Medical Consequences of Cannabis Use

Jag H. Khalsa, MS, PhD and Ruben Baler, PhD

 

National Institute on Drug Abuse, National Institutes of Health, Bethesda,

 

Janvier 2019

 

Disclaimer: The opinions in this paper are of authors and do not reflect the position of the National Institute on Drug Abuse, National Institutes of Health.

Abstract

Consumed by an estimated 2.5% of the world’s population, cannabis is the most popular illicit drug. Depending on age of onset, frequency, duration, and other variables, cannabis use can be associated with a broad spectrum of medical consequences, the range of which mirrors the physiological ubiquity and versatility of the endocannabinoid system. Importantly, the adverse consequences of cannabis use can progress to become overt clinical conditions, independently of the development of a cannabis use disorder. The purpose of this chapter is to present an updated overview of these adverse health effects of cannabis use and the implications of our current understanding vis á vis public health and research agendas moving forward.

Keywords: cannabis, cannabinoids, cannabis use disorder, marijuana, medical consequences, adverse effects, cardiovascular, respiratory.

 

Introduction

In 2016, according to nationally representative data, approximately 4 million Americans age 12 or older met criteria for a cannabis use disorder (CUD), the complex phenomenon whose many facets are aptly explored in other chapters of this book. However, since current cannabis users outnumber those who develop a CUD by a factor of around six (2), it is important to identify, study, and mitigate any adverse health effects of cannabis use that may end up affecting a significantly larger fraction of the population; and not just in the US. Indeed, it is estimated that close to 180 million people worldwide (or 2.5% of the total population)(148), are regular consumers of cannabis, an annual prevalence that is over 12-fold higher than that of cocaine or opiates. The lopsided ratio between the sizes of the non-addicted versus the addicted cannabis using populations is reminiscent of comparable relationships among users of tobacco and alcohol. The hard lessons we should have learned from the devastating toll of licit drug use over past decades should help us focus our public health attention on the potential impact of regular cannabis use on morbidity and mortality among large pools of non-addicted individuals. Even if the recognized non-CUD adverse health effects of cannabis prove marginal or linked exclusively to high frequency/potency, early onset, or heavy use, the sheer number of exposed individuals (including to second-hand smoke), combined with increased social acceptance and more permissive policies, make the topic of this chapter a critical public health matter. This is particularly true when we consider that specific subpopulations, such as the developing fetus or adolescents, older adults, and those suffering from other physical (e.g., HIV) or mental (e.g., schizophrenia) disorders, are likely to present a significantly higher vulnerability to specific adverse effects stemming from cannabis use.

 

Cannabis contains many phytocannabinoids, but THC is the one primarily responsible for the psychoactive effects sought by cannabis users. The adverse health effects that are the focus of this chapter, however, present a more complex picture for they can result not only from the action of specific phytocannabinoids (THC and others) but also from exposure to other compounds present in the plant or produced during its combustion (109), or to a growing family of synthetic derivatives with cannabimimetic effects (25, 75, 76). Activation of the endocannabinoid system (ECS) by THC and related molecules results in a variety of clinical effects as broadly outlined by the World Health Organization (WHO)(148), while cannabis smoke has been shown to contain many of the toxins, irritants and carcinogens that are present in tobacco smoke (109).

 

Not surprisingly, the use of cannabis has been associated with a wide range of medical consequences affecting almost all physiological systems. Thus, medical consequences of cannabis use have been frequently reported in the scientific literature, whether through case reports, ecological studies, or meta-analyses (57, 106). The cumulative body of work leaves no doubt that cannabis use, particularly if it is heavy, frequent, or long-term is associated with increased risk of specific clinical conditions. However, the strength of the underlying evidence is decidedly mixed, likely because, in most cases, the size or rarity of the observed effects combines with a long list of confounding factors to make the attribution of generalizability, mechanisms of action, and causal relationships, very difficult to ascertain. Such caveats notwithstanding, there is clear consensus that cannabis use can affect the respiratory and cardiovascular systems, in ways that could require clinical care. Here, we review the state of the science on these and other, somewhat less well documented potential or alleged medical consequences of cannabis use.

 

Respiratory/Pulmonary Complications

Given the overwhelming evidence linking tobacco smoke to multiple respiratory conditions, it would be reasonable to predict that regular inhalation of cannabis smoke be associated with a similar pattern of adverse environmental exposure consequences. The truth is that we know less than we would like to about the specific attributable effects of cannabis on pulmonary function. With the exception of the active ingredients (i.e., cannabinoids (40) and nicotine, respectively) cannabis smoke is known to contain many of the ̴6000 chemicals (e.g., carbon monoxide, vinyl chlorides, ammonia, acetaldehyde, formaldehyde, acrolein, phenols, nitrosamines, reactive oxygen species, and polycyclic aromatic hydrocarbons) found in tobacco smoke (69, 101, 113), some of which have carcinogenic or other harmful effects (67, 112). Although far fewer cannabis than tobacco cigarettes are generally smoked daily, the pulmonary consequences of smoking cannabis could theoretically be magnified by the greater deposition of smoked particles in the lung due to the deeper and more protracted nature of inhalation that is typical of cannabis compared to tobacco smoking styles. Indeed, according to an early study, smoking one cannabis joint leads to a higher pulmonary burden of insoluble particulates (tar) and carbon monoxide than smoking one cigarette with an equivalent amount of plant material (i.e., tobacco) (152). This hypothesized differential in toxicant burden seems consistent with the results of a recent animal study showing cannabis smoke being significantly more potent than tobacco smoke in inducing severe (and CB1 independent) airway hyperresponsiveness, inflammation, tissue destruction, and emphysema (64). However, even though cannabis smoke contains as many or perhaps more toxic, carcinogenic, and cocarcinogenic chemicals than tobacco smoke (66, 137), such as 50% more benzopyrene and nearly 75% more benzanthracene, on a gram per gram basis (137), the risks of pulmonary complications in humans appear to be relatively small and far lower than the devastating pulmonary outcomes caused by chronic tobacco smoking, particularly among occasional users with low cumulative doses (106). Unfortunately, we still have a poor understanding of the underlying pathophysiology of the adverse respiratory/pulmonary effects of cannabis smoking, for which there is limited, let alone convincing evidence, as described below.

 

Regular exposure to cannabis smoke may lead some smokers to experience airway inflammation (87, 128), explaining why regular smokers of cannabis are likely to experience chronic cough and produce larger than normal amounts of phlegm (95). A critical analysis of all the available data found substantial evidence that long-term cannabis smoking can result in symptoms of bronchitis (106). While the accumulated evidence regarding pulmonary function appears to point to a substantial association, the effect size may be quite modest. For example, a 2015 cross-sectional study of 12,500 patients attending a Scottish general practice, found that, while the cannabis using group did display impaired lung function, that impairment, after adjusting for confounders, consisted of a 0.3% increase in the prevalence of chronic obstructive pulmonary disease (COPD) for each additional joint-year of cannabis use (93). Another cross-sectional study of US adults (data from the 2007-2010 National Health and Nutrition Examination Survey combined cohort) found that exposures of up to 20 joint-years were not associated with adverse changes in spirometric measures of lung health (79).

 

Such modest effects notwithstanding, analysis of bronchoscopic biopsies taken from cannabis smokers often show histological changes in the bronchial mucosa (44) that are accompanied by increased expression of a panel of cell proliferation biomarkers (e.g., EGF, p53, erbB-2) commonly used as reliable correlates of field cancerization effects on bronchial epithelium (13). And yet, there is no conclusive evidence that cannabis smoking is associated with an increased incidence of lung cancer. In fact, a combined analysis of the six highest quality case-control studies of 2159 cancers and 2985 controls by the International Lung cancer Consortium (153), yielded an overall pooled odds ratio (OR) for habitual versus nonhabitual cannabis users or never-users of 0.96. Thus, the best available information does not support an association between cannabis use and lung cancer (68). Another conclusion to come out of a recent meta-analysis pertains to the lack of evidence of an association between cannabis use and increased risk of developing or exacerbating symptoms of asthma (106). These results are surprising, given that wheezing and other asthma-like symptoms are rather common among regular cannabis users, but the picture could still change once larger and better designed/controlled studies (including monitoring adherence to asthma medications) are implemented. However, they are consistent with the results of a recent reanalysis of the Dunedin birth cohort, which showed that, up to 20 years of cannabis use, unlike tobacco, was not associated with worse lung function, systemic inflammation, or metabolic health at age 38 (96).

 

The reasons behind these apparent paradoxes, above and beyond fundamental flaws in study design or power, are not fully understood, but some authors have speculated that THC’s activity as a bronchodilator (138, 139) and/or the observed anti-inflammatory effects of cannabis (136) may be at least partly responsible (123). Another possibility worth exploring is the alleged ability of some cannabinoids (both endogenous and plant-derived) to inhibit growth or trigger programed cell death among some cancer cells (34, 45). This or other cannabis-specific confounding factors may also help explain the moderate but unexpected evidence of a statistical association between cannabis smoking and higher forced vital capacity (FVC)(79) and the positive effect of acute but not chronic cannabis use on airway dynamics (106).

 

The last point suggests that future research that pays closer attention to dosage as a variable could expose more robust effects that have laid hidden in cross sectional studies, studies with small Ns, or that were based on traditionally low (and increasingly dated) or heterogeneous THC potencies. Similarly, the recent launch of a large and multifaceted longitudinal study of risk modifiers and early onset substance use (144) should help uncover weak associations or other significant if modest effect sizes.

 

Cardiovascular Complications

Close to 90 million Americans suffer from at least one cardiovascular condition, like hypertension, stroke, or myocardial infarct. Cardiovascular diseases (CVD) account for nearly 30% of all deaths in the United States (151). It is true that these forms of morbidity and mortality disproportionately impact older adults (83), who display a relatively low prevalence of current cannabis use (2% for 50 years vs   ̴20% among those 18 to 25 years of age)(7). However, the high prevalence of these conditions, combined with increasing acceptance, legality, and likely use of cannabis for recreational or medicinal purposes, justify the hypothesis (and concern) that even a modest mechanistic contribution to increased CVD risk could lead to a significant spike in the number of cases attributable to cannabis use. At the same time, it is worth mentioning that tobacco smoking, which is a well-known risk factor for CVD (73), is highly prevalent among older individuals (70), which makes tobacco a more formidable confounding factor to contend with when investigating any potential cannabis-CVD links.

 

Over the years, there has been a steady buildup of reports (mostly case reports and small studies) on the effects of acute or chronic cannabis exposure on a long list of cardiovascular, cerebrovascular, and peripheral vascular measures and functions (141). The preponderance of the evidence appears to support the notion that acute cannabis consumption can cause increased (20-100%) heart rate (14) and blood pressure (more specifically systolic blood pressure )(4, 14), although exceptions to the latter finding can also be found (36). Inconsistent results could be due to the complex effects of cannabinoids on central vs peripheral circulation. Indeed, cannabis use may impair the circulatory responses to standing, which could help explain the sporadic reports of orthostatic hypotension among some cannabis users (133), likely due to decreased vascular resistance (4). However, as tolerance develops, both the hyper and hypotensive effects of cannabis may attenuate over time and eventually disappear (72, 110). In addition, case studies have also associated cannabis use to increased risk of arrhythmia (35) (including ventricular tachycardia and potentially sudden death); ischemic stroke (141), particularly among healthy young patients (52); recurrent (129) or acute coronary syndrome with elevated ST segment (49); and myocardial infarction (MI), immediately or soon after smoking cannabis (24, 37, 94, 100, 142). Cannabis use has also been reported to be associated with peripheral atherosclerotic disease, sometimes referred to as cannabis arteritis (118, 131), a condition that is indistinguishable from thromboangiitis obliterans (Buerger’s disease)(74, 126) that has also been causally linked to tobacco smoking (53).

 

The mechanisms by which cannabis could affect so many facets of the circulatory system are poorly understood, but given that cannabis contains >500 different compounds, including >100 different cannabinoids (40), they are likely to involve multiple alternative pathways. Indeed, cannabinoid receptors of both types are expressed throughout the tissues that are relevant in this context, including the myocardium, vascular endothelial and smooth muscle cells, circulating blood cells, and the peripheral nervous system (including vagal afferent neurons), where cannabinoid receptors (CBRs) could be activated by endo, phyto, and synthetic cannabinoids (reviewed in (114)) and modulate the cardiovascular system.

 

For example, preclinical studies have shown that acute administration of Rimonabant, a CB1R antagonist can protect against the cardiodepressive effects of doxorubicin (DOX)-induced cardiotoxicity (104) and reduce blood pressure in a rat model of angiotensin II-dependent hypertension (132). At the physiological level, serious myocardial infarctions (MI) could result from increased myocardial oxygen demand (46, 54, 65, 146) or be triggered by increased parasympathetic activity leading to asystole (18, 97). In humans, there have been several case reports of cannabis consumption triggering acute coronary syndromes in young individuals, even in the absence of any known common risk factors (39, 49, 82). While these cases could be classified as anecdotal at this point, they do provide potential insights into more meaningful mechanistic questions to be addressed in larger studies. For example, some authors have suggested that cannabis may promote the generation of reactive oxygen species leading to oxidative stress, a known mechanism of stroke in humans (150).

 

However, primary and case studies such as these should be taken with a grain of salt, since evaluation of specific vascular effects attributable to cannabis is typically complicated by the presence of other drugs (e.g., alcohol, cocaine) in the system or the concomitant use of tobacco. Still, the temporal association between consumption of herbal mixture products containing synthetic cannabinoids, such as Spice and K2 (130), and a growing number of reported cases of myocardial ischemia (27) supports the notion that phytocannabinoids may contribute directly to some of the observed effects and warrant further research.

 

Other potential medical consequences

Reproductive/Endocrine System

There is a bidirectional relationship between the ECS and gonadal hormones, with endocannabinoids down-regulating hypothalamic-pituitary-gonadal-activity and gonadal hormones modulating protein expression in the ECS, and influencing human behavior (51). The hypothesis that cannabis use could perturb reproductive health hinges on at least three lines of evidence. First, chronic cannabis use may have adverse effects on multiple endocrine systems including prolactin, oxytocin, thyroid hormone and growth hormone (41) and estrogen (88); second, exogenous cannabinoids could interfere with an endocannabinoid signaling that is operative in all critical stages of pregnancy (92); and, third, there is preclinical evidence showing that cannabis can impair reproductive function, for example, chronic (36 weeks) THC exposure can cause testicular recrudescence, and lower sperm count, viability and motility in rodents (10). Despite some evidence in support of these arguments, the notion that cannabis use has a robust adverse effect on male (38) or female (19) fertility in humans remains largely hypothetical. It is possible, as it has been suggested, that the effects of cannabis use on spermatogenesis or testosterone levels may cross the threshold of detection among those whose fertility is already impaired (58), but the fact remains that the results of human research in this context have been inconsistent (21).

 

Pregnancy complications

We do know that a carefully calibrated ECS is essential for successful reproduction, a delicate balance that could be disrupted by exogenous cannabinoids (19). Thus, it is not surprising that, compared with non-using controls, women who used cannabis during their pregnancy had slightly increased odds of suffering from anemia (55). In addition, their cannabis exposed infants are more likely to suffer from lower birth weight and to need placement in the neonatal intensive care unit compared with infants whose mothers had not use cannabis during pregnancy (55). Finally, continued maternal marijuana use at 20 weeks’ gestation has been found to be associated with spontaneous preterm births (SPTB), independent of cigarette smoking status (89).

 

The potential medical consequences of cannabis use in this population are particularly worrisome when we consider that young pregnant women may be turning to cannabis in increasing numbers for its antiemetic properties, particularly during the first trimester of pregnancy, which is the period of greatest risk for the deleterious effects of fetal exposure to drugs (20, 127). Research and dissemination will play a critical role in counteracting the misleading messaging in multiple media outlets, including the internet, touting cannabis as a benign solution for the nausea that commonly accompanies pregnancy, including the severe condition known as hyperemesis gravidarum, that could in fact be exacerbated by exogenous cannabinoids (5)(see next section). A detailed review of the CUD during the perinatal period is covered in chapter 14 of this book.

 

Hyperemesis syndrome

Cannabinoid hyperemesis syndrome (CHS) refers to a clinical entity that used to be rare, under-recognized, or controversial. It was first described in 2004 (3) but has been observed with increased frequency among cannabis users (63, 77, 124). Affected individuals present to the emergency department with nausea, vomiting, and abdominal pain, a manifestation sometimes referred to as “cyclical vomiting” (119) that is difficult to treat but reported to subside with hot hydrotherapy (125), topical capsaicin in the periumbilical region (102), or stopping cannabis use altogether (17). Interestingly, a National Academy of Sciences Engineering and Medicine (NASEM) report makes no mention of this condition in its latest comprehensive review of the health effects of cannabis and cannabinoids (106), another likely reflection of the fluid nature of this field and the increasing use of cannabis and synthetic cannabinoids. Indeed, more than half of the 145 articles retrieved from PUBMED using the keywords cannabis/marijuana hyperemesis, were published just in the past three years.

 

The condition is paradoxical, since THC, the only FDA-approved cannabis-based medication, is prescribed to improve appetite and for the treatment of chemotherapy induced hyperemesis (42). It has been hypothesized that CHS may be the manifestation of an endocannabinoid system that, in vulnerable individuals, (e.g., deficits in the HPA axis response to stress) becomes unable to withstand the allostatic burden of a high-potency cannabis challenge (124) under conditions of stress or fasting, for example. Although many potential mechanisms have been proposed, including desensitization of CB1R, decreased GI motility, or dilation of splanchnic vasculature (reviewed in (135)), the actual mechanism(s) remains a mystery. Given the rapidly changing cannabis landscape, under-diagnosis of CHS could be on the rise, hence, physicians and health care staff should become more aware of the phenomenon and the standard operating procedures that have been proposed for its diagnosis, treatment and follow up (17).

 

Metabolic Effects

Endocannabinoid research has clearly established the role of these neurotransmitters in the regulation of appetitive behaviors, energy balance, insulin sensitivity, pancreatic β-cell function, and lipid metabolism (80, 90, 115, 149). Consistent with the metabolic involvement of the ECS, the literature is studded with examples of cannabis adverse effects on multiple related measures. For example, a cross sectional study found that compared to controls, chronic cannabis smokers reported significantly higher carbohydrate intake and percent calories from carbohydrates (although not total energy intake), and had higher visceral adiposity and lower adipocyte insulin resistance index (105). While these effects may explain the reported higher odds of displaying signs of prediabetes among young adults who use cannabis (9), recent analysis of all the available data failed to detect increased odds of developing diabetes among regular users of cannabis (9, 134). In fact, the limited evidence appears to suggest the opposite, namely, that cannabis use and risk of metabolic disease and diabetes might be inversely correlated (reviewed in (106), which is rather unexpected, given THC’s ability to increase appetite, and promote feeding and fat deposition (140).

 

Sleep Disorders

There are bidirectional effects between chronic cannabis use and sleep disorders or sleep problems (116). On one hand, acute or chronic smoking of cannabis is associated with poor sleep quality and inattention (91, 111) and impaired circadian entrainment (147), while CUD is associated with sleep disorders including insomnia (28, 29). On the other hand, poor sleep or other sleep problems also lead to the development of SUD or CUD among adolescent and young people (6, 62, 98, 99, 107). Both, preclinical and clinical studies have provided evidence that cannabinoids can affect circadian biology and sleep: rodent studies have found significant alterations of circadian rhythm profiles during THC administration (117), while acute THC administration appears to reduce rapid eye movement (REM) but increase slow wave sleep (120) in humans. However, it is likely that the system can develop tolerance to these effects since studies of chronic THC administration have produced opposite or inconsistent results (1, 11, 12, 121). Interestingly, results of a more recent study of chronic daily cannabis users suggest that higher evening levels of circulating THC or its metabolites may promote shorter sleep latency and facilitate falling asleep (50). However, a similarly designed experiment suggested that cannabis naïve individuals may be more likely to experience adverse effects after acute exposure to THC, like increased awake activity during sleep time that can counteract any residual sedative property of the drug (108). Finally, Nabilone, a synthetic cannabinoid that mimics THC, may reduce nightmares associated with PTSD, and improve sleep among patients with chronic pain (8).

 

The literature in this area is far from homogeneous, and rather inadequate for drawing solid conclusions or crafting clinical guidance. However, the involvement of the ECS in the regulation of circadian physiology is rather clear and may help explain, for example, why sleep disturbances are such a frequent sign of cannabis withdrawal syndrome (28, 47, 48). Importantly, unlike other cannabis withdrawal symptoms (22) that typically resolve after 2-3 weeks of abstinence (e.g., mood disturbances, gastrointestinal dysregulation), impaired sleep related to CUD may persist up to a month or longer (23, 145) making it a major risk factor for cannabis use relapse among people who are trying to quit or cut down on its use. Thus, clinicians would be well-advised to be on the alert for any sudden changes in sleep hygiene that could be related to acute cannabis exposure or to cannabis withdrawal.

 

Cancer

After many years of investigating the carcinogenic potential of regular cannabis use, the tide has definitely shifted, in recent years, with a more prominent research focus on cannabis and its emerging (albeit so far unproven) therapeutic role in cancer (71). As mentioned earlier, smoking cannabis has not been shown to increase the risk of developing lung cancer, however, the data here, and as it pertains to other types of cancer, suffer from the same limitations that bedevil the study of other clinical outcomes. They include small populations, reliance on self-reporting, poor stratification based on cannabis dosages, and a host of confounding and other hard to capture risk factors.

 

Cancer studies present particularly challenging methodological issues, like the targeting of multiple organs, dynamic staging, histopathological heterogeneity, and very long incubation periods. Given the limited quality of the available epidemiological evidence and the likelihood that the prevalence of regular cannabis use will continue to rise, it would be premature to dismiss outright a possible link between cannabis use and cancer. Indeed, there is currently evidence, albeit limited, suggesting chronic or frequent use of cannabis may be associated with testicular germ cell tumors as compared to non-users of cannabis (56). Future studies will have to address the limitations mentioned above and conduct far more rigorous studies vis á vis patient stratification and data collection, among others, if we are ever to establish, with a reasonable degree of certainty, whether and which types of cancer risk might be modulated by cannabis use.

 

Questions moving forward

The changing regulatory, scientific, and cultural landscape that influences the prevalence and usage patterns of cannabis requires we adopt a proactive stance vis á vis the potential for medical consequences that could affect large numbers of regular users around the globe. This realization translates into an urgent need to identify and address critical gaps in our knowledge, including possible consequences related to:

• Increasing THC potency

There is convincing (although not yet overwhelming)(59, 81) evidence that higher potency strains or extracts of cannabis are becoming widespread and increasingly available, a trend that may be fueled in part by the legalization wave sweeping the Nation. For example, a 2014 analysis of Twitter activity showed the highest popularity of dabs (cannabis concentrates reported to reach THC concentration in the 25 to 75% range (122)) was detected in states that allow recreational and/or medicinal cannabis use (31). This trend is handicapping the ability to derive meaningful lessons from older epidemiological studies that were based on significantly lower THC concentrations (41). The public health implications associated with high-potency cannabis are not yet clear (81), thus research in this area, particularly the impact on the developing brain, is urgently needed.

 

It is reasonable to expect that users of high-potency products could increase their risk of developing respiratory problems or experience psychotic symptoms (58). At the same time, we should also consider that experienced users may be able to titrate the dose delivered and effectively lower the risk of health effects while naïve users may be more likely to experience adverse (or even catastrophic) effects that could deter (or prevent) them from becoming repeat users (58).

 

• Overdose, poisoning, and cannabis edibles

According to the NASEM there is “minimal literature on cannabis-related overdose death in adults or children” thus, not enough evidence to support or reject the possibility of a cannabis overdose death. However, pediatric overdose injuries are increasingly a distinct possibility, particularly in States that have legalized cannabis (106). The US experience with pediatric cannabinoid overdose is consistent with seven cases (between the ages of 1 and 3 years of age) reported over a 3.5 year period in France (86) and another four recorded poisoning cases (between the ages of 2 and 14) in Spain (30). In general, if cannabis can cause poisoning, it has been in extremely rare occasions up until recently. An analysis of the National Poison Data Systems database involving more than 2 million human exposure cases in 2012 did not list cannabis among the top causes of death related to pharmaceutical products (32), and prior years only record isolated cases (106). The Drug Abuse Warning Network reported a significant increase in emergency department visits and rates for cannabis-only and cannabis-polydrug use between 2004 and 2011 (154). But deaths attributed to the consumption of cannabis containing edibles are beginning to appear in the literature (60), suggesting that increased availability and potency of cannabis products create the potential for an increased risk of adverse health effects related to cannabis use, including overdose, injury, and death. At a minimum, the emerging data strongly suggests that pediatric intensivists should be especially aware and vigilant with regards to the various pediatric symptoms that can be caused by ingestion of cannabinoid-containing products.

 

• Medicinal use

There is a wide and worrying gap between the strength of the scientific evidence and the intensity of the public’s (growing) acceptance of cannabis, cannabis-derived products, and purified cannabinoids for a bewildering array of medical conditions. This warrants a more careful approach to the study of the therapeutic benefit index and potential for specific adverse effects, particularly when dealing with patient subpopulations (e.g., HIV, immunosuppressed, elderly, chronic pain, mentally ill, pregnant women) that are likely to display increased vulnerabilities to iatrogenic harm. A related concern is the almost certainty of the emergence of a robust cannabis retail and advertisement environment, a development that requires a proactive research and surveillance stance (15, 85) in order not to make the same mistakes we continue to make in the domain of legal drugs (i.e., alcohol and tobacco) and other unhealthy (e.g., junk food) behaviors (78).

 

• Vaping adolescents

One increasingly popular way of self-administrating cannabis is the use of vaporizers or e-cigarettes (103). Lower temperature vaporization of cannabis has been postulated as safer than smoking, as it may deliver fewer high molecular weight components than smoked cannabis (16), but well-controlled, long-term studies with specific subpopulation will be needed to demonstrate, refute, or qualify this notion. Whether vaporizing cannabis is a safer alternative to smoking remains uncertain, as the reduction in toxic smoke components needs to be weighed against the hazards of acute intoxication and long-term consequences to the brain due to the formation and delivery of new potentially dangerous compounds, like acetaldehyde and formaldehyde (143). Of particular concern is the targeted marketing of these highly addictive devices to adolescents, whose developing brains are significantly more likely to experience adverse effects (e.g., addiction, abnormal reward sensitivity) than adults (84, 103).

 

• Synthetic cannabinoids

Research will be needed to understand the effects of synthetic compounds with different pharmacological profiles and/or higher affinities for cannabinoid receptors (33). Past studies of THC may not be applicable to explaining new effects seen, for example, on drivers under the influence of synthetic cannabinoids who may be more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of cannabis, as determined by Drug Recognition Expert (DRE, (61)) evaluation (26). However, the rise of synthetic cannabinoids presents a constantly changing and particularly evasive threat to public health, which will require more than additional basic research or tighter regulations. A targeted prevention and policy research agenda is needed to identify evidence-based interventions to inform/shape behavioral choices that mitigate the ever-changing risk of adverse health consequences from synthetic cannabinoids (43).

 

Conclusions

The types of (non-cognitive) medical consequences associated with cannabis use that appear to be supported by a substantial amount of evidence (i.e., strong evidence of a statistical significant link) are few and far between (106). Most other reported adverse health effects are supported by evidence that is limited in scope or of low quality. Given the rapid changes in cannabis policies and evolution of cannabinomimetic molecules, the large numbers of current users, and the concomitant rise in its medicinal and recreational use, the lack of conclusive evidence, either confirming or rejecting so many of the alleged health effects of cannabis use (whether acute or persistent, adverse or therapeutic) constitutes a grave public health concern. This should spur targeted efforts to a) design and deploy better surveillance instruments, b) conduct more basic cannabis research in animals and humans, and c) develop a prevention research and policy agenda that can address the many complex issues associated with today’s patterns of cannabis use.

 

 

 

 

References

1. Adams PM, and Barratt ES. Effect of chronic marijuana administration of stages of primate sleep-wakefulness. Biological psychiatry 10: 315-322, 1975.
2. Ahrnsbrak R, Bose J, Hedden SL, Lipari RN, and Park-Lee E. Key Substance Use and Mental Health Indicators in the United States: Results from the 2016 National Survey on Drug Use and Health. edited by (HHS) USDoHaHS. Rockville, MD: Substance Abuse and Mental Health Services Administration (SAMHSA), 2017.
3. Allen JH, de Moore GM, Heddle R, and Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut 53: 1566-1570, 2004.
4. Alshaarawy O, and Elbaz HA. Cannabis use and blood pressure levels: United States National Health and Nutrition Examination Survey, 2005-2012. Journal of hypertension 34: 1507-1512, 2016.
5. Andrews KH, and Bracero LA. Cannabinoid Hyperemesis Syndrome During Pregnancy: A Case Report. The Journal of reproductive medicine 60: 430-432, 2015.
6. Angarita GA, Emadi N, Hodges S, and Morgan PT. Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review. Addict Sci Clin Pract 11: 9, 2016.
7. Azofeifa A, Mattson ME, and Grant A. Monitoring Marijuana Use in the United States: Challenges in an Evolving Environment. Jama 316: 1765-1766, 2016.
8. Babson KA, Sottile J, and Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep 19: 23, 2017.
9. Bancks MP, Pletcher MJ, Kertesz SG, Sidney S, Rana JS, and Schreiner PJ. Marijuana use and risk of prediabetes and diabetes by middle adulthood: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetologia 58: 2736-2744, 2015.
10. Banerjee A, Singh A, Srivastava P, Turner H, and Krishna A. Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth defects research Part B, Developmental and reproductive toxicology 92: 195-205, 2011.
11. Barratt ES, and Adams PM. Chronic marijuana usage and sleep-wakefulness cycles in cats. Biological psychiatry 6: 207-214, 1973.
12. Barratt ES, Beaver W, and White R. The effects of marijuana on human sleep patterns. Biological psychiatry 8: 47-54, 1974.
13. Barsky SH, Roth MD, Kleerup EC, Simmons M, and Tashkin DP. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco. Journal of the National Cancer Institute 90: 1198-1205, 1998.
14. Benowitz NL, and Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clinical pharmacology and therapeutics 18: 287-297, 1975.
15. Berg CJ, Henriksen L, Cavazos-Rehg PA, Haardoerfer R, and Freisthler B. The emerging marijuana retail environment: Key lessons learned from tobacco and alcohol retail research. Addictive behaviors 81: 26-31, 2018.
16. Bloor RN, Wang TS, Spanel P, and Smith D. Ammonia release from heated ‘street’ cannabis leaf and its potential toxic effects on cannabis users. Addiction 103: 1671-1677, 2008.
17. Blumentrath CG, Dohrmann B, and Ewald N. Cannabinoid hyperemesis and the cyclic vomiting syndrome in adults: recognition, diagnosis, acute and long-term treatment. German medical science : GMS e-journal 15: Doc06, 2017.
18. Brancheau D, Blanco J, Gholkar G, Patel B, and Machado C. Cannabis induced asystole. J Electrocardiol 49: 15-17, 2016.
19. Brents LK. Marijuana, the Endocannabinoid System and the Female Reproductive System. The Yale journal of biology and medicine 89: 175-191, 2016.
20. Brown QL, Sarvet AL, Shmulewitz D, Martins SS, Wall MM, and Hasin DS. Trends in Marijuana Use Among Pregnant and Nonpregnant Reproductive-Aged Women, 2002-2014. Jama 317: 207-209, 2017.
21. Brown TT, and Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol 42: 90S-96S, 2002.
22. Budney AJ, Hughes JR, Moore BA, and Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. The American journal of psychiatry 161: 1967-1977, 2004.
23. Budney AJ, Moore BA, Vandrey RG, and Hughes JR. The time course and significance of cannabis withdrawal. Journal of abnormal psychology 112: 393-402, 2003.
24. Casier I, Vanduynhoven P, Haine S, Vrints C, and Jorens PG. Is recent cannabis use associated with acute coronary syndromes? An illustrative case series. Acta Cardiol 69: 131-136, 2014.
25. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, and Huestis MA. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend 144: 12-41, 2014.
26. Chase PB, Hawkins J, Mosier J, Jimenez E, Boesen K, Logan BK, and Walter FG. Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs. Clinical toxicology 54: 14-19, 2016.
27. Clark BC, Georgekutty J, and Berul CI. Myocardial Ischemia Secondary to Synthetic Cannabinoid (K2) Use in Pediatric Patients. The Journal of pediatrics 167: 757-761 e751, 2015.
28. Conroy DA, and Arnedt JT. Sleep and substance use disorders: an update. Curr Psychiatry Rep 16: 487, 2014.
29. Conroy DA, Kurth ME, Strong DR, Brower KJ, and Stein MD. Marijuana use patterns and sleep among community-based young adults. J Addict Dis 35: 135-143, 2016.
30. Croche Santander B, Alonso Salas MT, and Loscertales Abril M. [Accidental cannabis poisoning in children: report of four cases in a tertiary care center from southern Spain]. Archivos argentinos de pediatria 109: 4-7, 2011.
31. Daniulaityte R, Nahhas RW, Wijeratne S, Carlson RG, Lamy FR, Martins SS, Boyer EW, Smith GA, and Sheth A. “Time for dabs”: Analyzing Twitter data on marijuana concentrates across the U.S. Drug Alcohol Depend 155: 307-311, 2015.
32. Dart RC, Bronstein AC, Spyker DA, Cantilena LR, Seifert SA, Heard SE, and Krenzelok EP. Poisoning in the United States: 2012 emergency medicine report of the National Poison Data System. Annals of emergency medicine 65: 416-422, 2015.
33. Davis C, and Boddington D. Teenage cardiac arrest following abuse of synthetic cannabis. Heart, lung & circulation 24: e162-163, 2015.
34. De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, and Di Marzo V. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. British journal of pharmacology 168: 79-102, 2013.
35. Desai R, Patel U, Deshmukh A, Sachdeva R, and Kumar G. Burden of arrhythmia in recreational marijuana users. International journal of cardiology 2018.
36. Dines AM, Wood DM, Galicia M, Yates CM, Heyerdahl F, Hovda KE, Giraudon I, Sedefov R, Euro DENRG, and Dargan PI. Presentations to the Emergency Department Following Cannabis use–a Multi-Centre Case Series from Ten European Countries. Journal of medical toxicology : official journal of the American College of Medical Toxicology 11: 415-421, 2015.
37. Draz EI, Oreby MM, Elsheikh EA, Khedr LA, and Atlam SA. Marijuana use in acute coronary syndromes. Am J Drug Alcohol Abuse 43: 576-582, 2017.
38. du Plessis SS, Agarwal A, and Syriac A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. Journal of assisted reproduction and genetics 32: 1575-1588, 2015.
39. Duchene C, Olindo S, Chausson N, Jeannin S, Cohen-Tenoudji P, and Smadja D. [Cannabis-induced cerebral and myocardial infarction in a young woman]. Revue neurologique 166: 438-442, 2010.
40. ElSohly M, and Gul W. Constituents of cannabis sativa. In: Handbook of Cannabis, edited by Pertwee RG. Oxford: Oxford University Press, 2014, p. 22.
41. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, and Church JC. Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States. Biological psychiatry 79: 613-619, 2016.
42. FDA. MARINOL (dronabinol) capsules, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf (accessed 4/27/2018).
43. Fischer B, Russell C, Sabioni P, van den Brink W, Le Foll B, Hall W, Rehm J, and Room R. Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations. American journal of public health 107: 1277, 2017.
44. Fligiel SE, Roth MD, Kleerup EC, Barsky SH, Simmons MS, and Tashkin DP. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 112: 319-326, 1997.
45. Fonseca BM, Correia-da-Silva G, and Teixeira NA. Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis. Journal of physiology and biochemistry 2018.
46. Franz CA, and Frishman WH. Marijuana Use and Cardiovascular Disease. Cardiol Rev 24: 158-162, 2016.
47. Gates P, Albertella L, and Copeland J. Cannabis withdrawal and sleep: A systematic review of human studies. Subst Abus 37: 255-269, 2016.
48. Gates PJ, Albertella L, and Copeland J. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev 18: 477-487, 2014.
49. Ghannem M, Belhadj I, Tritar A, Moukala T, Amri N, Noury A, and Zaghdoudi M. [Cannabis and acute coronary syndrome with ST segment elevation]. Ann Cardiol Angeiol (Paris) 62: 424-428, 2013.
50. Gorelick DA, Goodwin RS, Schwilke E, Schroeder JR, Schwope DM, Kelly DL, Ortemann-Renon C, Bonnet D, and Huestis MA. Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers. The American journal on addictions 22: 510-514, 2013.
51. Gorzalka BB, and Dang SS. Minireview: Endocannabinoids and gonadal hormones: bidirectional interactions in physiology and behavior. Endocrinology 153: 1016-1024, 2012.
52. Goyal H, Awad HH, and Ghali JK. Role of cannabis in cardiovascular disorders. Journal of thoracic disease 9: 2079-2092, 2017.
53. Grotenhermen F. Cannabis-associated arteritis. VASA Zeitschrift fur Gefasskrankheiten 39: 43-53, 2010.
54. Gunawardena MD, Rajapakse S, Herath J, and Amarasena N. Myocardial infarction following cannabis induced coronary vasospasm. BMJ Case Rep 2014: 2014.
55. Gunn JK, Rosales CB, Center KE, Nunez A, Gibson SJ, Christ C, and Ehiri JE. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ open 6: e009986, 2016.
56. Gurney J, Shaw C, Stanley J, Signal V, and Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer 15: 897, 2015.
57. Hall W, and Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 374: 1383-1391, 2009.
58. Hall W, and Pacula R. Cannabis use and dependence: public health and public policy

Cambridge: Cambridge University Press

2003.

59. Hall W, and Swift W. The THC content of cannabis in Australia: evidence and policy implications Australian and New Zealand Journal of Public Health 24: 503-508, 2000.
60. Hancock-Allen JB, Barker L, VanDyke M, and Holmes DB. Notes from the Field: Death Following Ingestion of an Edible Marijuana Product–Colorado, March 2014. MMWR Morbidity and mortality weekly report 64: 771-772, 2015.
61. Hartman RL, Richman JE, Hayes CE, and Huestis MA. Drug Recognition Expert (DRE) examination characteristics of cannabis impairment. Accident; analysis and prevention 92: 219-229, 2016.
62. Hasler BP, Kirisci L, and Clark DB. Restless Sleep and Variable Sleep Timing During Late Childhood Accelerate the Onset of Alcohol and Other Drug Involvement. J Stud Alcohol Drugs 77: 649-655, 2016.
63. Heard K, Marlin MB, Nappe T, and Hoyte CO. Common marijuana-related cases encountered in the emergency department. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 74: 1904-1908, 2017.
64. Helyes Z, Kemeny A, Cseko K, Szoke E, Elekes K, Mester M, Sandor K, Perkecz A, Kereskai L, Mark L, Bona A, Benko A, Pinter E, Szolcsanyi J, Ledent C, Sperlagh B, and Molnar TF. Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation. American journal of physiology Lung cellular and molecular physiology 313: L267-L277, 2017.
65. Hodcroft CJ, Rossiter MC, and Buch AN. Cannabis-associated myocardial infarction in a young man with normal coronary arteries. J Emerg Med 47: 277-281, 2014.
66. Hoffman D BK, Gori GB, Wynder EL. On the Carcinogenicity of Marijuana Smoke. In: Recent Advances in Phytochemistry, edited by Runeckles VCSpringer, Boston, MA, 1975, p. 63-81.
67. Hoffmann D, Gori G, and Wynder E. On the Carcinogenicity of Marijuana Smoke. In: Recent Advances in Phytochemistry, edited by Runeckles VC. New York: Plenum Press, 1975, p. 63-81.
68. Huang YH, Zhang ZF, Tashkin DP, Feng B, Straif K, and Hashibe M. An epidemiologic review of marijuana and cancer: an update. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24: 15-31, 2015.
69. Huber GL, First MW, and Grubner O. Marijuana and tobacco smoke gas-phase cytotoxins. Pharmacology, biochemistry, and behavior 40: 629-636, 1991.
70. Jamal A, D. , Homa M, O’Connor E, Babb SD, Caraballo RS, Singh T, Hu SS, and B.A. K. Current Cigarette Smoking Among Adults—United States, 2005–2014. Morbidity and Mortality Weekly Report 64: 1233-1240, 2015.
71. Jett J, Stone E, Warren G, and Cummings KM. Cannabis Use, Lung Cancer, and Related Issues. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13: 480-487, 2018.
72. Jones RT. Cardiovascular system effects of marijuana. Journal of clinical pharmacology 42: 58S-63S, 2002.
73. Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A, and Yusuf S. Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors. Circulation research 121: 677-694, 2017.
74. Jouanjus E, Lapeyre-Mestre M, and Micallef J. Cannabis use: signal of increasing risk of serious cardiovascular disorders. J Am Heart Assoc 3: e000638, 2014.
75. Kaneko S. Motor vehicle collisions caused by the ‘super-strength’ synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014. Forensic toxicology 35: 244-251, 2017.
76. Karila L, Benyamina A, Blecha L, Cottencin O, and Billieux J. The Synthetic Cannabinoids Phenomenon. Current pharmaceutical design 22: 6420-6425, 2016.
77. Kast KA, and Gershengoren L. Cannabinoid Hyperemesis Syndrome and the Consulting Psychiatrist: A Case Study of Diagnosis and Treatment for an Emerging Disorder in Psychiatric Practice. Journal of psychiatric practice 24: 51-55, 2018.
78. Kelly B, Baur LA, Bauman AE, and King L. Tobacco and alcohol sponsorship of sporting events provide insights about how food and beverage sponsorship may affect children’s health. Health promotion journal of Australia : official journal of Australian Association of Health Promotion Professionals 22: 91-96, 2011.
79. Kempker JA, Honig EG, and Martin GS. The effects of marijuana exposure on expiratory airflow. A study of adults who participated in the U.S. National Health and Nutrition Examination Study. Annals of the American Thoracic Society 12: 135-141, 2015.
80. Kim W, Lao Q, Shin YK, Carlson OD, Lee EK, Gorospe M, Kulkarni RN, and Egan JM. Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. Science signaling 5: ra23, 2012.
81. King LA, Carpentier C, and Griffiths P. Cannabis potency in Europe. Addiction 100: 884-886, 2005.
82. Kocabay G, Yildiz M, Duran NE, and Ozkan M. Acute inferior myocardial infarction due to cannabis smoking in a young man. Journal of cardiovascular medicine 10: 669-670, 2009.
83. Kochanek KD, Murphy SL, Xu JQ, and Tejada-Vera B. Deaths: Final data for 2014. National Vital Statistics Reports 65(4):1–121. . edited by HHS. Hyattsville, MD: National Center for Health Statistics., 2016.
84. Kong G, and Krishnan-Sarin S. A call to end the epidemic of adolescent E-cigarette use. Drug Alcohol Depend 174: 215-221, 2017.
85. Krauss MJ, Sowles SJ, Sehi A, Spitznagel EL, Berg CJ, Bierut LJ, and Cavazos-Rehg PA. Marijuana advertising exposure among current marijuana users in the U.S. Drug Alcohol Depend 174: 192-200, 2017.
86. Le Garrec S, Dauger S, and Sachs P. Cannabis poisoning in children. Intensive care medicine 40: 1394-1395, 2014.
87. Lee MH, and Hancox RJ. Effects of smoking cannabis on lung function. Expert Rev Respir Med 5: 537-546, 2011.
88. Lee SY, Oh SM, and Chung KH. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds. Toxicol Appl Pharmacol 214: 270-278, 2006.
89. Leemaqz SY, Dekker GA, McCowan LM, Kenny LC, Myers JE, Simpson NA, Poston L, Roberts CT, and Consortium S. Maternal marijuana use has independent effects on risk for spontaneous preterm birth but not other common late pregnancy complications. Reproductive toxicology 62: 77-86, 2016.
90. Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, Yin S, Gao P, Shan X, Pickel J, Bataller R, O’Hare J, Scherer T, Buettner C, and Kunos G. Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142: 1218-1228 e1211, 2012.
91. Ly C, and Gehricke JG. Marijuana use is associated with inattention in men and sleep quality in women with Attention-Deficit/Hyperactivity Disorder: a preliminary study. Psychiatry Res 210: 1310-1312, 2013.
92. Maccarrone M, Bab I, Biro T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, and Zimmer A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends in pharmacological sciences 36: 277-296, 2015.
93. Macleod J, Robertson R, Copeland L, McKenzie J, Elton R, and Reid P. Cannabis, tobacco smoking, and lung function: a cross-sectional observational study in a general practice population. The British journal of general practice : the journal of the Royal College of General Practitioners 65: e89-95, 2015.
94. Marchetti D, Spagnolo A, De Matteis V, Filograna L, and De Giovanni N. Coronary thrombosis and marijuana smoking: a case report and narrative review of the literature. Drug testing and analysis 8: 56-62, 2016.
95. Martinasek MP, McGrogan JB, and Maysonet A. A Systematic Review of the Respiratory Effects of Inhalational Marijuana. Respiratory care 61: 1543-1551, 2016.
96. Meier MH, Caspi A, Cerda M, Hancox RJ, Harrington H, Houts R, Poulton R, Ramrakha S, Thomson WM, and Moffitt TE. Associations Between Cannabis Use and Physical Health Problems in Early Midlife: A Longitudinal Comparison of Persistent Cannabis vs Tobacco Users. JAMA psychiatry 73: 731-740, 2016.
97. Menahem S. Cardiac asystole following cannabis (marijuana) usage–additional mechanism for sudden death? Forensic science international 233: e3-5, 2013.
98. Mike TB, Shaw DS, Forbes EE, Sitnick SL, and Hasler BP. The hazards of bad sleep-Sleep duration and quality as predictors of adolescent alcohol and cannabis use. Drug Alcohol Depend 168: 335-339, 2016.
99. Miller MB, Janssen T, and Jackson KM. The Prospective Association Between Sleep and Initiation of Substance Use in Young Adolescents. J Adolesc Health 60: 154-160, 2017.
100. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, and Muller JE. Triggering myocardial infarction by marijuana. Circulation 103: 2805-2809, 2001.
101. Moir D, Rickert WS, Levasseur G, Larose Y, Maertens R, White P, and Desjardins S. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chemical research in toxicology 21: 494-502, 2008.
102. Moon AM, Buckley SA, and Mark NM. Successful Treatment of Cannabinoid Hyperemesis Syndrome with Topical Capsaicin. ACG case reports journal 5: e3, 2018.
103. Morean ME, Kong G, Camenga DR, Cavallo DA, and Krishnan-Sarin S. High School Students’ Use of Electronic Cigarettes to Vaporize Cannabis. Pediatrics 136: 611-616, 2015.
104. Mukhopadhyay P, Batkai S, Rajesh M, Czifra N, Harvey-White J, Hasko G, Zsengeller Z, Gerard NP, Liaudet L, Kunos G, and Pacher P. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. Journal of the American College of Cardiology 50: 528-536, 2007.
105. Muniyappa R, Sable S, Ouwerkerk R, Mari A, Gharib AM, Walter M, Courville A, Hall G, Chen KY, Volkow ND, Kunos G, Huestis MA, and Skarulis MC. Metabolic effects of chronic cannabis smoking. Diabetes Care 36: 2415-2422, 2013.
106. NASEM. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research Washingtonm, DC: Committe on the Health effects of marijuana: An Evidence Review and Research Agenda, 2017.
107. Nguyen-Louie TT, Brumback T, Worley MJ, Colrain IM, Matt GE, Squeglia LM, and Tapert SF. Effects of sleep on substance use in adolescents: a longitudinal perspective. Addict Biol 2017.
108. Nicholson AN, Turner C, Stone BM, and Robson PJ. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. Journal of clinical psychopharmacology 24: 305-313, 2004.
109. Novotný M, Merli F, Wiesler D, Fencl M, and Saeed T. Fractionation and capillary gas chromatographic—mass spectrometric characterization of the neutral components in marijuana and tobacco smoke condensates. Journal of Chromatography A 238: 141-150, 1982.
110. Nowlan R, and Cohen S. Tolerance to marijuana: heart rate and subjective “high”. Clinical pharmacology and therapeutics 22: 550-556, 1977.
111. Ogeil RP, Phillips JG, Rajaratnam SM, and Broadbear JH. Risky drug use and effects on sleep quality and daytime sleepiness. Hum Psychopharmacol 30: 356-363, 2015.
112. Okamoto T, Chan PC, and So BT. Effect of tobacco, marijuana and benzo(a)pyrene on aryl hydrocarbon hydroxylase in hamster lung. Life sciences Pt 2: Biochemistry, general and molecular biology 11: 733-741, 1972.
113. Owen KP, Sutter ME, and Albertson TE. Marijuana: respiratory tract effects. Clinical reviews in allergy & immunology 46: 65-81, 2014.
114. Pacher P, Steffens S, Hasko G, Schindler TH, and Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nature reviews Cardiology 15: 151-166, 2018.
115. Pagotto U, Marsicano G, Cota D, Lutz B, and Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine reviews 27: 73-100, 2006.
116. Pasch KE, Latimer LA, Cance JD, Moe SG, and Lytle LA. Longitudinal bi-directional relationships between sleep and youth substance use. J Youth Adolesc 41: 1184-1196, 2012.
117. Perron RR, Tyson RL, and Sutherland GR. Delta9 -tetrahydrocannabinol increases brain temperature and inverts circadian rhythms. Neuroreport 12: 3791-3794, 2001.
118. Peyrot I, Garsaud AM, Saint-Cyr I, Quitman O, Sanchez B, and Quist D. Cannabis arteritis: a new case report and a review of literature. Journal of the European Academy of Dermatology and Venereology : JEADV 21: 388-391, 2007.
119. Phillips HR, 3rd, and Smith DA. A patient with a curious case of cyclical vomiting. JAAPA : official journal of the American Academy of Physician Assistants 30: 1-3, 2017.
120. Pivik RT, Zarcone V, Dement WC, and Hollister LE. Delta-9-tetrahydrocannabinol and synhexl: effects on human sleep patterns. Clinical pharmacology and therapeutics 13: 426-435, 1972.
121. Pranikoff K, Karacan I, Larson EA, Williams RL, Thornby JI, and Hursch CJ. Effects of marijuana smoking on the sleep EEG. Preliminary studies. JFMA, the Journal of the Florida Medical Association Florida Medical Association 60: 28-31, 1973.
122. Raber JC, Elzinga S, and Kaplan C. Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbing. The Journal of toxicological sciences 40: 797-803, 2015.
123. Ribeiro LI, and Ind PW. Effect of cannabis smoking on lung function and respiratory symptoms: a structured literature review. NPJ primary care respiratory medicine 26: 16071, 2016.
124. Richards JR. Cannabinoid Hyperemesis Syndrome: Pathophysiology and Treatment in the Emergency Department. The Journal of emergency medicine 54: 354-363, 2018.
125. Richards JR, Lapoint JM, and Burillo-Putze G. Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment. Clinical toxicology 56: 15-24, 2018.
126. Rivera-Chavarria IJ, and Brenes-Gutierrez JD. Thromboangiitis obliterans (Buerger’s disease). Annals of medicine and surgery 7: 79-82, 2016.
127. Roberson EK, Patrick WK, and Hurwitz EL. Marijuana use and maternal experiences of severe nausea during pregnancy in Hawai’i. Hawai’i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health 73: 283-287, 2014.
128. Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, and Tashkin DP. Airway inflammation in young marijuana and tobacco smokers. American journal of respiratory and critical care medicine 157: 928-937, 1998.
129. Safaa AM, Markham R, and Jayasinghe R. Marijuana-induced recurrent acute coronary syndrome with normal coronary angiograms. Drug Alcohol Rev 31: 91-94, 2012.
130. Salani DA, and Zdanowicz MM. Synthetic cannabinoids: the dangers of spicing it up. Journal of psychosocial nursing and mental health services 53: 36-43, 2015.
131. Santos RP, Resende CI, Vieira AP, and Brito C. Cannabis arteritis: ever more important to consider. BMJ case reports 2017: 2017.
132. Schaich CL, Shaltout HA, Brosnihan KB, Howlett AC, and Diz DI. Acute and chronic systemic CB1 cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats. Physiological reports 2: 2014.
133. Sidney S. Cardiovascular consequences of marijuana use. Journal of clinical pharmacology 42: 64S-70S, 2002.
134. Sidney S. Marijuana Use and Type 2 Diabetes Mellitus: a Review. Current diabetes reports 16: 117, 2016.
135. Sorensen CJ, DeSanto K, Borgelt L, Phillips KT, and Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. Journal of medical toxicology : official journal of the American College of Medical Toxicology 13: 71-87, 2017.
136. Tashkin DP. Does cannabis use predispose to chronic airflow obstruction? The European respiratory journal 35: 3-5, 2010.
137. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc 10: 239-247, 2013.
138. Tashkin DP, Reiss S, Shapiro BJ, Calvarese B, Olsen JL, and Lodge JW. Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects. The American review of respiratory disease 115: 57-65, 1977.
139. Tashkin DP, Shapiro BJ, and Frank IM. Acute pulmonary physiologic effects of smoked marijuana and oral (Delta)9 -tetrahydrocannabinol in healthy young men. The New England journal of medicine 289: 336-341, 1973.
140. Teixeira D, Pestana D, Faria A, Calhau C, Azevedo I, and Monteiro R. Modulation of adipocyte biology by delta(9)-tetrahydrocannabinol. Obesity 18: 2077-2085, 2010.
141. Thomas G, Kloner RA, and Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Am J Cardiol 113: 187-190, 2014.
142. Tormey WP. Cannabis, possible cardiac deaths and the coroner in Ireland. Irish journal of medical science 181: 479-482, 2012.
143. Troutt WD, and DiDonato MD. Carbonyl Compounds Produced by Vaporizing Cannabis Oil Thinning Agents. Journal of alternative and complementary medicine 23: 879-884, 2017.
144. Uban KA, Horton MK, Jacobus J, Heyser C, Thompson WK, Tapert SF, Madden PAF, Sowell ER, and Adolescent Brain Cognitive Development S. Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data. Developmental cognitive neuroscience 2018.
145. Vandrey RG, Budney AJ, Hughes JR, and Liguori A. A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend 92: 48-54, 2008.
146. Velibey Y, Sahin S, Tanik O, Keskin M, Bolca O, and Eren M. Acute myocardial infarction due to marijuana smoking in a young man: guilty should not be underestimated. Am J Emerg Med 33: 1114-1113, 2015.
147. Whitehurst LN, Fogler K, Hall K, Hartmann M, and Dyche J. The effects of chronic marijuana use on circadian entrainment. Chronobiol Int 32: 561-567, 2015.
148. WHO. Management of Substance Abuse: Cannabis http://www.who.int/substance_abuse/facts/cannabis/en/.
149. Witkamp RF. The role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite. Molecular aspects of medicine 2018.
150. Wolff V, and Jouanjus E. Strokes are possible complications of cannabinoids use. Epilepsy & behavior : E&B 70: 355-363, 2017.
151. Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, and Stroke Statistics S. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 133: e38-360, 2016.
152. Wu TC, Tashkin DP, Djahed B, and Rose JE. Pulmonary hazards of smoking marijuana as compared with tobacco. The New England journal of medicine 318: 347-351, 1988.
153. Zhang LR, Morgenstern H, Greenland S, Chang SC, Lazarus P, Teare MD, Woll PJ, Orlow I, Cox B, Brhane Y, Liu G, and Hung RJ. Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. Int J Cancer 136: 894-903, 2015.
154. Zhu H, and Wu LT. Trends and Correlates of Cannabis-involved Emergency Department Visits: 2004 to 2011. Journal of addiction medicine 10: 429-436, 2016.