Background: VA use of prescribed stimulants (PS) has been skyrocketing. PS are beneficial for many Veterans but can also cause serious risks ranging from cardiac problems, psychosis, mania, substance abuse, and overdose. These risks have not been well-quantified inside or outside of the VA, and because of Veterans’ high rates of physical and mental health conditions, these risks may be particularly high in Veterans. PS will be the focus of VA’s next Psychotropic Drug Safety Initiative (PDSI) starting January 2022. Significance: PS are potent and useful medications, but are not equally safe for all patients. This study will use the VA’s very large nationwide databases to comprehensively quantify the risks from PS and identify those patient groups at greatest risk of adverse effects. Thus, this study will help providers decide who to start on stimulants, and how to manage patients once started. Because of the upcoming initiative, our study will be useful to the VA as it seeks to improve PS safety and may have rapid impacts on improving care. Innovation and Impact: This study will provide: 1) the first comprehensive look at the magnitude and frequency of many PS risks; 2) a unique resource to support VA’s program offices as they set quality improvement targets and seek to improve PS prescribing practices during and after the PDSI; 3) an opportunity to confirm or refute the reported association between PS and mortality risks in patients receiving PS “off label”; 4) the first systematic investigation about events during PS treatment, including tox screens and the detection of duplicate prescriptions,that may signal increased risks for adverse effects; 5) a chart review examining whether undiagnosed substance use may contribute to PS risks; 6) development of a risk score to communicate our findings to providers, and help facilitate their discussions of PS risks with patients. Specific Aims: Aim 1: Identify Patients at Particular Risk from PS; Aim 2: Identify Other Prescribing Practices at or after PS Initiation Associated with Increased PS Risks; Aim 3: Develop Risk Scores (RS) to Facilitate Risk Perception & Collaborative Decision-Making re: PS. Methodology: This study primarily uses the VA’s large and detailed clinical databases, analyzed by high- dimensional propensity scores and marginal structural models. These methods help address confounding, which can sometimes lead to inaccurate conclusions from database information. Some of these methods also can be implemented rapidly to provide a broad survey of risks, allowing the VA to use Veteran-specific data to prioritize their safety efforts as the PDSI proceeds. Automated chart extraction concerning duplicate prescriptions and a manual chart review concerning substance use will add detail to these PS risk assessments. Risk scores for several different outcomes will be constructed by assessing risk factors identified in Aim 1 & 2 plus those identified by random forest methods by iterative mixed effect...