Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

The joint NIDA-NIAAA CPN Section conducts translational and clinical sudies to identify possible novel medications for addiction. We are particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors and its potential role as a therapeutic target for drug addiction. Evidence from preclinical and clinical studies suggest that the ghrelin system, might represent a novel pharmacological target for AUD treatment. To test whether GHS-R1a antagonism may represent a pharmacotherapy for AUD, we developed a translational project to assess the effect of a GHS-R1a antagonist manufactured by Pfizer. First, a Phase 1b clinical study (14-AA-0042) was completed and published, indicating that this GHS-R1a inverse agonist is safe and tolerable, when co-administered with alcohol and does not affect alcohol PK (Lee et al., Mol Psychiatry 2020). By using a reverse translational bed-to-bench approach, we also discovered a major metabolite of this novel compound (Adusumalli et al., Drug Metab Dispos. 2019) and additional work on this metabolite is ongoing. Based on these findings, we moved to the next phase of the project and completed a Phase 2a clinical study (16-AA-0080) to assess the efficacy of this novel GHS-R1a inverse agonist in reducing alcohol craving and its potential effects on food craving/choices in treatment-seeking patients with AUD. This study was completed, and data analysis is ongoing. In addition, we recently started another clinical protocol to test the safety and efficacy of a Ghrelin-O-Acyl-Transferase (GOAT) inhibitor in non-treatment-seeking individuals with AUD (19-DA-N075). Recruitment for this protocol has begun and is undergoing. We are continuing work on the effects of IV ghrelin on a variety of behavioral and neuroendocrine outcomes in AUD individuals. We recently completed a comprehensive neuroendocrine analysis of our IV ghrelin study conducted the the NIH IRP (see Farokhnia et al., Mol Psychiatry 2018), showing that IV ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1 (GLP-1), pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session (Farokhnia et al., Int J Neuropsychopharmacol 2021). We also evaluated the effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals. Results found profound anti-inflammatory effects for IV ghrelin, but no effects for ghrelin receptor blockade (Farokhnia et al., Brain Research 2020). Consistent with our increasing interest in the crosstalk between alcohol use and inflammatory pathways, we also investigated the effect of acute alcohol consumption on plasma cytokine concentrations in heavy-drinking individuals, using data from our human laboratory studies, and found that oral alcohol administration reduced TNF- concentrations and increased IL-6 concentrations (Lee & Abshire et al., Drug Alcohol Depend 2021). Given that the ghrelin system is being studied as a potential pharmacotherapeutic target for AUD, it is also important to understand the effects of alcohol in the endogenous ghrelin system. To do so, we conducted a series of clinical and preclinical experiments showing that alcohol administration reduces blood concentration of acyl- and total-ghrelin levels, but this reduction is not dependent on the ghrelin receptor, GOAT enzyme activity, or acyl-ghrelin secretion from the gastric mucosa. We also found that having a diagnosis of AUD, compared to controls, does not influence central expression of the ghrelin system genes in post-mortem tissue (Deschaine & Farokhnia at al., Addict Biol 2021). In another population-based study, in collaboration with NCI, we found higher total ghrelin levels among individuals who drank alcohol than those who did not, but no significant association between the quantity of daily alcohol intake and blood ghrelin concentrations (Farokhnia et al., Drug Alcohol Depend 2021). In addition to the ghrelin system, we have started to investigate other gut-brain neuroendocrine pathway in relation to alcohol use and addictive behaviors in general. Following up on some early work from our group showing that the GLP-1 system is involved in alcohol seeking behaviors (see Suchankova et al., Transl Psychiatry 2015), in collaboration with UCLA, we examined the effects of long-acting GLP-1 analogues and found that both semaglutide and liraglutide suppressed voluntary alcohol intake in male Wistar rats, with semaglutide having more specific and robust effects (Marty & Farokhnia et al., Front Neurosci 2020). We are continuing this line of work with testing different doses of semaglutide in a preclinical model of alcohol binge drinking (drinking in the dark) as well as alcohol dependence (vapor exposure), plus some electrophysiology work in collaboration with Scripps Research Institute to understand the effects semaglutide on GABA transmission in the central amygdala and infralimbic cortex of nave and alcohol-dependent rodents (Chuong & Farokhnia et al., in preparation). In a series of secondary analyses, we have also found that alcohol administration leads to reduction in peripheral GLP-1 levels in heavy drinking individuals and chronic exposure to alcohol, operationalized as an AUD diagnosis, is associated with increased GLP-1R gene expression in the hippocampus and PFC (Farokhnia et al., in preparation). Finally, in collaboration with Reza Momenan lab at NIAAA, we conducted an imaging-genetics study showing the genetic variation at the GLP-1R is differentially associated with brain functional connectivity, mainly in the salience and default mode networks, in individuals with low versus high severity of alcohol use (Farokhnia & Fede et al., in preparation). A clinical protocol to test the safety and efficacy of semaglutide as a treatment for alcohol and nicotine co-use in under development. Following up on our early translational work showing that the aldosterone-mineralocorticoid receptor (MR) is involved in alcohol drinking and related outcomes across three species (Aoun et al., Mol Psychiatry 2018), we have started to investigate this neuroendocrine system as a potential pharmacotherapeutic target for AUD. In collaboration with Kaiser Permanente North California, we conducted a retrospective high-dimensional propensity score-matched cohort study showing that dispensation of spironolactone (an MR antagonist) was associated with significant reduction in weekly alcohol use. Individuals with high severity of alcohol use at baseline showed greater reduction in alcohol use and a significant dose-response was also found (Palzes et al., Neuropsychopharmacology 2021). We have replicated these pharmacoepidemiology findings in a larger dataset in collaboration with Yale/VA and have generated preclinical data showing that spironolactone reduces alcohol drinking in both mice and rats (Farokhnia, Rentsch, Chuong, McGinn et al., in preparation). Based on these promising results, we have started to conceptualize/design a clinical protocol testing MR antagonism as a potential pharmacotherapeutic approach for AUD. We have also continued our work on the role of gut microbiome in AUD. Our clinical protocol in this regard (17-AA-0093) was completed and data analysis is ongoing. In parallel, in collaboration with Dr. Weerts (JHU) and Dr. Fraser (UMB), we conducted a study investigating the gut microbiome and metabolomics in a baboon model of binge-drinking and found that chronic excessive drinking was associated with gut dysbiosis and changes in microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose (Piacentino et al., Transl Psychiatry 2021).