A larger controlled study failed to reproduce a widely cited interaction between COMT genotype and amphetamine-related executive performance. Its null findings place an important limit on using the earlier result as a personal prediction of stimulant benefit.
Wardle and colleagues recruited 200 healthy young adults for counterbalanced, double-blind sessions involving placebo and 5, 10 and 20 mg oral d-amphetamine. They examined card sorting and n-back working memory, with smaller usable samples for individual task analyses.
This was primary human experimental research. The earlier report included both performance and imaging; this replication addressed behavioral outcomes and did not replicate the imaging component. Those scopes should remain separate.
Amphetamine increased processing speed and produced expected cardiovascular effects, demonstrating that active dosing had measurable consequences. Nevertheless, COMT groups did not show the predicted baseline executive-performance differences or the proposed improvement-versus-impairment pattern after dosing.
A nominal quadratic genotype interaction for n-back performance did not survive correction for multiple testing. Direct comparisons at the highest dose between the homozygous genotype groups also did not confirm the earlier interaction. Thus, the conclusion does not rest simply on treating every nominal finding as negative.
The authors considered differences in dosing, task setting, repeated testing and sample characteristics. Task-comprehension exclusions reduced the n-back sample, while practice effects could limit sensitivity. These limitations preserve uncertainty about small or context-specific effects; they do not restore the original large behavioral claim.
The result does not prove that COMT has no biological relevance or that every possible imaging association is absent. It does show that this genotype–task relationship was not sufficiently stable here to justify a clinical prediction rule. Neither genotype nor a laboratory task score identifies drug concentration or impairment at a particular incident.
Read our analysis of the earlier COMT working-memory imaging finding.
Does COMT genotype influence the effects of d-amphetamine on executive functioning?. doi:10.1111/gbb.12012.