Polymorphisms in COMT have been associated with acute amphetamine response. In a landmark study (Mattay et al. 2003), healthy volunteers completed the Wisconsin Card Sorting Test (WCST; Heaton et al. 1993) after placebo or amphetamine, and underwent fMRI while performing the N-back working memory task (Kirchner 1958). Amphetamine administration reduced prefrontal cortical activity at all working memory loads when compared to placebo in individuals homozygous for the val allele. This was interpreted as a more efficient physiological response; this reduction was associated with improved reaction time and no decrease in accuracy on the task. Conversely, amphetamine increased prefrontal cortical activity in the most difficult part of the working memory task in met homozygotes. This was interpreted as a reduction in efficiency, because increased prefrontal cortical activity was associated with increased reaction time and decreased accuracy. The authors proposed that amphetamine increased dopamine levels above an optimum level in met/met individuals and thus negatively impacted cortical function. In contrast, in val/val individuals, amphetamine increased the lower pre-drug dopamine levels so that they were closer to optimal and thus enhanced function. The
