LAUSR

BACKGROUND AND AIMS Cocaine Use Disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment. DESIGN Our drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration, and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD. SETTING The study utilized TriNetX to access EHRs from over 90 million patients worldwide. Genetic and functional level analysis used DisGeNet, Search Tool for Interactions of Chemicals, and Kyoto Encyclopedia of Genes and Genomes databases. PARTICIPANTS 7,742 CUD patients who received anesthesia (3,871 ketamine-exposed and 3,871 anesthetic-controlled) and 7,910 CUD patients with depression (3,955 ketamine-exposed and 3,955 antidepressant-controlled) were identified after propensity score-matching. MEASUREMENTS EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription. FINDINGS Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics (Hazard Ratio (HR): 1.98, 95% confidence interval [CI]: 1.42-2.78). Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR: 4.39, 95% CI: 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling, and cocaine abuse/dependence. CONCLUSIONS Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder.