From Bumps to Binges: Overview of Deaths Associated with Cocaine in England, Wales and Northern Ireland (2000-2019).

The UK, as the "cocaine capital of Europe," currently accounts for ∼75% of all cocaine-related hospital admissions in Europe. This study aims to analyze the trends in cocaine-related deaths in England, Wales and Northern Ireland over 20 years (2000-2019). Cases reported to the National Programme on Substance Abuse Deaths (NPSAD) occurring between 2000 and 2019 where cocaine was detected at post-mortem (PM) were extracted for analysis. A total of 5,339 cases were retrieved, with an increase in the rate of reporting over time. Cocaine was deemed a cause of death and quantified in PM blood samples along with its major metabolite benzoylecgonine in 685 cases. Of these 685 cases, 25% (n = 170/685) occurred following acute use, 22% (n = 154/685) following chronic/binge use, 40% (n = 271/685) in combination with morphine, 4% (n = 29/685) in drug packer/swallower circumstances and 9% (n = 61/685) in a suicide context. Cardiac complications were evident in 22% of cases (n = 154/685). The average concentration of cocaine detected in cardiac cases (900 ng/mL) was considerably lower than that detected in cases where acute (19,100 ng/mL) or chronic/binge (6,200 ng/mL) dosing was evident. This is the first cocaine-related mortality study in these geographical areas. Deaths following cocaine use continue to rise despite its Class A drug listing in the UK. While underlying and external risk factors including polydrug use, cardiac complications and mental health can all contribute to the incidence of fatal drug toxicity following cocaine use, this study demonstrates that the risk of a cocaine overdose cannot be attributed to a specific blood concentration range.

Metabolites of Cannabis Induce Cardiac Toxicity and Morphological Alterations in Cardiac Myocytes.

Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250-100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Cocaine Induces Cytoskeletal Changes in Cardiac Myocytes: Implications for Cardiac Morphology.

Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1-10 µg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-ß3) and increased expression of ezirin within three hours of 1 µg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5-10 µg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.