Abstract
For decades, researchers have explored the therapeutic potential of the vagus nerve through vagus nerve stimulation (VNS). Initially developed for epilepsy, VNS has since been applied to treat resistant depression, stroke recovery, and inflammatory conditions. Transcutaneous VNS (tVNS) now offers a noninvasive alternative, fueling clinical trials in disorders ranging from rheumatoid arthritis and migraines to long COVID-19. Mechanistic studies suggest that afferent and efferent vagal fibers modulate immune responses, mood regulation, and neurotransmitter systems. The SPARC initiative has accelerated mapping of vagal circuits, enabling more precise approaches to stimulation. Despite progress, the results remain mixed: while some patients experience lasting symptom relief, others respond no better than to placebo. Depression studies, in particular, highlight both the promise and the complexity of VNS, as inflammation, motivation circuits, and gut-brain signaling emerge as key modulators. Next-generation closed-loop devices and circuit-specific targeting may improve efficacy and reduce adverse effects. VNS research thus lies at the intersection of neuromodulation, psychiatry, and immunology-offering hope for hard-to-treat conditions, yet demanding rigorous trials to separate myths from medicine. In this article, we review the current clinical and experimental applications of tVNS, analyze its mixed efficacy across psychiatric, immunological, and neurological disorders, and highlight the mechanistic insights, stimulation parameters, and emerging technologies that may shape next-generation therapies.