DESCRIPTION (provided by applicant): This R21 application addresses the leading preventable cause of premature death in the United States, cigarette smoking. The most widely used treatment to help smokers quit is nicotine replacement therapy, but its success rates are only about 20% at six months. Based on a model of the smoking behavior involving nicotine, sensory, and habit effects, oral nicotine delivery in flavored beverages has been studied in two pilot projects to build on the concept of nicotine replacement therapy. This study continues the development of oral nicotine further by adding a placebo control group in a smoking cessation trial. The study is a two-group, parallel-design, placebo-controlled, randomized clinical trial. One-hundred healthy adult volunteers motivated to quit smoking will be randomized to receive either nicotine solution (active condition) or Iobeline solution (control condition). Subjects will be instructed to add the solution to the beverages of their choice every hour as needed for smoking urges for 6 weeks. All subjects will receive a self-help cessation manual, and brief individual counseling. Community volunteers will be recruited from the local metropolitan area by newspaper advertisements. Inclusion criteria are: 1) age from 18-65 years 2) smoking at least 10 cigarettes per day 3) desire to quit smoking 4) willingness to set a "quit date" within 14 days of enrollment. Major exclusion criteria are: 1) any ongoing medical problem requiring monitoring 2) prescription medication 3) pregnancy or breastfeeding. Baseline data collection includes smoking history, nicotine dependence questionnaire, smoking withdrawal and motivation questionnaires. Subjects will return on the quit date, every week for 6 weeks during treatment, then every month for 6 months. At each return visit subjects will complete an exhaled carbon monoxide test, and questionnaires regarding smoking withdrawal and solution tolerability. The primary outcome is continuous smoking abstinence 6 months after the quit date. Other outcomes include continuous smoking abstinence at 1 and 3 months, smoking withdrawal symptoms, side effects of treatment, treatment compliance, and sensory effects of treatment solutions. This study tests the preliminary efficacy of a promising novel nicotine replacement therapy compared to placebo. If efficacious, further research into its safety, efficacy, and mechanisms will be in order.