Impairment of memory and plasma flunitrazepam levels

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males with similar levels of education were given placebo or flunitrazepam (1, 2 or 4 mg) in a double-blind, random-sequence study. Volunteers completed a battery of tests at night, 3.5 h after taking the drug and in the morning, 10 h afterward. Blood samples were collected for drug analysis before and after the nocturnal tests and before morning tests. At night, only the highest dose of flunitrazepam (4 mg) induced significant changes in psychomotor sedation, attention, working memory, and prose immediate recall. Doses of 2 and 4 mg flunitrazepam significantly reduced the mean scores of explicit memory (morning tests). Z-scores, calculated from differences between flunitrazepam and placebo, revealed that 2 mg flunitrazepam impaired memory but not alertness or attention. Linear regression analysis of the relationship between plasma levels of flunitrazepam and its effects (Z-scores) indicated that there was a significant positive correlation between peak levels of flunitrazepam at night and impairment of night attention and explicit memory, i.e. delayed recall of prose (r = 0.59, P < 0.01) and trigrams (r = 0.55, P < 0.81). However, memory and attention Z-scores as a function of plasma levels fitted with nonlinear regression analysis to the E-max model had higher correlation coefficients. To produce an effect equal to 50% of the maximum effect for memory impairment, concentrations (EC50) were 6.1 and 6.4 ng/ml for prose and trigrams delayed recall; but for attention they were much higher, at 13.2 ng/ml. The overall results indicate that higher concentrations were needed to impair attention than were required to impair memory.