Evaluate whether a 4mg/day or 6/mg day dose of extended-release guanfacine produces pharmacokinetic/dynamic (PK/PD) properties similar to 3mg/day immediate release guanfacine.

Inclusion Criteria:

• Age 18-65
• Able to read, write and comprehend English
• Smoker
• Able to take oral medications and willing to adhere to medication regimen
• Provide evidence of a stable living residence in the last 2 months, have reasonable transportation to the study site, and have no plans to move within the next 3 months or unresolved legal problems.

Exclusion Criteria:

• Any significant current medical conditions that would contraindicate smoking

• Current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) abuse or dependence of other substances, other than nicotine dependence or alcohol abuse

• Positive test results at intake appointment on urine drug screens for illicit drugs

• Past 30 day use of psychoactive drugs including anxiolytics and antidepressants

• Women who are pregnant or nursing

• Suicidal, homicidal or evidence of current mental illness such as schizophrenia, bipolar disorder or major depression, or anxiety disorders

• Meeting DSM-IV criteria for current attention deficit hyperactivity disorder (ADHD)

• Individuals who are currently taking medications known to be effective for smoking cessation or are regular users of other tobacco products in the past 30 days

• Only one member per household can participate in the study

• Specific exclusions for administration of guanfacine not already specified include:

  • 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
  • Impaired liver (as indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3x normal)
  • Renal function (as indicated by estimated creatinine clearance <60cc/min)
  • Treatment with any antihypertensive drug or any alpha-adrenergic blocker
  • Use of any central nervous system depressant (e.g., phenothiazines, barbiturates, benzodiazepines)
  • Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin), or consumption of grapefruit juice

• Subjects may have not donated blood in the past 8 weeks or have been involved in other investigational studies that involve substantial blood draws or medications unknown to us