The overarching goal of this line of research is to increase smoking abstinence rates using a combination of existing pharmacotherapies. The aim of the current study is to assess the safety and compliance as well as obtain preliminary estimates of efficacy and effect on craving and nicotine withdrawal of combination therapy with bupropion SR and varenicline. We will compare the efficacy estimates in this study with historical smoking abstinence rates with varenicline. To accomplish our aims, we will enroll 38 cigarette smokers in an open-label, phase II clinical trial.

Subjects will be eligible to participate if they: 1) are at least 18 years of age; 2) have smoked 10 or more cigarettes per day for at least 6 months; and 3) are motivated to stop smoking.

Subjects will be excluded if they have: 1) an unstable medical condition; 2) unstable angina, myocardial infarction, or coronary angioplasty within the past 3 months or an untreated cardiac dysrhythmia; 3) personal history of seizures; 4) closed head trauma with any loss of consciousness or amnesia in the last 5 years; 5) ever history of closed head trauma with > 30 minutes of loss of consciousness or amnesia or resulting in skull fracture or subdural hematoma/brain contusion; 6) a history or psychosis, bipolar disorder, bulimia or anorexia nervosa); 7) have current depression as assessed by Center for Epidemiologic Studies Depression (CES-D); 8) have active substance abuse other than nicotine; 9) have used an investigational drug within the last 30 days; 10) are currently using a behavioral or pharmacologic tobacco treatment and unwilling or unable to discontinue use; 11) use of bupropion or varenicline in the previous 3 months; 12) current (past 14 days) use of antipsychotic or antidepressant; 13) an allergy to bupropion or varenicline; 14) untreated hypertension or baseline systolic blood pressure > 180 or diastolic > 100; 15) have another member of their household already participating in this study.

The primary aims and hypotheses of this study are:

1. To obtain preliminary evidence of efficacy of 12 weeks of combination therapy with bupropion SR and varenicline for increasing the point prevalence smoking abstinence rates at 12 weeks among cigarette smokers.

   Hypothesis: The combination of bupropion SR plus varenicline for 12 weeks will increase the point prevalence smoking abstinence rates at 12 weeks among cigarettes smokers.

2. To obtain preliminary evidence of efficacy of combination therapy with bupropion SR and varenicline for decreasing craving and nicotine withdrawal symptoms among cigarette smokers trying to achieve smoking abstinence.

Hypothesis: 12 weeks of combination therapy with bupropion SR and varenicline will significantly decrease craving and nicotine withdrawal among cigarette smokers trying to achieve smoking abstinence.

Inclusion Criteria:

• at least 18 years of age
• have smoked 10 or more cigarettes per day for at least 6 months
• are motivated to stop smoking.

Exclusion Criteria:

• an unstable medical condition
• unstable angina, myocardial infarction, or coronary angioplasty within the past 3 months or an untreated cardiac dysrhythmia
• personal history of seizures
• closed head trauma with any loss of consciousness or amnesia in the last 5 years
• ever history of closed head trauma with > 30 minutes of loss of consciousness or amnesia or resulting in skull fracture or subdural hematoma/brain contusion
• a history or psychosis, bipolar disorder, bulimia or anorexia nervosa)
• have current depression as assessed by Center for Epidemiologic Studies Depression (CES-D)
• have active substance abuse other than nicotine
• have used an investigational drug within the last 30 days
• are currently using a behavioral or pharmacologic tobacco treatment and unwilling or unable to discontinue use
• use of bupropion or varenicline in the previous 3 months
• current (past 14 days) use of antipsychotic or antidepressant
• an allergy to bupropion or varenicline
• untreated hypertension or baseline systolic blood pressure > 180 or diastolic > 100
• have another member of their household already participating in this study.

6 months