PROJECT SUMMARY/ABSTRACT In response to RFA-DA-22-037: Accelerating the Pace of Drug Abuse Research Using Existing Data, this competing continuation (renewal) "Trajectories of Nonmedical Prescription Drug Misuse" builds on our prior R01 and will combine national panel data with other national data sources (eg, death records) to assess longitudinal relationships among trajectories of medical use of prescription drugs, nonmedical prescription drug misuse (PDM), other drug use, polysubstance use (PSU), substance use disorder (SUD) symptoms, drug overdose death, and all-cause mortality from adolescence up to older adulthood. This renewal will focus on prescription opioids, sedatives/tranquilizers, and stimulants because most US adults are prescribed these medications over their lifespan, all have high misuse potential, and there have been important changes in the prescribing of these medications (eg, major increases in opioid prescribing from 1990 to 2010 followed by sharp declines and major increases in stimulant therapy among US middle-aged and older adults). Prospective studies are needed to examine whether the discontinuation, initiation, or developmental timing of medical use of prescription drugs are associated with increased adverse consequences. US drug overdose deaths reached an all-time high in 2021, and most are PSU-involved. An important literature gap, as over 90% of PDM is PSU-involved, is the lack of national studies examining the longitudinal relationships between trajectories of medical use of prescription drugs and PDM or other drug use. We propose secondary analyses using the Monitoring the Future (MTF) panel data which features over 40 independent cohorts of 103,957 high school seniors (modal age 18) who completed biennial follow-ups to ages 29-30 and follow-ups every five years to age 60, resulting in up to 13 waves. The MTF panel data and other linked sources (eg, National Death Index) provide a unique opportunity for innovative analysis to examine associations and risk/protective factors from adolescence up to older adulthood. This renewal aims to: (1) identify the temporal ordering of medical use of prescription opioids, sedatives/tranquilizers, and stimulants, and other drug use (eg, PDM) from adolescence up to older adulthood (age 60); (2) examine longitudinal associations between trajectories of medical use of prescription drugs, PDM and adverse consequences (eg, all-cause mortality, drug overdose death, SUD symptoms) up to older adulthood; (3) assess if adults who discontinue or initiate medical use of prescription opioids, sedatives/ tranquilizers, or stimulants are more likely to transition to PDM and adverse consequences; and (4) determine the individual, relationship, community, and societal, risk and protective factors of high-risk trajectories of medical use of prescription drugs and PDM using a developmental social- ecological model. For all aims, we will examine variations by age, cohort, sex, race/ethnicity, and e...