A placebo controlled study was carried out to examine the dose-response relationships for diazepam (5, 10 and 20 mg) on human performance in tests which examine aspects of the driving task, when givenalone and in combination with a "social" dose of alcohol (0.75 g/kg) and to investigate the relationship between psychomotor impairment and the concentrations of diazepam and alcohol in the blood. Blood samples (to establish pharmacokinetic parameters) were taken at regular intervals across the 300 minute sessions and psychomotor testing (to determine pharmacodynamic parameters) was carried out at the completion of each sample collection. The pharmacokinetic parameters for diazepam established in this study agree with previous findings. Alcohol was found to significantly modify the metabolism of diazepamby reducing its conversion to the less active, N-desmethyldiazepam, thus increasing the net effect of the drug. Impairment was not found for the lowest dose of diazepam (5 mg), although impairment was reliably encountered with higher doses (10 and 20 mg) and with all doses of diazepam combined with alcohol. Alcohol taken concomitantly with diazepam caused greater and longer-lasting psychomotor impairment than the same dose of diazepam was taken alone. The combined effects of alcohol and diazepam were additive. Onset/offset phase analysis, correlation analysis and hysteresis plots confirmed the complexity of the relationship between plasma diazepam concentration and objective and subjective measures of impairment. Examination of receptor-bound diazepam concentrations may reduce this complexity. Subjects reported a reduction in sedation, cognition, coordination and willingness to drive after taking diazepam alone and in combination with alcohol. Strong evidence for rebound impairment was found, which has important social implications and requires further investigation. (A)
Abstract