Lithium exerts its mood-stabilizing behavioral and physiological effects through a peripheral gut-brain axis mechanism in which lithium activates enterochromaffin cell Trpm2 channels to trigger 5-HT and substance P release, which in turn activates vagal-brainstem pathways that coordinate reductions in arousal, body temperature, heart rate, and aggressive behavior—a mechanism conserved from rodents to humans that challenges the prevailing view that lithium acts directly on the brain.

Lithium, introduced 75 years ago by John Cade1, remains the most effective mood stabilizer for bipolar disorder2. Lithium is proposed to modulate an array of cellular pathways, many ubiquitous to all cells, with pleiotropic roles unlinked to bipolar disorder or lithium responsiveness in genome-wide association studies3,4. These mechanisms cannot explain lithium’s specific effects on mood and behaviour. We demonstrate that lithium’s primary action is in the periphery, not in the brain itself. Lithium acts in the gut to trigger behavioural and physiological changes, akin to those associated with a torpor-like state, that protect individuals from ingested toxins. Lithium activates gastrointestinal enterochromaffin (EC) cells via their Trpm2 cation channels to modulate afferent vagal and area postrema inputs to the brain. Eliminating these inputs by focal brain lesions eliminates lithium’s effects, as does ablation of EC cells or their Trpm2 expression. Lithium’s Trpm2-dependent activation of EC cells also occurs in human gut tissue, providing translational relevance for our discovery. These findings challenge the prevailing perception that lithium acts directly on the brain. Via a previously unsuspected gut-brain pathway, lithium engages brain circuitry that reduces arousal and interaction with the external world, therapeutic goals in the manic phase of bipolar disorder.