According to the NASEM report, there is a moderate level of evidence of a statistical association between cannabis use and the development of substance dependence and/or substance abuse disorder for alcohol, tobacco, and illicit drugs.Multiple cohort studies have demonstrated these results.Four separate discordant twin studies have found that the twin who used marijuana was more likely to use other substances even after controlling for environmental and genetic influences.Although some studies reported that medical cannabis has resulted in improvements in opiate-related deaths,Colorado has had an increase in poisoning and deaths from opiates and methamphetamines since 2010, with the highest in 2017. These rates have increased nationwide as well and the influence of cannabis in Colorado is difficult to discern. Nevertheless, the increase in overdose deaths in Colorado is alarming. These data are shown in Figure 6.25 Although animal studies do not consistently translate to human effects, rat studies can provide some mechanistic clues. After exposure to tetrahydrocannabinol , rats have an increased behavioral sensitization response to not only THC but also opiates and nicotine.Studies also demonstrate that these behavioral changes in rats correspond to neuronal activity changes in mesolimbic dopamine neurons in the ventral tegmental area and nucleus accumbens and that cross tolerance results with exposure to morphine, amphetamines, and cocaine.Repeat morphine self-administration has been shown to be significantly lower in CB1 knockout mice and opiate withdrawal symptoms significantly less when the knockout mice are administered naloxone.The effect of cannabinoids on the cardiovascular system is complex and an area of ongoing research.
Of concern to practicing emergency physicians is ST-segment elevation myocardial infarctions and acute stroke presentations with a close temporal relationship with cannabis grow racks use, which have been documented in multiple case reports in otherwise young, healthy, male patients.The NASEM summary found there was a limited level of evidence of a statistical association between acute cannabis use and triggering an acute myocardial infarction , ischemic stroke, or subarachnoid hemorrhage.The WHO review states: “There is evidence that cannabis use can trigger coronary events. Recent case reports and case series suggest that cannabis smoking may increase cardiovascular disease risk in younger cannabis smokers who are otherwise at relatively low risk.”6 CDPHE found moderate evidence that marijuana use increases risk of ischemic stroke in individuals younger than 55 years of age and limited evidence that acute marijuana use increases risk of myocardial infarction.The main case crossover study cited for the AMI findings demonstrated that the risk for AMI associated with cannabis use during the hour preceding symptoms of AMI was elevated 4.8 times over baseline . This risk was substantially reduced following that hour.A review of nationwide inpatient sample data from 2010 to 2014 demonstrated a 32% increase in inpatient admissions for primary diagnosis of myocardial infarction and secondary diagnosis of cannabis use disorder . The overall mean age of patients was 41 years old. These patients also had longer lengths of stay, higher hospitalization costs, and higher levels of morbidity due to AMI following hospitalization than non-cannabis users.84 In a study reviewing secondhand marijuana smoke exposure, the authors found that one minute of exposure substantially impaired endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco secondhand smoke.The pathophysiological basis of these events is not fully understood and a full discussion is beyond the scope of this review. In short summary, it may encompass a complex interaction between exogenous cannabinoids and the endocannabinoid system, autonomic nervous system, oxidative stress, direct cellular effects on the endothelium, and pro-coagulant effects.Exposure to THC causes activation of the sympathetic nervous system and inhibition of the parasympathetic nervous system.These effects include elevated heart rate, serum norepinephrine levels, elevated supine blood pressure, and increases in left ventricular systolic function.Smoking results in decreasing oxygen delivery to the heart and other vital organs and may be further compromised by increasing carboxyhemoglobin levels.
The impaired myocardial oxygen demand-to-supply ratio following cannabis smoking has been shown to reduce the time to onset of symptoms during exercise in patients with stable angina.Direct effects of cannabis on blood vessels are complex due to the differing compounds in cannabis and the functional properties of the blood vessels examined.Studies are inconsistent regarding the effects on vasoconstriction and dilation. Cannabis has been consistently shown to produce vasodilation with resultant orthostatic hypotension,but it has also been implicated in vasoconstrictive arteritis mechanisms.A large review article suggested that there are three phases in cardiovascular parameters affected by the endocannabinoid system and that different chemical constituents of the cannabis plant have varying effects at different target organs, which may account for the differences.Transient vasospasm and reduction in cerebral blood flow are well described and may underlie changes in coronary, cerebral, and peripheral arterial systems leading to end organ ischemia.Myocardial blood flow has been shown to correlate inversely with circulating plasma levels of endocannabinoids.Cannabis has also been shown to be a potent source of cellular oxidative stress through formation of reactive oxygen species, and this may contribute to endothelial dysfunction and promote regional arterial vasospasm.THC has also recently shown a dose-dependent procoagulant effect.This ex vivo observation has been supported by reports of thrombotic coronary artery occlusion in young individuals without underlying atherosclerosis.There are also cannabinoid receptors on the surface of platelets and THC has been shown to increase the surface expression of glycoprotein IIb–IIIa and P select in in a concentration-dependent manner resulting in platelet activation.Figure 7 summarizes these effects.Varying cultivation techniques and end-product alterations further complicate the understanding of the physiological effects of cannabis. Cannabis plants can be altered to achieve higher growth rates, changes in potency, and increased bud production. These techniques can include use of varying soil types, fertilizers, and pesticides that can result in physiological effects. These changes may also result in exposures to possible fungal agents such as powdery mildew and botrytis; budworm or mite infestations have been reported in the literature. Historically, there have been reports of bacterial contamination with salmonella, enterobacter, streptococcus, and klebsiella, as well as case reports of fungal spore contaminants, including mycotoxin‐ producing strains of aspergillus.There are three pathways through which cannabis may be contaminated with heavy metal substances.
Firstly, cannabis is able to remove heavy metals from substrate soils and deposit these in its tissues by virtue of its bio-accumulative capacity. Secondly, cross‐contamination may occur during processing . Thirdly, post‐processing adulteration may occur, whereby metals may be added to the preparation to increase weight and thereby appreciate its street value. There are case reports of lead and arsenic poisoning from cannabis.Pesticides are also commonly used in cannabis cultivation. In a report from Washington State, laboratory analysis revealed that 84.6% of legalized cannabis products contained significant quantities of pesticides including insecticides, fungicides, miticides, and herbicides. These comprised a wide array of different substances and encompassed proven carcinogens , endocrine disruptors, as well as a variety of developmental, reproductive, and neurological toxins.There are also changes in end-product concentrations through post-processing of the plant. These changes include creation of oils, waxes/shatter, and dabs. Oils are created by removing the hydrophobic components such as THC with a heated butane solvent. THC concentrations may reach up to 55.7%.Waxes and shatter are concentrated and solidified oil with THC concentration reaching up to 90% THC.Dabs are composed of heated wax and are inhaled off of an object such as a nail, which even further concentrates THC content over 90%.Preparation of these concentrated products has also led to fires and explosion injuries in amateur production attempts in garages, tool sheds, and vacant homes.In Colorado 29 patients with butane hash-oil burns were admitted to the University of Colorado Burn Center from 2008-2014. Zero cases presented prior to medical liberalization, 19 during medical liberalization , and 12 from January–June 2014 at the study’s conclusion. The median total body surface area burn size was 10% . Median length of hospital admission was 10 days. Six required intubation for airway protection while 19 required skin grafting.Marijuana shop employees not trained in medicine or pharmacology are giving medical advice that may be harmful to patients. A recent study in Colorado found that employees are giving medical advice 70% of the time to use cannabis for treatment of nausea and vomiting in pregnancy and few dispensaries encouraged discussion with a healthcare provider without prompting.The author has personally had patients bring in products recommended by dispensary workers with a recommended potency and frequency of use and report being advised to stop their usual medications and use the cannabis product instead.
Cannabis dispensaries provide medical advice and offer treatment without medical training even when this may harm the patient.There are potential therapeutic intervention targets for cannabinoids. In general, these therapeutic targets require a high ratio of cannabidiol compounds , and are from products that significantly differ from those found in commercial dispensaries. The NASEM report found substantial evidence that cannabis grow system or cannabinoids are effective for the treatment of chronic pain in adults, as an antiemetic for chemotherapy-induced nausea and vomiting, and for improving patient-reported multiple sclerosis spasticity symptoms. They also found moderate evidence that cannabis or cannabinoids are effective for improving short-term sleep outcomes associated with obstructive sleep apnea, fibromyalgia, chronic pain, and multiple sclerosis.Studies have also demonstrated that cannabinoids may improve cardiovascular outcomes.92,117 Likely the most significant treatment implication has been in patients with refractory epilepsy, most commonly in patients with Dravet’s syndrome and Lennox-Gestault syndrome, but also in other patients. This has led to the U.S. Food and Drug Administration approving Epidiolex in June 2018 for the treatment of Dravet’s syndrome and Lennox-Gestault syndrome.Despite these potential medicinal uses, current Colorado legal distribution of cannabis products goes through an intermediary bud tender before making it to the patient which may not consistently promote therapeutic benefit; there is insufficient training of dispensary staff to serve this purpose.The potential positive health effects of cannabis rest on which of the multiple species and hybrids are studied and their specific chemical composition. One of the difficulties in determining the physiological effects of cannabis is that “marijuana,” or “cannabis,” can refer to multiple species of plants with widely varying chemical compounds and corresponding variable physiological effects. The cannabis genus includes multiple species, most commonly Cannabis sativa and Cannabis indica, and within those are hybrids specifically developed by growers to achieve a specific effect. For example, the commonly used term, hemp, refers to a variety of Cannabis sativa that is fast growing and can be spun into usable fiber for paper, textiles, clothing, bio-fuel, animal feed, and other industrial uses. Hemp has low concentrations of THC and higher concentrations of CBD. The differences in composition offer different potential treatment effects. For example, the effect for pain control cited in the NASEM review was primarily found with nabiximols , a cannabis extract mouth spray that delivers a dose of 2.7 mg of THC and 2.5 mg of CBD.For comparison, a typical marijuana cigarette or joint contains 0.5 g of marijuana and THC content ranges from 12-23%; therefore, a typical joint contains 60-115 mg of THC, 20-40 times the medicinal dose. The NASEM cautioned that many of the cannabis products sold in state regulated markets bear little resemblance to those available for research at the federal level in the U.S.This is further complicated in that commonly sold cannabis products are often mislabeled for CBD and THC content. One study showed only 17% of dispensary products were accurately labeled.Scientific studies, particularly for treatment of pain, have been limited by a substantial bias, and results have varied.Some demonstrate improvement in pain10 with coinciding decreases in opiate abuse,while others show the opposite.The conflict between federal and state laws on the medical use of cannabis products, the lack of consistency among state laws, and the availability of artisanal products in dispensaries, with high variability between composition of products, have caused significant confusion for researchers and limited the ability to fully and accurately research the true effects of commonly available dispensary cannabis products.This was not a systematic review of the literature but rather a summary of selected research including several large reviews from the NASEM, the WHO, and the CDPHE. There is undoubtedly much literature, some of it conflicting, not cited here. However, as other states and countries wrestle with decriminalization and legalization of cannabis for personal use and sale, it is crucial to report the Colorado experience as a cautionary tale. This review summarizes a large body of research for practicing emergency physicians who are increasingly confronted with questions and patients who use cannabis.