Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal

It is well-documented that benzodiazepine sedative/hypnotics produce robust dose-dependent memory-impairing effects. However, benzodiazepines also induce marked sedation, as reflected in changes in observer and subjective ratings of arousal and impaired psychomotor performance. Thus, it is possible that the observed amnestic effects are secondary to more global sedative effects, and do not reflect a specific, primary, benzodiazepine effect on memory mechanisms. This study was designed to use the non-specific stimulant d-amphetamine to dissociate the sedative and memory-impairing effects of the benzodiazepine triazolam. Across four sessions, 20 healthy adult volunteers received via oral capsule administration placebo, 0.25 mg/70 kg triazolam alone, 20 mg/70 kg d-amphetamine sulfate alone, and triazolam (0.25 mg/ 70 kg) and d-amphetamine (20 mg/70 kg) conjointly, in a double-blind, staggered dosing, cross-over design. d-Amphetamine significantly reversed the effects of triazolam on all participant rating and psychomotor performance-based measures of sedative effects, and selectively reversed the memory-impairing effects of triazolam on some measures (e.g. working memory assessed by a 2-back task, episodic memory assessed by free recall, metamemory), but not others (e.g. working memory assessed by a digit recall task, episodic memory assessed by recognition memory). Results suggest that benzodiazepines do have specific effects on memory that are not merely a by-product of the drugs' sedative effects, and that the degree to which sedative effects contribute to the amnestic effects may vary as a function of the particular memory process being assessed. In addition to enhancing the understanding of the mechanisms underlying benzodiazepine-induced amnesia, these results may also contribute to a better understanding of the complex relationship between specific memory processes and level of arousal.