Unveiling the metabolic signatures of kratom use in humans via NMR-based blood plasma metabolomics

Consumption of herbal-based beverages can alter metabolite profiles, reflecting metabolic changes related to their potential health effects. Kratom is traditionally consumed in Southeast Asia as a decoction to treat various ailments. In recent years, kratom has gained substantial popularity in Western countries for a range of off-label uses, however, reports of its adverse effects, including fatalities, have raised safety concerns. Because changes in metabolite profiles can indicate alterations in health status, metabolomics provides a valuable tool for assessing the potential benefits and risks of kratom. Although animal studies suggest that kratom influences metabolic pathways and behavior, human data remain limited. Therefore, this study aimed to characterize changes in blood plasma metabolites and associated metabolic pathways in regular kratom users using an NMR-based metabolomics approach. Blood plasma samples were collected from 37 regular kratom users and 12 control subjects (non-users), and analyzed using NMR spectroscopy. Multivariate analysis revealed a clear separation between the two groups, indicating distinct plasma metabolite profiles. A total of 17 metabolites were identified as different between the two groups based on ¹H CPMG, JRES and HSQC spectra. Among these, glycine, formate, dimethylamine and N-methyltyramine were significantly increased, whereas pyruvate, ʟ-pyroglutamic acid and citrate were significantly reduced in kratom users compared with non-users. Metabolite enrichment and pathway analyses revealed perturbations in glycine, serine, and threonine metabolism; pyruvate metabolism; glyoxylate and dicarboxylate metabolism; citrate cycle; glycolysis or gluconeogenesis; and glutathione metabolism in kratom users. The biological relevance of these metabolites and pathways is discussed. Overall, these findings provide a better understanding of the metabolic alterations associated with long term kratom consumption in humans.