Abstract
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.