Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2-Metabolome, immunome, synaptome.

The second part of this paper builds upon and expands the epigenomic-aging perspective presented in Part 1 to describe the metabolomic and immunomic bases of the epigenomic-aging changes and then considers in some detail the application of these insights to neurotoxicity, neuronal epigenotoxicity, and synaptopathy. Cannabinoids are well-known to have bidirectional immunomodulatory activities on numerous parts of the immune system. Immune perturbations are well-known to impact the aging process, the epigenome, and intermediate metabolism.

Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1-aging and epigenomics.

Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks.

Cannabis- and Substance-Related Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Study.

Recent European data facilitate an epidemiological investigation of the controversial cannabis-cancer relationship. Of particular concern were prior findings associating high-dose cannabis use with reproductive problems and potential genetic impacts. Cancer incidence data age-standardised to the world population was obtained from the European Cancer Information System 2000-2020 and many European national cancer registries.

The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance.

Background: Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of αβ2δ gamma-aminobutyric acid A receptors.

Objective: To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data.

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration.

As global interest in the therapeutic potential of cannabis and its' derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients.

Geospatiotemporal and Causal Inferential Study of European Epidemiological Patterns of Cannabis- and Substance-Related Congenital Orofacial Anomalies.

Introduction: Since high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe.

Methods: CA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

Patterns of Cannabis- and Substance-Related Congenital General Anomalies in Europe: A Geospatiotemporal and Causal Inferential Study.

Introduction: Recent series of congenital anomaly (CA) rates (CARs) have showed the close and epidemiologically causal relationship of cannabis exposure to many CARs. We investigated these trends in Europe where similar trends have occurred.

Methods: CARs from EUROCAT.

An intervention at an adult inpatient unit to engage people with schizophrenia and work goals with supported employment.

Objective: Test an intervention for individuals with schizophrenia at an Adult Inpatient Unit with employment and social inclusion goals, compared to treatment as usual.

Method: A single-blind, randomised, controlled trial assigned 25 participants to treatment as usual and 26 participants to receive an Individual Placement and Support (IPS) Disability Employment Service (DES) information pack and an offer of support from a nurse. Outcomes were measured at 6 and 12 months using Job Acquisition, IPS DES employment provider, Activity Participation Questionnaire-Revised, Brief Psychiatric Rating Scale, and Adult Hope Scale questionnaires, and Digit Span and Trail Making tests.

Novel Insights into Potential Cannabis-Related Cancerogenesis from Recent Key Whole Epigenome Screen of Cannabis Dependence and Withdrawal: Epidemiological Commentary and Explication of Schrott et al.

Whilst the cannabis-cancer link has been traditionally described as controversial recent whole nation and whole continent studies have demonstrated that well documented laboratory-based multimodal cannabinoid genotoxicity is indeed reflected in numerous cancer types in larger epidemiological series. A recent longitudinal human sperm epigenome-wide DNA methylation screen in both cannabis dependence and cannabis withdrawal has revealed remarkable insights into the manner in which widespread perturbations of DNA methylation may lead to cancerogenic changes in both the exposed and subsequent generations as a result of both cannabis exposure and withdrawal. These results therefore powerfully strengthen and further robustify the causal nature of the relationship between cannabinoid exposure and cancerous outcomes well beyond the previously published extensive mechanistic literature on cannabinoid genotoxicity.

European Epidemiological Patterns of Cannabis- and Substance-Related Congenital Neurological Anomalies: Geospatiotemporal and Causal Inferential Study.

Introduction. Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations.

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis.

Background: Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality.

Methods: Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results.

Epidemiological Patterns of Cannabis- and Substance- Related Congenital Uronephrological Anomalies in Europe: Geospatiotemporal and Causal Inferential Study.

Introduction: Recent reports linking prenatal and community cannabis exposure to elevated uronephrological congenital anomaly (UCA) rates (UCAR's) raise the question of its European epidemiology given recent increases in community cannabinoid penetration there.

Methods: UCAR data from Eurocat. Drug use data from European Monitoring Centre for Drugs and Drug Addiction.

Long-Term Management of Generalised Anxiety Disorder with Low-Dose Continuous Infusions of Flumazenil: A Case Series.

Background: Generalised anxiety disorder (GAD) is a common anxiety disorder associated with social and occupational impairment. Recently, a theory was postulated that dysfunctional gamma aminobutyric acid type A receptors (GABA) are implicated in anxiety symptomology, which could be corrected by flumazenil, an antagonist at the benzodiazepine binding site on the GABA receptor.

Method: Participants had a primary diagnosis of GAD and were treated initially with an eight-day continuous low-dose flumazenil infusion (total 32 mg at a rate of 4 mg/24 h).

Socioeconomic, Ethnocultural, Substance- and Cannabinoid-Related Epidemiology of Down Syndrome USA 1986-2016: Combined Geotemporospatial and Causal Inference Investigation.

Background: Down syndrome (DS) is the commonest of the congenital genetic defects whose incidence has been rising in recent years for unknown reasons. This study aims to assess the impact of substance and cannabinoid use on the DS Rate (DSR) and assess their possible causal involvement.

Methods: An observational population-based epidemiological study 1986-2016 was performed utilizing geotemporospatial and causal inferential analysis.

Is the Precipitation of Anxiety Symptoms Associated with Bolus Doses of Flumazenil a Barrier to Its Use at Low Continuous Doses in Benzodiazepine Withdrawal?

Introduction: Benzodiazepines (BZDs) are used in the management of anxiety and sleep disorders; however, chronic use is associated with tolerance and dependence. During withdrawal, symptoms of anxiety are often severe and problematic for patients and may lead to relapse or maintenance on low doses of BZDs. Low, continuous doses of flumazenil reduce BZD withdrawal symptoms in several studies; however, bolus doses are known to induce anxiety and precipitate panic.

State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA.

Background: The cause of the worldwide doubling-tripling of testicular cancer rates (TCRs) in recent decades is unknown. Previous cohort studies associated cannabis use with TCR including dose-response relationships but the contribution of cannabis to TCRs at the population level is unknown. This relationship was tested by analyzing annual trends across US states and formally assessed causality.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r > 0.

Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study.

Introduction: Laboratory data link cannabinoid exposure to chromosomal mis-segregation errors. Recent epidemiological reports confirm this link and raise concern that elevated chromosomal congenital anomaly rates (CCAR) may be occurring in Europe which is experiencing increased cannabis use, daily intensity of use and cannabinoid potency.

Methods: CCAR data from Eurocat.

European epidemiological patterns of cannabis- and substance-related congenital cardiovascular anomalies: geospatiotemporal and causal inferential study.

As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est.

European Epidemiological Patterns of Cannabis- and Substance-Related Body Wall Congenital Anomalies: Geospatiotemporal and Causal Inferential Study.

As body wall congenital anomalies (BWCAs) have a long history of being associated with prenatal or community cannabis exposure (CCE), it was of interest to investigate these epidemiological relationships in Europe given the recent increases in cannabis use prevalence, daily intensity, and Δ9-tetrahydrocannabinol (THC) potency. Methods: This study makes use of BWCA data from Eurocat, drug exposure data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Results: The mapping analysis showed that BWCARs increased in France, Spain, and the Netherlands.

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study.

The use of Δ8THC is increasing at present across the USA in association with widespread cannabis legalization and the common notion that it is "legal weed". As genotoxic actions have been described for many cannabinoids, we studied the cancer epidemiology of Δ8THC. Data on 34 cancer types was from the Centers for Disease Control Atlanta Georgia, substance abuse data from the Substance Abuse and Mental Health Services Administration, ethnicity and income data from the U.