Inclusion Criteria:

• · Males and females between 18 and 55 years old will be eligible for this study. Females must not be pregnant as determined by pregnancy screening, nor breast feeding, and must be using acceptable birth control methods during study participation.

  • Current opioid dependence as evidenced by documentation of prior treatment for opioid dependence or signs of withdrawal, self-reported history of opioid dependence for consecutive 12 month period and a positive urine for opiates.
  • Subjects must fulfill DSM-IV criteria for opioid dependence.
  • Subjects must have a history of cocaine use, with a reported street cocaine use of a minimum of 1/2 gram during the preceding 30 days.
  • Subjects must meet DSM-IV criteria for cocaine dependence or abuse, and have laboratory confirmation of recent cocaine use (positive urine for cocaine) during the month prior to study entry.
  • Subjects must be treatment-seekers for opioid and cocaine use.
  • Subjects must have smoked at least 10 cigarette per day for at least one year. Varenicline's safety has only been studied in smokers.

Exclusion Criteria:

• · History of heart disease, left ventricular hypertrophy, ischemic ECG changes, chest pain, arrhythmia, hypertension.

  • History of severe renal or hepatic diseases.
  • History of psychosis, schizophrenia, bipolar or major depressive disorder.
  • History of seizure disorder.
  • Current diagnosis of alcohol, benzodiazepine and other drug abuse or dependence (other than opiates, cocaine, and nicotine).
  • Current use of over-the-counter or prescription psychoactive drugs (antidepressant, anxiolytics, antipsychotics, mood stabilizers, psychostimulants).
  • Liver function tests (ALT or AST) greater than 3 times normal.
  • Known allergy to varenicline or methadone.