[DRAFT] The Endocannabinoid System – Ch 5: Death & The ECS

Introduction

High-strength products including extracts for inhalation, sold as concentrates (i.e., wax and shatter) and resin (i.e., hash), are reported to be over 65% THC. Edibles, which are increasing in popularity, are sold in units that contain multiple doses (usually around 10 mg THC). These products are at high risk for eliciting an adverse reaction, unintentional over-intoxication, and toxicity in the pediatric population. Edibles are often visibly appealing and produced as baked goods or candy, making them enticing to children. Furthermore, because of the delayed onset of effects with the oral route of administration, people frequently eat more units without taking into account delayed effects, resulting in a long-lasting, over-intoxication. An additional variable related to edibles that make them high-risk products is that the labeling is frequently inaccurate, with some products containing much more THC than described on the package.

One impact of expanded legal access to cannabis and especially cannabis-derived products, such as gummy bears, chocolate squares, and other items that resemble candy, is the increasing rate of child poisonings. Both poison control centers and emergency departments in affected states in the US have been reporting historically high rates of pediatric cannabis-related presentations suggesting one unintended consequence of expanded legal access for adults has been increased inadvertent access for children. Moreover, with the greater availability of legal cannabis, rates of use and heavy use (i.e., daily or near-daily use) have increased dramatically among adults. Use can worsen psychomotor skills and cognitive performance that have become issues of concern for drivers of motorized vehicles and those persons engaged in safety-critical occupations. Driving is an everyday activity done by people ranging from the ages of 16 – 80 worldwide. Even though driving is not the most self-aware activity, it does not change the fact that a person’s life (even multiple people) depends on the ability of the driver to use their vehicle as responsibly as possible. Driving is essential for functionality, which is why the use of substances that impair our ability to drive may be counterproductive; a split second can make the difference between life and death. For such reasons, it is crucial to focus on the relationship between cannabis and driving and to state some kind of regulations regarding these two.

Also, although smoked cannabis use is often associated with significant changes in heart rate and cardiac output, amongst other physiological changes, it has been rarely considered in the forensic literature as a significant contributory or causal factor in sudden unexpected death. While there is no legal access to recreationally used synthetic cannabinoids, products that are intended to mimic the effects of THC (i.e., Spice, K2), there have been several notable epidemics of synthetic cannabinoids across the United States. Synthetic cannabinoids have caused a large number of emergency presentations to hospitals for adverse cardiovascular events including numerous deaths, particularly for the more potent analogs acting on the CB1 receptor. Using large amounts (approximately 20 mg + THC equivalent), especially among individuals with low or no tolerance, can lead to symptoms of anxiety and panic, symptoms of psychosis such as paranoia, derealization, depersonalization, illusions, or hallucinations (auditory and/or visual), and delirium. Evidence suggests that cannabis use may be associated with suicidality in adolescence.

Literature

A review published by Monash University and the Victorian Institute of Forensic Medicine in Australia went over case reports of admissions to hospitals for cardiovascular events in conjunction with epidemiological studies, and case reports of sudden death attributed, at least in part, to the use of synthetic cannabinoids. These publications show that the use of cannabis is not without its risks of occasional serious medical emergencies and sudden death, with reports of at least 35 persons presenting with significant cardiovascular emergencies who had recently smoked a cannabis preparation. At least 13 deaths from a cardiovascular mechanism have been reported from the use of this drug which is very likely to be an underestimate of the true incidence of its contribution to sudden death. In addition, many cases of stroke and vascular arteritis have also been reported with the latter often involving a limb amputation. While it is a drug with widespread usage among the community with relatively few deaths when faced with a circumstance of very recent use (within a few hours), a positive blood concentration of THC, and a possible cardiac-related or cerebrovascular cause of death this drug should be considered, at least, a contributory cause of death in cases of sudden or unexpected death.

Additionally, six case reports have been published linking the recent use of cannabis with sudden death. In all of these cases, the authors believed cannabis use was a significant contributor to their deaths. Eight of these deaths had a positive THC concentration in blood ranging from 2 to 22 ng/mL (median 4 ng/mL); four were positive for urinary cannabinoids and in only one case no measurement for cannabinoids was conducted. However, in all cases, recent use of cannabis was regarded as the trigger for heart failure and no other drugs were implicated. However, as seen in the larger scale retrospective studies and the systematic reviews the evidence for a link between cannabis use and increased risk of cardiovascular death is not clear. Anyone of the symptoms and cardiovascular diseases mentioned earlier could have arisen for other reasons including in the setting of rhythm disturbance and arrest, and previous undiagnosed channelopathies. People have arrhythmias and heart attacks they do not use cannabis, or indeed other drugs, and most cannabis users are likely also to have smoked tobacco for much of their lives, which is another significant risk factor for premature cardiovascular disease.

Moreover, a collaboration between several international academic and health institutions including the University of Toronto, University of Manchester, University of Cape Town, and Groote Schuur Hospital among others. In this cross-sectional survey, they investigated the association of cannabis use and suicidal attempts in 86,254 adolescents from 21 LMICs (low- and middle-income countries), adjusting for potential confounders. Their results indicate that cannabis use is associated with a greater likelihood of suicide attempts in adolescents living in LMICs. Their findings also suggest that any cannabis use during the past 30 days or during a lifetime is associated with a greater likelihood of suicide attempts. Furthermore, these associations remained robust and significant after adjustment for relevant confounders including the use of other substances and socio-demographic variables.

Furthermore, a review published by the Columbia University in the USA provided an overview of the changing US epidemiology of cannabis use and associated problems. Evidence suggests national increases in the US in cannabis potency, prenatal and unintentional childhood exposure; and in adults, increased use, CUD, cannabis-related emergency room visits, and fatal vehicle crashes. An important type of harm related to cannabis use is the increased risk for injury or fatality due to intoxication while driving. The primary psychoactive component of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs the motor and cognitive functions needed for safe driving making clear the causal role of cannabis in this public health problem. Cannabis use while driving has been shown to substantially increase the risk for motor vehicle crashes and is implicated in fatal and nonfatal crashes. In Canada, where medical marijuana has been legal since 2001, cannabis-attributable driving harms and costs are substantial. In addition to motor vehicle crashes, cannabis has also been implicated in fatal injuries among US pilots. Nonetheless, there are no known cases of fatal overdose from cannabis use in the epidemiologic literature.

Additionally, a chapter of the book Cannabis Use Disorders by researchers in the Columbia University Medical Center in the USA went over the issues related to cannabis and cannabinoid intoxication, accidental overdose, and toxicity. Incidents of accidental overdose that are reported appear to be most frequent in the younger pediatric population (<7 years of age) and are usually due to ingestion of oral products. Furthermore, rates of cannabis overdose incidents are highest in states with permissive cannabis laws. Pharmacological approaches to treating cannabis intoxication or overdose most often included the use of sedative hypnotics such as clonazepam or lorazepam. These may be best suited for patients with anxiety, panic, and restlessness. Antipsychotics can also be used for treatment, especially for patients with more severe psychotic symptoms such as paranoia, delusions, hallucinations, or extreme behavioral dysregulation. Generally, c-generation agents such as risperidone or olanzapine are preferred. Although less commonly used, beta-blockers have also been shown to reduce the severity of cardiovascular effects such as tachycardia and palpitations. Moreover, cannabinoid hyperemesis syndrome (cyclic vomiting syndrome) has become a more widely recognized clinical entity in the past few years given increased rates of heavy use of high-strength cannabis. Acute treatment often relies on a sedative-hypnotic, such as lorazepam, and antipsychotics with an antiemetic, such as promethazine or ondansetron, for breakthrough nausea. Some patients further benefit from non-opioid pain medications such as nonsteroidal anti-inflammatories when their presentation is accompanied by abdominal pain.

Further, treatment of overdose from synthetic cannabinoids can be much more challenging especially when complicated by persistent agitation and violence. Importantly, some drugs believed by users to be synthetic “cannabinoids” can contain cathinones, stimulants, or adulterated with such agents which can complicate clinical presentations and symptoms respond to treatment. Unless symptoms are severe, treatment for synthetic cannabinoid toxicity usually entails supportive care, including supplemental oxygen, cardiac monitoring, and intravenous fluids to address the fluid imbalance, and electrolyte depletion. For psychiatric disturbances including agitation, hostility, and anxiety, patients are usually treated with benzodiazepines. Cases with severe toxicity require hospital admission, sometimes to the intensive care unit. Respiratory depression has been reported to necessitate endotracheal intubation; recovery of normal respiration was observed within 24 hours. Severe hypotension has been reported to require the use of vasopressors.

Limitations

In regards to the review published by Monash University and the Victorian Institute of Forensic Medicine in Australia, many of the cases on which the article was based were published before cannabis was both medicinally and recreationally legalized, therefore the most likely origin of the drug was probably from the black market. As a consequence, the cannabis products could have been adulterers causing such additives to play a significant role in the death of the people showcased. Likewise, the collaboration between several international academic and health institutions including the University of Toronto, University of Manchester, University of Cape Town, and Groote Schuur Hospital among others presented several limitations. First, as with many other school-based surveys, this is a cross-sectional study, and hence the direction of causality cannot be established. Second, evidence indicates that chronic cannabis use may be associated with the development of depressive disorders. Evidence suggests that anxiety and insomnia are strongly related to depression in adolescents. Third, we controlled our findings to the use of other substances (e.g. alcohol). However, the use of alcohol in the past 30 days may not necessarily reflect the presence of problematic drinking or an alcohol use disorder. Fourth, although food insecurity is closely related to socioeconomic status, a more comprehensive measure of socioeconomic status could have been more appropriate. Finally, their findings are based on self-reported data.

Conclusions

Given the increase in cannabis availability, emerging trends in available products, and the widespread emergence of synthetic cannabinoid use, awareness of signs and symptoms of intoxication, overdose, and clinical management is becoming increasingly relevant to psychiatric and general medical providers. Cannabis and synthetic cannabinoid toxicity is an immediate public health issue. Cases of drug abuse and unintentional exposure related to cannabis and cannabis-derived products are increasing across the country and specifically in states that have legalized cannabis for medical and recreational purposes. As laws permit greater access and use, and as cannabis products continue to diversify, rates of unintentional intoxication are predicted to increase. While cannabis toxicity is usually mild and resolves soon after exposure, there have been severe cases reported that require medical attention. A pediatric population is an age group that’s of high risk for unintentional exposure and most severe outcomes. With increases in rates of cannabis and synthetic cannabinoid toxicity, potential therapeutics to address severe effects are urgently needed. In addition to the common therapeutics used that target specifically symptomology, agents that work directly to reverse cannabinoid toxicity rapidly will be critical for care. Therefore, policymakers have had to respond quickly and devise ways to safeguard against unintentional overdose. Some of these policies include (1) enhancing and verifying labeling of contents, (2) requiring child-proof packaging, and (3) requiring warning labels. Moreover, cannabis use should be taken into account in the prevention and assessment of suicidal behaviors in adolescence. For example, universal, school-based interventions may be effective for the prevention of risk behaviors including cannabis use among the youth.

On the other hand, the usage of cannabis and cannabinoids while driving should only be allowed if it is prescribed specifically for such activity. Drivers should be conscious and avoid the usage of heavy machinery while they are medicated. Legislation that prohibits driving while under the influence of alcohol is enforceable because roadside breathalyzer tests can detect whether a driver has exceeded a legal blood alcohol concentration (BAC) limit indicating impairment that is standardized nationwide. Unfortunately, no parallel tests or devices exist for cannabis. Cannabis metabolites can be detected in blood, blood plasma, oral fluid, and urine, although the presence of such metabolites does not necessarily indicate the likelihood of acute intoxication, as BAC does. An accurate ‘breathalyzer’ test for cannabis that could be used on a widespread basis has not yet been developed. This area is greatly in need of scientific advancement. Nevertheless, roadside drug testing using various methods of testing has been introduced in a number of countries, and several US states that have legalized cannabis use, eg, California, Colorado, Oregon, and Massachusetts, are experimenting with different forms of roadside testing for driving under the influence of cannabis, including biological and behavioral tests (eg, asking drivers to indicate their ability to balance). For the time being, the SFST (standardized field sobriety test) in conjunction with laboratory tests should probably be the standard protocol (for an immediate solution) to identify intoxicated people unable to drive.

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