Dextromethorphan for Restless Legs Syndrome: Testing the Glutamate Theory

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder associated with hyperarousal, an urge to move the legs, and significant sleep disruption. While dopaminergic dysfunction and iron deficiency have been implicated in its pathophysiology, emerging evidence also suggests roles for adenosinergic and glutamatergic systems. We report the case of a 45-year-old woman with severe, treatment-refractory RLS who experienced substantial and sustained symptom improvement with oral dextromethorphan (DXM), initially taken for an unrelated upper respiratory infection. Her prior therapies included dopamine agonists, which resulted in augmentation, and gabapentin, which was poorly tolerated. Upon initiating over-the-counter DXM at 30 mg nightly, the patient reported near-complete resolution of RLS symptoms, reflected by a mild to moderate International Restless Legs Scale (IRLS) score of 12 and a significant reduction in insomnia severity. DXM, a noncompetitive NMDA receptor antagonist with anti-inflammatory properties, may exert therapeutic effects through modulation of central glutamatergic activity and enhancement of adenosine tone. There is limited literature supporting the use of DXM for the treatment of RLS, and further research is needed to validate its potential as a therapeutic option. These findings underscore the importance of exploring novel, mechanism-based approaches for RLS treatment, particularly in patients who do not respond to standard therapies.