We failed to identify a significant load × session interaction in the DLPFC. This may be because of the complex nonlinear relationship known to exist between prefrontal neuronal recruitment, baseline cortical dopamine levels, task difficulty, and performance.22,41,90 When the high-load condition was examined in isolation, we found that sensitization was associated with prefrontal hyperactivity, in the absence of any performance deficits. Ten of the 11 participants in each group in this study were heterozygous for the Val/Met polymorphism of COMT, and thus, variation in baseline dopamine level due to this polymorphism was theoretically minimized. In accordance with this intermittent (Val/Met) phenotype, we found that amphetamine and placebo groups showed very little difference in prefrontal activation during session 1 (short-term amphetamine exposure), with both groups demonstrating a linear recruitment of the prefrontal cortex up to the high-load condition, but importantly, neuronal recruitment diminished as WM capacity was exceeded (consistent with the inverted-U load-activity curve). The shifting of this curve to the left in patients with schizophrenia is thought to lead to the same hyperrecruitment, followed by hypoactivity, at far lower-load cognitive challenges (ie, hypofrontality). Our findings are suggestive of a similar frontal “inefficiency” as that seen in patients, albeit with a far smaller magnitude more akin to the effects of short-term amphetamine use in Met-Met homozygotes. Thus, the cortical effects of sensitization in humans are to some degree equivalent to those associated with gaining a COMT methionine allele (Val/Met to Met/Met).