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Mexiletine is the first choice drug in the treatment of non-dystrophic myotonias. However, 30% of patients experience little benefit from mexiletine due to poor tolerability, contraindications and limited efficacy likely based on pharmacogenetic profile. Safinamide inhibits neuronal voltage-gated sodium and calcium channels and shows anticonvulsant activity, in addition to a reversible monoamine oxidase-B inhibition. We evaluated the preclinical effects of safinamide in an animal model of Myotonia Congenita, the ADR (arrested development of righting response) mouse. In vitro studies were performed using the two intracellular microelectrodes technique in current clamp mode. We analyzed sarcolemma excitability in skeletal muscle fibers isolated from male and female ADR (adr/adr) and from Wild-Type (wt/wt) mice, before and after the application of safinamide and the reference compound mexiletine. In ADR mice, the maximum number of action potentials (N-spikes) elicited by a fixed current is higher with respect to that of WT mice. Myotonic muscles show an involuntary firing of action potential called after-discharges. A more potent activity of safinamide compared to mexiletine has been demonstrated in reducing N-spikes and the after-discharges in myotonic muscle fibers. The time of righting reflex (TRR) before and after administration of safinamide and mexiletine was evaluated in vivo in ADR mice. Safinamide was able to reduce the TRR in ADR mice to a greater extent than mexiletine. In conclusion, safinamide counteracted the abnormal muscle hyperexcitability in myotonic mice both in vitro and in vivo suggesting it as an effective drug to be indicated in Myotonia Congenita., Competing Interests: Declaration of competing interest Silvia Vailati, Elsa Melloni, Gloria Padoani are employees of Zambon SpA, and Carla Caccia is a consultant of Zambon SpA. The International patent application PCT/EP2019/063733 entitled “Safinamide for treating myotonia” was filed on May 28, 2019 in the name of Zambon S.p.A. Designated inventors are Desaphy J.F., Pierno S., Conte D., Melloni E., Vailati S., Padoani G., and Caccia C., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)