Acute Modafinil Exposure Induces Neurobehavioral Alterations in Zebrafish: Implications for Off-Label Cognitive...

Modafinil (2-(benzhydrylsulfinyl)acetamide) is a psychostimulant commonly prescribed for sleep disorders such as narcolepsy, excessive daytime sleepiness, and obstructive sleep apnea. Recently, its use has extended beyond clinical indications, with neurotypical individuals adopting it as a smart drug to enhance alertness and cognitive performance. This study used a zebrafish translation model to assess toxicity associated with the off-label use of modafinil by neurotypical individuals. Animals were exposed for 15 min to one of three concentrations of the drug (200, 400, or 600 mg L^-1); the control group was not exposed to modafinil (0 mg L^-1). After exposure, the fish underwent behavioral assessments that included the novel tank, social preference, light-dark, forced swimming, and Y-maze tests. Biochemical analyses of cortisol, nonprotein thiols, total protein, lipid peroxidation, and mitochondrial complex activity were then conducted. Exposure to modafinil elicited significant neurobehavioral changes, characterized by hyperlocomotion, enhanced endurance, and anxiogenic-like behavior. Biochemically, total protein levels were increased at the highest drug concentrations, whereas lipid peroxidation rose at lowest 200 mg L^-1 of modafinil. Conversely, cortisol levels, nonprotein thiols, and mitochondrial complex activity showed no significant changes. In conclusion, our findings indicated that acute exposure to modafinil can induce marked neurobehavioral changes. This suggests that its unsupervised use as a cognitive enhancer may entail substantial neurological risks for neurotypical individuals.