Background Cognitive deficits contribute strongly to functional disability in schizophrenia. The cost of identifying and testing candidate procognitive agents is substantial. Conceivably, candidate drugs might be first identified by positive effects on cognitive domains in sensitive subgroups of healthy subjects. Here, we examined whether the MATRICS Consensus Cognitive Battery (MCCB) detected procognitive drug effects in subgroups of healthy individuals. Methods The effects of 20 mg amphetamine (AMPH) on MCCB performance were tested in a double-blind, placebo-controlled crossover study of 60 healthy adults. AMPH effects were compared in subgroups of subjects characterized by low vs. high placebo MCCB scores, and by extreme values on personality subscales associated with schizophrenia-relevant biomarkers. Results AMPH produced autonomic and subjective effects, but did not significantly change MCCB composite scores or individual domain scores across the inclusive sample of 60 subjects. AMPH-induced MCCB changes were significantly (inversely) related to placebo MCCB performance: among individuals with lower placebo scores, AMPH enhanced performance, while among individuals with higher placebo scores, it impaired performance. A potential impact of regression to the mean was assessed, and could not be ruled out. Both placebo MCCB performance and AMPH effects on MCCB scores were significantly related to personality domains associated with schizophrenia-linked genetic- and/or neurophysiological substrates. Conclusions Among healthy adults, AMPH effects on MCCB performance were detected only among specific subgroups, and in specific cognitive domains. Strategies that utilize drug-induced changes in MCCB performance in healthy subjects to screen for candidate procognitive drugs should consider the use of “enriched” subgroups with specific neurocognitive or personality characteristics.