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ABSTRACT: Previous modeling of the kinetics of uptake and elimination of anesthetic drugs from the site of action has used measures derived from the electroencephalogram. Such measures lag the current brain activity because of the time needed to acquire a signal sample and derive the measure. With a direct measure of anesthetic activity, we could model brain uptake more exactly. In volunteers, using a double-blind single-session design, we made repeated measurements using a well-known psychomotor test, the 2 target tapping test, during the washin and washout of 30% nitrous oxide. We also assessed maximal drug effect with a test of cognitive function, the digit symbol substitution test. Concentration at the site of action was modeled from end-tidal measurements, using a simple exponential washin and washout function, with half-times between 0.5 and 3 minutes. Comparisons were made within subjects, using 0 and 5% nitrous oxide. We studied 20 subjects. Nitrous oxide, at 30%, consistently reduced performance of the digit symbol substitution test. Tapping frequency was also reduced, but the effect was less consistent, and only 9 of 20 subjects showed a significant individual reduction in tapping frequency. In these subjects, the relationship between the modeled brain concentration and drug effect was better with a half-time set at 2 minutes, compared with 1.5 or 3 minutes. Given in subanesthetic concentrations, nitrous oxide has rapid onset and offset, consistent with a half-time of 2 minutes. This value is less than the values expected from studies during anesthesia using processed electroencephalogram, but consistent with measures of blood flow to active cerebral tissue in conscious subjects. Studies of performance in conscious subjects may aid further studies of anesthetic kinetics.