Based on previous animal work, the present study investigated whether individual differences in motor activity in a novel environment predicted reinforcing and behaviorally activating effects of D-amphetamine (0, 5, 10 and 20 mg p.o.) in healthy adults. When exposed to a novel environment, 18 participants had high levels of motor activity (high responders; HR) and six had low levels (low responders; LR). These group differences were used to predict effects of D-amphetamine on drug reinforcement, salivary cortisol, motor activity, subjective effects, and acoustic startle reflex in subsequent sessions. Unlike observations in rodents, (1). dose-dependent reinforcing effects of D-amphetamine were evident but without group differences; (2). motor activity was greater in HR but did not vary with D-amphetamine dose; and (3). cortisol levels were not related to the reinforcing effects of D-amphetamine. Startle reflex amplitudes were greater in HR following placebo, but D-amphetamine 20 mg equalized this group difference. There was a trend towards less prepulse inhibition of the acoustic startle reflex in HR compared to LR. LR reported greater overall negative effect following amphetamine administration, but this was not consistently related to dose. Finally, participants with high sensation-seeking personality scores exhibited less prepulse inhibition. The results are discussed in terms of the extant literature.