Abstract The growing worldwide burden of cannabis use disorders (CUDs) sharply contrasts the number of brain-based studies on the underlying mechanisms. CUDs are currently the most prevalent of all illicit substance use disorders and long-term abstinence is achieved by less than 20%. Moreover, changes in legal climate across countries warrant direct investigations of potential effects of cannabis-related culture on the mechanisms underlying CUDs. Previous studies in cannabis users by the two PI's suggest a crucial role of abnormal fronto- limbic-parietal brain response during reward processing and cognitive control in the course and maintenance of CUDs. In response to NIH's call for International Research Collaboration on Drug Abuse and Addiction Research, this proposal will bring together two expert PIs from the U.S. and the Netherlands (NL) with focus on neurobiological mechanisms of CUDs. This proposal will leverage the high impact findings by the two PIs in order to determine cross-cultural similarities and differences in mechanisms associated with CUDs. Moreover, it will establish an international collaboration that capitalizes on a unique population of Dutch cannabis users with long-term unhindered access to legal cannabis, compared to a sample of U.S. cannabis users. Using cross-sectional and longitudinal approaches, this proposal will uncover common underlying neurobiological mechanisms in a cross-cultural sample of individuals with CUDs and evaluate their relationship with DSM 5 CUD symptom severity (Specific Aim 1). We will also assess how cultural environmental moderates these mechanisms (Specific Aim 2). To that end, 50 cannabis users from the U.S. (PI Filbey) and 50 matched cannabis users from the NL (PI Cousijn) in addition to 50 matched controls per site will be examined using task-based and resting state fMRI, cognitive measures and self-reports to determine individual and cultural- level effects on the severity of CUDs. This proposal will integrate the unique expertise of two leading cannabis researchers, thereby, creating a unique opportunity to increase our fundamental knowledge of the neurocognitive mechanisms underlying CUDs. Identification of individual and cultural mechanisms of CUD in a cross-cultural population can reveal new brain-based markers of CUDs that inform prevention and intervention development as well as public health policies.