Microbiome-derived metabolites in substance use disorders: Mechanisms and implications

Substance use disorders (SUDs) are a public health crisis with high mortality rates and significant societal costs. Current brain-targeted pharmacotherapies are often ineffective or poorly tolerated. Emerging evidence highlights the gut microbiome's role in influencing neurobiological and behavioral responses to drugs of abuse. This diverse microbial community communicates with the brain via neuroactive metabolites, immune modulation, and peripheral nervous system signaling. In SUDs, gut-derived metabolites such as short-chain fatty acids, tryptophan derivatives, neurotransmitters, bile acids, and immune molecules directly affect drug and alcohol use behaviors, as demonstrated in clinical and preclinical studies. Shared mechanisms across substances suggest these metabolites modulate addiction-like phenotypes. This review summarizes the role of gut microbiome-derived metabolites in addiction, their mechanisms of action, and neurobehavioral effects. It also discusses current methodologies for studying gut metabolites in SUDs and identifies critical research gaps. Advancing our understanding of the gut-brain axis may reveal novel therapeutic targets, paving the way for more effective SUDs treatments.