Associations Between Canada's Cannabis Legalization and Emergency Department Presentations for Transient Cannabis-Induced Psychosis and Schizophrenia Conditions: Ontario and Alberta, 2015-2019.

OBJECTIVE: Cannabis legalization in many jurisdictions worldwide has raised concerns that such legislation might increase the burden of transient and persistent psychotic illnesses in society. Our study aimed to address this issue. METHODS: Drawing upon emergency department (ED) presentations aggregated across Alberta and Ontario, Canada records (April 1, 2015-December 31, 2019), we employed Seasonal Autoregressive Integrated Moving Average (SARIMA) models to assess associations between Canada's cannabis legalization (via the Cannabis Act implemented on October 17, 2018) and weekly ED presentation counts of the following ICD-10-CA-defined target series of cannabis-induced psychosis (F12.5; n = 5832) and schizophrenia and related conditions ("schizophrenia"; F20-F29; n = 211,661), as well as two comparison series of amphetamine-induced psychosis (F15.5; n = 10,829) and alcohol-induced psychosis (F10.5; n = 1,884). RESULTS: ED presentations for cannabis-induced psychosis doubled between April 2015 and December 2019. However, across all four SARIMA models, there was no evidence of significant step-function effects associated with cannabis legalization on post-legalization weekly ED counts of: (1) cannabis-induced psychosis [0.34 (95% CI -4.1; 4.8; P = 0.88)]; (2) schizophrenia [24.34 (95% CI -18.3; 67.0; P = 0.26)]; (3) alcohol-induced psychosis [0.61 (95% CI -0.6; 1.8; P = 0.31); or (4) amphetamine-induced psychosis [1.93 (95% CI -2.8; 6.7; P = 0.43)]. CONCLUSION: Implementation of Canada's cannabis legalization framework was not associated with evidence of significant changes in cannabis-induced psychosis or schizophrenia ED presentations. Given the potentially idiosyncratic rollout of Canada's cannabis legalization, further research will be required to establish whether study results generalize to other settings.

Polysubstance use poisoning deaths in Canada: an analysis of trends from 2014 to 2017 using mortality data.

BACKGROUND: Over the past decade, rates of drug poisoning deaths have increased dramatically in Canada. Current evidence suggests that the non-medical use of synthetic opioids, stimulants and patterns of polysubstance use are major factors contributing to this increase. METHODS: Counts of substance poisoning deaths involving alcohol, opioids, other central nervous system (CNS) depressants, cocaine, and CNS stimulants excluding cocaine, were acquired from the Canadian Vital Statistics Death Database (CVSD) for the years 2014 to 2017. We used joinpoint regression analysis and the Cochrane-Armitage trend test for proportions to examine changes over time in crude mortality rates and proportions of poisoning deaths involving more than one substance. RESULTS: Between 2014 and 2017, the rate of substance poisoning deaths in Canada almost doubled from 6.4 to 11.5 deaths per 100,000 population (Average Annual Percent Change, AAPC: 23%, p < 0.05). Our analysis shows this was due to increased unintentional poisoning deaths (AAPC: 26.6%, p < 0.05) and polysubstance deaths (AAPC: 23.0%, p < 0.05). The proportion of unintentional poisoning deaths involving polysubstance use increased significantly from 38% to 58% among males (p < 0.0001) and 40% to 55% among females (p < 0.0001). Polysubstance use poisonings involving opioids and CNS stimulants (excluding cocaine) increased substantially during the study period (males AAPC: 133.1%, p < 0.01; females AAPC: 118.1%, p < 0.05). CONCLUSIONS: Increases in substance-related poisoning deaths between 2014 and 2017 were associated with polysubstance use. Increased co-use of stimulants with opioids is a key factor contributing to the epidemic of opioid deaths in Canada.

Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration.

Cells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to downregulate an Arf6-dependent recycling pathway for ß1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors. Importantly, the phenotypes of decreased cell adhesion and increased cell migration observed following Rab35 knock down are consistent with the epithelial-mesenchymal transition, a feature of invasive cancer cells, and we show that Rab35 expression is suppressed in a subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a key molecular mechanism that efficiently coordinates the inverse intracellular sorting and cell surface levels of cadherin and integrin receptors for cell migration and differentiation.

Service-level barriers to and facilitators of accessibility to treatment for problematic alcohol use: a scoping review.

Introduction: Services to treat problematic alcohol use (PAU) should be highly accessible to optimize treatment engagement. We conducted a scoping review to map characteristics of services for the treatment of PAU that have been reported in the literature to be barriers to or facilitators of access to treatment from the perspective of individuals with PAU. Methods: A protocol was developed a priori, registered, and published. We searched MEDLINE®, Embase, the Cochrane Library, and additional grey literature sources from 2010 to April 2022 to identify primary qualitative research and surveys of adults with current or past PAU requiring treatment that were designed to identify modifiable characteristics of PAU treatment services (including psychosocial and pharmacologic interventions) that were perceived to be barriers to or facilitators of access to treatment. Studies of concurrent PAU and other substance use disorders were excluded. Study selection was performed by multiple review team members. Emergent barriers were coded and mapped to the accessibility dimensions of the Levesque framework of healthcare access, then descriptively summarized. Results: One-hundred-and-nine included studies reported an extensive array of unique service-level barriers that could act alone or together to prevent treatment accessibility. These included but were not limited to lack of an obvious entry point, complexity of the care pathway, high financial cost, unacceptably long wait times, lack of geographically accessible treatment, inconvenient appointment hours, poor cultural/demographic sensitivity, lack of anonymity/privacy, lack of services to treat concurrent PAU and mental health problems. Discussion: Barriers generally aligned with recent reviews of the substance use disorder literature. Ranking of barriers may be explored in a future discrete choice experiment of PAU service users. The rich qualitative findings of this review may support the design of new or modification of existing services for people with PAU to improve accessibility. Systematic Review Registration: Open Science Framework doi: 10.17605/OSF.IO/S849R.

Evaluating how has care been affected by the Ontario COVID-19 Opioid Agonist Treatment Guidance: Patients' and prescribers' experiences with changes in unsupervised dosing.

BACKGROUND: The COVID-19 pandemic has exacerbated the opioid crisis. Opioid-related deaths have increased and access to treatment services, including opioid agonist treatment (OAT), has been disrupted. The Ontario COVID-19 OAT Treatment Guidance document was developed to facilitate access to OAT and continuity of care during the pandemic, while supporting physical distancing measures. In particular, the Guidance expanded access to unsupervised OAT dosing. It is important to evaluate the changes in unsupervised OAT dosing after the release of the Ontario COVID-19 OAT Guidance based on patients' and prescribers' reports. METHOD: Online questionnaires were developed collaboratively with people with lived and living expertise, prescribers, clinical experts, and researchers. Patients (N = 402) and prescribers (N = 100) reported their experiences with changes in unsupervised dosing during the first six months of the pandemic. RESULTS: Many patients (57%) reported receiving additional unsupervised OAT doses (i.e., take away doses). Patients who received additional unsupervised doses were not significantly more likely to report adverse health outcomes compared to patients who did not receive additional unsupervised doses. Patients with additional unsupervised doses and prescribers agreed that changes in OAT care were positive (e.g., reported an improved patient-prescriber relationship and more openness between patient and prescriber). Prescribers and some patients reported the need for continued flexibility in unsupervised doses after the pandemic restrictions lift. CONCLUSIONS: Results support the need to re-evaluate historical approaches to OAT care delivery, particularly unsupervised doses. It is crucial to implement policies, regulations, and supports to reduce barriers to OAT care during the pandemic and once the pandemic response restrictions are eased. Flexibility in OAT care delivery, particularly unsupervised dosing, will be key to providing patient-centred care for persons with opioid use disorder.

Service-level barriers to and facilitators of access to services for the treatment of alcohol use disorder and problematic alcohol use: protocol for a scoping review.

INTRODUCTION: Prior to the COVID-19 pandemic, substance use health services for treatment of alcohol use disorder and problematic alcohol use (AUD/PAU) were fragmented and challenging to access. The pandemic magnified system weaknesses, often resulting in disruptions of treatment as alcohol use during the pandemic rose. When treatment services were available, utilisation was often low for various reasons. Virtual care was implemented to offset the drop in in-person care, however accessibility was not universal. Identification of the characteristics of treatment services for AUD/PAU that impact accessibility, as perceived by the individuals accessing or providing the services, will provide insights to enable improved access. We will perform a scoping review that will identify characteristics of services for treatment of AUD/PAU that have been identified as barriers to or facilitators of service access from the perspectives of these groups. METHODS AND ANALYSIS: We will follow scoping review methodological guidance from the Joanna Briggs Institute. Using the OVID platform, we will search Ovid MEDLINE including Epub Ahead of Print and In-Process and Other Non-Indexed Citations, Embase Classic+Embase, APA PsychInfo, Cochrane Register of Controlled Trials, the Cochrane Database of Systematic Reviews and CINAHL (Ebsco Platform). Multiple reviewers will screen citations. We will seek studies reporting data collected from individuals with AUD/PAU or providers of treatment for AUD/PAU on service-level factors affecting access to care. We will map barriers to and facilitators of access to AUD/PAU treatment services identified in the relevant studies, stratified by service type and key measures of inequity across service users. ETHICS AND DISSEMINATION: This research will enhance awareness of existing evidence regarding barriers to and facilitators of access to services for the treatment of alcohol use disorder and problematic alcohol use. Findings will be disseminated through publications, conference presentations and a stakeholder meeting. As this is a scoping review of published literature, no ethics approval was required.

Psychotic disorder and cannabis use: Canadian hospitalization trends, 2006-2015. / Troubles psychotiques et consommation de cannabis : évolution des hospitalisations au Canada, 2006-2015.

INTRODUCTION: Given the recent and impending changes to the legal status of nonmedical cannabis use in Canada, understanding the effects of cannabis use on the health care system is important for evaluating the impact of policy change. The aim of this study was to examine pre-legalization trends in hospitalizations for mental and behavioural disorders due to the use of cannabis, according to demographics factors and clinical conditions. METHODS: We assessed the total number of inpatient hospitalizations for psychiatric conditions with a primary diagnosis of a mental or behavioural disorder due to cannabis use (ICD-10-CA code F12) from the Hospital Mental Health Database for ten years spanning 2006 to 2015, inclusive. We included hospitalizations from all provinces and territories except Quebec. Rates (per 100 000 persons) and relative proportions of hospitalizations by clinical condition, age group, sex and year are reported. RESULTS: Between 2006 and 2015, the rate of cannabis-related hospitalizations in Canada doubled. Of special note, however, is that hospitalizations during this time period for those with the clinical condition code "mental and behavioural disorders due to use of cannabinoids, psychotic disorder" (F12.5) tripled, accounting for almost half (48%) of all cannabis-related hospitalizations in 2015. CONCLUSION: Further research is required to investigate the reasons for the increase in hospitalizations for cannabis-related psychotic disorder. The introduction of high-potency cannabinoid products and synthetic cannabinoids into the illicit market are considered as possible factors.

Tumour necrosis factor-mediated homeostatic synaptic plasticity in behavioural models: testing a role in maternal immune activation.

The proinflammatory cytokine tumour necrosis factor-alpha (TNFα) has long been characterized for its role in the innate immune system, but more recently has been found to have a distinct role in the nervous system that does not overlap with other proinflammatory cytokines. Through regulation of neuronal glutamate and GABA receptor trafficking, TNF mediates a homeostatic form of synaptic plasticity, but plays no direct role in Hebbian forms of plasticity. As yet, there is no evidence to suggest that this adaptive plasticity plays a significant role in normal development, but it does maintain neuronal circuit function in the face of several types of disruption. This includes developmental plasticity in primary sensory cortices, as well as modulating the response to antidepressants, chronic antipsychotics and drugs of abuse. TNF is also a prominent component of the neuroinflammation occurring in most neuropathologies, but the role of TNF-mediated synaptic plasticity in this context remains to be determined. We tested this in a maternal immune activation (MIA) model of neurodevelopmental disorders. Using TNF-/- mice, we observed that TNF is not required for the expression of abnormal social or anxious behaviour in this model. This indicates that TNF does not uniquely contribute to the development of neuronal dysfunction in this model, and suggests that during neuroinflammatory events, compensation between the various proinflammatory cytokines is the norm.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

Microglial TNF-α Suppresses Cocaine-Induced Plasticity and Behavioral Sensitization.

Repeated administration of cocaine results in the development of behavioral sensitization, accompanied by a decrease in excitatory synaptic strength in the nucleus accumbens (NAc) through an unknown mechanism. Furthermore, glial cells in the NAc are activated by drugs of abuse, but the contribution of glia to the development of addictive behaviors is unknown. Tumor necrosis factor alpha (TNF-α), an inflammatory cytokine released by activated glia, can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons. Here we show that repeated administration of cocaine activates striatal microglia and induces TNF-α production, which in turn depresses glutamatergic synaptic strength in the NAc core and limits the development of behavioral sensitization. Critically, following a period of abstinence, a weak TLR4 agonist can reactivate microglia, increase TNF-α production, depress striatal synaptic strength, and suppress cocaine-induced sensitization. Thus, cytokine signaling from microglia can regulate both the induction and expression of drug-induced behaviors.

The adaptive significance of adult neurogenesis: an integrative approach.

Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and OB, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially relevant selective contexts.