Randomized Crossover Trial to Compare Abuse Liability of Intravenous Remimazolam Versus Intravenous Midazolam and Placebo in Recreational Central Nervous System Depressant Users

Remimazolam (RMZ) is a new and ultra‐fast‐acting, short‐duration intravenous benzodiazepine, a drug class associated with abuse potential. This trial was designed to compare the abuse potential of remimazolam with placebo and midazolam (MDZ), a well‐characterized member of the same pharmacological class in healthy, recreational drug users 18‐55 years‐of‐age, who demonstrated good drug tolerance and were able to discriminate between midazolam and placebo. At equipotent intravenous doses selected to produce effects ranging from mild/moderate to relatively strong sedation without loss of consciousness (RMZ: 5, 10 mg versus MDZ: 2.5, 5 mg), peak scores (E(max) or E(min), respectively) for drug liking, good/bad/any effects, and sedation (drowsiness and relaxation) were significantly greater than placebo for both active drugs and were broadly comparable between RMZ and MDZ. In contrast, areas under the effect‐time curves (TA_AUE) were notably lower for RMZ versus MDZ, particularly for measures of good and any effects, reflecting the shorter duration of action and consistent with the more rapid observed plasma clearance for RMZ versus MDZ and the lack of an active RMZ metabolite. Scores for willingness to take drug again were also lower for RMZ versus MDZ, but not significantly so. We concluded that the abuse potential of RMZ is comparable to or lower than that of MDZ, a drug known to have a low potential for intravenous abuse.