ABSTRACT Electronic Nicotine Delivery Systems (ENDS) are the most significant entry into the market for nicotine in decades, disrupting patterns of nicotine use as well as other substances such as combustible tobacco and cannabis. The rapid rise in vaping has caused public health professionals concern, particularly with respect to high use among youth, leading to significant efforts at regulation. At the same time, there is increasing evidence that under proper circumstances, ENDS may be an effective smoking cessation aid and harm reduction tool. As a result, ENDS regulation is likely to have broad impact, affecting the use of not only ENDS, but also combustible cigarettes and other vaped products (i.e., cannabis), and differentially affecting use and outcomes for youth, young adults, and adults. A comprehensive effort is needed to understand the potentially far-reaching consequences of ENDS policy. Federal, state, and local governments have instituted efforts to control youth ENDS use and protect non-users from ENDS vapor. Public policies may be placed principally into five categories: 1) raising the legal purchasing age to 21, 2) restricting or prohibiting sales of flavored products, 3) limiting stores where ENDS may be used or sold, 4) restricting where ENDS may be used (e.g., clean indoor air laws), and 5) taxing ENDS . Schools have also instituted policies and programs to curb ENDS use. In the proposed research, we will obtain publicly available data on ENDS policy enactment and use qualitative methods (key informant interviews) to investigate the adoption and implementation of ENDS policies by states nationally and by localities and schools in eastern Massachusetts. Next, we will leverage natural experiments induced by policy introductions at different places and times to rigorously evaluate how these specific ENDS control efforts, individually and in combination, affect ENDS, tobacco, and cannabis use among youth, young adults, and adults. To this end, our analyses will combine policy data from public documents, databases, and our interviews with large national datasets (e.g., the Youth Risk Behavior Surveillance System and the Behavioral Risk Factor Surveillance System) and a limited-access local data set from eastern Massachusetts (the MetroWest Adolescent Health Survey) from 2014-2025. Analyzing data from this extended period will allow adequate follow-up after major recent state and national policy changes as well as the major disruptions of the COVID-19 pandemic. Using our estimates of how policies impact these substance use outcomes, we will conduct simulation analyses using the Simulation of Tobacco and Nicotine Outcomes and Policy (STOP) microsimulation model to project the potential short- and long-term impact of alternate ENDS control policy configurations on behaviors and health. These complementary efforts, synthesizing new, high-quality inputs and analyses, will provide a comprehensive assessment of the impact of ENDS control ...