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.