Gut microbiome features in methamphetamine use disorder: external validation of a candidate marker panel and exploratory multi-omics associations

Methamphetamine use disorder (MUD) is a chronic, relapsing disorder with symptoms most pronounced during withdrawal, yet objective biomarkers remain lacking. Although gut microbial alterations have been reported in substance use disorders, their potential as candidate markers, longitudinal patterns, and symptom associations in MUD remain unclear. Gut microbiota profiles were analysed in 103 participants with MUD and 80 healthy controls.

Longitudinal analyses included 52 participants with MUD assessed at baseline and after 1, 3, and 6 months of withdrawal. Paired microbiome-metabolome profiling was performed in 29 participants with MUD at baseline and 1 month and in 29 matched healthy controls. A 30-taxon candidate microbial marker panel distinguished MUD from controls, achieving an external validation AUC of 0.821 (95% CI, 0.653-0.990).

PERMANOVA detected no significant overall compositional change in the candidate marker panel across the withdrawal time points. Individual marker taxa nevertheless followed four distinct temporal trajectories. Exploratory multi-omics analyses identified associations between Ruminococcus gnavus and depressive symptoms, and between microbial L-arginine biosynthesis and sleep disturbance during early withdrawal.

Plasma dopamine and caffeine were associated with components of these microbe-symptom relationships. This study identifies a candidate gut microbial marker panel for MUD and provides hypothesis-generating multi-omics insights into withdrawal-related symptoms. This work was supported by National Key R&D Program of China (Grant #2018YFC1311600 and 2016YFC1306900 to Yanqing Tang), Joint Funds of the National Natural Science Foundation of China (Grant #U24A20700 to Yanqing Tang), Science and Technology Innovation 2030 - Major Project on Brain Science and Brain-like Research (Grant #2021ZD0200600 and 2021ZD0200700 to Yanqing Tang), and Scientific Research Staring Foundation for Ph.D. of Liaoning Province (Grant #2024-BSLH-313 to Linzi Liu).

The authors received no specific funding for this work. These authors contributed equally: Linzi Liu, Zijing Deng. Department of Psychiatry, Shengjing Hospital of China Medical University, Shenyang, PR China Linzi Liu, Zijing Deng, Yifang Zhou, Ting Sun, Huaqian Zhu, Tao Ma, Yu’ang Liu & Yanqing Tang Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, PR China Department of Psychiatry, First Hospital of China Medical University, Shenyang, PR China Institute of Neuroscience and Medicine, Brain and Behaviour (INM-7), Research Center Jülich, Jülich, Germany Institute of Systems Neuroscience, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany Associated Youth Services of Peel, Mississauga, ON, Canada Department of Psychiatry (Ward 1), Shenyang Mental Health Center, Shenyang, PR China Department of Genetics, Shenyang Maternity and Child Health Hospital, Shenyang, PR China The authors declare no competing interests.

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