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Comorbidity between post-traumatic stress disorder (PTSD) and substance use disorder may be explained by a prospective trauma risk conferred by both conditions. The current study modeled concurrent and prospective associations of trauma, PTSD symptoms, and substance use (SU) behavior among trauma exposed youth (ages 8-20). Clinical interviews assessed trauma exposure, PTSD symptom severity, and SU behavior at baseline and at six- and 12-month follow up study visits (N = 2,069). Structural equation models assessed the associations of trauma, PTSD symptoms, and SU behavior. Lifetime trauma was associated with more severe PTSD symptoms and SU behaviors, whereas trauma exposure during the study was only associated with PTSD symptoms. PTSD symptom severity was prospectively associated with trauma exposure. PTSD symptom severity and SU behavior at follow-up study visits were prospectively associated. These results highlight the dynamic interplay between trauma, PTSD symptoms, and SU behavior during youth, a developmental period during which complex psychiatric presentations can have longstanding consequences for health., Competing Interests: Declaration of competing interest JL, JC, CGD, SLC, AB, AT, LT, IL, CD, and KDW have no biomedical financial interests or potential conflicts of interest. PJR serves on a data safety monitoring board for Sunovion Pharmaceuticals. DJN has received research support from Eli Lilly, Glaxo SmithKline (GSK), Janssen, the National Alliance for Research on Schizophrenia and Depression (NARSAD), Navitor, Sage Therapeutics, Takeda Pharmaceuticals, the Texas Health & Human Services Commission, and Wyeth. He has served on speakers' bureaus and/or received honoraria from Astra-Zeneca, Eli Lilly, GSK, Pfizer and Wyeth. He has served on advisory boards for GSK, Janssen, Merck, and Sage Therapeutics. He has served as a consultant to Sage Therapeutics. Neither he nor family members have ever held equity positions in biomedical or pharmaceutical corporations. CBN, in the last three years, served as a consultant to AbbVie, ANeuroTech (division of Anima BV), Signant Health, Magstim, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, Pasithea Therapeutic Corp., EcoR1, GoodCap Pharmaceuticals, Inc., Senseye, Clexio, EmbarkBio, SynapseBio, BioXcel Therapeutics. He is a stockholder with Seattle Genetics, Antares, Inc., Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, Precisement Health, Relmada Therapeutics. He has served on advisory boards for ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Heading Health, Pasithea Therapeutic Corp., Sage. He has served on the Board of Directors for Gratitude America, ADAA, Lucy Scientific Discovery, Inc. He holds the following patents: Method and devices for transdermal delivery of lithium (US 6375,990B1); Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7148,027B2)., (Copyright © 2024. Published by Elsevier B.V.)