Advancing Substance Use Disorder Treatment Using Genomics and Metabolomics

Advancing our understanding of genetic, metabolic, and environmental factors in substance use disorder (SUD) could lead to more effective therapies. In 2022, 16.5% of the U.S. population was diagnosed with SUD, yet current treatments lack efficacy for all patients, making a precision medicine approach crucial. This dissertation explores SUD's relationship with tryptophan (TRP) metabolism through the kynurenine pathway (KP) as a potential therapeutic target. Chapter I reviews current knowledge on SUD and KP. Chapter II identifies how SUD alters KP metabolite concentrations, identifying a reduced concentration of the neuroprotective metabolite, kynurenic acid (KA) and elevated concentrations of the neurotoxic metabolite, quinolinic acid (QA). Chapter III examines genetic variants in KP enzyme genes, revealing significant differences between SUD and control groups that may predispose individuals to SUD by altering neurotoxic and neuroprotective metabolite levels. Chapter IV describes a validated mass-spectrometry method to quantify TRP metabolites in urine. Clinical analysis showed elevated kynurenine (p = .011) and quinolinic acid (p = .003) in SUD samples, suggesting KP dysregulation in SUD. Future research should combine metabolite quantification with genetic analysis to further identify the genetic impact on KP metabolite imbalances. Chapter V synthesizes findings, limitations, and future directions, for SUD research. Together, these studies reveal KP's potential as a therapeutic target and provide tools for monitoring SUD treatment efficacy, laying the groundwork for precision medicine approaches in SUD treatment.