Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

The joint NIDA-NIAAA CPN Section is focused on understanding the role of the gut-liver-brain axis and other peripheral-central mechanisms underlying addiction and their potential as novel pharmacotherapeutic targets. Growing evidence suggest that blocking the ghrelin receptor (GHSR) may represent a novel pharmacotherapeutic approach for alcohol use disorder (AUD). In a set of experiments, we tested the effects of six GHSR blockers on alcohol binge-like drinking in male and female mice. Systemic administration of JMV2959, PF-5190457, PF-6870961, and HM-04 reduced alcohol intake in both male and female mice; YIL-781 decreased intake in males, but LEAP2 (a recently discovered endogenous ghrelin antagonist) did not reduce intake in mice of either sex. We also administered LEAP2 and JMV2959 intracerebroventricularly and found that central administration of both compounds decreased alcohol intake, particularly in high-drinking animals (Richardson et al., Neuropharmacology 2023). In a Phase 1b clinical trial, we previously showed that the GHSR blocker PF-5190457, co-administered with alcohol, is safe, tolerable, and does not influence alcohol pharmacokinetics (Lee et al., Mol Psychiatry 2020). As the next step, we completed a Phase 2a clinical trial in individuals with AUD to assess the efficacy of PF-5190457 in reducing cue-induced alcohol craving and its potential impact on food craving/choices and brain fMRI measures (Faulkner et al., in preparation). Studies suggest that suppressing the ghrelin system by inhibiting Ghrelin-O-Acyl-Transferase (GOAT), the enzyme responsible for ghrelin acylation/activation, may also reduce alcohol intake. Therefore, to target the ghrelin system from a different angel, we are conducting another clinical trial to test the safety and efficacy of GLWL-01, a GOAT inhibitor, in non-treatment-seeking individuals with AUD (recruitment ongoing). There has been growing interested in the role of the GLP-1 system in addictive behaviors and its potential as a pharmacotherapeutic target, especially given that GLP-1 analogues are already FDA-approved and used in clinical practice for type 2 diabetes mellitus and obesity. We performed a set of analyses to shed light on the bidirectional link between alcohol use and the GLP-1 system in humans, and found that A) genetic variants on the GLP-1R gene, that result in amino-acid substitutions and putative changes in the GLP-1R, were differentially associated with within-network brain functional connectivity among individuals with high versus low severity of alcohol use; B) alcohol intake, with different doses and routes of administration, reduced peripheral GLP-1 levels in heavy-drinking individuals with AUD; and C) GLP-1R gene expression in postmortem brain tissues was higher in individuals with a history of AUD, compared to controls, specifically in the hippocampus and prefrontal cortex (Farokhnia, Fede et al., Sci Rep 2022; Farokhnia et al., Addict Biol 2022). On the behavioral pharmacology side, we previously showed that two long-acting GLP-1 analogues, namely liraglutide and semaglutide, suppressed voluntary alcohol intake in male Wistar rats; semaglutide also reduced alcohol preference without influencing water intake (Marty, Farokhnia, et al., Front Neurosci 2020). Subsequently, we conducted a comprehensive set of behavioral and electrophysiological experiments with semaglutide and found that A) semaglutide dose-dependently reduced binge-like alcohol drinking in male and female mice, with a similar effect on the intake of other caloric/noncaloric solutions; B) semaglutide reduced binge-like and dependence-induced alcohol drinking in male and female rats; and C) semaglutide increased sIPSCs frequency in the central amygdala and infralimbic cortex neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats (Chuong, Farokhnia, Khom, et al., JCI Insight 2023). Collectively, these data, along with anecdotal reports from individuals taking semaglutide for other indications, provide support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD. We have obtained approval from the NIH IRB to start a clinical trial testing the safety and efficacy of semaglutide in individuals AUD. This is a 20-week, outpatient, randomized, between-subject, double-blind, placebo-controlled trial with weekly subcutaneous injections of semaglutide up to 2.4 mg/week. Outcomes include real-world safety (e.g., number of adverse events) and efficacy (e.g., number of drinks per weeks) measures, as well as experimental medicine procedures (e.g., cue-reactivity, brain fMRI). Fibroblast growth factor 21 (FGF21) is a peptide hormone, mainly produced by the liver, and involved in energy homeostasis and lipid/glucose metabolism. Increasing evidence suggest that FGF21 signaling modulates alcohol intake and plays a protective role against alcohol-induced liver injury (Wang et al., Cell Rep Med 2022). To better understand the crosstalk between alcohol intake and FGF21, we measured serum FGF21 concentrations in AUD individuals who underwent alcohol cue-reactivity, priming, and self-administration in a bar-like laboratory. A robust increase in serum FGF21 concentrations was found after alcohol self-administration and percent change in FGF21 levels positively correlated with the amount of alcohol self-administered (Farokhnia et al., Drug Alcohol Depend 2023). FGF21 analogues have shown promise in preclinical models and may represent a novel pharmacotherapeutic approach for AUD and alcohol-associated liver disease. We have also continued our work on non-pharmacological elements of the gut-brain axis in relation to alcohol use, including a completed clinical protocol on gut microbiome/metabolome in AUD (Piacentino, Vizioli et al., in preparation) and a survey study on the role and correlates of bariatric surgery in alcohol and other substance use (Speed et al., in preparation). As a key peripheral-central neuroendocrine pathway, growing evidence suggest that the aldosterone/mineralocorticoid receptor (MR) system is involved in alcohol seeking and consumption and might be a potential pharmacotherapeutic target for AUD. In a series of rodent experiments, we studied the effects of the prototypic MR antagonist spironolactone and found that spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice, without influencing drinking of a non-alcohol-containing sweet solution, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. In addition, spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. We also conducted two propensity score-matched pharmacoepidemiologic studies, using electronic health records from Kaiser Permanente North California and the US Department of Veterans Affairs (VA), and found that spironolactone prescription for other indications was associated with reductions in alcohol use (Palzes et al., Neuropsychopharmacology 2021; Farokhnia, Rentsch, Chuong, McGinn et al., Mol Psychiatry 2022). Based on these data, we started a randomized, double-blind, placebo-controlled, ascending dose, Phase 1b study with spironolactone in individuals with AUD (recruitment ongoing). The primary objective of this study is to examine safety/tolerability and pharmacokinetic/pharmacodynamic properties of spironolactone, co-administered with alcohol, and to build the foundation for a phase 2 clinical trial.