ABSTRACT The use of prescription stimulants in adults has increased dramatically, with a five-fold increase in use of amphetamines between 2004 and 2019. Coinciding with increased prescribing of stimulants, there has been an acceleration of fatal overdoses involving illicit psychostimulants. During the COVID-19 pandemic, stimulant- related fatal overdoses reached the highest point on record, with 20,054 fatal overdoses involving cocaine and 23,352 involving methamphetamine in 2020 alone. While it is well-established that rising rates of prescription opioid use was associated with an increase in heroin use in turn fueling increases in fatal overdoses, it is not yet known if rising prescription stimulant use is associated with transition to illicit stimulants and overdoses involving illicit stimulants. This is of critical importance given high rates of fentanyl contamination in the illicit stimulant supply and counterfeit stimulant pills obtained from illegitimate online pharmacies. In addition to potential harmful effects, there are also some RCT’s suggesting prescription stimulants may promote short-term abstinence in individuals with pre-existing substance use disorders. Whether these benefits translate to reductions in overdose is unknown. The current application will fill a critical gap by using real-world evidence to identify the consequences of prescription stimulant use on drug overdoses. Our multidisciplinary research team will use robust real-world data sources linking prescription drug monitoring program data, state-wide all-payer claims data, emergency medical service data, emergency department visit and hospital discharge data, substance abuse treatment data and vital records (death certificate/toxicology) for ~ 10 million individuals from two states, Massachusetts and Oregon. In response to the NIDA program announcement RFA-DA-22-037 “Accelerating the Pace of Drug Abuse Research Using Existing Data, we will address three aims: 1) We will use a priori definition of high risk use, supported by preliminary data, to define the impact of high risk prescription stimulant use on the risk of fatal and non-fatal overdoses involving stimulants and/or polysubstance use; 2) We will assess the potential therapeutic role of prescription stimulants in preventing drug overdoses in individuals with stimulant and opioid use disorders; and 3) We will use group-based trajectory modeling to identify longitudinal stimulant prescribing patterns that may aid in predicting overdose. Aim 3 complements the other aims by capturing heterogeneity in prescribing patterns that may be associated with protective or increased risk of overdose. Given prescription stimulants are one of the most widely prescribed classes of medications in the United States, it is imperative to understand the risks/benefits of these medications with the overall goal of reducing stimulant-related overdose.