per day (CPD) and are considered "light smokers." Most light smokers will either maintain a chronic light smoking habit or increase their level of smoking during their lifetime. Importantly, light smokers are at risk for adverse health consequences and increased all-cause mortality. While multiple factors such as reinforcement behavior, diminished autonomy, economic constraints and tobacco control policies influence light smoking, nicotine dependence appears particularly important in 5 to 10 CPD smokers. Despite the high prevalence of light smoking and its increased healthcare burden, few studies have evaluated the efficacy of pharmacotherapy for this group of smokers. Varenicline, which targets symptoms of nicotine dependence, has been shown to increase smoking abstinence rates in moderate to heavy smokers (≥ 10 cigarettes per day). However, varenicline has not been evaluated in subjects who smoke < 10 CPD. In the current proposal we will investigate the efficacy of varenicline for smoking cessation in 5 to 10 CPD light smokers who wish to quit. This study will be conducted as a double-blind, placebo-controlled, randomized clinical trial at the Mayo Clinic, enrolling 224 eligible participants who smoke 5 to 10 CPD. Participants will receive behavior therapy and either varenicline or placebo for 12 weeks with follow up through 26 weeks. We will determine if varenicline increases smoking abstinence in light smokers at end-of-treatment and 26 weeks as compared to placebo.

Inclusion Criteria:

1. Subjects must be ≥ 18 years of age;
2. smokes 5 to 10 CPD for at least 6 months;
3. express interest in quitting smoking;
4. indicate ability to complete all study visits; and
5. provide written informed consent to participate in the study.
6. Subject is a female subject of non-childbearing potential or a female subject of childbearing potential - who is using contraceptives and has a negative pregnancy test result;
7. Subject is in good health as determined by the investigator;
8. Subject has the ability to participate fully in all aspects of the study and keep scheduled appointments.

Exclusion Criteria:

1. An active medical condition such as unstable angina, myocardial infarction, or coronary angioplasty within the past 3 months or an untreated cardiac dysrhythmia;

2. History of renal failure;

3. Cancer [excluding non-melanoma skin cancer] not in remission;

4. Psychosis or bipolar disorder;

5. Current unstable or untreated moderate or severe depression as assessed by the CES-D;

6. have, as defined by the C-SSRS (Columbia-Suicide Severity Rating Scale), current non-specific suicidal thoughts, or have a lifetime history of a suicidal attempt (defined as "potentially self-injurious act committed with at least some wish to die, as a result of act.");

7. Substance dependence other than nicotine, defined as:

   a. Patient has a recent history (past month) of heavy alcohol consumption as defined by NIAAA: i. Men: More than 4 drinks on any day or 14 per week ii. Women: More than 3 drinks on any day or 7 per week. b. Use of cocaine, heroin, club drugs (i.e., MDMA/"ecstasy"), methamphetamine, or hallucinogens (e.g., LSD) at any time during the past month.

   c. Use of marijuana on a weekly basis for the past month

8. An allergy to varenicline;

9. Current use of a behavioral or pharmacologic tobacco dependence treatment and unwilling or unable to discontinue use;

10. Another member of their household already participating in this study; and

11. Current treatment with another investigational drug (within 30 days of study entry).

12. Has an unstable medical condition;

13. Subject has untreated hypertension or baseline systolic blood pressure > 180 or diastolic > 100;

14. Women of child-bearing potential, or who are pregnant, lactating or likely to become pregnant during the trial and are unwilling to use an acceptable form of contraception during the medication phase will also be excluded. All female subjects of childbearing potential must have a negative pregnancy test and must agree to use approved contraception during participation in the study.

Serious Adverse Events were collected for the entire 6 months of study. Non-serious adverse events were collected for the 3 month-treatment phase.