The Family Smoking Prevention Control Act of 2009 gave the US FDA the authority to regulate nicotine levels in many tobacco products, including cigarettes. Reducing nicotine content of cigarettes may be a reasonable strategy to reduce the reinforcing properties of cigarette smoking; however, there are some data to suggest otherwise. Empirical evidence from controlled studies, including our group, shows that some smokers compensate for lower nicotine yield by smoking more intensely or by smoking more daily cigarettes. Recently, low nicotine content (LNC) cigarettes have been produced for evaluation through NIDA. These LNC cigarettes have low nicotine content compared to regular cigarettes; a departure in design from the low nicotine yield cigarettes currently available. Two questions arise that we propose to address: 1) Will individuals smoke LNC cigarettes more intensely or smoke more each day, thereby maintaining desired nicotine levels, and as a result continue to be exposed to significant toxin levels, and 2) are there subgroups of smokers more vulnerable to these adaptive smoking behaviors with LNCs and resulting associated risks. One subgroup of particular interest involves a heritable difference in response to nicotine. Previous research from our team, including the parent grant to this application, has shown that faster nicotine metabolizers, defined by genotype or a nicotine metabolite biomarker, are more susceptible to more intense smoking behaviors which increase exposure to cigarette toxins. It is unknown how nicotine metabolism rate may affect compensation when smoking LNC cigarettes. Thus, the proposed studies will address this key question. Another tobacco product, little cigars, may also pose an emerging problem. Little cigars (both small and medium) are significantly less expensive than cigarettes, and likely increasingly used to cheaply obtain desired nicotine levels. When cigar tax rates changed, several cigar-producing companies responded by slightly increasing small cigar weights up to a medium weight, which is lower taxed and regulated. Also, the perceived risks of little cigars are generally underestimated, leading to more intense use increased exposures. In this application we propose two experiments. Both studies will compare differences in smoking behavior and toxin exposure, with LNC cigarettes in slow vs. rapid nicotine metabolizers in Study 1; and when smoking little cigars in slow vs. rapid metabolizers in Study 2. A well validated phenotypic marker of nicotine metabolism rate will be used to select equal numbers of each. This supplement is tied to the parent grant U01 DA020830, which is testing the role of genetically variable nicotine metabolism rate on differing cessation treatments. PUBLIC HEALTH RELEVANCE: This application is designed to provide empirical science to inform FDA on the effect smoking low nicotine content cigarettes will have on use patterns and harm exposure. Additionally, this application will examine the effect of switching from cigarettes to little cigars, a growing health concern, on use and harm exposure. Both studies will use a validated, phenotypic marker of nicotine metabolism rate that may identify those individuals at greatest risk of harm exposure when using these tobacco products.