THE INTERACTIONS OF MIDAZOLAM AND FLUMAZENIL ON HUMAN-MEMORY AND COGNITION

Background. Previous research has been unable to show unequivocally wh ether flumazenil can reverse completely, partially, or not at all the memory effects of benzodiazepines. The effects of midazolam on implici t memory are also unknown. The behavioral effects of flumazenil by its elf, and the acute reversal of benzodiazepine effects, are also contro versial. The current study was designed to investigate these questions . Methods. Using a prospective randomized, double-blind crossover stud y design, memory was assessed using both direct (free recall and recog nition) and indirect (word completion) measures. Other cognitive effec ts were assessed using the digit symbol substitution task. Sedation an d other mood effects were assessed using subjective rating scales. Sev enty-two healthy subjects were assigned to three equal groups accordin g to the dose of midazolam received (0, 0.05, and 0.1 mg/kg). Each sub ject received varying doses of flumazenil (0, 1, and 3 mg) in three se ssions, at least 1 week apart. After baseline administration of the ta sks, midazolam was administered. The assessments were repeated 20 min later, followed by administration of flumazenil. The assessments were repeated 5 and 30 min after administration of flumazenil. After a 2-h recovery period, delayed memory tests were given. Results. Both doses of midazolam decreased all scores in the memory and digit symbol subst itution tests and mood ratings. Flumazenil reversed both the sedative and the memory effects of the benzodiazepine. The reversal was as comp lete with the 1-mg dose of flumazenil as with the 3-mg dose. Flumazeni l by itself, and the acute reversal of midazolam effects, caused no si gnificant behavioral reactions. Conclusions. Midazolam impairs explici t and implicit memory. Flumazenil reverses both the sedative and memor y effects of the drug. Flumazenil, in the doses used, has no intrinsic actions.