enzyme stability69,70 the Met158 allele is three- to fourfold less active.71 Because of its higher activity, the Val158 allele was predicted to lower dopamine level in the frontal cortex. Congruent with this hypothesis, the Val158 allele has been associated with inefficient frontal lobe function evaluated with different psychological and neuroimaging methodologies.72–74 Also, in a pharmacogenetic study, the COMT inhibitor tolcapone improved executive function in val/val homozygotes, but not in individuals homozygous for the met allele, indicating that this drug might correct the higher COMT activity, and consequent lower dopamine level, of Val carriers.75 On the other hand, Met158, although associated with better cognitive performance, is associated with decreased stress resilience and increased anxiety. This allele has been associated with increased anxiety in women,76 which might be explained because COMT promoters are down-regulated by estrogens.77 The Met allele has also been associated with increased pain–stress response and a lower pain threshold,42,78 and with increased amygdala reactivity to unpleasant stimuli.79 Results from studies exploring the association between COMT and addiction are mixed. Some studies failed to find evidence for an associations80; some indicate Val158 as the risk alleles and others indicate the Met158 alleles as the risk allele. The Val158 allele was
