INTERACTIVE EFFECTS OF SUBANESTHETIC KETAMINE AND SUBHYPNOTIC LORAZEPAM IN HUMANS

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with ps ychotogenic and dissociative effects in healthy humans. These cognitiv e and perceptual effects in humans are reportedly reduced by benzodiaz epine premedication. This study assessed the interactive effects of a ketamine (IV bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy su bjects completed 4 test days involving the oral administration of lora zepam or matched placebo 2h prior to the IV infusion of ketamine or pl acebo. Ketamine: I) produced behaviors similar to the positive and neg ative symptoms of schizophrenia as assessed by the Brief Psychiatric R ating Scale (BPRS); 2) evoked perceptual alterations as measured by th e Clinician-Administered Dissociative States Scale (CADSS); 3) impaire d performance on the Wisconsin Card Sorting Test (WCST) and other test s sensitive to frontal cortical impairment; and 4) had amnestic effect s. Lorazepam produced attention impairments, concrete proverb interpre tations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to de crease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, includin g psychosis. Further, lorazepam exacerbated the sedative, attention-im pairing, and amnestic effects of ketamine. There was no evidence of ph armacokinetic interaction between these medications. These data sugges t that subhypnotic lorazepam and ketamine show a spectrum of interacti ve effects, ranging from antagonism to potentiation.