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

IF 5.5 3区 医学 Q1 CLINICAL NEUROLOGY
Journal of Psychopharmacology Pub Date : 2025-07-01 Epub Date: 2025-07-17 DOI:10.1177/02698811251330746
Nirmal Singh, Ismene Petrakis, Brian Pittman, Christina Luddy, John H Krystal, Deepak Cyril DSouza
{"title":"Interactions of alcohol and the benzodiazepine inverse agonist in healthy male volunteers.","authors":"Nirmal Singh, Ismene Petrakis, Brian Pittman, Christina Luddy, John H Krystal, Deepak Cyril DSouza","doi":"10.1177/02698811251330746","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>In a randomized, double-blind, placebo-controlled, within-subject design, healthy male volunteers (<i>n</i> = 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":"39 7","pages":"715-725"},"PeriodicalIF":5.5000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/02698811251330746","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/17 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

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.

健康男性志愿者中酒精与苯二氮卓类反激动剂的相互作用
背景:人们对开发药物逆转酒精(乙醇)中毒越来越感兴趣,类似于纳洛酮用于阿片类药物。gaba能调节提供了一种逆转酒精效应的潜在途径,特别是通过苯二氮卓类部分逆激动剂靶向突触外GABA-A受体。我们检验了一种苯二氮卓类药物部分逆激动剂iomazenil可以对抗酒精中毒的假设。方法:在随机、双盲、安慰剂对照、受试者内设计中,健康男性志愿者(n = 33)被静脉注射酒精(乙醇)或安慰剂,随后静脉注射碘马西尼或安慰剂。双相酒精影响量表,评估酒精的兴奋和镇静作用,被用作主要结果测量。对于二级测量,视觉模拟量表用于评估“高”,“嗜睡”,“嗡嗡”和“焦虑”。此外,所有受试者都被要求对他们认为饮用的标准酒精饮料的数量进行评级。结果:与安慰剂相比,酒精产生更大的镇静和刺激作用。与安慰剂相比,Iomazenil产生了预期的焦虑增加的效果。然而,Iomazenil并没有减弱酒精中毒的镇静或刺激作用。同样,iomazenil并没有显著改变酒精产生的“兴奋”、“昏昏欲睡”、“焦虑”或“兴奋”的感觉。结论:尽管GABA-A受体被认为介导与乙醇中毒相关的主观效应,但本研究未能证明苯二氮卓类药物部分逆激动剂iomazenil对乙醇中毒的显著衰减。本研究提出了关于特定GABA-A受体亚型在乙醇中毒中的作用以及GABA-A受体亚型功能必须降低到何种程度以减轻人类乙醇中毒的问题。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Psychopharmacology
Journal of Psychopharmacology 医学-精神病学
CiteScore
8.60
自引率
4.90%
发文量
126
审稿时长
3-8 weeks
期刊介绍: The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信