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Variation in the catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with executive cognition and working memory, presumably mediated by the prefrontal cortex. Here, we extend these observations by examining two measures of cognitive function, lapses in attention and visuo-spatial-motor speed of processing, in both the drug-free state and after administration of d-amphetamine.Healthy Caucasian male and female participants (n=161) participated in a double-blind, crossover design study where they received placebo or d-amphetamine (10 and 20 mg). The outcome measures included self-reported mood states, a simple reaction time task, and a task measuring visuo-spatial-motor speed of processing. We first evaluated whether the genotypic groups differed on any of the measures in the absence of drug administration, including a measure of personality. We then determined whether the genotypic groups differed in their responses to acute doses of d-amphetamine (10 or 20 mg).We found that without drug, val/val and val/met carriers showed greater lapses in attention on the reaction time task than met/met carriers, but the genotypic groups did not differ on the visuo-spatial-motor speed of processing task. Val/val carriers scored higher on a personality measure of extraversion than val/met and met/met carriers. Compared with placebo, the lower dose of d-amphetamine (10 mg) improved lapses in attention and visuo-spatial-motor speed of processing in val/val carriers, and decreased lapses in attention in val/met carriers. The highest dose of d-amphetamine (20 mg) improved performance on lapses in attention and visuo-spatial-motor speed of processing tasks in both val/val and val/met carriers, but not in met/met carriers. None of the genotypic groups differed on mood states, either with or without drug administration.The results of this study extend earlier findings with the COMT genotypes to additional measures of cognition, and suggest that the presence of the val allele is associated with poorer performance and greater improvement with a stimulant drug. The results further suggest that this polymorphism does not affect the mood-altering effects of d-amphetamine, consistent with the preferential influence of COMT in cortical regions.