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

Mapping metabolic "signatures" can provide new insights into addictive mechanisms and potentially identify biomarkers and therapeutic targets. 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. 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. 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. 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.