Integrated metabolomics and gut microbiota analysis to explore the potential mechanism of levo-tetrahydropalmatine against ketamine addiction
Yan Du, Qing Ma, Xingcui Gao, Hongliang Su, Keming Yun, Li Du
Frontiers in Pharmacology November 19, 2025 DOI: 10.3389/fphar.2025.1698866 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | levo-tetrahydropalmatine (l-THP) |
| Topics | Addiction Ketamine Esketamine |
| Keywords | Metabolomics Gut flora Mechanism biology Intervention counseling Pharmacology Bioinformatics Gut–brain axis |
| Key points | l-THP attenuated ketamine-induced rewarding effects and hippocampal pathology, and altered serum and urine metabolites and gut microbiota composition. |
Abstract
Introduction: Metabolic and gut microbiota (GM) disturbance play a significant role in the complex pathogenesis of substance dependence. Although levo-tetrahydropalmatine (l-THP) demonstrates therapeutic potential in drug addiction, the underlying mechanism remains elusive.
Methods: The efficacy of l-THP was assessed using a conditioned place preference (CPP) paradigm. In this research, we combined metabolomics with gut microbiota analysis to investigate the potential mechanisms underlying l-THP’s intervention in ketamine (KET) addiction.
Results: L-THP effectively relieved hippocampus (Hip) pathological changes and attenuated KET-induced rewarding effects. Metabolomic profiling of serum and urine samples revealed a total of 194 distinct metabolites, including 3-methoxytyramine, 3-hydroxyphenylacetic acid, and phosphorylcholine, involving glycerophospholipid metabolism, tyrosine metabolism, phenylalanine metabolism, dopaminergic synapse, teichoic acid biosynthesis, staurosporine biosynthesis, and lysine biosynthesis metabolism pathways. L-THP also enriched Firmicutes, Lactobacillus , Dubosiella , unclassified_ Clostridia _UCG_014, and Ligilactobacillus while decreasing the levels of Bacteroidota , Campylobacterota , Patescibacteria , unclassified_ Bacilli , UCG_005, Prevotella , and Romboutsia. Moreover, Spearman’s correlation analysis showed that discriminative metabolites were closely correlated with special bacteria.
Conclusion: The findings demonstrated that l-THP might serve as a promising intervention strategy for KET addiction by regulating serum and urine metabolism and gut microbiota.