Opioid use disorder (OUD) has reached epidemic levels, and current medications, while lifesaving, fail to address negative affect and cognitive impairment, leading to high relapse rates even years after drug cessation. Ketamine, an anesthetic and rapid-acting antidepressant, shows promise for treating OUD, including managing acute withdrawal symptoms, negative affect during protracted abstinence, and preventing return to opioid use. This review examines preclinical and clinical research on ketamine and its metabolites as novel therapeutic strategies. Evidence demonstrates that ketamine and its metabolites can modulate pathophysiological processes in OUD, suggesting a promising role in treatment and relapse prevention.
A single dose of (2R,6R)-hydroxynorketamine (HNK) reverses some but not all gene expression changes in the hippocampus of mice after three weeks of opioid abstinence, while also normalizing their behavior. Transcriptomic analysis identified 206 differentially expressed genes in untreated abstinent mice compared to controls; after HNK treatment, 55 of those genes were reversed, including Transthyretin and Cd5. However, 186 residual differentially expressed genes remained, enriched for immune and fear regulation pathways, indicating an intermediate molecular state despite behavioral recovery. Machine learning highlighted Il1rapl1 and Ctla2b as top predictors of treatment response. HNK did not alter behavior in opioid-naive mice, showing its context-dependent effects.