Francois Ricordeau, Sebastien Arthaud, Leila Langbour, Silvia Melzi, Aurelie Richard-Mornas, Hannah Doudoux, Benjamin Rolland, Laure Peter-Derex, Christelle Peyron
Narcolepsy type 1 is characterized by cataplexy, for which current treatments targeting monoaminergic, histaminergic, and GABAergic pathways may be ineffective or poorly tolerated. We report the case of a 34-year-old man with narcolepsy type 1, intolerant to standard therapies, who experienced marked and sustained cataplexy reduction with morning intranasal ketamine, with symptom recurrence upon discontinuation. To confirm this observation, ketamine was compared with vehicle in a crossover study in orexin knockout mice implanted for polysomnography. Ketamine dramatically reduced time spent in cataplexy (-76%, p = 0.008) without affecting sleep architecture. These translational findings suggest ketamine as a potential anticataplectic agent, warranting further clinical investigation. ANN NEUROL 2026.