Faulkner Monica L, Farokhnia Mehdi, Lee Mary R, Farinelli Lisa, Browning Brittney D, Abshire Kelly, Daurio Allison M, Munjal Vikas, Deschaine Sara L, Boukabara Selim R, Fortney Christopher, Sherman Garrick, Schwandt Melanie, Akhlaghi Fatemeh, Momenan Reza, Ross Thomas J, Persky Susan, Leggio Lorenzo
Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
JCI Insight. 2024 Dec 20;9(24):e182331. doi: 10.1172/jci.insight.182331.
BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.
背景
研究已证明胃饥饿素在与酒精相关的行为和饮酒方面所起的作用。生长激素促分泌素受体（GHSR）是胃饥饿素的受体，在多种动物模型中，阻断该受体已显示可减少酒精摄入及与奖赏相关的行为。我们之前开展了一项人体研究，在重度饮酒者中测试GHSR反向激动剂/竞争性拮抗剂PF-5190457，并证明了其与酒精联合使用时的安全性。在此，我们针对酒精使用障碍（AUD）患者开展了一项IIa期实验医学研究，以调查PF-5190457对与酒精和食物相关结果的影响。
方法
42名AUD患者（n = 29名完成者）参与了一项随机、双盲、安慰剂对照研究，他们在2个受试者内平衡阶段接受每日2次100mg的PF-5190457（或安慰剂）。参与者在类似酒吧的实验室中完成了一项酒精线索反应性（CR）实验，并在类似自助餐厅的虚拟现实（VR）环境中完成了一项虚拟食物选择实验。一部分参与者（n = 12）在脑功能磁共振成像（fMRI）实验期间执行了CR任务。
结果
PF-5190457并未减少线索引发的酒精渴望。PF-5190457减少了在VR环境中选择的虚拟卡路里（P = 0.04）。在fMRI实验中，PF-5190457并未影响CR任务期间的神经激活。
结论
本研究提供了人体证据，证明阻断GHSR在与食物选择相关行为中的作用，并强调了未来针对AUD中胃饥饿素系统进行研究的必要性。
试验注册
ClinicalTrials.gov（注册号NCT02707055）。
资助
美国国立药物滥用研究所和美国国立酒精滥用与酒精中毒研究所ZIA-DA000635；美国国立转化医学推进中心UH2/UH3-TR000963。
