Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers.