IMPAIRMENT OF MEMORY AND PLASMA FLUNITRAZEPAM LEVELS

Flunitrazepam was administered to volunteers in three different oral d oses. The effects on psychomotor sedation, attention, working memory a nd explicit memory were then assessed at various intervals after dosin g and compared with levels of the drug in the plasma. Three groups of 12 healthy males with similar levels of education were given placebo o r flunitrazepam (1, 2 or 4 mg) in a double-blind, random-sequence stud y. Volunteers completed a battery of tests at night, 3.5 h after takin g the drug and in the morning, 10 h afterward. Blood samples were coll ected for drug analysis before and after the nocturnal tests and befor e morning tests. At night, only the highest dose of flunitrazepam (4 m g) induced significant changes in psychomotor sedation, attention, wor king memory, and prose immediate recall. Doses of 2 and 4 mg flunitraz epam significantly reduced the mean scores of explicit memory (morning tests). Z-scores, calculated from differences between flunitrazepam a nd placebo, revealed that 2 mg flunitrazepam impaired memory but not a lertness or attention. Linear regression analysis of the relationship between plasma levels of flunitrazepam and its effects (Z-scores) indi cated that there was a significant positive correlation between peak l evels 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 analy sis to the E-max model had higher correlation coefficients. To produce an effect equal to 50% of the maximum effect for memory impairment, c oncentrations (EC50) were 6.1 and 6.4 ng/ml for prose and trigrams del ayed recall; but for attention they were much higher, at 13.2 ng/ml. T he overall results indicate that higher concentrations were needed to impair attention than were required to impair memory.