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Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics.", Competing Interests: Nicholas M Boulis is a consultant for Abbott, UCB, Novo Nordisk, Treefrog, UniQure, and Coave. He serves on the scientific advisory board for Above and Beyond NB LLC. Raymond T. Bartus was a consultant and advisor for Above and Beyond NB LLC. Malú G Tansey is a consultant for INmune Bio, Longevity, and Prevail Therapeutics. She serves on the scientific advisory board for the Garfield Weston Foundation, the Michael J Fox Foundation, the Quebec Parkinson’s Network, and the Alzheimer’s Association. She receives research support from the NIH, the MJ Fox Foundation, and the Parkinson’s Foundation. Above and Beyond NB LLC’s riluzole formulation is protected by a use patent issued June 18th 2019 (N°10,322,114)., (Copyright: © 2023 Keifer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)