Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

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The joint NIDA-NIAAA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical inpatient and outpatient studies to identify possible novel medications for addiction. Under the leadership of Lorenzo Leggio, M.D., Ph.D., the CPN team is particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors. Both preclinical and human approaches are in progress or under development to shed light on the possible role of the gut-liver-brain axis in alcohol and substance use disorders. Evidence from preclinical and clinical studies suggest that the ghrelin system, might represent a novel pharmacological target for treatment (reviewed in: Zallar et al. 2017; Morris et al., 2018; Farokhnia et al., 2019). Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use has never been tested in humans. To test this hypothesis, the CPN Section developed a translational project to assess the role of a GHS-R1a antagonist manufactured by Pfizer as a novel medication for AUD. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. First, a Phase 1b clinical study (protocol 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. Very preliminary results also suggested that this compound reduces alcohol- and food-cue induced cravings in our bar-lab (Lee et al., Molecular Psychiatry 2020). A secondary analysis from the same study also indicates that this novel compound is safe on endocrine-related outcomes and its effects on some hormone levels suggest potential mechanisms requiring further investigation (Lee et al., Neuropharmacology 2020). Furthermore, by using a reverse translational bed-to-bench approach, we 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 promising findings, we moved to the next phase of the project and completed a Phase 2a clinical study (protocol 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. We are continuing work on the effects of IV ghrelin on a variety of behavioral and neuroendocrine outcomes in AUD individuals. Consistent with the complex interplay between ghrelin, addiction and the HPA axis (which we reviewed in Morris et al., 2018), we reported that, compared to placebo, IV ghrelin leads to an increase in cortisol and aldosterone blood levels (Haass-Koffler et al., Neuropharmacology 2019). Furthermore, we recently completed a comprehensive neuroendocrine analysis of our IV ghrelin study conducted the the NIH IRP (see Farokhnia et al., Molecular Psychiatr 2018), showing that IV ghrelin, compared to placebo, increased blood levels of glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), cortisol, prolactin, and aldosterone, and decreased blood levels of leptin and insulin in heavy drinking individuals with alcohol dependence who also received IV alcohol (Farokhnia et al., under review). Considering the well-established interplay between the ghrelin system and inflammatory pathways, as well as the role of the neuroimmune system in AUD, 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 effects for ghrelin receptor blockade, confirming the safety of the GHS-R1a inverse agonist compound (Farokhnia et al., Brain Research 2020). Consistent with our increasing interest in the crosstalk between alcohol use and inflammatory pathways, we also acquired and analyzed samples from two previously conducted studies in AUD patients and healthy controls, and found that peripheral proinflammatory markers are upregulated in abstinent alcohol-dependent patients but are not affected by cognitive bias modification (Portelli et al., Drug and Alcohol Dependence 2019). We have also continued our work on oxytocin as another endocrine target involved in addictive behaviors. In collaboration with Dr. Tanda (NIDA IRP MDP), we recently completed a study on the effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels (Lee et al., Ann N Y Acad Sci. 2019). In another study, we recently showed, in collaboration with Dr. Kathleen Grant (OHSU), that labeled oxytocin, administered via the intranasal route, reaches the brain in rhesus macaques (Lee et al., Nature Communications 2020). Expanding our work on neuroendocrine correlates of alcohol use, we also conducted, in collaboration with Dr. Dorit Ron (UCSF), a translational study in rats and humans, looking at brain-derived neurotrophic factor (BDNF) in relation to alcohol use. We found that serum BDNF levels are negatively correlated with alcohol intake in both rats with rapid and late onset of heavy alcohol, but increased expression of the micro RNAs targeting BDNF was detected only in the rapid onset rats (Ehinger et al., Addiction Biology 2020). We also found that, among non-treatment-seeking individuals with alcohol dependence and high trait anxiety, serum BDNF concentrations were negatively correlated with average drinks per drinking days and positively correlated with obsessive compulsive drinking scale and state-trait anxiety inventory scores (Portelli, Farokhnia, et al., Alcohol 2020). We have also expanded our focus on psychoneuroendocrinology to other drugs of abuse beyond alcohol. In addition to our previous work on neuroendocrine effects of IV cocaine (Bouhlal et al., Drug and Alcohol Dependence 2017), we recently looked at the effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism. In collaboration with Dr. Marilyn Huestis (NIDA IRP), we found that cannabis administration significantly reduced blood insulin and GLP-1 concentrations (Farokhnia et al., Translational Psychiatry 2020). Finally, in collaboration with Dr. Kim Janda (TSRI), and using a ghrelin vaccine and a GHS-R1a antagonist, we showed that the influence of the ghrelin receptor on cocaine reward is not directly dependent on peripheral acyl-ghrelin (Wenthur et al., Scientific Reports 2019). Increasing evidence suggests a role of the gut microbiota in neuropsychiatric disorders. A systematic review conducted by our team (Temko et al., Alcohol and Alcoholism 2017) indicates that the understanding of the role of the gut microbiota in AUD is very limited and deserves additional investigation. Therefore, the CPN lab developed a translational and clinical project to investigate the role of the gut microbiota in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. This clinical study (17-AA-0093) was completed and data analysis is ongoing. In parallel, we are conducting a study investigating the gut microbiome and metabolomics in a baboon model of binge-drinking -- a model developed by Dr. Elise Weerts at JHU. This project is in fact in collaboration with Dr. Weerts (JHU) and Dr. Fraser (UMB) and analyses are under way.