• To evaluate the efficacy of 12 weeks of combination therapy with varenicline and bupropion SR compared to varenicline alone for increasing the prolonged and point prevalence smoking abstinence rates at 12 weeks in cigarettes smokers. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

• To evaluate the efficacy of 12 weeks of combination therapy with varenicline and bupropion SR compared to varenicline alone for increasing the prolonged and point prevalence smoking abstinence rates at 26 and 52 weeks in cigarettes smokers. [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
  
• To evaluate the efficacy of combination therapy with varenicline and bupropion SR compared to varenicline alone for decreasing tobacco craving and nicotine withdrawal symptoms among cigarette smokers trying to achieve smoking abstinence. [ Time Frame: 3, 6, and 12 months ] [ Designated as safety issue: No ]
  
• To evaluate the efficacy of 12 weeks of combination therapy with varenicline and bupropion SR compared to varenicline alone for attenuating weight gain after smoking cessation. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

Cigarette smoking is the single most important preventable cause of morbidity, mortality and excess health care costs in the United States and accounts for 30% of U.S. cancer deaths. Varenicline and bupropion SR (sustained-release) are non nicotine pharmacotherapies FDA-indicated for the treatment of tobacco dependence in cigarette smokers. Although varenicline has proven greater efficacy than bupropion SR, both medications are associated with high end-of-treatment smoking abstinence rates. However, almost two-thirds of smokers treated with varenicline report smoking at 6 months. Because varenicline and bupropion SR have different mechanisms of action and different neuropharmacologic targets, combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy. In our recent pilot study of combination therapy with varenicline and bupropion SR, we observed treatment to be well-tolerated with 7-day point prevalence smoking abstinence rates of 71% (95% CI: 54-85%) at 3 months and 58% (95% CI: 41-74%) at 6 months. Determining the efficacy of combination therapy compared to single-agent therapy has immediate and important clinical implications. In this study, we will conduct a randomized, multicenter, controlled clinical trial evaluating the efficacy of combination therapy with varenicline and bupropion SR compared to varenicline and placebo in 450 cigarette smokers at the Mayo Clinic in Rochester, MN, and the University of Minnesota in Minneapolis, MN.