-
Alcohol and Alcoholism (Oxford,... Jan 2024Ethanol metabolism plays an essential role in how the body perceives and experiences alcohol consumption, and evidence suggests that modulation of ethanol metabolism can... (Review)
Review
Ethanol metabolism plays an essential role in how the body perceives and experiences alcohol consumption, and evidence suggests that modulation of ethanol metabolism can alter the risk for alcohol use disorder (AUD). In this review, we explore how ethanol metabolism, mainly via alcohol dehydrogenase and aldehyde dehydrogenase 2 (ALDH2), contributes to drinking behaviors by integrating preclinical and clinical findings. We discuss how alcohol dehydrogenase and ALDH2 polymorphisms change the risk for AUD, and whether we can harness that knowledge to design interventions for AUD that alter ethanol metabolism. We detail the use of disulfiram, RNAi strategies, and kudzu/isoflavones to inhibit ALDH2 and increase acetaldehyde, ideally leading to decreases in drinking behavior. In addition, we cover recent preclinical evidence suggesting that strategies other than increasing acetaldehyde-mediated aversion can decrease ethanol consumption, providing other potential metabolism-centric therapeutic targets. However, modulating ethanol metabolism has inherent risks, and we point out some of the key areas in which more data are needed to mitigate these potential adverse effects. Finally, we present our opinions on the future of treating AUD by the modulation of ethanol metabolism.
Topics: Humans; Alcoholism; Ethanol; Aldehyde Dehydrogenase, Mitochondrial; Aldehyde Dehydrogenase; Alcohol Dehydrogenase; Alcohol Drinking; Acetaldehyde
PubMed: 37950904
DOI: 10.1093/alcalc/agad077 -
Psychiatric Services (Washington, D.C.) Sep 2023Evaluation of the effectiveness of integration of depression and alcohol use disorder care into primary health care in low- and middle-income countries (LMICs) is... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Evaluation of the effectiveness of integration of depression and alcohol use disorder care into primary health care in low- and middle-income countries (LMICs) is limited. The authors aimed to quantify the effectiveness of integrating mental health care into primary care by examining depression and alcohol use disorder outcomes. The study updates a previous systematic review summarizing research on care integration in LMICs.
METHODS
Following PRISMA guidelines, the authors included studies from the previous review and studies published from 2017 to 2020 that included adults with alcohol use disorder or depression. Studies were evaluated for type of integration model with the typology developed previously. A meta-analysis using a random-effects model to assess effectiveness of integrated interventions was conducted. Meta-regression analyses to examine the impact of study characteristics on depression and alcohol use disorder outcomes were conducted.
RESULTS
In total, 49 new articles were identified, and 74 articles from the previous and current studies met inclusion criteria for the meta-analysis. Overall random effect sizes were 0.28 (95% CI=0.22-0.35) and 0.17 (95% CI=0.11-0.24) for studies targeting care integration for depression or for alcohol use disorder, respectively, into primary care in LMICs. High heterogeneity within and among studies was observed. No significant association was found between country income level and depression and alcohol use outcomes. However, differences in effect sizes between types of integration model were statistically significant (p<0.001).
CONCLUSIONS
Integration of mental health care into primary health care in LMICs was found to improve depression and alcohol use disorder outcomes. This evidence should be considered when designing interventions to improve mental health screening and treatment in LMICs.
Topics: Adult; Humans; Depression; Developing Countries; Alcoholism; Primary Health Care
PubMed: 36852551
DOI: 10.1176/appi.ps.20220267 -
Frontiers in Neuroendocrinology Oct 2023Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral... (Review)
Review
Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral and physiological responses. The purpose of the current review is to update and to expand upon contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. Steroids important in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, the reciprocal interactions between these axes, the effects of chronic alcohol use on steroid levels, and the genomic and rapid membrane-associated effects of steroids and neurosteroids in models of alcohol drinking and withdrawal are described. Importantly, comparison between males and females highlight some divergent effects of sex- and stress-steroids on alcohol drinking- and withdrawal-related behaviors, and the distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of alcohol use disorder.
Topics: Male; Animals; Female; Alcohol Drinking; Alcoholism; Ethanol; Steroids; Disease Models, Animal
PubMed: 37558184
DOI: 10.1016/j.yfrne.2023.101094 -
British Journal of Pharmacology Mar 2024Neuropeptides and G protein-coupled receptors (GPCRs) have long been, and continue to be, one of the most popular target classes for drug discovery in CNS disorders,... (Review)
Review
Neuropeptides and G protein-coupled receptors (GPCRs) have long been, and continue to be, one of the most popular target classes for drug discovery in CNS disorders, including alcohol use disorder (AUD). Yet, orphaned neuropeptide systems and receptors (oGPCR), which have no known cognate receptor or ligand, remain understudied in drug discovery and development. Orphan neuropeptides and oGPCRs are abundantly expressed within the brain and represent an unprecedented opportunity to address brain function and may hold potential as novel treatments for disease. Here, we describe the current literature regarding orphaned neuropeptides and oGPCRs implicated in AUD. Specifically, in this review, we focus on the orphaned neuropeptide cocaine- and amphetamine-regulated transcript (CART), and several oGPCRs that have been directly implicated in AUD (GPR6, GPR26, GPR88, GPR139, GPR158) and discuss their potential and pitfalls as novel treatments, and progress in identifying their cognate receptors or ligands.
Topics: Humans; Alcoholism; Receptors, G-Protein-Coupled; Ligands; Neuropeptides; Central Nervous System Diseases
PubMed: 38073127
DOI: 10.1111/bph.16301 -
Biomedicine & Pharmacotherapy =... Aug 2023Gamma-hydroxybutyric acid (GHB), both a metabolic precursor and product of gamma-aminobutyric acid (GABA), is a central nervous system depressant used for the treatment...
Gamma-hydroxybutyric acid (GHB), both a metabolic precursor and product of gamma-aminobutyric acid (GABA), is a central nervous system depressant used for the treatment of narcolepsy-associated cataplexy and alcohol withdrawal. However, administration of GHB with alcohol (ethanol) is a major cause of hospitalizations related to GHB intoxication. In this study, we investigated locomotor behavior as well as metabolic and pharmacokinetic interactions following co-administration of GHB and ethanol in rats. The locomotor behavior of rats was evaluated following the intraperitoneal administration of GHB (sodium salt, 500 mg/kg) and/or ethanol (2 g/kg). Further, time-course urinary metabolic profiling of GHB and its biomarker metabolites glutamic acid, GABA, succinic acid, 2,4-dihydroxybutyric acid (OH-BA), 3,4-OH-BA, and glycolic acid as well as pharmacokinetic analysis were performed. GHB/ethanol co-administration significantly reduced locomotor activity, compared to the individual administration of GHB or ethanol. The urinary and plasma concentrations of GHB and other target compounds, except for 2,4-OH-BA, were significantly higher in the GHB/ethanol co-administration group than the group administered only GHB. The pharmacokinetic analysis results showed that the co-administration of GHB and ethanol significantly increased the half-life of GHB while the total clearance decreased. Moreover, a comparison of the metabolite-to-parent drug area under the curve ratios demonstrated that the metabolic pathways of GHB, such α- and β-oxidation, were inhibited by ethanol. Consequently, the co-administration of GHB and ethanol aggravated the metabolism and elimination of GHB and enhanced its sedative effect. These findings will contribute to clinical interpretation of GHB intoxication.
Topics: Rats; Animals; Sodium Oxybate; Alcoholism; Substance Withdrawal Syndrome; Ethanol; gamma-Aminobutyric Acid
PubMed: 37301134
DOI: 10.1016/j.biopha.2023.114992 -
Genes, Brain, and Behavior Oct 2023Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes... (Review)
Review
Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes and consequences of alcohol-related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene-brain-behavior framework. COGA is a family based, diverse (~25% self-identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7-97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome-wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD. This overview provides the framework for the development of COGA as a scientific resource in the past three decades, with individual reviews providing in-depth descriptions of data on and discoveries from behavioral and clinical, brain function, genetic and functional genomics data. The value of COGA also resides in its data sharing policies, its efforts to communicate scientific findings to the broader community via a project website and its potential to nurture early career investigators and to generate independent research that has broadened the impact of gene-brain-behavior research into AUD.
Topics: Humans; Female; Male; Alcoholism; Genome-Wide Association Study; Genotype; Brain; Electroencephalography
PubMed: 37736010
DOI: 10.1111/gbb.12864 -
Journal of Psychopharmacology (Oxford,... Dec 2023Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur in patients who have experienced trauma. This comorbidity leads to a vicious... (Review)
Review
Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur in patients who have experienced trauma. This comorbidity leads to a vicious cycle where PTSD symptoms beget heavy drinking and vice versa. There are no FDA-approved medications to treat PTSD-AUD; therefore, individuals suffering from this comorbidity are treated with medication approved to treat the disorders separately or with off-label pharmacological interventions. However, these medications are limited in their efficacy for treating PTSD-AUD comorbidity. Emerging research on the nonclassical psychedelic drug 3,4-methylenedioxymethamphetamine (MDMA) suggests that it may be an effective drug used in conjunction with psychotherapy. The following reviews the current research for clinical pharmacotherapies, as well as MDMA-integrative psychotherapy as they pertain to PTSD and AUD in isolation and co-occurrence. Future directions for the role of psychedelic-integrative therapy for the treatment of this comorbidity are discussed.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Alcoholism; Stress Disorders, Post-Traumatic; Hallucinogens; Psychotherapy; Comorbidity
PubMed: 38009477
DOI: 10.1177/02698811231200880 -
Addiction (Abingdon, England) Jul 2024Whether alcohol-related DNA methylation has a causal effect on psychiatric disorders has not been investigated. Furthermore, a comprehensive investigation into the...
BACKGROUND AND AIMS
Whether alcohol-related DNA methylation has a causal effect on psychiatric disorders has not been investigated. Furthermore, a comprehensive investigation into the causal relationship and underlying mechanisms linking alcohol consumption and psychiatric disorders has been lacking. This study aimed to evaluate the causal effect of general alcohol intake and pathological drinking behaviors on psychiatric disorders, alcohol-associated DNA methylation on gene expression and psychiatric disorders, and gene expression on psychiatric disorders.
DESIGN
Two-sample design Mendelian randomization (MR) analysis. Various sensitivity and validation analyses, including colocalization analysis, were conducted to test the robustness of the results.
SETTING
Genome-wide association study (GWAS) data mainly from GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetics of DNA Methylation Consortium (GoDMC) and Psychiatric Genomics Consortium (PGC) with European ancestry.
PARTICIPANTS
The GWAS summary data on general alcohol intake (drinks per week, n = 941 280), pathological drinking behaviors (including alcohol use disorder [AUD, n = 313 959] and problematic alcohol use [PAU, n = 435 563]) and psychiatric disorders (including schizophrenia, major depressive disorder and bipolar disorder, n = 51 710-500 199) were included. Alcohol-related DNA methylation CpG sites (n = 9643) and mQTL data from blood (n = 27 750) and brain (n = 1160), BrainMeta v2 and GTEx V8 eQTL summary data (n = 73-2865) were also included.
MEASUREMENTS
Genetic variants were selected as instrumental variables for exposures, including drinks per week, AUD, PAU, alcohol-related DNA methylation CpG sites (mQTL) and genes selected (eQTL).
FINDINGS
Pathological drinking behaviors were associated with an increased risk of psychiatric disorders after removing outliers or controlling for alcohol consumption. MR analysis identified 10 alcohol-related CpG sites with colocalization evidence that were causally associated with psychiatric disorders (P = 1.65 × 10-7.52 × 10). Furthermore, the expression of genes (RERE, PTK6, GATAD2B, COG8, PDF and GAS5) mapped to these CpG sites in the brain, led by the cortex, were significantly associated with psychiatric disorders (P = 1.19 × 10-3.51 × 10).
CONCLUSIONS
Pathological drinking behavior and alcohol-related DNA methylation appear to have a causal effect on psychiatric disorders. The expression of genes regulated by the alcohol-related DNA methylation sites may underpin this association.
Topics: Humans; DNA Methylation; Mendelian Randomization Analysis; Genome-Wide Association Study; Alcohol Drinking; Mental Disorders; Schizophrenia; Alcoholism; Bipolar Disorder; Depressive Disorder, Major; Causality; Gene Expression; Multiomics
PubMed: 38523595
DOI: 10.1111/add.16465 -
Neuropharmacology Aug 2023The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous...
The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous alcohol withdrawal (SAW) in mice. Increasing doses of ethanol were administered to C57BL/6J male mice for 15 days (2.5, 3 and 3.5 g/kg/12 h, p. o.), and SAW was studied at 6, 12, 24, and 72 h after the last ethanol administration. The efficacy of acute CBD (10, 20, and 40 mg/kg, i. p.) to regulate behavioral changes induced by SAW was explored at 6 h. Gene expression analyses of cannabinoid receptors 1 (Cnr1) and 2 (Cnr2), mu-opioid receptor (Opmr1), and proopiomelanocortin (Pomc) in the nucleus accumbens (NAcc), and Pomc and tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), were carried out by real time-PCR. Pearson correlation was used to identify potential associations between the gene expression data and the anxiety-like behaviors. Biostatistical studies suggest associations between gene expression data and the anxiogenic behaviors in mice exposed to the SAW model and treated with VEH and 40 mg/kg of CBD. Mice exposed to the SAW model showed significant somatic withdrawal signs, anxiety-like behaviors, and remarkable changes in the gene expression of all brain targets at 6 h. CBD dose-dependently normalized the behavioral, somatic withdrawal signs and anxiety-like behaviors and modulated gene expression changes in the NAcc, but not in the VTA. The results of this study suggest that CBD may regulate specific alcohol withdrawal-associated alterations. However, further studies are required to explore the possible mechanisms involved.
Topics: Male; Animals; Mice; Cannabidiol; Alcoholism; Pro-Opiomelanocortin; Substance Withdrawal Syndrome; Mice, Inbred C57BL; Brain; Ventral Tegmental Area; Ethanol
PubMed: 37085012
DOI: 10.1016/j.neuropharm.2023.109549 -
Preventive Medicine Sep 2023Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediational role of sleep duration in this...
Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediational role of sleep duration in this association is unclear. A total of 116, 014 participants in the United States, from the Behavioral Risk Factor Surveillance System (BRFSS) survey in 2020 were involved in the study. The effects of ACE status, different ACEs, and ACE scores on short sleep duration were examined using binary logistic regression analysis, and the association of ACE status, different types of ACEs, and ACE scores with diabetes and the mediating role of short sleep duration were observed. Path analysis was used to investigate short sleep duration as pathways between different types of ACEs and diabetes in adulthood. For the different types of ACEs, alcohol abuse in the household (OR = 1.13, 95%CI 1.08; 1.18), witnessing domestic violence (OR = 1.17, 95%CI 1.11; 1.23), emotional abuse (OR = 1.11, 95%CI 1.06; 1.16), physical abuse (OR = 1.22, 95%CI 1.17; 1.28), sexual abuse (OR = 1.25, 95%CI 1.18; 1.32) and short sleep duration (OR = 1.26, 95%CI 1.21; 1.32) independently increased the odds of diabetes. There was also an indirect relationship between alcohol abuse in the household, witnessing domestic violence, physical abuse, sexual abuse, and diabetes via short sleep duration. Short sleep duration plays a partial mediating role between ACEs and diabetes, including alcohol abuse in the household, witnessing domestic violence, physical and sexual abuse.
Topics: Humans; United States; Child; Adverse Childhood Experiences; Sleep Duration; Alcoholism; Domestic Violence; Diabetes Mellitus; Child Abuse
PubMed: 37494972
DOI: 10.1016/j.ypmed.2023.107643