The Therapeutic Potential of Ketamine as a Treatment for Amyotrophic Lateral Sclerosis: A Narrative Review Focusing on Sigma-1 Receptor Modulation, Mitochondrial Function, and Neuroplasticity

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration. Current Food and Drug Administration (FDA)-approved treatments provide only modest benefits and do not substantially alter disease trajectory, underscoring a critical unmet need for novel therapeutic strategies. Recent advances in understanding ALS pathophysiology have revealed important roles for mitochondrial dysfunction, endoplasmic reticulum stress, protein aggregation, and sigma-1 receptor dysregulation in disease progression. Ketamine, a well-established anesthetic with emerging applications as a rapid-acting antidepressant, has been reported to act through multiple mechanisms that may address key pathological features of ALS. Beyond its well-characterized N-methyl-D-aspartate (NMDA) receptor antagonism, ketamine may act as a sigma-1 receptor agonist and has been reported to promote neuroplasticity via brain-derived neurotrophic factor (BDNF)-mechanistic target of rapamycin (mTOR) signaling, exert anti-inflammatory effects, modulate mitochondrial function, enhance protein clearance, and facilitate sigma-1 receptor trafficking from astrocytes to neurons. This review examines the mechanistic rationale for ketamine as a potential therapeutic agent in ALS, focusing on sigma-1 receptor signaling, mitochondrial bioenergetics, protein aggregate clearance, and neuroplasticity. We discuss the convergence of ALS pathophysiology and ketamine’s pharmacological mechanisms, proposing low-dose sublingual ketamine as a candidate for clinical investigation, and note that similar pathophysiological mechanisms in other neurodegenerative diseases may warrant parallel investigation.