Interactions of alcohol and the benzodiazepine inverse agonist in healthy male volunteers

Abstract

Background:

There is growing interest in developing pharmacological agents to reverse alcohol (ethanol) intoxication, akin to naloxone for opioids. GABAergic modulation offers a potential pathway for reversing alcohol effects, specifically by targeting extrasynaptic GABA-A receptors with a benzodiazepine partial inverse agonist. We tested the hypothesis that iomazenil, a benzodiazepine partial inverse agonist, can counteract alcohol intoxication.

Methods:

In a randomized, double-blind, placebo-controlled, within-subject design, healthy male volunteers (n = 33) were administered intravenous alcohol (ethanol) or placebo, followed by intravenous iomazenil or placebo. Biphasic Alcohol Affects Scale, which assesses the stimulant and sedative effects of alcohol, was used as the primary outcome measure. For secondary measures, the Visual Analog Scale was used to assess “high,” “drowsiness,” “Buzzed,” and “anxiety.” In addition, all subjects were asked to rate the number of standard alcohol drinks they believed had been administered.

Results:

Alcohol produced greater sedation and stimulation when compared to placebo. Iomazenil produced the expected effect of increased anxiety compared to the placebo. However, Iomazenil did not attenuate the sedative or stimulatory effects of alcohol intoxication. Similarly, iomazenil did not significantly change feelings of “High,” “Drowsy,” “Anxious,” or “Buzzed” produced by alcohol.

Conclusions:

Although GABA-A receptors are thought to mediate the subjective effects associated with ethanol intoxication, this study failed to demonstrate a significant attenuation of ethanol intoxication by the benzodiazepine partial inverse agonist, iomazenil. This study raises questions as to the role of particular GABA-A receptor subtypes in ethanol intoxication and the extent to which GABA-A receptor subtype function must be reduced to attenuate human ethanol intoxication.