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.

Attributable fractions for substance use in relation to crime.

AIMS: Building upon an existing methodology and conceptual framework for estimating the association between the use of substances and crime, we calculated attributable fractions that estimate the proportion of crimes explained by alcohol and six other categories of psychoactive substances. DESIGN: Cross-sectional surveys. SETTING: Canadian federal correctional institutions. PARTICIPANTS: Canadian men (n = 27 803) and women (n = 1335) offenders who began serving a custodial sentence in a Canadian federal correctional institution between 2006 and 2016. MEASUREMENTS: Offenders completed the computerized assessment of substance abuse, a self-report tool designed to assess (1) whether the offence for which they were convicted would have occurred had they not been intoxicated from alcohol or another substance, (2) whether they committed the offence to support their alcohol or other substance use and (3) whether they were dependent on alcohol (alcohol dependence scale) or another substance (drug abuse screening test). Offences were grouped into four mutually exclusive categories: violent crimes, non-violent crimes, impaired driving and substance-defined crimes. This study focused on violent and non-violent crime categories. Substances assessed were: alcohol, cannabis, opioids, other central nervous system (CNS) depressants, cocaine, other CNS stimulants and other substances. FINDINGS: According to offender self-report, 42% of all violent and non-violent crime would probably not have occurred if the perpetrator had not been under the influence of, or seeking, alcohol or other substances. Between 2006 and 2016, 20% of violent crimes and 7% of non-violent crimes in Canada were considered attributable to alcohol. In contrast, all other psychoactive substance categories combined were associated with 26% of all violent crime and 25% of non-violent crime during the same time-frame. CONCLUSIONS: Attributable fraction analyses show that more than 42% of Canadian crime resulting in a custodial sentence between 2006 and 2016 would probably not have occurred if the perpetrator had not been under the influence of or seeking alcohol or other drugs. Attributable fractions for alcohol and substance-related crime are a potentially useful resource for estimating the impact of alcohol and other substances on crime.

Estimation of the impacts of substance use on workplace productivity: a hybrid human capital and prevalence-based approach applied to Canada.

OBJECTIVE: Policy makers require evidence-based estimates of the economic costs of substance use-attributable lost productivity to set strategies aimed at reducing substance use-related harms. Building on a study by Rehm et al. (2006), we provide estimates of workplace costs using updated methods and data sources. METHODS: We estimated substance use-attributable productivity losses due to premature mortality, long-term disability, and presenteeism/absenteeism in Canada between 2007 and 2014. Lost productivity was estimated using a hybrid prevalence and incidence approach. Substance use prevalence data were drawn from three national self-report surveys. Premature mortality data were from the Canadian Vital Statistics Death Database, and long-term disability and workplace interference data were from the Canadian Community Health Survey. RESULTS: In 2014, the total cost of lost productivity due to substance use was $15.7 billion, or approximately $440 per Canadian, an increase of 8% from 2007. Substances responsible for the greatest economic costs were alcohol (38% of per capita costs), tobacco (37%), opioids (12%), other central nervous system (CNS) depressants (4%), other CNS stimulants (3%), cannabis (2%), cocaine (2%), and finally other psychoactive substances (2%). CONCLUSION: In 2014, alcohol and tobacco represent three quarters of substance use-related lost productivity costs in Canada, followed by opioids. These costs provide a valuable baseline that can be used to assess the impact of future substance use policy, practice, and other interventions, especially important given Canada's opioid crisis and recent cannabis legalization.

Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation.

Background: Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear. Method: Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training. Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM. Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.

Effects of intracerebral ventricular administration of gastrin-releasing peptide and its receptor antagonist RC-3095 on learned fear responses in the rat.

Several lines of evidence have implicated bombesin and its mammalian analogue, gastrin-releasing peptide (GRP), in the mediation and/or modulation of the stress response. However, the physiological role of GRP in mediating conditioned fear responses remains to be elucidated. The objective of the present study was to characterize the role(s) of GRP and its receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) BB((6-14)) (RC-3095) in fear-related responses using two animal models of conditioned fear. To this end, the effects of intracerebroventricular (i.c.v.) administration of GRP (0.062, 0.30, 3.0 nmol) and RC-3095 (0.3, 3.0 and 9.0 nmol) were assessed in the conditioned emotional response (CER) and the fear-potentiated startle (FPS) paradigms. In the CER paradigm, i.c.v. administration of GRP dose-dependently (all doses) attenuated the expression of both contextual and cued fear as reflected by a reduction in freezing behavior to both the context (cage where shock was received) and cue (tone paired with shock). Conversely, pretreatment with RC-3095 (high dose), blocked the reduction of contextual and cued fear normally observed over time. Further, in the FPS paradigm, i.c.v. administration of GRP significantly attenuated the fear-potentiated startle response at medium and high doses without affecting basal startle amplitude. In contrast, pretreatment with RC-3095 at the highest dose (9.0 nmol) significantly increased the basal startle amplitude without affecting fear-potentiation, suggesting elevated fear at the onset of testing. These data provide further evidence that GRP is involved in conditioned fear responses.

Effects of corticosterone on corticotrophin-releasing hormone and gastrin-releasing peptide release in response to an aversive stimulus in two regions of the forebrain (central nucleus of the amygdala and prefrontal cortex).

Previous research has shown that chronic corticosterone treatment increases the expression of corticotrophin-releasing hormone (CRH) mRNA at the central nucleus of the amygdala (CeA). Like CRH, gastrin-releasing peptide (GRP) appears to be involved in mediation of the stress response and is released at the CeA during exposure to an acute stressor. Using in-vivo microdialysis, this study examined the effects of corticosterone treatment on the release of CRH and GRP in response to an airpuff challenge at two forebrain regions, the CeA and medial prefrontal cortex. Adrenally intact rats were treated with corticosterone by systemic implants over a 14-day period prior to microdialysis probe insertion. We found that, at both regions, the airpuff-induced CRH and GRP release were enhanced in the corticosterone pellet-implanted rats as compared with the release observed in the vehicle-implanted control rats. These findings suggest that chronic corticosterone exposure potentiates the stressor-elicited release of CRH and GRP. As cortisol dysregulation has frequently been reported in people with psychiatric conditions, such as anxiety disorders or depression, a better understanding of the glucocorticoid-mediating regulation of CRH and GRP may provide insight into the underlying neurochemical mechanisms involved in both adaptive fear-type responses and maladaptive responses leading to pathology.

Role of gastrin-releasing peptide and neuromedin B in anxiety and fear-related behavior.

Bombesin (BB)-like peptides have been implicated in the mediation and/or modulation of the stress response. However, the impact of manipulating this peptidergic system has only been assessed in a limited number of anxiety and fear paradigms. Given that different behavioral paradigms reflect different aspects of anxiety, the objective of the present investigation was to assess the effects of two mammalian BB-related peptides, namely gastrin-releasing peptide (GRP) and neuromedin B (NMB), in paradigms thought to reflect fear and anxiety-related behaviors. To this end, the effects of central (3rd ventricular; i.c.v.) administration of GRP (0.30 nmol), GRP receptor (BB(2)) antagonist, [Leu(13)-(CH(2)NH)Leu(14)]-BN (1.26 nmol), NMB-30 (0.29 nmol), NMB (BB(1)) receptor antagonist, BIM 23127 (1.70 nmol) and a mixed BB(1)/BB(2) receptor antagonist, PD 176252 (0.621 nmol) were assessed in the elevated plus maze (EPM) and in a fear potentiated startle paradigm (a model thought to reflect conditioned fear). The BB(1) receptor antagonist and the mixed BB(1)/BB(2) receptor antagonist elicited anxiolytic effects in the EPM, whereas, the BB(2) receptor antagonist was without effect. In the fear potentiated startle paradigm, pretreatment with either the BB(1) receptor antagonist or the BB(2) receptor agonist attenuated the fear potentiated startle response, without affecting basal startle amplitude. These data suggest that NMB and GRP do affect the stress response. However, whereas NMB manipulations affected both anxiety and fear responses, GRP alterations selectively affected fear-related responses.

The role of gastrin-releasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat.

RATIONALE: Bombesin (BB), an amphibian peptide, was shown to affect the expression of the stress response. However, the physiological role of the mammalian counterparts of BB in mediating anxiety and fear responses remain to be characterized. OBJECTIVE: This study examined the effects of gastrin-releasing peptide (GRP), a mammalian analogue of BB, and its receptor antagonist, BW2258U89, on conditioned emotional response (CER), using fear conditioning. MATERIALS AND METHODS: The effects of these compounds on contextual and cued fear conditioning were assessed after direct bilateral infusions into the prelimbic (PrL) cortex, infralimbic (IL) cortex or central nucleus of the amygdala (CeA). RESULTS: GRP (300 ng) microinjected into each of the three target nuclei significantly reduced freezing to contextual cues. Similarly, in the cued portion of CER, GRP administered to the IL cortex significantly reduced freezing. Administration of BW2258U89 resulted in dose-dependent and site-specific effects. At the IL cortex, the 50 ng dose decreased freezing to both contextual and cued fear conditioning. At the CeA, the 300 ng dose also decreased freezing, but at the 50 ng dose, it increased contextual freezing. At the PrL cortex, BW2258U89 did not affect freezing. CONCLUSIONS: These results illustrate that (1) GRP system(s) can significantly affect the expression of learned fear, (2) some of the relevant brain sites mediating these effects include the PrL, IL and the CeA, and (3) such effects may be dependent upon whether responses were evoked by environmental contextual fear cues or by specific auditory cues that were explicitly paired with an aversive stimulus.

Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.

The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that these compounds may represent a novel class of anxiolytic agents.