PK/PD Comparison of Guanfacine ER and IR

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