COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.
Level 2 - randomized trial
Individual randomized double-blind placebo-controlled trial
PubMed 22364739 · doi:10.1016/j.biopsych.2011.12.023
What was done
Thirty-four COMT Met158Met and 33 COMT Val158Val men received a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. Cognitive outcomes were assessed using the 2-back working memory task and a gambling task measuring risk aversion.
What was found
In the placebo condition, Met-COMT individuals outperformed Val-COMT individuals on the 2-back task and were more risk averse. Tolcapone produced opposite effects across genotypes: it worsened 2-back performance and decreased risk aversion in Met-COMT participants, whereas it improved 2-back performance and increased risk aversion in Val-COMT participants, reversing baseline genotype differences. No numerical values or effect sizes were reported in the abstract.
Why it matters
This study shows that functional genetic variation can completely invert the direction of a cognitive drug effect, providing direct evidence for the inverted-U model of prefrontal dopamine signaling.
Limits
The study evaluated only a small sample of 67 men split into four subgroup cells, tested only an acute single dose, excluded heterozygous (Val/Met) individuals, and reported no numerical data or precision estimates in the abstract.