Smoking continues to be the leading cause of preventable death in the U.S., accounting for one in five deaths each year. Varenicline (Chantix) is a partial nicotinergic agonist and is the most efficacious monotherapy for successful smoking cessation; however, long-term abstinence with varenicline only ranges from 20% – 40%. One contributing factor to this low effectiveness may be poor medication adherence due to nonspecific side effects (i.e., side effects not explained by the pharmacology of the medication, but possibly due to negative medication expectancies or nicotine withdrawal symptoms that are mistakenly attributed to medication use). Nonspecific side effects have been linked to negative outcomes such as nonadherence, discontinuing effective treatment, and attempts to treat these symptoms with additional medications. The current proposal will utilize the double-blind balanced placebo design to differentiate expectancies versus pharmacologic mechanisms of varenicline administered for two weeks to smokers seeking treatment. The double- blind balanced placebo design includes a cross-balanced medication administration (active medication v. placebo) and instructional set (told truth v. deception) resulting in four groups of smokers seeking treatment: (1) told therapeutic dose (TD) medication + received TD medication; (2) told TD medication + received placebo; (3) told low dose (LD) medication+ received TD dose medication; (4) told LD medication + received placebo. Ecological momentary assessments (EMA) in the form of Daily Dairies delivered via smartphone will assess real-time side effects, withdrawal symptoms, cigarettes smoked, medication use, and reasons for medication non-adherence. The specific aims for this proposal will examine the main effects and interaction of instructional set and pharmacology on medication adherence (Aims 1 and 2) and evaluate moderators of pharmacology and expectancy effects on medication adherence (Exploratory Aim). Assessing expectancies and physiological barriers (i.e., non-specific side effects) to varenicline medication adherence will identify targets to improve medication adherence and to develop behavioral interventions that can modify and reframe negative expectancies and experiences. The specific aims of this project will be completed in conjunction with a formal training plan, sponsored by Dr. Karen Cropsey, Dr. Peter Hendricks, Dr. Michael Businelle, Dr. Richard Shelton, and Dr. Sylvie Mrug. This training plan includes: 1) pharmacological research development, 2) EMA methodology, 3) advanced longitudinal data analysis, and 4) research dissemination and mentorship.