The goal of this research is to identify placebo mechanisms that influence cigarette smoking, as well as the pharmacological, contextual, and individual difference factors that modulate their influence. Systematic study of placebo effects should increase our understanding of smoking behavior and provide specific directions for manipulating these effects to help people quit smoking; the leading preventable cause of morbidity and mortality in the United States. Denicotinized (DN) cigarettes are a powerful tool used to study placebo effects as they provide the experience of smoking in the absence of the direct pharmacological effects of nicotine. Many prior studies investigating placebo effects in smoking have compared smokers' reactions to DN and nicotine cigarettes under double-blind conditions, and have consistently shown that DN cigarettes produce rewarding and reinforcing effects. However, double-blind studies often overlook the important role of expectancy in placebo responding and may underestimate the magnitude of placebo effects that occur under natural conditions when smokers expect nicotine ingestion. The Balanced Placebo Design (BPD) overcomes this limitation by testing the independent and interactive effects of dose expectancy (expect nicotine or DN cigarette) and actual dose (given nicotine or DN cigarette) with smokers experiencing one of the following four manipulations: 1. Expect Nicotine/Given Nicotine; 2. Expect Nicotine/Given DN; 3. Expect DN/Given Nicotine; and 4. Expect DN/Given DN. Prior smoking research using the BPD, albeit scant at this time, has shown that expecting nicotine can indeed enhance the rewarding and reinforcing effects of DN and nicotine cigarettes. The proposed studies use the BPD methodology to advance our knowledge of placebo mechanisms underlying smoking behavior. Study 1 examines smokers' subjective, cognitive, and behavioral reactions to smoking while varying expected and actual nicotine dose as well as the length of prior smoking abstinence; an important contextual and motivational factor that has yet to be systematically evaluated. Study 2 employs the BPD and a 10-day laboratory model of smoking cessation to examine smokers' reactions to lapse cigarettes (smoked after 4 days of abstinence) that vary in expected and actual nicotine dose. A fifth group will not have a smoking lapse. Immediate subjective, cognitive, and behavioral responses to the lapse cigarettes are assessed and smoking behavior is tracked for 6 days with monetary incentives provided for abstinence. In both studies the associations between the experimental manipulations and individual differences such as gender, nicotine dependence level, personality, and the expected effects of smoking (i.e., response expectancies) are investigated. It is hypothesized that expectancy will play an instrumental role in immediate reactions to nicotine and DN cigarettes as well as in lapse to relapse progression. The results of this investigation will shed light on powerful placebo-based determinants of smoking behavior that at this time are poorly understood. PUBLIC HEALTH RELEVANCE: Findings from these studies may provide specific directions for the development of innovative therapies that manipulate placebo mechanisms (e.g., expectancy challenges) along with other therapeutic elements to decrease the rewarding effects of smoking, stop smoking lapses from turning into relapses, and increase overall rates of smoking cessation. Cigarette smoking is the single largest preventable cause of morbidity and mortality in the United States, and thus research aimed at decreasing rates of smoking has very high public health significance.