The NASEM, CDPHE, and WHO reports state there is substantial evidence of a statistical association between marijuana smoking and worse respiratory symptoms and more frequent chronic bronchitis episodes. These data were based primarily on a systematic review by Tetrault et al. from 14 studies that assessed the association between long-term cannabis smoking respiratory symptoms including chronic cough , increased sputum production , and wheezing . There is also evidence of a statistical association between the cessation of cannabis smoking and improvements in respiratory symptoms. On histology, this is associated with a reduction in ciliated cells and increase in mucus secretion from the larger number of mucus-secreting cells. Reported exposures to children less than age 10 have sharply increased in Colorado following recreational marijuana legalization. A retrospective cohort study of hospital admissions and regional poison control center cases between January 1, 2009–December 31, 2015 at a tertiary-care children’s hospital found that the mean rate of marijuana-related visits to the children’s hospital increased from 1.2 per 100,000 population in the two years prior to legalization to 2.3 per 100,000 after . The median age of exposure was 2.4 years. The majority were exposure to an infused edible product ; 65% were observed in the ED or UC; 21% were admitted to an inpatient ward; and 15% were admitted to the intensive care unit. Two of these children required respiratory support. The median length of stay for all patients was 11 hours, ebb and flow rolling benches and the median length of stay for admitted patients was 26 hours. Annual RPC pediatric marijuana cases increased more than five-fold from 2009 to 2015 .
Colorado had an average increase in RPC cases of 34% per year while the remainder of the United States had an increase of 19% . In a follow-up study in October 2018, the same author found that despite multiple public health interventions in legislation after 2014 , the incidence of children’s hospital visits and RPC calls has continued to rise in Colorado with an observed doubling of children’s hospital visits in 2017 compared to 2016. Edibles are sold as cookies, candies, and sodas with advertising that appeals to children. 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 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. 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, rolling grow benches 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 pain 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. Although the author practices in Colorado, the information is likely generalizable. This review clearly reflects the author’s biases, yet its composition was motivated by alarming experience in everyday practice. Discussions of cannabis’ effects are relevant not only to the healthcare system, but to legal, business, environmental, legislative, and other branches within a public health framework. This article does not address those other facets. Neither have numerous other physiological effects of cannabis been reviewed here. Many of the previous research studies have focused on cannabis with a much lower THC level limiting applicability to cannabis sold at dispensaries today. Finally, the words “marijuana” and “cannabis” were used interchangeably throughout the article. This was done to maintain the wording from the studies cited consistent with their original language. No difference should be implied with the alternating use of these terms. Cannabis legalization has led to significant health consequences, particularly to EDs and hospitals in Colorado. The most concerning include psychosis, suicide, and other substance abuse. There are deleterious effects on the brain and some of these may not be reversible with abstinence. Other significant health effects include increases in fatal motor vehicle collisions, adverse effects on cardiovascular and pulmonary systems, inadvertent pediatric exposures, cannabis contaminants exposing users to infectious agents, heavy metals, and pesticides, and hash-oil burn injuries due to preparation of concentrates. Finally, cannabis dispensary workers not trained in medicine are giving medical advice that could be harmful to patients. Cannabis research may offer opportunities for novel treatment of seizures, spasticity from multiple sclerosis, nausea and vomiting from chemotherapy, chronic pain, improvements in cardiovascular outcomes, and sleep disorders. However, progress has been difficult due to absent standardization of the chemical composition of cannabis products and limitations on research secondary to federal classification of cannabis. Given these factors and the Colorado experience, other states should carefully evaluate whether and how to decriminalize or legalize non-medical cannabis use. Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia. Some cannabinoids, the hallmark constituents of Cannabis, as well as analogues thereof have been investigated extensively for their potential medical applications. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a variety of human ailments. However, greater study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, low abundances of nearly all of the several dozens of known cannabinoids in planta, and their structural complexity, which limits bulk chemical synthesis. Here, we report the complete biosynthesis of the major cannabinoids cannabigerolic acid , Δ9 -tetrahydrocannabinolic acid , cannabidiolic acid , Δ9 -tetrahydrocannabivarinic acid , and cannabidivarinic acid in Saccharomyces cerevisiae from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway as well as the Cannabis genes encoding the enzymes involved in olivetolic acid biosynthesis, a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity, and corresponding cannabinoid synthases. Furthermore, we established a biosynthetic approach, harnessing the promiscuity of several pathway genes, for the production of cannabinoid analogues.