Among subjects participating in 14 placebo-controlled drug cross-over studies, left-handers showed a greater drug-related change in their electroencephalograms (EEGs) than did right-handers. Response differences between left- and right-handers were not hemisphere-specific. Further, the magnitude of EEG changes correlated with handedness scores. A greater effect of centrally active substances in left-handers may, in part, explain the high incidence of left-handers among those with certain brain-related pathologies and the evolution of right-hander predominance in the general population.