Acute anxiogenic effect of lisdexamphetamine dimesylate in zebrafish: implications of off-label cognitive enhancement use

The off-label use of lisdexamphetamine dimesylate (LDX), a prodrug of dextroamphetamine, for cognitive enhancement has raised concerns due to its potential risk effects in neurotypical individuals. This study investigates the acute toxic effects of LDX exposure in zebrafish (<i>Danio rerio</i>), used here as a translational model. Zebrafish were exposed to 70, 100, and 140 mg/L^-1 of LDX to assess changes in anxiety-related, social-related and exploratory behaviors and cognitive function through novel tank test, social preference test, spatial memory test, and light-dark test, respectively. We also evaluated the occurrence of lipid peroxidation and changes in the total protein content after LDX treatments. Our findings reveal that acute LDX exposure significantly increases anxiety-like behaviors, as evidenced by increased bottom-dwelling and decreased top-dwelling times in novel tank tests, without enhancing cognitive function. The concentrations also cause increases in lipid peroxidation and total protein content, making this finding likely to be directed at the fish's inflammatory response. Our results highlight that acute use of LDX does not improve cognition, but causes an anxiogenic effect, and showed oxidative damage by increasing total proteins, highlighting potential health risks associated with non-medical use of LDX, particularly among neurotypical individuals seeking cognitive benefits.