Publications by authors named "Lorenzo Leggio"

196 Publications

A neuroimaging investigation into the role of peripheral metabolic biomarkers in the anticipation of reward in alcohol use.

Drug Alcohol Depend 2021 Apr 16;221:108638. Epub 2021 Feb 16.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD 20814, USA; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI 02903, USA; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA; Department of Neuroscience, Georgetown University Medical Center, Washington DC 20057, USA. Electronic address:

Background: The relationship between alcohol use and metabolism has focused on the effects of alcohol use on metabolic factors. Metabolic factors, such as triglycerides, cholesterol, and glucose, have been shown to be associated with increased risk for heavy alcohol consumption and alcohol use disorder (AUD). It's been suggested that changes in metabolic factors may play a role in reward seeking behaviors and pathways. Studies on feeding behavior and obesity revealed the role of triglycerides in neural response to food cues in neurocircuitry regulating reward and feeding behaviors. This study aimed to explore the relationship of peripheral metabolism, alcohol use, and reward processing in individuals that use alcohol.

Methods: Ninety participants from a previously collected dataset were included in the analysis. Participants were treatment seeking, detoxified individuals with AUD and healthy individuals without AUD, with the following metabolic biomarkers: triglyceride, glucose, high- and low-density cholesterol, and HbA1c levels. Participants completed a neuroimaging version of the Monetary Incentive Delay task (MID).

Results: Correlations on peripheral metabolic biomarkers, alcohol use, and neural activity during reward anticipation and outcome during the MID task were not significant. Mediation models revealed triglycerides and high-density cholesterol had significant effects on left anterior insula during anticipation of potential monetary loss and this effect was not mediated by alcohol use.

Conclusion: Limbic recruitment by anticipation of monetary rewards revealed an independent relationship with peripheral metabolism and was not affected by individual differences in alcohol use, despite the effects of alcohol use on metabolic markers and reward processing neural circuitry.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108638DOI Listing
April 2021

Cardiovascular Consequences of Excessive Alcohol Drinking via Electrocardiogram: A Systematic Review.

J Addict Nurs 2021 Jan-Mar 01;32(1):39-45

Abstract: There is a link between excessive alcohol drinking and an increased risk to develop cardiovascular disease, including alcoholic cardiomyopathy. This association warrants further research on the potential utility for the electrocardiogram (ECG) in the participatory management of the chronic consequences of alcohol use disorder (AUD). Our goal is to enhance understanding about the pernicious role alcohol plays on cardiac health using the ECG, an accessible, cost-effective, validated tool to inform novel targeted treatments for AUD. In this systematic review of human studies, we examine the relationship between abnormal clinically significant changes to ECG variables and excessive alcohol drinking with the goal of identifying key patterns specific to quantity of alcohol consumed. Three independent reviewers and one consensus reviewer, adhering to the PRISMA guidelines, conducted an initial review on studies published from database inception to April 19, 2019, using PubMed, Embase, CINAHL and COCHRANE databases. The initial search generated 2,225 articles. The final selected number included 153 original articles. This systematic review provides evidence of patterns of clinically significant changes to ECG variables as a consequence of excessive alcohol consumption. Future directions include investigating whether a real-time assessment, such as the ECG, in conjunction with other key behavioral and cardiac measures, can help clinicians and patients realize the progressive and insidious cardiac damage because of excessive alcohol consumption. This theory-guided nurse science review supports the development of personalized symptom monitoring to deliver tailored feedback that illuminate risk factors as a potentially transformative approach in the management of AUD.
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http://dx.doi.org/10.1097/JAN.0000000000000384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927905PMC
March 2021

Addiction as a brain disease revised: why it still matters, and the need for consilience.

Neuropsychopharmacology 2021 Feb 22. Epub 2021 Feb 22.

Department of Population Health Sciences, Unit Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.

The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.
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http://dx.doi.org/10.1038/s41386-020-00950-yDOI Listing
February 2021

New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies.

Expert Opin Pharmacother 2021 Mar 1:1-13. Epub 2021 Mar 1.

Central Clinical School, Sydney School of Medicine, Faculty of Medicine & Health, University of Sydney, NSW, Australia.

: The number of medications approved for AUD is small and they generally have limited efficacy. We need new pharmacotherapies for the management of AUD.: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD.: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and introduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.
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http://dx.doi.org/10.1080/14656566.2021.1892641DOI Listing
March 2021

Sensory cue reactivity: Sensitization in alcohol use disorder and obesity.

Neurosci Biobehav Rev 2021 May 12;124:326-357. Epub 2021 Feb 12.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA; National Institute of Nursing Research, Bethesda, MD, USA. Electronic address:

Neuroimaging techniques to measure the function of the human brain such as electroencephalography (EEG), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), are powerful tools for understanding the underlying neural circuitry associated with alcohol use disorder (AUD) and obesity. The sensory (visual, taste and smell) paradigms used in neuroimaging studies represent an ideal platform to investigate the connection between the different neural circuits subserving the reward/executive control systems in these disorders, which may offer a translational mechanism for novel intervention predictions. Thus, the current review provides an integrated summary of the recent neuroimaging studies that have applied cue-reactivity paradigms and neuromodulation strategies to explore underlying alterations in neural circuitry as well in treatment strategies in AUD and obesity. Finally, we discuss literature on mechanisms associated with increased alcohol sensitivity post-bariatric surgery (BS) which offers guidance for future research to use sensory percepts in elucidating the relation of reward signaling in AUD development post-BS.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.014DOI Listing
May 2021

Neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals: Findings from a randomized, double-blind, placebo-controlled human laboratory study.

Int J Neuropsychopharmacol 2021 Feb 9. Epub 2021 Feb 9.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD.

Background: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder (AUD). Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals.

Methods: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included two experimental alcohol administration paradigms: intravenous alcohol self-administration (IV-ASA) and intravenous alcohol clamp (IV-AC). Each paradigm consisted of two counterbalanced sessions of IV ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), gastric inhibitory peptide (GIP), insulin, insulin-like growth factor-1 (IGF-1), cortisol, prolactin, and aldosterone.

Results: Despite some statistical differences, findings were consistent across the two alcohol administration paradigms: IV ghrelin, compared to placebo, increased blood concentrations of GLP-1, PP, 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 versus placebo session.

Conclusion: These findings, gathered from a clinically relevant sample of heavy-drinking individuals with AUD, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.
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http://dx.doi.org/10.1093/ijnp/pyab004DOI Listing
February 2021

The influence of anxiety symptoms on clinical outcomes during baclofen treatment of alcohol use disorder: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2021 Jan 14;125:296-313. Epub 2021 Jan 14.

Faculty of Medicine, University of Southampton, Southampton, UK. Electronic address:

Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with the GABA receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.
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http://dx.doi.org/10.1016/j.neubiorev.2020.12.030DOI Listing
January 2021

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats.

Front Neurosci 2020 23;14:599646. Epub 2020 Dec 23.

Laboratory of Neuropharmacology, Section of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States.

Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.
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http://dx.doi.org/10.3389/fnins.2020.599646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785877PMC
December 2020

Interventions and Manipulations of Interoception.

Trends Neurosci 2021 01;44(1):52-62

School of Nursing, University of Washington, Seattle, WA, USA; Osher Center for Integrative Medicine, University of Washington, Seattle, WA, USA.

Interoceptive pathways may be manipulated at various levels to develop interventions to improve symptoms in a range of disorders. Primarily through the lens of the respiratory system, we outline various pathways that can be manipulated at neural, behavioral, and psychological levels to change the representation of and attention to interoceptive signals, which can alter interconnected physiological systems and improve functioning and adaptive behavior. Interventions can alter interoception via neuromodulation of the vagus nerve, slow breathing to change respiratory rate and depth, or awareness processes such as mindfulness-based interventions. Aspects of this framework may be applied to other physiological systems and future research may integrate interventions across multiple levels of manipulation or bodily systems.
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http://dx.doi.org/10.1016/j.tins.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805576PMC
January 2021

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs.

Alcohol Alcohol 2020 Dec 15. Epub 2020 Dec 15.

Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 7 Greenhouse Road, Kingston, RI 02881, USA.

Aims: A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions.

Methods: A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted.

Results: Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss).

Conclusions: The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.
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http://dx.doi.org/10.1093/alcalc/agaa129DOI Listing
December 2020

A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.

Clin Pharmacokinet 2021 Apr 5;60(4):471-484. Epub 2020 Nov 5.

Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Office 495 A, Avedisian Hall, 7 Greenhouse Road, Kingston, RI, 02881, USA.

Background And Objectives: The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics.

Methods: Plasma concentration-time data from non-heavy (n = 35) and heavy drinkers (n = 12) were pooled for the population pharmacokinetic model development. The influence of various covariates including alcohol consumption status was evaluated. The accuracy, precision, and robustness of the model were also evaluated using bootstrapping and visual predictive checks.

Results: A two-compartment model best described the pharmacokinetics of PF-5190457. The apparent volume of distribution of 44.5 L, apparent clearance of 72.0 L/h, apparent peripheral volume of distribution of 271 L, apparent distributional clearance of 28.7 L/h, and first-order absorption rate constant of 0.27/h were accurate and precise. The apparent volume of distribution was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower maximum plasma concentration in heavy drinkers compared with non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50 mg.

Conclusions: This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence.

Trial Registration: ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349.
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http://dx.doi.org/10.1007/s40262-020-00942-7DOI Listing
April 2021

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

Alcohol Clin Exp Res 2020 10 30;44(10):2097-2108. Epub 2020 Sep 30.

Department of Behavioral and Social Sciences (CLH-K, VML, LL), Center for Alcohol and Addiction Studies, School of Public Health, Brown University, Providence, Rhode Island.

Background: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD.

Aims: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome.

Methods: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes.

Results: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD.

Conclusions: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.
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http://dx.doi.org/10.1111/acer.14428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722230PMC
October 2020

Investigating the link between serum concentrations of brain-derived neurotrophic factor and behavioral measures in anxious alcohol-dependent individuals.

Alcohol 2020 12 13;89:75-83. Epub 2020 Aug 13.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, Bethesda, MD, United States; Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, United States; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, United States. Electronic address:

Brain-derived neurotrophic factor (BDNF) plays a role in different neurophysiological processes, including those involved in alcohol- and anxiety-related behaviors. Preclinical and clinical studies indicate that chronic excessive alcohol use leads to a downregulation of BDNF production in the periphery and in the brain. In addition, a decrease in BDNF concentrations in the blood has been reported to be associated with increased anxiety levels. Non-treatment-seeking alcohol-dependent individuals with high trait anxiety were studied to assess whether serum BDNF concentrations may be linked to self-reported levels of alcohol drinking, anxiety, and other behavioral measures. Participants had a current diagnosis of alcohol dependence, high trait anxiety score, and were not seeking treatment for alcohol dependence or anxiety. A fasting blood sample was collected from each participant and serum BDNF was measured using an enzyme-linked immunosorbent assay (ELISA). Behavioral data were collected on the same day, including measures of alcohol drinking, craving, dependence severity, and anxiety. Bivariate correlations were run between BDNF levels and behavioral measures. Serum BDNF concentrations were negatively correlated with average drinks per drinking days (r = -0.41, p = 0.02) and positively correlated with obsessive-compulsive drinking scale (r = 0.48, p = 0.007) and state-trait anxiety inventory (r = 0.52, p = 0.003) scores. These findings shed light on the possible role of the BDNF system in the neurobiology of alcohol- and anxiety-related behaviors.
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http://dx.doi.org/10.1016/j.alcohol.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722014PMC
December 2020

New Challenges in Addiction Medicine: COVID-19 Infection in Patients With Alcohol and Substance Use Disorders-The Perfect Storm.

Am J Psychiatry 2020 09 14;177(9):805-807. Epub 2020 Jul 14.

NIDA Intramural Research Program, Baltimore (all authors); National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (Leggio), and National Institute of Neurological Disorders and Stroke Intramural Research Program (Spagnolo), Bethesda, Md.;Department of Neuroscience, Imaging, and Clinical Science, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy (Montemitro).

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http://dx.doi.org/10.1176/appi.ajp.2020.20040417DOI Listing
September 2020

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity.

Drug Alcohol Depend 2020 09 2;214:108155. Epub 2020 Jul 2.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, United States; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, United States.

Background: Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. Genetic information can improve drug discovery rates by facilitating the identification of novel biological targets and potential drugs for repurposing.

Methods: The present study utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify additional risk genes for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). iRIGS incorporates several genomic features and closeness of these genes in network space to compute a posterior probability for protein coding genes near each SNP. We subsequently used the Target Central Resource Database to search for drug-protein interactions for these newly identified genes and previously identified risk genes for alcohol consumption.

Results: We identified several genes that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, which is critical for liver function and linked to anxiety and cocaine self-administration, and PRKCE, which has been linked to alcohol self-administration. Notably, only a minority of the SNPs (18.4 %) were linked to genes with confidence (>0.75), underscoring the need to apply multiple methods to assign function to loci. Finally, some previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs, some of which are candidates for managing hepatotoxicity.

Conclusions: This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight additional molecular targets and drug repurposing candidates for treating AUD and ALD.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423741PMC
September 2020

Brief Report: Relationship Between Cotinine Levels and Peripheral Endogenous Concentrations of Oxytocin, β-Endorphin, and Orexin in Individuals With Both Alcohol and Nicotine Use Disorders.

Am J Addict 2021 01 2;30(1):88-91. Epub 2020 Jun 2.

Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, Rhode Island.

Background And Objectives: In this secondary analysis of a pilot clinical trial with individuals with alcohol and nicotine use disorders, we investigate the relationship between serum concentrations of oxytocin, β-endorphin, melatonin, α-melanocyte-stimulating hormone, substance P, and orexin, with objective biomarkers (salivary cotinine and serum γ-glutamyl transferase [GGT]) as well as with self-reported smoking and alcohol drinking.

Methods: Biomarkers for a total of N = 19 participants were analyzed using multiplexed, competitive format immune-assay (peptides) and enzyme competitive immunoassay (saliva). A regression analysis using Pearson's correlation coefficient was utilized to determine correlations. We controlled for multiple comparisons, checked for collinearities, and ran two-sided statistical tests.

Results: We found significant positive correlations for cotinine and oxytocin (P = .002), β-endorphin (P = .008), and orexin (P < .001), but not for either GGT or self-reported smoking or alcohol drinking.

Conclusion And Scientific Significance: These preliminary results suggest a relationship between cotinine and oxytocin, β-endorphin, and orexin, which opens up new potential hypotheses on the potential role of these endocrine pathways in tobacco smokers. (Am J Addict 2021;30:88-91).
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http://dx.doi.org/10.1111/ajad.13064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944578PMC
January 2021

Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.

Brain Res 2020 08 24;1740:146851. Epub 2020 Apr 24.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, United States; Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, United States; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, United States. Electronic address:

The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F = 3.345, p = 0.030) and IL-10 (F = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.
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http://dx.doi.org/10.1016/j.brainres.2020.146851DOI Listing
August 2020

Peptide-Liganded G Protein-Coupled Receptors as Neurotherapeutics.

ACS Pharmacol Transl Sci 2020 Apr 18;3(2):190-202. Epub 2020 Mar 18.

Department of Physiology, Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico.

Peptide-liganded G protein-coupled receptors (GPCRs) are a growing fraction of GPCR drug targets, concentrated in two of the five major GPCR structural classes. The basic physiology and pharmacology of some within the rhodopsin class, for example, the enkephalin (μ opioid receptor, MOR) and angiotensin (ATR) receptors, and most in class B, all the members of which are peptide receptors, are well-known, whereas others are less so. Furthermore, with the notable exception of opioid peptide receptors, the ability to translate from peptide to "drug-like" (i.e., low-molecular-weight nonpeptide) molecules, with desirable oral absorption, brain penetrance, and serum stability, has met with limited success. Yet, peripheral peptide administration in patients with metabolic disorders is clinically effective, suggesting that "drug-like" molecules for peptide receptor targets may not always be required for disease intervention. Here, we consider recent developments in GPCR structure analysis, intracellular signaling, and genetic analysis of peptide and peptide receptor knockout phenotypes in animal models. These lines of research converge on a better understanding of how peptides facilitate adaptive behaviors in mammals. They suggest pathways to translate this burgeoning information into identified drug targets for neurological and psychiatric illnesses such as obesity, addiction, anxiety disorders, and neurodegenerative diseases. Advances centered on the peptide ligands oxytocin, vasopressin, GLP-1, ghrelin, PACAP, NPY, and their GPCRs are considered here. These represent the spectrum of progress across the "virtual pipeline", of peptide receptors associated with many established drugs, those of long-standing interest for which clinical application is still under development, and those just coming into focus through basic research.
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http://dx.doi.org/10.1021/acsptsci.0c00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155190PMC
April 2020

The future of translational research on alcohol use disorder.

Addict Biol 2021 03 14;26(2):e12903. Epub 2020 Apr 14.

National Institute on Drug Abuse, Baltimore, Maryland, USA.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.
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http://dx.doi.org/10.1111/adb.12903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554164PMC
March 2021

Differential correlation of serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use.

Addict Biol 2021 03 5;26(2):e12890. Epub 2020 Mar 5.

Department of Neurology, University of California, San Francisco, San Francisco, California.

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the two-bottle choice paradigm (IA20%2BC) and measured circulating levels of BDNF protein and miRs targeting BDNF in the serum of Long-Evans rats before and after 8 weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified, whereas 70% of the rats gradually escalate their alcohol intake (late onset), and 30% of alcohol users exhibit a very rapid onset of drinking (rapid onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both rapid onset and late onset rats. In contrast, increased expression of the miRs targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the rapid onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Together, these data suggest that rats exhibit both late and rapid onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the rapid onset rats.
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http://dx.doi.org/10.1111/adb.12890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483353PMC
March 2021

Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study.

Transl Psychiatry 2020 02 19;10(1):71. Epub 2020 Feb 19.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, USA.

As perspectives on cannabis continue to shift, understanding the physiological and behavioral effects of cannabis use is of paramount importance. Previous data suggest that cannabis use influences food intake, appetite, and metabolism, yet human research in this regard remains scant. The present study investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. This was a randomized, crossover, double-blind, placebo-controlled study. Twenty participants underwent four experimental sessions during which oral cannabis, smoked cannabis, vaporized cannabis, or placebo was administered. Active compounds contained 6.9 ± 0.95% (~50.6 mg) ∆9-tetrahydrocannabinol (THC). Repeated blood samples were obtained, and the following endocrine markers were measured: total ghrelin, acyl-ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and insulin. Results showed a significant drug main effect (p = 0.001), as well as a significant drug × time-point interaction effect (p = 0.01) on insulin. The spike in blood insulin concentrations observed under the placebo condition (probably due to the intake of brownie) was blunted by cannabis administration. A significant drug main effect (p = 0.001), as well as a trend-level drug × time-point interaction effect (p = 0.08) was also detected for GLP-1, suggesting that GLP-1 concentrations were lower under cannabis, compared to the placebo condition. Finally, a significant drug main effect (p = 0.01) was found for total ghrelin, suggesting that total ghrelin concentrations during the oral cannabis session were higher than the smoked and vaporized cannabis sessions. In conclusion, cannabis administration in this study modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin, in cannabis users. Understanding the mechanisms underpinning these effects may provide additional information on the cross-talk between cannabinoids and physiological pathways related to appetite and metabolism.
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http://dx.doi.org/10.1038/s41398-020-0756-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031261PMC
February 2020

Five Priority Areas for Improving Medications Development for Alcohol Use Disorder and Promoting Their Routine Use in Clinical Practice.

Alcohol Clin Exp Res 2020 01 5;44(1):23-35. Epub 2019 Dec 5.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1111/acer.14233DOI Listing
January 2020

Development and validation of an assay for a novel ghrelin receptor inverse agonist PF-5190457 and its major hydroxy metabolite (PF-6870961) by LC-MS/MS in human plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Nov 8;1130-1131:121820. Epub 2019 Oct 8.

Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island Kingston, RI, USA. Electronic address:

PF-5190457 is a selective and potent ghrelin receptor inverse agonist presently undergoing clinical trials to treat alcohol use disorder (AUD). We describe the development and validation of a selective and sensitive liquid chromatography-tandem mass spectrometry-based method for quantification of PF-5190457 and its recently discovered hydroxy metabolite PF-6870961 in human plasma. Analytes were extracted after simple protein precipitation using methanol (2.5 ng mL tacrine as an internal standard). A gradient liquid chromatography method was used to separate the analytes on an Acquity UPLC BEH C18 analytical column. The separation was achieved at a flow rate of 0.25 mL min and the total chromatographic runtime was 11.30 min. Positive electrospray ionization and multiple reaction monitoring mode were used for the quantification of all the analytes. The calibration curves from six validation runs were linear with a correlation coefficient of ≥0.996 for the concentration range of 1-1000 ng mL and 2-250 ng mL for PF-5190457 and PF-6870961, respectively. The retention time for PF-5190457, PF-6870961 and tacrine were 4.4, 3.8, and 4.6 min, respectively. The lower limit of quantification for PF-5190457 and PF-6870961 was 1 and 2 ng mL, respectively. The inter-assay precision and accuracy results obtained were within the Food and Drug Administration recommended ±15% limit of nominal values. All the analytes were found to be stable under varied stability conditions. The recovery of PF-5190457 and PF-6870961 ranged from 95 to 103%. Further, the application of the method was demonstrated by measuring the concentration of PF-5190457 and its hydroxy metabolite in patient plasma samples from 100 mg dose.
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http://dx.doi.org/10.1016/j.jchromb.2019.121820DOI Listing
November 2019

Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies.

Handb Exp Pharmacol 2020 ;258:443-462

Division of Medications Development, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

Compared to other medical disorders, including other brain diseases, the number of medications approved for alcohol use disorder (AUD) is very small. Disulfiram, naltrexone (oral and long-acting), and acamprosate are approved by the US Food and Drug Administration (FDA) to treat patients with AUD. These medications are also approved in other countries, including in Europe, where the European Medicines Agency (EMA) also approved nalmefene for AUD. Furthermore, baclofen was recently approved for AUD in France. These approved medications have small effect sizes, which are probably the consequence of the fact that they only work for some patients, yet a personalized approach to match the right medication with the right patient is still in its infancy. Therefore, research is needed to expand the armamentarium of medications that clinicians can use to treat their patients, as well as to better develop personalized approaches. This book chapter reviews other medications, beyond those approved by the FDA, that have shown efficacy in clinical trials, as well as medications which are still in the early stages of evaluation in human studies.
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http://dx.doi.org/10.1007/164_2019_295DOI Listing
September 2020

Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers.

Neuropharmacology 2020 06 23;170:107788. Epub 2019 Sep 23.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, USA; Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, USA; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA. Electronic address:

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085971PMC
June 2020

Peripheral proinflammatory markers are upregulated in abstinent alcohol-dependent patients but are not affected by cognitive bias modification: Preliminary findings.

Drug Alcohol Depend 2019 11 11;204:107553. Epub 2019 Sep 11.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Basic Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, USA; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, USA; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA. Electronic address:

Background: Inflammatory pathways are known to be negatively affected in patients with alcohol use disorder (AUD). Cognitive bias modification (CBM), an emerging behavioral treatment that involves the 're-training' of cognitive biases using computerized tasks, has been reported to reduce alcohol craving and relapse rates. The aim of this study was to compare peripheral concentrations of the proinflammatory biomarkers IL-18, IL-6, IL-1β, TNF-α and CRP in AUD patients versus controls and to identify whether CBM treatment affected these biomarkers in AUD patients.

Methods: This 3-week double-blind randomized controlled study tested 36 male abstinent AUD patients receiving CBM or placebo-training, who were also compared to 18 male healthy controls. The approach avoidance task (AAT) was used to test the AUD patients before and after training. CBM training took place over 6 sessions, using a joystick-based approach-avoidance task. Blood samples were collected after the pre- and post-AAT test sessions for the AUD groups, and during an outpatient appointment with the controls.

Results: AUD patients, versus controls, presented with significantly higher plasma levels of TNF- α (P < 0.0001) and CRP (P = 0.0031). No changes in the CBM versus placebo groups were noted in IL-18, TNF-α and CRP concentrations following pre-post change or within group pretest- posttest analysis. IL-6 and IL-1β levels fell under the lower detection limit, thus were not included in the final analyses.

Conclusions: This study confirms that the inflammatory system is altered in AUD. This was the first study that investigated whether CBM training affected proinflammatory markers in AUD patients.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913873PMC
November 2019

Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis.

Pharmacol Res 2019 10 6;148:104447. Epub 2019 Sep 6.

Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, S.S. 554, km. 4.500, I-09042, Monserrato, CA, Italy. Electronic address:

There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings. PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 min after opioid administration (Delta-VASPI at 30'), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system. Globally, we included 40 comparisons (6794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 min after their administration [Delta-VASPI at 30': mean difference, MD = 0.42 (-0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = -0.30 (-0.41; -0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = -36.42 (-57.86; -14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = -16.09 (-40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results. In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women.
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http://dx.doi.org/10.1016/j.phrs.2019.104447DOI Listing
October 2019

Using Machine Learning to Classify Individuals With Alcohol Use Disorder Based on Treatment Seeking Status.

EClinicalMedicine 2019 Jul 17;12:70-78. Epub 2019 Jun 17.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.

Objective: The authors used a decision tree classifier to reduce neuropsychological, behavioral and laboratory measures to a subset of measures that best predicted whether an individual with alcohol use disorder (AUD) seeks treatment.

Method: Clinical measures (N = 178) from 778 individuals with AUD were used to construct an alternating decision tree (ADT) with 10 measures that best classified individuals as treatment or not treatment-seeking for AUD. ADT's were validated by two methods: using cross-validation and an independent dataset (N = 236). For comparison, two other machine learning techniques were used as well as two linear models.

Results: The 10 measures in the ADT classifier were drinking behavior, depression and drinking-related psychological problems, as well as substance dependence. With cross-validation, the ADT classified 86% of individuals correctly. The ADT classified 78% of the independent dataset correctly. Only the simple logistic model was similar in accuracy; however, this model needed more than twice as many measures as ADT to classify at comparable accuracy.

Interpretation: While there has been emphasis on understanding differences between those with AUD and controls, it is also important to understand, within those with AUD, the features associated with clinically important outcomes. Since the majority of individuals with AUD do not receive treatment, it is important to understand the clinical features associated with treatment utilization; the ADT reported here correctly classified the majority of individuals with AUD with 10 clinically relevant measures, misclassifying < 7% of treatment seekers, while misclassifying 38% of non-treatment seekers. These individual clinically relevant measures can serve, potentially, as separate targets for treatment.

Funding: Funding for this work was provided by the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Drug Abuse (NIDA) and the Center for Information Technology (CIT).

Research In Context: Evidence Before This Study: Less than 10% of persons who meet lifetime criteria for Alcohol Use Disorder (AUD) receive treatment. As the etiology of AUD represents a complex interaction between neurobiological, social, environmental and psychological factors, low treatment utilization likely stems from barriers on multiple levels. Given this issue, it is important from both a research and clinical standpoint to determine what characteristics are associated with treatment utilization in addition to merely asking individuals if they wish to enter treatment. At the level of clinical research, if there are phenotypic differences between treatment and nontreatment-seekers that directly influence outcomes of early-phase studies, these phenotypic differences are a potential confound in assessing the utility of an experimental treatment for AUD. At the level of clinical practice, distinguishing between treatment- and nontreatment-seekers may help facilitate a targeted treatment approach. Previous efforts to understand the differences between these populations of individuals with AUD leveraged the multidimensional data collected in clinical research settings for AUD that are not well suited to traditional regression methods.Added Value of This Study: Alternating decision trees are well suited to deep-phenotyping data collected in clinical research settings as this approach handles nonparametric, skewed, and missing data whose relationships are nonlinear. This approach has proved to be superior in some cases to conventional clinical methods to solve diagnostic problems in medicine. We used a decision tree classifier to understand treatment- and non-treatment seeking group differences. The decision tree classifier approach chose a subset of factors arranged in an alternating decision tree that best predicts a given outcome. Assuming that the input measures are clinically relevant, the alternating decision tree that is generated has clinical value. Unlike other machine learning approaches, in addition to its predictive value, the nodes in the tree and their arrangement in a hierarchy have clinical utility. With the "if-then" logic of the tree, the clinician can learn what features become important and which recede in importance as the logic of the tree is followed. The decision tree classifier approach reduced 178 characterization measures (both categorical and continuous) in multiple domains to a decision tree comprised of 10 measures that together best classified subjects by treatment seeking status (yes/no).Implications After All the Available Evidence: We leveraged a large data set comprised of 178 clinical measures and using the decision tree approach, we have reduced these to a subset of 10 measures that accurately classified individuals with alcohol dependence by treatment utilization. From this analysis, drinking behavior variables and depression measures are strong treatment seeking predictors. Having identified a cluster of factors that predicts treatment seeking, we can assess the influence of these factors directly on the clinical study outcome measures themselves. In clinical practice these factors can be separate targets for treatment. In clinical research, the group differences my directly influence research outcomes for treatment of AUD.
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http://dx.doi.org/10.1016/j.eclinm.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677650PMC
July 2019