Alcohol misuse leads to a range of health complications and induces various metabolic perturbations that impacts multiple physiological systems, including the cardiovascular system, liver, and gut microbiota. However, limited research has been reported on these metabolic profile changes, particularly using models of alcohol dependence such as after chronic intermittent ethanol (CIE) vapor exposure. This study investigated CIE-induced metabolomic alterations of CIE were investigated using fecal, liver, and serum samples of adult male and female C57BL/6J mice following 72 hr withdrawal. Significant metabolite changes were observed in both fecal and liver extracts and these changes were sex-specific. Both liver and fecal metabolites had systematic changes, while blood serum influences were limited after CIE. Female fecal samples showed higher metabolite perturbations than male samples according to PCA studies. The female samples showed significant butyrate downregulation and acetate upregulation, which are critical microbial products as beneficial microbe cell energy sources and influence intestinal absorption in the host. In addition, the female fecal samples showed significant downregulation of branched-chain amino acids including leucine, isoleucine, and valine, while male samples showed downregulation of glucose and taurine, with upregulated phenylalanine and tyrosine. In contrast, in the liver study, phenylalanine and tyrosine were upregulated while taurine was downregulated in females. Both sexes showed downregulation of liver glycine and glucose. These data indicate that CIE induces sex-specific metabolic perturbations in the mouse liver and fecal metabolome, and have implications for guy disturbances and liver damage observed following alcohol dependence. This study provides potential targets for future examination of mechanisms and treatment approaches for alcohol dependence.

Elevated liver enzymes remain a clinically important adverse effect of antiretroviral therapy (ART) in people living with HIV (PLHIV). Although dolutegravir (DTG)-based ART is recommended as first-line therapy in Ethiopia, evidence on the burden and factors associated with elevated liver enzymes among PLHIV receiving these regimens remains limited. To assess the prevalence and factors associated with elevated liver enzymes among PLHIV receiving DTG-based ART at Debre Markos Comprehensive Specialized Hospital (DMCSH) in Northwest Ethiopia. An institutional-based cross-sectional study was conducted among 417 PLHIV who had been receiving a DTG-based regimen for at least six months at the ART clinic of DMCSH between March 1, 2024, and June 30, 2024. Socio-demographic and behavioral data were collected using a semi-structured questionnaire, anthropometric measurements were obtained, and clinical data were extracted from medical records using a standardized checklist. Data were entered into Epidata version 4.6 and analyzed using SPSS version 26. Binary and multivariable logistic regression analyses were conducted to identify factors associated with elevated liver enzymes. Variables with a p-value < 0.05 in the final model were considered statistically significant. The overall prevalence of elevated liver enzymes was 21.1% (95% CI: 17.4-25.5). Of these, 17.3% were classified as Grade 1 elevations, whereas only 3.8% were classified as Grade 2 or Grade 3 elevations. Age ≥ 60 years (AOR = 3.1, 95% CI: 1.08-8.94, p = 0.036), alcohol consumption (AOR = 1.98, 95% CI: 1.27-4.02; p = 0.036), cluster of differentiation 4-positive T-cell count (CD4 + T-cell count) < 500 cell/mm[3] (AOR = 1.84, 95% CI = 1.08-3.85, p = 0.024), and isoniazid (INH) prophylaxis (AOR = 2.04, 95% CI = 1.17-3.58; p = 0.012) were significantly associated with elevated liver enzymes. Elevated liver enzymes were relatively common among PLHIV receiving DTG-based ART; however, the majority of cases were classified as Grade 1 elevations. Age ≥ 60 years, alcohol consumption, CD4 + T-cell count < 500 cell/mm[3], and INH prophylaxis were independently associated with elevated liver enzymes. These findings suggest that increased clinical vigilance and consideration of liver enzyme monitoring may be beneficial for patients with these associated factors, particularly when clinically indicated.

Stark absorption spectroscopy provides quantitative information on charge redistribution of a chromophore, specifically its difference dipole moment (Δd⃑) and change in polarizability , concurrent with photoexcitation. Δd⃑ and have been the focus of fundamental studies of quantum theory and electron transfer and, more recently, have garnered interest in light harvesting, nonlinear optics, and quantum information science. In this work, we quantify the photophysical and electro-optical properties of six conjugated organic molecules-two field standards, two common dyes, and two substituted thienotetracenes. Specifically, we quantify their transition energies, transition dipole moments (μ), |Δd⃑|, , and ζ, the angle between μ and |Δd⃑|, using a high-sensitivity Stark absorption spectrometer. We first characterized two field standards, flavin mononucleotide and 8-hydroxypyrene-1,3,6-trisulfonic acid, in water:glycerol. The |Δd⃑|, , and ζ values we measured for their first two electronic transitions generally agreed with those reported in past literature precedents, validating our approach. Next, we characterized two common dyes, rhodamine B and Nile blue A, in ethanol. The Δd⃑ values for their first electronic transition generally agreed with the corresponding values reported in the literature obtained via the solvatochromic approach. Lastly, we characterized the first electronic transition of two thienotetracenes, which differ by the presence and absence of a biomolecule-compatible tag, a N-hydroxysuccinimide (NHS) ester group, attached directly to the thienotetracene core. We found that the presence of the NHS ester group increases |Δd⃑|, likely due to its electron withdrawing nature, and decreases . Overall, all six molecules were moderately-strong light absorbers (μ ∼ 3-9 D) with appreciable |Δd⃑| (∼2-7 D) and ranging from 0-200 Å[3]. This work demonstrates the broad applicability and robustness of Stark spectroscopy and will ideally open the door for future researchers interested in the technique.

Both genetic and epigenetic factors influence the development and pathology of alcohol use disorder (AUD), which is further associated with changes in learning, memory, and synaptic plasticity. Histone acetylation is an epigenetic mechanism that changes the chromatin architecture, influencing gene transcription, which may further impact neuronal signaling, cognition, and addiction-related behaviors. In this review, we summarize the existing literature on how alcohol exposure impacts histone acetylation and the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Overall, alcohol appears to dynamically regulate histone acetylation and the expression and activity of HATs and HDACs in a brain region-, alcohol quantity-, exposure paradigm-, and sex-specific manner. While general patterns exist, more work is needed to elucidate the precise mechanisms through which alcohol changes histone marks across a variety of experimental and biological conditions, thus changing downstream gene expression. We suggest here that a more nuanced understanding of the relationship between histone acetylation and alcohol consumption is needed. Going forward, unbiased molecular techniques for profiling histone marks across the genome will allow for greater precision in determining the impact of alcohol on epigenetic regulation of transcription. However, these approaches must be performed with consideration to differences in mode and quantity of alcohol exposure, as well as withdrawal time and sex, in order for this research to uncover therapeutic targets for future treatment options. Overall, comprehensive, unbiased studies may yield novel insights into the regulatory role of alcohol-induced epigenetic modifications in the pathophysiology and neuropsychiatric correlates of AUD.

Background: Alcohol use disorder (AUD) is a grave mental health condition that can result in significant health and social consequences. The medications Naltrexone and Nalmefene are indicated for the treatment of AUD, with Naltrexone having received the most extensive research attention. Methods: The majority of papers assessing universal measures of alcohol consumption employed two primary metrics: total alcohol consumption (TAC) and the number of days per month where individuals engaged in heavy drinking (HDD). Indicators pertaining to the maintenance of complete abstinence were excluded due to the absence of sufficient data. The safety of both substances was also assessed, as were the frequency of side effects and independent patient dropout. The study also incorporated practical factors of the therapy, such as the route of administration, dosage regimen, and the drug's patient convenience, which can have a significant impact on adherence to therapy. Results: Nalmefene, administered in an "as needed" regimen, demonstrated statistically significant activity in reducing HDD and total alcohol consumption (TAC) among patients with AUD, particularly those with elevated World Health Organization (WHO) DRL risk. Preliminary findings from the ESENSE1 (Efficacy of Nalmefene in Alcohol Dependence; the first phase III study), ESENSE 2 (Efficacy of Nalmefene in Alcohol Dependence, the second phase III study), and SENSE (the final phase III long term-safety and cost-effectiveness study) studies indicate a substantial decrease in HDD and TAC following the initial month of treatment. These effects persist throughout the subsequent follow-up period. Several Japanese studies have corroborated the effectiveness of Nalmefene, demonstrating its efficacy across both short-term and long-term applications. Furthermore, these studies have substantiated its safety profile, indicating that there is no inherent risk of addiction or the emergence of withdrawal symptoms. The mild nature of adverse events (most commonly nausea and dizziness) led to a relatively low discontinuation rate of Nalmefene treatment. A subsequent study, employing a recognized methodology, corroborated the efficacy of psychosocial support in enhancing treatment outcomes. Meta-analyses demonstrate that Naltrexone exhibits comparable efficacy in reducing the frequency and severity of alcohol consumption. In select populations, the injectable form (LAI) of this pharmaceutical agent facilitates less frequent dosing, which is advantageous for the treatment process. A comparison of Nalmefene and Naltrexone reveals that the latter does not demonstrate a significant impact on the likelihood of individuals returning to heavy alcohol consumption. Conclusions: In the treatment of AUD, both naltrexone and nalmefene have been shown to yield positive outcomes, particularly in terms of reducing the HDD and TAC. According to the World Health Organization (WHO) classification, Nalmefene is indicated for individuals with a high risk of developing serious conditions. It has been demonstrated to produce rapid and sustained results while exhibiting a favorable safety profile, characterized by the absence of significant adverse effects. Naltrexone is a medication that has proven to be effective. LAI may have a positive impact on the efficacy of treatment.

Monoacylglycerol lipase (MAGL) is the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), a key regulator of endocannabinoid system tone, thereby influencing synaptic function and neuroinflammation. These processes are central to the neurobiology of substance use disorders (SUDs), yet the contribution of MAGL to addiction remains fragmented across studies. With growing interest in MAGL as a therapeutic and imaging target, a comprehensive synthesis is timely. This systematic review aimed to evaluate whether exposure to substances of abuse alters MAGL expression or activity, and whether manipulating MAGL function affects SUD-relevant outcomes. Following the PRISMA 2020 guidelines, we screened preclinical studies that assessed MAGL directly in the context of substance exposure. A total of 42 studies met the inclusion criteria. Chronic substance exposure led to modest, region-specific changes in MAGL protein expression. In the hippocampus, alcohol increased MAGL levels. In the striatum, levels were largely unchanged across substances. In the prefrontal cortex, changes were only seen after repeated stimulant exposure. Findings for opioids and ketamine were mixed and inconsistent across regions. MAGL inhibition consistently reduced withdrawal-like behaviors across cannabis, opioid, and nicotine models, but effects on reward-related behaviors were more variable - reducing opioid-related reward while showing less consistent effects in other models. Collectively, these findings from preclinical models of SUDs suggest a more robust role for MAGL in withdrawal-like-states than in reward. They highlight the need to better understand the dynamic endocannabinoid adaptations, including cannabinoid receptor function and 2-AG signaling, that shape addiction-related behaviors.

Objective: Mental and behavioral disorders due to psychoactive substance use, as defined by ICD-10 codes F10-F19, include a spectrum of substance use disorders such as acute intoxication, withdrawal, harmful use, and dependence related to alcohol, opioids, stimulants, cannabis, tobacco, and other substances. These conditions significantly increase the risk of suicide, yet national trends in suicide-related mortality among affected individuals remain underexplored. This study aimed to evaluate national trends in suicide and self-harm mortality among individuals with these disorders from 1999 to 2023. Methods: We conducted a retrospective analysis of U.S. death certificate data from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database (1999-2023). Decedents with mental and behavioral disorders due to psychoactive substance use were identified using ICD-10 codes F10-F19, encompassing acute intoxication, withdrawal, harmful use, and dependence. Suicide and self-harm deaths were defined by ICD-10 codes U03, X60-X84, and Y87. Age-adjusted mortality rates (AAMRs) per million and average annual percentage changes (AAPCs) were estimated using Joinpoint regression. Analyses were stratified by sex, age, race/ethnicity, and metropolitan status. Results: Between 1999 and 2023, 37,473 suicide-related deaths were identified among U.S. individuals with mental and behavioral disorders due to psychoactive substance use. AAMRs increased from 2.2 to 5.7 per million (AAPC: 3.31; p < .01). Males had higher mortality than females (6.6 vs. 2.9), though females had a steeper rate of increase over time. Middle-aged adults had the highest AAMR (8.2), followed by younger (6.9), older adults (3.4) and children and adolescents (1.1). Non-Hispanic (NH) American Indian/Alaska Native individuals (AI/AN) had the highest AAMR (13.5), followed by NH White (6.2), Hispanic/Latino (1.6), NH Black (1.6), and NH Asian/Pacific Islander (API) (1.4). From 1999 to 2000, non-metropolitan areas had higher AAMRs than metropolitan areas (6.5 vs. 4.3), with significant increases in both settings. Conclusions: Suicide-related mortality among individuals with mental and behavioral disorders due to psychoactive substance use has increased significantly increased in the United States from 1999 to 2023, demonstrating substantial disparities by sex, age, race/ethnicity, and geographic region. These findings highlight the critical need for integrated approaches in suicide prevention and substance-related treatment settings.

Dysregulation of the dynorphin (DYN) / kappa-opioid receptor (KOR) system is heavily implicated in symptoms of alcohol use disorder (AUD) including negative affective-like states that can drive maladaptive behavioral regulation. Substantial efforts have been made towards understanding the neurobiology of DYN / KOR dysregulation; however, the role of dynorphinergic islands of Calleja within the ventral striatum remain poorly understood. Presently, adult male Wistar rats were trained to self-administer 10% alcohol, exposed to either air or alcohol vapor for eight weeks, and alcohol self-administration and 22-kHz ultrasonic vocalizations (USVs) assessed during acute withdrawal. Subsequently, brains were extracted during acute withdrawal and DYN A-like immunoreactivity was measured in the ventral striatum. Alcohol vapor-exposed rats demonstrated increased alcohol consumption and 22-kHz USVs compared to air-exposed controls. Vapor-exposed rats additionally demonstrated increased DYN A-like immunoreactivity in the islands of Calleja. Moreover, the average DYN A neuron size positively correlated with the number of 22-kHz USVs in vapor exposed animals, but not in air-exposed controls. The present findings identify the islands of Calleja as a novel DYN-associated region that may be recruited during alcohol dependence with enhanced DYN plasticity in the islands of Calleja contributing to affective dysregulation in AUD and other neuropsychiatric conditions.

Quetiapine-induced pancreatitis is a rare but serious adverse effect of second-generation antipsychotics, often linked to metabolic derangements such as hypertriglyceridemia and diabetic ketoacidosis. We report a 78-year-old woman found unresponsive at home, with a history of nausea and vomiting in the preceding days. Laboratory evaluation revealed significantly elevated lipase and liver enzymes, and imaging confirmed acute pancreatitis. She had experienced multiple prior episodes of pancreatitis during long-term quetiapine therapy. Common causes, including alcohol use, gallstones, hypertriglyceridemia, hypercalcemia, and autoimmune disease, were rigorously excluded. Medication review revealed long-term quetiapine use. Quetiapine was discontinued during hospitalization, leading to rapid clinical improvement, and no other medications or risk factors were implicated. The temporal relationship between quetiapine use and symptom onset, along with resolution upon drug withdrawal, suggests probable quetiapine-induced pancreatitis. The recurrence during prolonged therapy highlights the potential for cumulative or direct drug toxicity, independent of metabolic derangements, and underscores the importance of monitoring for adverse effects in high-risk populations. Clinicians should be aware that quetiapine can rarely cause recurrent acute pancreatitis, possibly via direct toxicity, and maintain vigilance in elderly patients or those on long-term therapy.