Despite FDA-approved treatments for opioid use disorder (OUD), opioid misuse continues to be a major public health problem in the United States, with opioid overdoses increasing especially over the last year (1). Innovative treatments are needed, especially for OUD patients with comorbid serious mental illness, whose overdose rates are much higher (2). Recently, a novel electronic health record (EHR) data-mining approach was used to examine data collected across 21 years (1999-August 2020) on the associations of FDA-approved medications with the diagnosis of Opioid Use Disorder in Remission among patients with comorbid psychiatric illness, with the goal of identifying candidate medications for re-use in OUD. The study found that patients diagnosed with schizophrenia and Opioid Use Disorder who were prescribed olanzapine were nearly two times (Adjusted Odds Ratio 1.9) more likely to have a diagnosis of OUD in Remission, as compared to patients who were not prescribed olanzapine (3). Though correlational, this finding suggested that olanzapine may be a helpful antipsychotic medication for patients with opioid use disorder and symptoms of comorbid serious mental illness (SMI). If beneficial, olanzapine could help reduce the (otherwise-elevated) rate of overdose in this very challenging patient group. Taking inspiration from the data-mining study, NIDA Division of Therapeutic and Medical Consequences would like to investigate the potential benefit of olanzapine in a clinically relevant prospective study, to be conducted within the two NIDA UG1 Clinical Laboratories, located at the University of Pennsylvania School of Medicine and at the Medical College of Virginia at Virginia Commonwealth University. The function of these UG1 laboratories is to screen promising candidate medications for clinical benefit, using the Administrative Supplement mechanism. Given the early stage of the literature, we propose a two-site, n=48 (UPenn, n=24; VCU, n=24) observational study of olanzapine in OUD patients with symptoms of serious mental illness (SMI), on a stable dose of buprenorphine-naloxone for at least two weeks. The specified outcomes (e.g., illicit opioid use, other drug use, sleep, MAT adherence, clinic attendance/retention, thought and mood disorder symptoms) on olanzapine will be examined for change (improvement) across the 8-week trial (6 weeks after medication induction phase). Enrollment will occur across 18 months, preceded by a 3- month start-up/regulatory period, and followed by a 3-month period for cleaning, combining and analyzing data across the two study sites.