Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Neurol Res and Elmer Press Inc
Journal website https://jnr.elmerpub.com

Review

Volume 16, Number 3, September 2026, pages 127-140

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

Figures

↓  Figure 1. The therapeutic potential of ketamine for ALS: manuscript structure and key concepts. This schematic summarizes the structure and key concepts of the manuscript across four thematic columns. Column 1 (red): ALS disease burden, including epidemiology, prognosis, current FDA-approved treatments, and the critical unmet need. Column 2 (purple): ALS pathogenesis, encompassing genetic factors (C9orf72, SOD1, TARDBP, FUS, SIGMAR1) and core pathophysiological mechanisms: Sigma-1 receptor dysfunction, mitochondrial dysfunction, ER stress/UPR dysregulation, protein aggregation, neuroinflammation, and synaptic loss. Column 3 (teal): ketamine pharmacology, including route and dose (low-dose sublingual, 50–200 mg), enantiomer-specific properties, and six proposed mechanisms of action ordered as they appear in the manuscript. Column 4 (amber): therapeutic convergence and clinical proposal, showing how each ketamine mechanism addresses a corresponding ALS pathophysiological target, and proposing low-dose sublingual ketamine as a candidate for systematic clinical investigation. ALS: amyotrophic lateral sclerosis; BDNF: brain-derived neurotrophic factor; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum–associated degradation; FDA: Food and Drug Administration; MAM: mitochondria-associated endoplasmic reticulum membrane; mTOR: mechanistic target of rapamycin; NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NMDA: N-methyl-D-aspartate; OXPHOS: oxidative phosphorylation; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS: reactive oxygen species; S1R: sigma-1 receptor; UPR: unfolded protein response.
Figure 1.
↓  Figure 2. Ketamine as a candidate therapy for ALS: mechanistic rationale. The schematic illustrates the mechanistic rationale for investigating low-dose sublingual ketamine as a candidate therapeutic agent in amyotrophic lateral sclerosis (ALS). Left column (blue): six major pathophysiological pillars of ALS, each contributing to progressive motor neuron degeneration. Central column (teal): ketamine’s six proposed mechanisms of action, including NMDA receptor antagonism, sigma-1 receptor (S1R) agonism (R-enantiomer/arketamine selective), mitochondrial protection, anti-inflammatory effects, UPR modulation, and neuroplasticity enhancement via BDNF-TrkB-mTOR signaling. Right column (teal): proposed therapeutic benefits converging on motor neuron preservation. All mechanisms are based on preclinical and/or mechanistic evidence; anti-inflammatory effects are cited as “reported” reflecting evolving evidence. Clinical validation in ALS is pending. ALS: amyotrophic lateral sclerosis; BDNF: brain-derived neurotrophic factor; ERAD: endoplasmic reticulum–associated degradation; MAM: mitochondria-associated endoplasmic reticulum membrane; mTOR: mechanistic target of rapamycin; NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NMDA: N-methyl-D-aspartate; OXPHOS: oxidative phosphorylation; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS: reactive oxygen species; S1R: Sigma-1 receptor; TrkB: tropomyosin receptor kinase B; UPR: unfolded protein response.
Figure 2.