PROJECT SUMMARY Drug overdose resulted in 106,699 deaths in the U.S. in 2021, an age- adjusted rate of 32.4 per 100,000 population, a 14% increase over 2020, and the highest rate ever recorded.1 Beyond overdose, injection opioid and methamphetamine use are driving up rates of HIV infection, hepatitis C virus (HCV) infection, and endovascular and soft tissue bacterial infections.2 The overdose crisis has also affected Canada and Mexico, leading to a call for a North American approach to addressing the overdose crisis. Simulation models provide a structured environment for decision makers to compare the predicted effects of proposed policy alternatives over an extended time horizon on population-level outcomes such as overdose, HIV, and HCV. Several public agencies are currently funding overdose simulation modeling efforts in North America, including NIDA, CDC, FDA, the Canadian Institutes of Health Research (CIHR), and Canadian provincial agencies. Our goal is to improve the speed, validity, effective knowledge translation, and