The novel design of this study combines a laboratory paradigm to evaluate stress-induced smoking behavior and smoking-related reinforcement, followed by a 12-week treatment phase to evaluate clinical outcomes.

Using a double-blind, this Phase 2 study will randomize 140 smokers to a parallel group design (varenicline + guanfacine vs. varenicline alone). Following titration to steady state levels, the investigators will evaluate sex differences in medication effects on stress-induced smoking behavior and smoking-related reinforcement in the laboratory, and on abstinence outcomes during a subsequent 12-week treatment period.

Inclusion Criteria:

1. Age 18+
2. Able to read and write English
3. SMOKER: 10 or more cigarettes per day for at least the past year, Carbon Monoxide (CO) > 10 ppm at intake
4. Able to take oral medications and willing to adhere to medication regimen
5. Provide evidence of a stable living residence in the last 2 months prior to randomization, have reasonable transportation arrangements to the study site, have no plans to move within the next 3 months, and have no unresolved legal problems
6. Motivated to quit smoking (8 or greater on the Contemplation Ladder)

Exclusion Criteria:

1. Subjects with any significant current medical conditions (neurological, cardiovascular [including hypertension or hypotension: sitting BP >160/100 or <90/60mmHg at baseline screening], endocrine, thyroid, renal, liver), seizures, delirium or hallucinations, or other unstable medical conditions
2. Current Diagnostic and Statistical Manual of Mental Disorders (DSM-V) alcohol or substances use disorders, other than mild alcohol use disorder or tobacco use disorder
3. Subjects who have a positive test result at intake appointment on urine drug screens conducted for illicit drugs
4. Past 30 day use of psychoactive drugs excluding anxiolytics and antidepressants (however, see #10; barbiturates, benzodiazepines are exclusionary)
5. Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or IUD)
6. Suicidal, homicidal or evidence of current (past 6-month) severe mental illness such as schizophrenia or bipolar disorder
7. meeting DSM-V criteria for current (past-6 month) attention deficit hyperactivity disorder (ADHD)
8. Individuals who are currently taking medications known to be effective for smoking cessation (e.g., FDA smoking cessation medications, nortriptyline, clonidine) or are regular users of e-cigarettes or other tobacco projects (pipe, cigar, smokeless tobacco) in the past 30 days
9. Only one member per household can participate in the study
10. Specific exclusions for administration of guanfacine not already specified: EKG evidence at baseline screening of any clinically significant conduction abnormalities or arrhythmias; known intolerance for guanfacine or any alpha blocker; history of fainting, syncopal attacks, heart failure or myocardial infarction, or impaired liver (aspartate aminotransferase [AST], alanine aminotransferase [ALT] > 3x normal) or renal function (estimated creatinine clearance <60 cc/min); treatment with any antihypertensive drug or any alpha-blocker; use of any central nervous system (CNS) depressant (e.g., phenothiazines, barbiturates, benzodiazepines)
11. Specific exclusions for the administration of varenicline not already specified: known intolerance to varenicline or taking H2blockers (e.g., Cimetidine), quinolones, or trimethoprim.

During 3 week titration period

Adverse events were collected with SAFTEE assessment.