Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans

To assess the pharmacologic effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short-term effects of diazepam and alprazolam over a range of doses.

This was a placebo, within-subject, randomized, double-blind study conducted in 28 male volunteers. They were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish 150 mg secobarbital from placebo and to report positive subjective effects. Subjects randomly received placebo and the two middle doses of diazepam, bretazenil, and alprazolam for the first 7 days of the study and, depending on their clinical response, received either the highest or the lowest dose of each drug for the remaining 3 days. Pharmacologic effects were assessed by use of objective tests (e.g., psychomotor performance), subject-rated questionnaires (e.g., Profile of Mood States), and observer-rated scales.

All three drugs were clearly distinguishable from placebo on most measures. Diazepam and alprazolam produced dose-related psychomotor and memory impairment, whereas bretazenil produced a flatter slope. Both alprazolam and diazepam produced dose-dependent increases in subject and observer-rated sedation and liking, whereas bretazenil showed increases compared with placebo, but these effects were not dose dependent.

Results from the study supported the view that bretazenil may have a partial agonist pharmacologic profile. Scores on subjective effects scales considered important for abuse liability assessment suggest a lower abuse liability of bretazenil than diazepam and alprazolam.