Toxicological evaluation, postmortem case descriptions, and pharmacological activity of N,N-dimethylpentylone and related analogues.

Identification of N,N-dimethylpentylone (DMP) in counterfeit "Ecstasy" and "Molly" tablets poses risk to public health due to its adverse effects. Little information is available regarding the pharmacological activity or relevant blood or tissue concentrations of DMP, and even less is known about other structurally related beta-keto methylenedioxyamphetamine analogues on recreational drug markets, such as N-propyl butylone. Here, a novel toxicological assay utilizing liquid chromatography-tandem quadrupole mass spectrometry (LC-QQQ-MS) was developed and validated for the quantitation of DMP and five related synthetic cathinones (eutylone, pentylone, N-ethyl pentylone (NEP), N-propyl butylone, and N-cyclohexyl butylone), with chromatographic resolution from isomeric variants and quantitation performed by standard addition.

Responsible Use of Population Neuroscience Data in the ABCD: Towards Standards of Accountability and Integrity.

This editorial focuses on the issue of data misuse that is increasingly evidenced in social media as well as some premiere scientific journals. This issue is of critical importance to open science projects in general, and ABCD in particular, given the broad array of biological, behavioural and environmental information collected on this American sample of 12,000 youth and parents. ABCD data are already widely used with over 1,200 publications and twice as many citations per year as expected (relative citation index based on year, field and journal).

Optimizing retention strategies for opioid use disorder pharmacotherapy: The retention phase of the CTN-0100 trial (RDD).

Introduction And Background: The three medications approved to address OUD are effective in decreasing opioid use and morbidity and mortality; however, their utility is limited by high rates of dropout from treatment. The CTN-0100 trial will develop an evidence base for strategies to improve retention on buprenorphine and extended-release naltrexone.

Research Design And Methods: The National Drug Abuse Treatment Clinical Trials Network (CTN) study CTN-0100, "Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy" (RDD), is a multicenter, randomized, non-blinded trial enrolling more than a thousand patients from 18 community-based substance use disorder treatment programs.

Prevalence of cannabis consumption methods among people with medically recommended and nonmedical cannabis use in the United States.

Aims: Some cannabis consumption methods (e.g. smoking, vaping, dabbing) are associated with more harms than others (e.

Repetitive grooming behavior following aversive stimulus coincides with a decrease in anterior hypothalamic area activity.

The anterior hypothalamic area (AHA) is a key brain region for orchestrating defensive behaviors. Using in vivo calcium imaging in mice, we observed that AHA neuronal activity increases during foot shock delivery and foot-shock associated auditory cues. We found that following shock-induced increases in AHA activity, a decrease in activity coincides with the onset of grooming behavior.

Accumbal acetylcholine signals associative salience.

Learning in dynamic environments requires animals to not only associate cues with outcomes but also to determine cue salience, which modulates how quickly related associations are updated. While dopamine (DA) in the nucleus accumbens core (NAcc) has been implicated in learning associations, the mechanisms of salience are less understood. Here, we tested the hypothesis that acetylcholine (ACh) in the NAcc encodes cue salience.

Extracellular RNA communication: A decade of NIH common fund support illuminates exRNA biology.

The discovery that extracellular RNAs (exRNA) can act as endocrine signalling molecules established a novel paradigm in intercellular communication. ExRNAs can be transported, both locally and systemically in virtually all body fluids. In association with an array of carrier vehicles of varying complexity, exRNA can alter target cell phenotype.

Phase 1b/2a safety study of lemborexant as an adjunctive treatment for insomnia to buprenorphine-naloxone for opioid use disorder: A randomized controlled trial.

Background: Evidence supports the common incidence of sleep disturbance in opioid use disorder (OUD) as a potential marker of disrupted orexin system functioning. This study evaluated the initial safety and tolerability of a challenge dose of lemborexant, a dual orexin antagonist, as an adjunct to buprenorphine/naloxone.

Methods: Patients (18-65 years old) with OUD receiving sublingual buprenorphine/naloxone, with a Pittsburgh Sleep Quality Index total score of 6 or higher, were recruited from outpatient clinics.

Ligand Reorganization for End-Point Binding Free Energy Calculations: Identifying Preferred Poses of Fentanyls in the μ Opioid Receptor.

We have developed a method that uses energy landscapes of unbound and bound ligands to compute reorganization free energies for end-point binding free-energy calculations. The method is applied to our previous simulations of fentanyl derivatives bound to the μ opioid receptor in different orientations. Whereas the mean interaction energy provides an ambiguous ranking of binding poses, interaction entropy and ligand reorganization strongly penalize geometric decoys such that native poses observed in CryoEM structures are best ranked.

Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation.

Lymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinson's disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of α-synuclein (αSyn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic αSyn propagation.

Opioid use disorder prevalence in 57 New York counties from 2017 to 2019: A Bayesian evidence synthesis.

Introduction: Prevalence estimates of opioid use disorder (OUD) at local levels are critical for public health planning and surveillance, yet largely unavailable across the US especially at the local county level.

Methods: We used a Bayesian evidence synthesis approach to estimate the prevalence of OUD for 57 counties across New York State for 2017-2019 and compare rates of OUD across counties as well as assess the extent of undiagnosed OUD. We developed a generative model to assess conditional probabilistic relations between different subgroups of the OUD population defined by diagnosis, treatment, and overdose fatality.

N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3.

Most adhesion GPCRs undergo autoproteolytic cleavage during receptor biosynthesis, resulting in non-covalently bound N- and C-terminal fragments (NTF and CTF) that remain associated during receptor trafficking to the plasma membrane. While substantial evidence supports increased G protein signaling when just the CTF is expressed, there is an ongoing debate about whether NTF removal is required to initiate signaling in the context of the wild-type receptor. Here, we use adhesion GPCR latrophilin-3 (ADGRL3) as a model receptor to investigate tethered agonist-mediated activation.

Miniscope Imaging of Nucleus Accumbens Neural Activity in Freely Behaving Rats: Virus Injection, Gradient Index Lens Implantation, Recording Strategies, and Analytical Methods.

In vivo calcium imaging in freely moving rats using miniscopes provides valuable information about the neural mechanisms of behavior in real time. A gradient index (GRIN) lens can be implanted in deep brain structures to relay activity from single neurons. While such procedures have been successful in mice, few reports provide detailed procedures for successful surgery and long-term imaging in rats, which are better suited for studying complex human behaviors.

Global Epidemiology of Alcohol-Related Liver Disease, Liver Cancer, and Alcohol Use Disorder, 2000-2021.

Background/aims: Alcohol represents a leading burden of disease worldwide, including alcohol use disorder (AUD) and alcohol-related liver disease (ALD). We aim to assess the global burden of AUD, ALD, and alcohol-attributable primary liver cancer between 2000-2021.

Methods: We registered the global and regional trends of AUD, ALD, and alcohol-related liver cancer using data from the Global Burden of Disease 2021 Study, the largest and most up-to-date global epidemiology database.

Sex disparities in outcome of medication-assisted therapy of opioid use disorder: Nationally representative outpatient clinic data.

Question: The opioid epidemic causes massive morbidity, and males have substantially greater overdose mortality rates than females. It is unclear whether there are sex-related disparities at different stages in the trajectory of opioid use disorders (OUD), from large samples in the community.

Goal: To determine sex disparities in non-medical opioid use (NMOU) at the end of treatment with medications for opioid use disorder (MOUD), using national data.

Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence.

Importance: The extent to which neuroanatomical variability associated with early substance involvement, which is associated with subsequent risk for substance use disorder development, reflects preexisting risk and/or consequences of substance exposure remains poorly understood.

Objective: To examine neuroanatomical features associated with early substance use initiation and to what extent associations may reflect preexisting vulnerability.

Design, Setting, And Participants: Cohort study using data from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study.

The curious case of dopaminergic prediction errors and learning associative information beyond value.

Transient changes in the firing of midbrain dopamine neurons have been closely tied to the unidimensional value-based prediction error contained in temporal difference reinforcement learning models. However, whereas an abundance of work has now shown how well dopamine responses conform to the predictions of this hypothesis, far fewer studies have challenged its implicit assumption that dopamine is not involved in learning value-neutral features of reward. Here, we review studies in rats and humans that put this assumption to the test, and which suggest that dopamine transients provide a much richer signal that incorporates information that goes beyond integrated value.

Does semaglutide reduce alcohol intake in Danish patients with alcohol use disorder and comorbid obesity? Trial protocol of a randomised, double-blinded, placebo-controlled clinical trial (the SEMALCO trial).

Introduction: Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies.

Bariatric surgery and alcohol and substance use: A case-control survey study.

Purpose: Studies suggest alcohol and/or other substance misuse may develop after bariatric surgery (BS), but findings are not consistent or conclusive.

Procedures: This cross-sectional online survey investigated alcohol and other substance use, via a modified version of the Alcohol Use Disorders Identification Test, before and after bariatric surgery, compared to a non-bariatric surgery sample. Data were anonymously collected via Qualtrics from adults who reported alcohol or substance use (BS, n = 328; non-BS, n = 292).