Alterations in tryptophan and purine metabolism in cocaine addiction: A metabolomic study

Background: Mapping metabolic "signatures" can provide new insights into addictive mechanisms and potentially identify biomarkers and therapeutic targets. Objective: We examined the differences in metabolites related to the tyrosine, tryptophan, purine, and oxidative stress pathways between cocaine-dependent subjects and healthy controls. Several of these metabolites serve as biological indices underlying the mechanisms of reinforcement, toxicity, and oxidative stress. Methods: Metabolomic analysis was performed in 18 DSM-IV-diagnosed cocaine-dependent individuals with at least 2 weeks of abstinence and ten drug-free controls. Plasma concentrations of 37 known metabolites were analyzed and compared using a liquid chromatography electrochemical array platform. Multivariate analyses were used to study the relationship between severity of drug use [Addiction Severity Index (ASI) scores] and biological measures. Results: Cocaine subjects showed significantly higher levels of n-methylserotonin (p< 0.0017) and guanine (p<0.0031) and lower concentrations of hypoxanthine (p<0.0002), anthranilate (p<0.0024), and xanthine (p<0.012), compared to controls. Multivariate analyses showed that a combination of n-methylserotonin and xanthine contributed to 73% of the variance in predicting the ASI scores (p< 0.0001). Logistic regression showed that a model combining n-methylserotonin, xanthine, xanthosine, and guanine differentiated cocaine and control groups with no overlap. Conclusions: Alterations in the methylation processes in the serotonin pathways and purine metabolism seem to be associated with chronic exposure to cocaine. Given the preliminary nature and cross-sectional design of the study, the findings need to be confirmed in larger samples of cocaine-dependent subjects, preferably in a longitudinal design.