Lithium as a disease-modifying therapy for Parkinson’s disease: mechanisms, preclinical evidence, and clinical prospects

Parkinson’s disease (PD), the second most common neurodegenerative disorder, involves progressive dopaminergic neuron loss and α-synuclein aggregation. Current treatments, such as levodopa and dopamine agonists, offer symptomatic relief but do not slow neurodegeneration, underscoring the need for disease-modifying therapies. Lithium, a long-used mood stabilizer, shows neuroprotective potential via multiple mechanisms: inhibition of glycogen synthase kinase-3β (GSK-3β), enhancement of autophagy, suppression of neuroinflammation, and reduction of oxidative stress. Evidence from in vitro, animal, and early clinical studies suggests lithium can preserve dopaminergic neurons, improve motor function, and reduce neurodegenerative biomarkers, including serum neurofilament light chain. Preclinical models indicate that low-dose lithium (0.2–0.6 mM serum) improves striatal dopamine integrity, limits microglial activation, and decreases α-synuclein pathology, though study designs show substantial heterogeneity. Preliminary human trials with microdose lithium aspartate hint at slowed PD progression, though robust phase 3 data are lacking. Key challenges include optimizing formulations (e.g., lithium orotate vs. carbonate), minimizing renal and thyroid risks, and identifying responsive patient subgroups. Comparative evaluation with other experimental therapies, such as glucagon-like peptide-1 agonists and immunotherapies, highlights lithium’s appeal as a cost-effective, repurposed candidate. This review synthesizes molecular and translational evidence, emphasizes research gaps such as long-term safety and standardized dosing, and aims to guide future clinical trial design and therapeutic strategies for PD.