Cognitive and motor performance are critical in many circumstances and are impaired by sleep deprivation. We administered placebo, tyrosine 150 mg/kg, caffeine 300 mg/70 kg, phentermine 37.5 mg and D-amphetamine 20 mg at 15.30 h following overnight sleep deprivation and compare their effects on cognitive and motor performance in healthy young men. Tests of visual scanning, running memory, logical reasoning, mathematical processing, the Stroop task, four-choice serial reaction time, time wall take, pursuit tracking, visual vigilance, Trails (B) task and long-term memory were evaluated at standardized intervals before, during and after sleep deprivation and drugs. Performance decrements with sleep deprivation occurred in visual scanning, running memory, logical reasoning, mathematical processing, the Stroop test, the time wall test, tracking and visual vigilance. Interestingly, with sleep deprivation some tests improved and others did not deteriorate. Improvements with medication following sleep deprivation were seen in running memory, logical reasoning, mathematical processing, tracking and visual vigilance. Although less effective than D-amphetamine, tyrosine improved performance on several tests. We conclude that all drugs tested improved at least some aspects of cognitive and motor performance after sleep deprivation. As a naturally occurring amino acid, and thus amenable to nutritional strategies, tyrosine may deserve further testing.