PROJECT SUMMARY Tobacco and cannabis are two of the most commonly abused substances in the United States. Further, simultaneous cannabis and tobacco polysubstance use (CT-PSU) is not insubstantial and is trending upwards as cannabis use is legalized in an increasing number of states. This upward trend is of particular concern because, compared to use of cannabis without tobacco, CT-PSU is associated with greater cannabis dependence, psychosocial problems, and poorer cessation outcomes, as well as with additive health risks, relative to either substance alone. Determination of mechanisms underlying CT-PSU will require coordinated epidemiological, preclinical, and human laboratory studies. Yet, the models and measures in each discipline that are used most often to examine CT-PSU were developed to investigate single drug use and may not capture unique features of CT-PSU. In the proposed project, patterns of CT-PSU will be characterized through development and implementation of novel survey measures that focus specifically on CT-PSU (R21 phase). In addition, a procedure for inhaled nicotine self-administration in mice will be established and validated simultaneously with epidemiological data collection. Subsequently, results from both efforts will guide decisions regarding experimental parameters to be used to investigate the effects of Δ9-tetrahydrocannabinol (THC; primary psychoactive substituent of cannabis) on inhaled nicotine’s reinforcing effects (i.e., “chasing”) and the reinforcing effects of both drugs administered simultaneously (e.g., as in blunts or spliffs) in mice and in human tobacco smokers and non-smokers. This translationally relevant approach will result in the establishment of better models through which to investigate CT-PSU, with the ultimate goals of discovery of its underlying mechanisms and development of targeted treatment approaches.