Lidocaine for Depressive Symptoms and Comorbid Pain: A Narrative Review of Mechanisms, Evidence, and Safety

Depression, a globally prevalent mental health disorder, poses significant treatment challenges, particularly in treatment-resistant cases. Increasing evidence suggests a strong bidirectional relationship between chronic pain and depression, underpinned by shared neurobiological mechanisms, including dysregulation of glutamatergic signaling and neuroinflammatory processes. In this narrative review, we synthesize preclinical and clinical findings on lidocaine, a local anesthetic that has attracted interest for its potential neuropsychiatric effects. Proposed pharmacological mechanisms of lidocaine, including sodium channel blockade, N-methyl-D-aspartate (NMDA) receptor antagonism, and anti-inflammatory properties, which together may contribute to its putative mood-modulating properties. Clinical evidence to date remains limited and heterogenous, consisting largely of small-sample controlled trials, observational studies, and investigations primarily conducted in pain populations rather than in primary depressive disorders. Despite some studies suggest rapid but transient improvements in depressive symptoms, challenges such as transient effects, dosing optimization, and safety considerations remain. Addressing these gaps through robust clinical trials and exploring biomarkers for personalized treatment could unlock the full potential of lidocaine in bridging pain management and psychiatry, offering a novel avenue for treating complex cases of depression.