Combining Varenicline and Guanfacine for Smoking Cessation

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 torandomization, have reasonable transportation arrangements to the study site, haveno 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 orsubstances use disorders, other than mild alcohol use disorder or tobacco usedisorder

3. Subjects who have a positive test result at intake appointment on urine drug screensconducted 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 ofbirth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptivesponge, double barrier [diaphragm or condom plus spermicide], or IUD)

6. Suicidal, homicidal or evidence of current (past 6-month) severe mental illness suchas schizophrenia or bipolar disorder

7. meeting DSM-V criteria for current (past-6 month) attention deficit hyperactivitydisorder (ADHD)

8. Individuals who are currently taking medications known to be effective for smokingcessation (e.g., FDA smoking cessation medications, nortriptyline, clonidine) or areregular users of e-cigarettes or other tobacco projects (pipe, cigar, smokelesstobacco) 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: EKGevidence at baseline screening of any clinically significant conductionabnormalities or arrhythmias; known intolerance for guanfacine or any alpha blocker;history of fainting, syncopal attacks, heart failure or myocardial infarction, orimpaired liver (aspartate aminotransferase [AST], alanine aminotransferase [ALT] > 3x normal) or renal function (estimated creatinine clearance <60 cc/min); treatmentwith any antihypertensive drug or any alpha-blocker; use of any central nervoussystem (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.