The results of a recently completed study demonstrated that postmenopausal women were more sensitive to triazolam-induced psychomotor performance impairment when progesterone was administered concomitantly. That clinical evidence agrees with the emerging in vitro information regarding the rapid membrane effects of a progesterone metabolite that positively modulates the [small gamma, Greek]-aminobutyric acid-A-benzodiazepine receptor complex. The objective of this study in premenopausal women was to determine whether the response to a benzodiazepine is altered when endogenous progesterone concentrations are high (luteal phases of a menstrual cycle) compared with when progesterone concentrations are low (follicular phases of a menstrual cycle). The pharmacokinetics and pharmacodynamics of oral alprazolam were evaluated in twelve healthy, normally menstruating women who were not receiving oral contraceptive agents. On two separate occasions, once during each phase of the menstrual cycle, the women randomly received an oral alprazolam 2-mg dose. Blood samples were collected, and psychomotor performance tests were conducted at selected times before and after dosing. These data show that fluctuations of endogenous progesterone across the menstrual cycle do not influence alprazolam pharmacodynamics. Despite endogenous progesterone concentrations being significantly higher during the midluteal than during the midfollicular drug administrations, no differences were observed in either the digit-symbol substitution test, card sorting by suit, or sedation scores on these two occasions. No pharmacokinetic differences were observed between the two menstrual cycle-phase drug administrations. In conclusion, the lack of changes during the menstrual cycle in demonstrable cognitive impairment and pharmacokinetics after alprazolam administration is reassuring. This implies that a dose adjustment made on the basis of menstrual timing is not required. (J Clin Psychopharmacol 1999;19:233-239)