The time course of diphenhydramine concentrations and effects on both mental performance and subjective feelings of drowsiness were assessed in 15 healthy men. Subjects received single oral doses of diphenhydramine, 50 mg, and placebo in this double-blind crossover study. Diphenhydramine plasma concentrations and central nervous system actions were assessed for 24 hours after each treatment. Cognitive impairment was assessed with an automobile driving simulator and digit symbol substitution scores, whereas drowsiness was self-assessed on a visual analog scale. Diphenhydramine produced significant feelings of drowsiness for up to 6 hours after the dose, whereas significant mental impairment was apparent for only 2 hours. Despite the difference in duration of these effects, drowsiness and mental impairment have parallel slopes when effects are related to diphenhydramine concentrations. These data suggest that although the apparent diphenhydramine concentration thresholds to produce drowsiness are lower (30.4 to 41.5 ng/ml) than those needed to produce mental impairment (58.2 to 74.4 ng/ml), these effects have profiles consistent with their being manifestations of the same pharmacologic effect.

Twelve healthy subjects with atopy received single doses of hydroxyzine, 25 mg, its metabolite cetirizine, 10 and 20 mg, and placebo in a four-way crossover study randomized by Latin square design. Skin wheal response to histamine, psychomotor effects, and serum concentrations of each drug were measured for 36 hours after each dose. Central nervous system (CNS) effects were measured with critical flicker frequency, Stroop word testing, and visual analog scales. All three active treatments (cetirizine, 10 mg, cetirizine, 20 mg, and hydroxyzine) produced an equivalent suppression of skin wheal response to histamine that was significantly greater than placebo (P less than 0.01). Hydroxyzine produced a significant change compared with placebo in all three CNS parameters. Neither cetirizine, 10 mg, nor cetirizine, 20 mg, produced any significant change in CNS parameters. Both the intensity and time course of CNS effects were related significantly (P less than 0.05) to hydroxyzine concentrations. The CNS changes measured after oral hydroxyzine are the result of the parent drug, whereas its metabolite cetirizine when administered alone produced significant antihistaminic effects without CNS changes.