Neurotransmitter Metabolic Disturbance in Methamphetamine Abusers: Focus on Tryptophan and Tyrosine Metabolic Pathways

Abstract

Methamphetamine (METH) abuse disrupts the homeostasis of neurotransmitter (NT) metabolism, contributing to a wide range of neurological and psychological disorders. However, the specific effects of METH on NT metabolism, particularly for the tryptophan (TRP) and tyrosine (TYR) metabolic pathways, remain poorly understood. In this study, serum samples from 78 METH abusers and 79 healthy controls were analyzed using Ultra-High-Performance Liquid Chromatography with Tandem Mass Spectrometry (UHPLC-MS/MS). A total of 41 substances, primarily from the TRP and TYR metabolic pathways, were detected and subjected to multivariate analysis. Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) revealed a significant separation of serum metabolites between METH abusers and controls, encompassing the disturbance of serotonergic, kynurenic, and microbial metabolism. In the serotonergic pathway, METH significantly reduced melatonin (MLT) levels and impaired the conversion of serotonin (5-HT) to N-acetylserotonin (NAS), a key precursor of MLT. In the kynurenic pathway, METH promoted a shift to the toxic metabolic pathway, evidenced by elevated levels of 3-hydroxykynurenine (3-HK) and quinolinic acid (QA). Furthermore, microbial metabolic pathway-related indole and its derivatives were markedly suppressed in METH abusers. Gender-specific differences were also observed, with NT metabolism in TRP and TYR pathways showing more pronounced alterations in male or female subgroups. Therefore, the current study provides a comprehensive overview of the disturbance in TRP- and TYR-associated NT metabolism caused by METH abuse and highlights NT metabolism as a promising therapeutic target for METH-induced neural and psychiatric disorders.

Keywords: methamphetamine; neurotransmitters; tryptophan metabolism; tyrosine metabolism.

Figure 1

PCA of the NTs and their metabolites in the serum of METH abusers and healthy controls. (A) Nonsupervised PCA score plot. (B) PLS-DA score plot. (C) OPLS-DA score plot. Red triangles represent the METH abusers’ serum metabolomes; blue dots represent the healthy controls’ serum metabolomes. (D) Permutation test. It verifies the prediction ability of the OPLS-DA model. p values of <0.05 were considered statistically significant. The permutation number was set to 100. (E) VIP plot of the serum metabolomes. VIP > 0.8. (F) Volcano plot. Red dots: upregulated metabolites; blue dots: downregulated metabolites; gray dots: no obviously affected metabolites.

Figure 2

The changed serum NTs and the dynamic metabolism of the TRP–kynurenic pathway in METH abusers. (A) Pathway schematic of TRP–kynurenic metabolism. Black arrows show the host pathway; blue arrows show the microbial pathway. Host enzymes with genomic evidence are marked in red; microbial enzymes with genomic evidence are marked in green. (B) Differences in absolute concentrations (ng/mL) of TRP–kynurenic metabolites and the statistically significant ratios in the TRP–kynurenic pathway. C, healthy controls. M, METH abusers. * p < 0.05; ** p < 0.01.

Figure 3

The changed serum NTs and the dynamic metabolism of the TRP–serotonergic pathway in METH abusers. (A) Pathway schematic of TRP–serotonergic metabolism. Black arrows indicate the host degradation pathway; host enzymes with genomic evidence are marked in red. (B) Differences in absolute concentrations (ng/mL) of TRP–serotonergic metabolites and the statistically significant ratios in the TRP–serotonergic pathway. C, healthy controls. M, METH abusers. * p < 0.05; ** p < 0.01.

Figure 4

The changed serum NTs and the dynamic metabolism of the TRP–microbial metabolic pathway in METH abusers. (A) Pathway schematic of TRP–microbial metabolism. Black arrows show the host pathway; blue arrows show the microbial pathway. Host enzymes with genomic evidence are marked in red; microbial enzymes with genomic evidence are marked in green. (B) Differences in absolute concentrations (ng/mL) of TRP–microbial metabolism and the statistically significant ratios in the TRP–microbial metabolic pathway. C, healthy controls. M, METH abusers. * p < 0.05; ** p < 0.01.

Figure 5

The changed serum NTs and the dynamic metabolism of the TYR–dopamine pathway in METH abusers. (A) Pathway schematic of TYR–dopamine metabolism. Black arrows indicate the host degradation pathway; host enzymes with genomic evidence are marked in red. (B,C) Differences in absolute concentrations (ng/mL) of TYR–dopamine metabolism, other amino acid NTs, and the statistically significant ratios. C, healthy controls. M, METH abusers. * p < 0.05; ** p < 0.01.

Figure 6

ROC curves distinguishing the controls and the METH abusers. Model 1 contained the TRP–microbial metabolic pathway. Model 2 contained the TRP–kynurenic pathway. Model 3 contained the TRP–serotonergic pathway.

Figure 7

Alterations in NTs and neuroactive metabolites from the t-test in METH abusers of different genders. (A,B) Heatmaps of statistically significant metabolites from the t-test in male and female METH abusers. C, healthy controls. M, METH abusers. hrM, METH abusers of higher exposure. hM, METH abusers of high exposure. mM, METH abusers of medium exposure. lM, METH abusers of low exposure. (C) Venn plot that illustrates differences in serum metabolites between male and female METH abusers, with overlapping areas indicating shared changes caused by METH use in both genders.