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Addiction Biology Jun 2024A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However,...
A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However, it has yet to be established whether AUD is associated with abnormal interhemispheric and intrahemispheric functional connection patterns. In the present study, we analysed resting-state functional magnetic resonance imaging data from 55 individuals with AUD and 32 healthy nonalcohol users. For each subject, whole-brain functional connectivity density (FCD) was decomposed into ipsilateral and contralateral parts. Correlation analysis was performed between abnormal FCD and a range of clinical measurements in the AUD group. Compared with healthy controls, the AUD group exhibited a reduced global FCD in the anterior and middle cingulate gyri, prefrontal cortex and thalamus, along with an enhanced global FCD in the temporal, parietal and occipital cortices. Abnormal interhemispheric and intrahemispheric FCD patterns were also detected in the AUD group. Furthermore, abnormal global, contralateral and ipsilateral FCD data were correlated with the mean amount of pure alcohol and the severity of alcohol addiction in the AUD group. Collectively, our findings indicate that global, interhemispheric and intrahemispheric FCD may represent a robust method to detect abnormal functional connection patterns in AUD; this may help us to identify the neural substrates and therapeutic targets of AUD.
Topics: Humans; Male; Alcoholism; Magnetic Resonance Imaging; Adult; Brain; Middle Aged; Prefrontal Cortex; Thalamus; Case-Control Studies; Gyrus Cinguli; Brain Mapping; Young Adult
PubMed: 38899438
DOI: 10.1111/adb.13398 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424 -
Frontiers in Public Health 2024American Indian/Alaska Native (AI/AN) communities are more likely to suffer negative consequences related to substance misuse. The COVID-19 pandemic exacerbated the...
INTRODUCTION
American Indian/Alaska Native (AI/AN) communities are more likely to suffer negative consequences related to substance misuse. The COVID-19 pandemic exacerbated the opioid poisoning crisis, in combination with ongoing treatment barriers resulting from settler-colonialism, systemic oppression and racial discrimination. AI/AN adults are at greatest risk of COVID-19 related serious illness and death. In collaboration with an Indigenous community advisory board and Tribal leadership, this study explored AI/AN treatment provider perceptions of client-relatives' (i.e., SUD treatment recipients) experiences during the pandemic from 2020 to 2022.
METHODS
Providers who underwent screening and were eligible to participate ( = 25) represented 6 programs and organizations serving rural and urban areas in Washington, Utah, and Minnesota. Participants engaged in audio-recorded 60-90 min semi-structured individual interviews conducted virtually via Zoom. The interview guide included 15 questions covering regulatory changes, guidance for telemedicine, policy and procedures, staff communication, and client-relatives' reactions to implemented changes, service utilization, changes in treatment modality, and perceptions of impact on their roles and practice. Interview recordings were transcribed and de-identified. Members of the research team independently reviewed transcripts before reaching consensus. Coding was completed in Dedoose, followed by analyses informed by a qualitative descriptive approach.
RESULTS
Five main domains were identified related to client-relative experiences during the COVID-19 pandemic, as observed by providers: (1) accessibility, (2) co-occurring mental health, (3) social determinants of health, (4) substance use, coping, and harm reduction strategies, and (5) community strengths. Providers reported the distinctive experiences of AI/AN communities, highlighting the impact on client-relatives, who faced challenges such as reduced income, heightened grief and loss, and elevated rates of substance use and opioid-related poisonings. Community and culturally informed programming promoting resilience and healing are outlined.
CONCLUSION
Findings underscore the impact on SUD among AI/AN communities during the COVID-19 pandemic. Identifying treatment barriers and mental health impacts on client-relatives during a global pandemic can inform ongoing and future culturally responsive SUD prevention and treatment strategies. Elevating collective voice to strengthen Indigenous informed systems of care to address the gap in culturally-and community-based services, can bolster holistic approaches and long-term service needs to promote SUD prevention efforts beyond emergency response efforts.
Topics: Humans; COVID-19; Alaska Natives; Opioid-Related Disorders; Adult; Female; Male; Substance-Related Disorders; Indians, North American; American Indian or Alaska Native; SARS-CoV-2; Middle Aged; United States; Qualitative Research
PubMed: 38898893
DOI: 10.3389/fpubh.2024.1356033 -
BMC Public Health Jun 2024In Canada, substance-related accidental acute toxicity deaths (AATDs) continue to rise at the national and sub-national levels. However, it is unknown if, where, when,...
OBJECTIVES
In Canada, substance-related accidental acute toxicity deaths (AATDs) continue to rise at the national and sub-national levels. However, it is unknown if, where, when, and to what degree AATDs cluster in space, time, and space-time across the country. The objectives of this study were to 1) assess for clusters of AATDs that occurred in Canada during 2016 and 2017 at the national and provincial/territorial (P/T) levels, and 2) examine the substance types detected in AATD cases within each cluster.
METHODS
Two years of person-level data on AATDs were abstracted from coroner and medical examiner files using a standardized data collection tool, including the decedent's postal code and municipality information on the places of residence, acute toxicity (AT) event, and death, and the substances detected in the death. Data were combined with Canadian census information to create choropleth maps depicting AATD rates by census division. Spatial scan statistics were used to build Poisson models to identify clusters of high rates (p < 0.05) of AATDs at the national and P/T levels in space, time, and space-time over the study period. AATD cases within clusters were further examined for substance types most present in each cluster.
RESULTS
Eight clusters in five regions of Canada at the national level and 24 clusters in 15 regions at the P/T level were identified, highlighting where AATDs occurred at far higher rates than the rest of the country. The risk ratios of identified clusters ranged from 1.28 to 9.62. Substances detected in clusters varied by region and time, however, opioids, stimulants, and alcohol were typically the most commonly detected substances within clusters.
CONCLUSION
Our findings are the first in Canada to reveal the geographic disparities in AATDs at national and P/T levels using spatial scan statistics. Rates associated with substance types within each cluster highlight which substance types were most detected in the identified regions. Findings may be used to guide intervention/program planning and provide a picture of the 2016 and 2017 context that can be used for comparisons of the geographic distribution of AATDs and substances with different time periods.
Topics: Humans; Canada; Female; Male; Adult; Spatio-Temporal Analysis; Middle Aged; Adolescent; Young Adult; Substance-Related Disorders; Cluster Analysis; Aged
PubMed: 38898445
DOI: 10.1186/s12889-024-18883-2 -
BMC Public Health Jun 2024Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic...
BACKGROUND
Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic progress. The United States (US) also suffers a heavy burden, it is necessary to figure out the situation from multiple perspectives and take effective measures to deal with it. Therefore, using the data from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, we evaluated this topic.
METHODS
Annual data on DUDs-related burden were collected from the GBD study 2021. We calculated the indicator of estimated annual percentage change (EAPC) to evaluate the changing trend of burden. The Bayesian model for age-period-cohort was introduced to forecast the burden.
RESULTS
In 2021, the number and age-standardized rate of prevalence were particularly prominent, with 12,146.95 thousand and 3821.43 per 100,000, respectively. Higher burden was also observed in males, 15-45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia; and the national death-related burden with the highest increase (EAPC = 7.96). Other significant inverse associations were seen between EAPC, age-standardized rates, and socio-demographic index (SDI). Moreover, in the next 14 years, the projected DUDs burden remains exigent.
CONCLUSIONS
The burden of DUDs in the US is heavy and has been enlarging. This study proposes that greater attention should be paid to the strategies in males, the younger population, opioid use disorders, and low-SDI states implemented by decision-makers to achieve goals such as reducing burden.
Topics: Humans; United States; Male; Middle Aged; Adult; Female; Adolescent; Young Adult; Substance-Related Disorders; Bayes Theorem; Aged; Cost of Illness; Global Burden of Disease; Forecasting; Prevalence
PubMed: 38898398
DOI: 10.1186/s12889-024-19142-0 -
Nature Communications Jun 2024Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a...
Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA receptor modulation through transmembrane binding sites.
Topics: Receptors, GABA-A; Binding Sites; Cryoelectron Microscopy; Humans; Animals; Etomidate; Propofol; Quinazolinones; Allosteric Regulation; HEK293 Cells; Hypnotics and Sedatives
PubMed: 38898000
DOI: 10.1038/s41467-024-49471-y -
Translational Psychiatry Jun 2024Functional inhibition is known to improve treatment outcomes in substance use disorder (SUD), potentially through craving management enabled by underlying cerebral...
Functional inhibition is known to improve treatment outcomes in substance use disorder (SUD), potentially through craving management enabled by underlying cerebral integrity. Whereas treatment is challenged by a multitude of substances that patients often use, no study has yet unraveled if inhibition and related cerebral integrity could prevent relapse from multiples substances, that is, one's primary drug of choice and secondary ones. Individuals with primary alcohol, cannabis, or tobacco use disorders completed intensive Ecological Momentary Assessment (EMA) coupled with resting-state functional MRI (rs-fMRI) to characterize the extent to which inhibition and cerebral substrates interact with craving and use of primary and any substances. Participants were 64 patients with SUD and 35 healthy controls who completed one week EMA using Smartphones to report 5 times daily their craving intensity and substance use and to complete Stroop inhibition testing twice daily. Subsamples of 40 patients with SUD and 34 control individuals underwent rs-fMRI. Mixed Model Analysis revealed that reported use of any substance by SUD individuals predicted later use of any and primary substance, whereas use of the primary substance only predicted higher use of that same substances. Craving and inhibition level independently predicted later use but did not significantly interact. Preserved inhibition performance additionally influenced use indirectly by mediating the link between subsequent uses and by being linked to rs-fMRI connectivity strength in fronto-frontal and cerebello-occipital connections. As hypothesized, preserved inhibition performance, reinforced by the integrity of inhibitory neurofunctional substrates, may partake in breaking an unhealthy substance use pattern for a primary substance but may not generalize to non-target substances or to craving management.
Topics: Humans; Magnetic Resonance Imaging; Female; Male; Adult; Ecological Momentary Assessment; Substance-Related Disorders; Craving; Inhibition, Psychological; Middle Aged; Brain; Young Adult
PubMed: 38897999
DOI: 10.1038/s41398-024-02949-1 -
Ciencia & Saude Coletiva Jun 2024The rise in the study of sexualised drug use among gay, bisexual and other men who have sex with men (MSM), known as chemsex, has generated a multiplicity of data that...
The rise in the study of sexualised drug use among gay, bisexual and other men who have sex with men (MSM), known as chemsex, has generated a multiplicity of data that contribute to its problematisation as a public health issue through the link with HIV and addictions. The study of these practices, from a biomedical paradigm, has focused on risk and has contributed to its reduction as a unique and quantifiable phenomenon. This study aims to explore the experience of risk in the course of the practices, to find out what management strategies they employ in the face of risk and how they are generated. Semi-structured interviews were conducted with five chemsex practitioners in the Metropolitan Area of Barcelona and, subsequently, a thematic analysis was applied. The findings show how these men detect, assume and confront the risks present in these practices, where the type of relationships that take place and the social circle available to them are relevant. This study also highlights the creation of strategies based on experience and how the transmission of this knowledge among participants facilitates decision-making and risk management.
Topics: Humans; Male; Substance-Related Disorders; Homosexuality, Male; Interviews as Topic; Risk Management; Sexual and Gender Minorities; Qualitative Research; HIV Infections; Risk-Taking; Adult; Spain; Decision Making; Sexual Behavior; Middle Aged
PubMed: 38896677
DOI: 10.1590/1413-81232024296.10752023 -
JMIR Mental Health Jun 2024Internet-based cognitive behavioral interventions (iCBTs) are efficacious treatments for depression and anxiety. However, it is unknown whether adding human guidance is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Internet-based cognitive behavioral interventions (iCBTs) are efficacious treatments for depression and anxiety. However, it is unknown whether adding human guidance is feasible and beneficial within a large educational setting.
OBJECTIVE
This study aims to potentially demonstrate the superiority of 2 variants of a transdiagnostic iCBT program (human-guided and computer-guided iCBT) over care as usual (CAU) in a large sample of university students and the superiority of human-guided iCBT over computer-guided iCBT.
METHODS
A total of 801 students with elevated levels of anxiety, depression, or both from a large university in the Netherlands were recruited as participants and randomized to 1 of 3 conditions: human-guided iCBT, computer-guided iCBT, and CAU. The primary outcome measures were depression (Patient Health Questionnaire) and anxiety (Generalized Anxiety Disorder scale). Secondary outcomes included substance use-related problems (Alcohol Use Disorder Identification Test and Drug Abuse Screening Test-10 items). Linear mixed models were used to estimate the effects of time, treatment group, and their interactions (slopes). The primary research question was whether the 3 conditions differed in improvement over 3 time points (baseline, midtreatment, and after treatment) in terms of depression and anxiety symptoms. Results were analyzed according to the intention-to-treat principle using multiple imputation. Patients were followed exploratively from baseline to 6 and 12 months.
RESULTS
In both short-term and long-term analyses, the slopes for the 3 conditions did not differ significantly in terms of depression and anxiety, although both web-based interventions were marginally more efficacious than CAU over 6 months (P values between .02 and .03). All groups showed significant improvement over time (P<.001). For the secondary outcomes, only significant improvements over time (across and not between groups) were found for drug use (P<.001). Significant differences were found in terms of adherence, indicating that participants in the human-guided condition did more sessions than those in the computer-guided condition (P=.002).
CONCLUSIONS
The transdiagnostic iCBT program offers a practical, feasible, and efficacious alternative to usual care to tackle mental health problems in a large university setting. There is no indication that human guidance should be preferred over technological guidance. The potential preference of human support also depends on the scale of implementation and cost-effectiveness, which need to be addressed in future trials.
TRIAL REGISTRATION
International Clinical Trials Registry Platform NL7328/NTR7544; https://trialsearch.who.int/Trial2.aspx?TrialID=NL-OMON26795.
Topics: Humans; Cognitive Behavioral Therapy; Male; Female; Students; Universities; Young Adult; Adult; Therapy, Computer-Assisted; Internet-Based Intervention; Depression; Anxiety; Netherlands; Internet; Adolescent; Treatment Outcome
PubMed: 38896474
DOI: 10.2196/50503 -
Hepatology Communications Jul 2024The recent increase in the incidence of alcohol-associated hepatitis (AH) coincides with the obesity epidemic in the United States. However, current mouse models do not...
BACKGROUND
The recent increase in the incidence of alcohol-associated hepatitis (AH) coincides with the obesity epidemic in the United States. However, current mouse models do not fully replicate the combined insults of obesity, metabolic dysfunction-associated steatohepatitis, and alcohol. The aim of this study was to develop a new mouse model that recapitulates the robust inflammatory and fibrotic phenotype characteristic of human MetALD.
METHODS
Eight- to 10-week-old male C57BL/6 mice were fed chow or high fat-cholesterol-sugar diet (metabolic dysfunction-associated steatohepatitis diet) and in each group, some received alcohol in drinking water (ad libitum) and weekly alcohol binges (EtOH) for 3 months. The liver was assessed for features of AH.
RESULTS
MetALD mice displayed increased liver damage indicated by highly elevated ALT and bilirubin levels compared to all other groups. Liver steatosis was significantly greater in the MetALD mice compared to all other experimental groups. The inflammatory phenotype of MetALD was also recapitulated, including increased IL-6 and IL-1β protein levels as well as increased CD68+ macrophages and Ly6G+ neutrophils in the liver. Sirius red staining and expression of collagen 1, alpha-smooth muscle actin indicated advanced fibrosis in the livers of MetALD mice. In addition, indicators of epithelial-to-mesenchymal transition markers were increased in MetALD mice compared to all other groups. Furthermore, we found increased ductular reaction, dysregulated hedgehog signaling, and decreased liver synthetic functions, consistent with severe AH.
CONCLUSIONS
Alcohol administration in mice combined with metabolic dysfunction-associated steatohepatitis diet recapitulates key characteristics of human AH including liver damage, steatosis, robust systemic inflammation, and liver immune cell infiltration. This model results in advanced liver fibrosis, ductular reaction, decreased synthetic function, and hepatocyte dedifferentiation, suggesting a robust model of MetALD in mice.
Topics: Animals; Male; Mice; Disease Models, Animal; Mice, Inbred C57BL; Hepatitis, Alcoholic; Diet, High-Fat; Liver; Ethanol
PubMed: 38896082
DOI: 10.1097/HC9.0000000000000450