Cardiovascular Complications of Marijuana and Related Substances: A Review

Cardiovascular Complications of Marijuana and Related Substances: A Review Cardiol Ther (2018) 7:45–59 https://doi.org/10.1007/s40119-017-0102-x REVIEW Cardiovascular Complications of Marijuana and Related Substances: A Review . . . . Amitoj Singh Sajeev Saluja Akshat Kumar Sahil Agrawal . . Munveer Thind Sudip Nanda Jamshid Shirani Received: August 21, 2017 / Published online: December 7, 2017 The Author(s) 2017. This article is an open access publication established cardiovascular disease are at even ABSTRACT higher danger of such events following expo- sure to cannabis. The pathophysiological basis The recreational use of cannabis has sharply of these events is not fully understood and increased in recent years in parallel with its likely encompasses a complex interaction legalization and decriminalization in several between the active ingredients (particularly the countries. Commonly, the traditional cannabis major cannabinoid, D -tetrahydrocannabinol), has been replaced by potent synthetic and the endo-cannabinoid system, autonomic cannabinoids and cannabimimetics in various nervous system, as well as other receptor and forms. Despite overwhelming public perception non-receptor mediated pathways. Other com- of the safety of these substances, an increasing plicating factors include opposing physiologic number of serious cardiovascular adverse events effects of other cannabinoids (predominantly have been reported in temporal relation to cannabidiol), presence of regulatory proteins recreational cannabis use. These have included that act as metabolizing enzymes, binding sudden cardiac death, vascular (coronary, cere- molecules, or ligands, as well as functional bral and peripheral) events, arrhythmias and polymorphisms of target receptors. Tolerance to stress cardiomyopathy among others. Many of the effects of cannabis may also develop on the victims of these events are relatively young repeated exposures at least in part due to men with few if any cardiovascular risk factors. receptor downregulation or desensitization. However, there are reasons to believe that older Moreover, effects of cannabis may be enhanced individuals and those with risk factors for or or altered by concomitant use of other illicit drugs or medications used for treatment of Enhanced content To view enhanced content for this established cardiovascular diseases. Regardless article go to http://www.medengine.com/Redeem/ of these considerations, it is expected that the 68FCF06068C10492. current cannabis epidemic would add signifi- Electronic supplementary material The online cantly to the universal burden of cardiovascular version of this article (https://doi.org/10.1007/s40119- diseases. 017-0102-x) contains supplementary material, which is available to authorized users. A. Singh  S. Saluja  A. Kumar  S. Agrawal Keywords: Autonomic nervous system; M. Thind  S. Nanda  J. Shirani (&) Cannabis; Endocannabinoid system; Department of Cardiology, St. Luke’s University Marijuana; Myocardial infarction; Stress Health Network, Bethlehem, PA, USA e-mail: jamshid.shirani@sluhn.org 46 Cardiol Ther (2018) 7:45–59 cardiomyopathy; Stroke; Tetrahydrocannabinol; arteritis’’, ‘‘stress cardiomyopathy’’ and ‘‘ar- Vasculopathy rhythmia’’. All referenced material in selected articles were also reviewed carefully for poten- tially relevant reports. The results were thor- INTRODUCTION oughly examined for accuracy of content. The available literature was then categorized Cannabis sativa, the plant known as the original according to both relevance and the clarity of marijuana, was likely first cultivated in Central the presented data. Care was particularly taken Asia, and subsequently brought to other parts of to avoid inclusion of studies with designs that the world. Currently, cannabis grows naturally deviated from usual manners that cannabis is in many countries and is also cultivated indoors used recreationally. The final count of the through the use of hydroponic systems and manuscripts and documents used was 135 that artificial lighting [1, 2]. The plant has been long included 55 case reports, eight case series, 20 used as a medicinal herb or as a mood altering human experimental studies, 11 animal or substance [2]. More recently, a rise in recre- ex vivo studies, 20 databases or guidelines as ational use of cannabis has paralleled that of well as 22 review articles. legislations that have legalized or decriminal- ized the possession, sales, and cultivation of the Compliance with Ethics Guidelines plant [3]. According to the United Nations office on drugs and crime, the global recre- This article does not contain any new studies ational use of cannabis increased by 27% from with human or animal subjects performed by 1998 to 2009 [1]. In 2014, it was estimated that any of the authors. * 183 million people use cannabis worldwide with a steady rise since 2007 [4]. Today, can- nabis is the most frequently used psychoactive NATURAL FORMS OF CANNABIS substance after alcohol and tobacco [1]. The recreational cannabis ‘‘epidemic’’ has been In general, three naturally growing strains of accompanied by an increased number of case Cannabis (sativa, indica, and ruderalis) have been reports of serious cardiovascular complications recognized although interbreeding has pro- from across the globe. A recent systematic duced many more ‘‘hybrid’’ strains of the plants. review has identified 116 such cases published These strains differ in the content and propor- between January 2011 and March 2016 [5]. In tion of the two best recognized active ingredi- the context of the rising popularity of recre- ents, namely D -tetrahydrocannabinol (THC) ational cannabis (and its synthetic analogues) and cannabidiol (CBD). Additionally, the effects we aim to review potential cardiovascular of various cannabis strains may differ based on adverse events associated with the use of these the varying concentration and composition of substances. Furthermore, the potential patho- terpene resins [6]. The sativa strain contains the physiological mechanisms responsible for the highest level of THC, the psychoactive most serious cardiovascular events in users of cannabinoid that produces the euphoric effect cannabis are discussed. and has a relatively low content of CBD, the cannabinoid that may mitigate the euphoric and psychotropic effects of THC. The leaves and METHODS buds of the female plants have the highest content of THC and can be dried for smoking or To prepare this literature review, we performed made into other forms of consumable cannabis searches of PUBMED, MEDLINE and EMBASE including edibles, waxes, oils, liquid incense or databases using the phrases ‘‘marijuana’’, ‘‘can- vapor for both medical and recreational uses. nabis’’, ‘‘cannabinoids’’, ‘‘THC’’, ‘‘D -tetrahydro- Medically, cannabis has been used effectively cannabinol’’, ‘‘cardiovascular disease’’, ‘‘cardiac for treatment of otherwise refractory nausea disease’’, ‘‘heart disease’’, ‘‘stroke’’, ‘‘cannabis and vomiting following chemotherapy and Cardiol Ther (2018) 7:45–59 47 neuropathic pain associated with advanced SYNTHETIC CANNABINOIDS neurologic disorders and cancer, among others AND CANNABIMIMETICS [2, 7, 8]. It is important to note that in the United States, cannabis (marijuana) is still listed Synthetic THC compounds, dronabinol and by the Drug Enforcement Administration as a nabilone, have been marketed as capsules in the Schedule I substance, alongside hallucinogens United States since 1985 for treatment of nau- and heroin, according to the section 202 of the sea, vomiting and weight loss associated with Controlled Substances Act of 1970. Schedule I cancer chemotherapy and acquired immunod- drugs are substances with high potential for eficiency syndrome. A liquid form of dronabi- abuse, no currently established medical use, and nol has also been approved recently as an oral no accepted safety for use under medical solution by the United States Food and Drug supervision. Despite this, 42 states and the Administration for anorexia and weight loss District of Columbia have either legalized or associated with acquired immunodeficiency decriminalized medical uses of cannabis and syndrome and refractory nausea/vomiting related approved medications. associated with cancer chemotherapy. Illegally An important consideration in the uses of manufactured synthetic cannabinoids and cannabis has been the unpredictability of the cannabimimetics have been also mass produced dosage of the active ingredients of variously for recreational uses and have found appeal prepared forms. Accordingly, similar amounts among users because they are higher in potency of dried leaves/flowers, waxes/oils, or ingestible and conventional drug screening tests are forms of cannabis may contain vastly different unable to identify them. These substances quantities of active compounds. Additionally, include a family of more than 700 synthetic the route of administration may influence the compounds made by various chemical alter- absorption, bioavailability and serum concen- ations of THC to enhance its affinity for tration of the active compounds. In a study of cannabinoid receptors, augment downstream healthy volunteers, plasma THC concentration signal transduction and increase its duration of and clinical effects were similar after smoking action. Many synthetic compounds also have and intravenous injection while ingestion highly active metabolites [11]. Synthetic resulted in less predictable, delayed and lower cannabinoids are commonly sprayed onto dried peak plasma THC concentration [9]. Similar leaves and marketed under various names trends have been found for the psychotropic including Spice and K2. effects of inhaled versus orally ingested THC [10]. The potential physiologic effects of THC are also affected by concomitant use of other CARDIOVASCULAR PHYSIOLOGIC illicit drugs, smoking tobacco, and drinking EFFECTS OF CANNABINOIDS alcohol. The interaction of cannabis with med- ications used for prevention or treatment of The physiologic effects of cannabis are primarily cardiovascular diseases is largely unknown. mediated through the interaction of THC with There has been an ongoing attempt to stan- the endocannabinoid system, an endogenous dardize the shelf life, dosage and bioavailability signaling network involved in a wide range of of the active compounds contained in naturally processes including endothelial function, derived medical cannabis preparations. One metabolism, inflammation, and immunity. At such preparation, nabiximols, a botanical least 2 G protein-coupled membrane cannabi- metered dose oral spray that contains both THC noid receptors, CBR1 and CBR2, have been and CBD, has been approved in several coun- identified. CBR1 is extensively expressed within tries for treatment of spasticity, pain, and uri- the central, peripheral sensory and autonomic nary dysfunction in multiple sclerosis [7]. nervous systems and is the primary target of 48 Cardiol Ther (2018) 7:45–59 THC. A significant proportion of the cardiovas- cannabinoids used, duration of exposure and cular effects of cannabinoids are thus mediated other external and physiological factors that through activation of the sympathetic nervous affect vascular tone. Under controlled experi- system, as well as inhibition of the parasympa- mental conditions, cannabis is believed pre- thetic autonomic nervous system [12]. Smoking dominantly to cause an acute vasodilatory cannabis results in an immediate increase in response possibly through activation of tran- heart rate that may last more than 1 h after sient receptor potential ankyrin type-1 exposure [13]. This is followed by a substantial (TRPA1) ion channels on perivascular sensory rise in serum norepinephrine level at 30 min neurons [30]. However, this arteriolar vasodi- [13]. Further support for the role of CBR1-me- lation is not universal to all vascular beds as diated modulation of the autonomic nervous vasoconstriction has been seen in the coro- system in the chronotropic response to exoge- nary, cerebral and peripheral arterial systems nous cannabinoids is provided by studies that and has been directly responsible for many have demonstrated effectiveness of pretreat- instances of acute myocardial infarction (AMI), ment with propranolol, atropine, and rimona- stroke and peripheral arteriopathy [15, 31]. It bant (an inverse agonist of CBR1) in preventing has been shown that the contrasting effect of such a response [12, 14–17]. Additionally, cannabinoids (including THC) in various vas- inhibition of the parasympathetic activity is cular territories is primarily due to differing suggested by an exaggerated heart rate response endothelial vasodilator mechanisms that exist to atropine following cannabis smoking [15]. in these vascular beds [12, 32]. With respect to Acute exposure to cannabis may also result in coronary circulation, myocardial blood flow, as elevation of supine systolic blood pressure assessed by N-ammonia positron emission [18, 19] and may induce atrial fibrillation tomographic imaging during cold pressor test [20–22]. An epidemiological study has demon- and after pharmacologic vasodilation, is strated an association between elevated systolic shown to correlate inversely with circulating pressure and recent use of cannabis [23]. Along plasma levels of endocannabinoids [33]. In with tachycardia and hypertension [12, 24, 25], addition, cannabis has been shown to be a enhanced left ventricular systolic function as potent source of cellular oxidative stress assessed by circumferential fiber shortening through formation of reactive oxygen species (primarily driven by tachycardia) has been [34]. The latter may then contribute to reported following the use of cannabis [26]. The pathogenesis of endothelial dysfunction and summative result of autonomic nervous system promote regional arterial vasospasm through modulation by cannabis is an increase in car- CBR1 receptor-mediated pathway while inhi- diac workload and myocardial oxygen demand. bition of CBR1 is associated with decreased For those who use cannabis by smoking, oxygen oxidative stress and improved endothelial delivery to the heart and other vital organs may function [34]. also be compromised by an elevation in blood More recently, it was shown that THC carboxyhemoglobin levels [27]. The impaired prolongs lipopolysaccharide-stimulated tissue myocardial oxygen demand to supply ratio fol- factor protein expression in activated mono- lowing cannabis smoking has been shown to cytes that results in a dose-dependent proco- reduce the time to onset of symptoms during agulant effect [35]. This ex vivo observation exercise in patients with stable angina [25, 28]. has been supported by reports of thrombotic Ventricular fibrillation and appropriate coronary artery occlusion in young individuals implantable cardioverter defibrillator shock has without underlying atherosclerosis [36–38]. In been reported in a patient with ischemic car- addition, both CBR1 and CBR2 are present on diomyopathy shortly after smoking cannabis the cell membrane of human platelets and [29]. exposure to THC is shown to increases the The direct effects of cannabis on regional surface expression of glycoprotein IIb–IIIa and and organ-level blood flow is complex and P selectin in a concentration-dependent man- likely affected by type and dosage of ner [39]. Researchers have further established Cardiol Ther (2018) 7:45–59 49 Fig. 1 Flow diagram demonstrating pathophysiologic negative inotropic effect on cardiomyocytes and together pathways to common major adverse cardiovascular events with catecholamine surge may precipitate stress cardiomy- reported in users of cannabis and related chemicals. opathy. For those individuals who use cannabis by Although non-receptor and non-endocannabinoid recep- smoking, elevation of blood carboxyhemoglobin levels tor-mediated pathways have been identified, most patho- may contribute to reduction in oxygen supply to vital logic effects of cannabis are mediated through CBR1. organs including the heart. AMI acute myocardial infarc- Autonomic nervous system is a major contributor to the tion; CBR1 cannabinoid receptor 1, CVA cerebrovascular pathogenesis of most complications while oxidative stress, accident, MVO myocardial oxygen consumption (de- hypercoagulability and increased platelet aggregation mand), O oxygen, ROS reactive oxygen species potentiate such effects. CBR1 activation also has a direct that cannabinoids exert their effects on pla- CARDIOVASCULAR telets through non-receptor mediated path- COMPLICATIONS ways as their effect persists in the presence of OF CANNABINOID USE cannabinoid receptor antagonists [40]. Figure 1 summarizes the cardiovascular Adverse cardiovascular effects of cannabis have physiologic effects of cannabinoids based on been suspected for the last 45 years while the human studies and case reports of cardiovascu- last decade has witnessed a sharp rise in the lar events observed in temporal relation to reported incidence of such complications. marijuana use. Individual major adverse car- Between 2006 and 2010, 2% of all cannabis diovascular events are subsequently discussed in related events reported to the French Addic- more detail. Deviations from the scheme pro- tovigilance Network were cardiovascular in posed in Fig. 1 have been shown in animal nature [41]. Furthermore, the cardiovascular studies and in some clinical trials that have used complication rate rose from 1.1% in 2006 to large doses of cannabinoids often administered 3.6% in 2010 and the mortality rate from those by unnatural routes. In addition, counter-regu- complications was 25% [41]. Cannabis users latory mechanisms and tolerance to the effects presenting with cardiovascular emergencies are of cannabinoids exist and may play a role in often young and frequently have no other risk variable individual responses to these agents. factors for cardiovascular disease [42]. These 50 Cardiol Ther (2018) 7:45–59 Table 1 Reported adverse cardiovascular events associated Table 1 continued with cannabis, synthetic cannabinoids and Vasculopathy cannabimimetics S54–S57 Cannabis arteritis Acute coronary syndrome S58 Migratory thrombophlebitis S1–S3 Coronary thrombosis without atherosclerosis S59 Renal artery dissection S4 Recurrent coronary thrombosis S60 Central retinal vein occlusion Acute myocardial infarction Fetal cardiovascular complications S5–S8 Non-fatal S61 Maternal use and single ventricle physiology S4 Fatal S62 Maternal use and transposition of great arteries S10–S12 Worsening of stable angina Paternal use and membranous ventricular septal S13–S18 Coronary vasospasm S63 defects S19 Recurrent coronary vasospasm S64 Intra-uterine growth retardation S20,S21 Coronary no reflow Miscellaneous Cerebrovascular disease S65 Rhabdomyolysis S22–S28 Ischemic stroke Superscript notations refer to references listed in Supple- S29 Recurrent stroke with re-challenge mentary Appendix 1 S30, S31 Stroke with posterior circulation predilection S32–S33 growing concerns have lead other researchers to Cerebral vasospasm call for a registry in the United States similar to S34, S35 Reversible cerebral vasoconstriction syndrome the efforts of the French Addictovigilance Net- work discussed above [43, 44]. The most com- Synthetic cannabinoid and acute cerebrovascular S36 monly reported cardiovascular complications of event cannabis use have ranged from acute coronary Congestive heart failure syndrome (ACS) to cardiac arrhythmias, stroke, S37, S38 peripheral arteriopathy, stress cardiomyopathy Transient left ventricular regional ballooning (SC) and sudden death (Table 1). Although S39 Acute congestive heart failure these adverse events are primarily reported in recreational users of cannabis they have also Synthetic cannabinoids and acute congestive heart S40, S41 been observed in those using the cannabis for failure medically approved reasons. S42 Diastolic dysfunction Rhythm disturbances Acute Coronary Syndrome S43 Asystole and atrioventricular block The risk of AMI increases nearly fivefold within S44 Increase in premature ventricular contractions an hour of exposure to cannabis compared to S45 nonusers [45]. The population-attributable fac- Ectopic atrial rhythm tor for triggering an AMI by cannabis was found S46, S47 Atrial fibrillation to be relatively low in a meta-analysis of epi- S48 Ventricular tachycardia demiological studies published between 1960 S49 and 2010 [46]. However, the growing burden of Ventricular fibrillation cannabis use and availability of potent syn- S50–S53 Sudden cardiacdeath thetic cannabis will likely impact the overall risk of AMI attributable to cannabis. Cardiol Ther (2018) 7:45–59 51 Over the last four decades many case reports use has been linked to several adverse cardio- have temporally linked cannabis use to devel- vascular events, the evidence is strongest for opment of AMI [5]. In some instances, reintro- ischemic stroke [5]. Neurological symptoms duction of marijuana has also been associated were the most common reasons (44%) for hos- with recurrence of myocardial ischemia [47]. pitalization of cannabis users in French health- Many, but not all, cannabis users presenting care facilities from 2004 to 2007 [69]. with AMI have been young men with no pre- Additionally, ischemic stroke is the most com- existing coronary artery disease (CAD) and have monly reported adverse cardiovascular effect of had normal coronary angiograms [5, 48]. Toxi- cannabis use [5]. In a study of young individuals cology in such cases has often been positive for (age 18–44 years) admitted with stroke and cannabis only [31, 47–56], although routine substance abuse, cannabis was associated with urine toxicology may be negative in those using ischemic but not hemorrhagic events, while synthetic cannabinoids [57–59]. The latter may amphetamines were associated with predomi- have led to significant underestimation of the nantly hemorrhagic events [70]. A general cannabinoid associated AMI in the young. The population survey of Australians aged pathophysiology of marijuana induced coro- 20–64 years (n = 7455), past year cannabis use nary events is shown in Fig. 1 and involves a was associated with a 2.3-fold higher risk of series of interactions that lead to increased cerebrovascular ischemic events after adjust- myocardial oxygen demand [60–64], reduced ment for covariates related to stroke including oxygen supply [28, 61, 64], and a pro-coagulant tobacco smoking [71]. The risk was increased to [35] or pro-thrombotic [36–39] state. In many 4.7-fold if the participant used cannabis weekly instances, microvascular [54, 62] or epicardial or more often [71]. Similar results were reported coronary artery spasm [55, 56, 63] in the from the United States Nationwide Inpatient absence of atherosclerotic coronary artery dis- Sample, where cannabis use was found to be an ease have been described. In other cases, acute independent predictor of acute stroke and coronary thrombosis in the absence of angio- associated with a 2.26-fold increased likelihood graphic atherosclerosis as confirmed by of hospitalization with acute Ischemic stroke intravascular ultrasonography has been among those aged 25–34 years [72]. responsible for AMI [36, 37]. An extreme case of Further support for a causal relationship thrombotic total occlusion of the left main between cannabis use and ischemic stroke requiring emergent coronary artery bypass graft comes from numerous case reports over the last surgery has also been reported [38]. The three decades [73–75]. A recent series has threshold for precipitation of acute myocardial described 17 cases (age 15–63 years) of ischemic ischemia is likely lower in cannabis users with stroke temporally related to cannabis use [76]. established atherosclerotic CAD [28, 64, 65]. In Among the latter, five individuals had recur- general, AMI in cannabis users may be associ- rence of cerebrovascular ischemic symptoms on ated with higher short-term mortality [66]. The resuming cannabis use after hospital discharge latter may in part be related to the potential [76]. Interestingly, the ischemic strokes showed delay in seeking medical attention in young a predilection (53%) for the posterior cerebral individuals with impaired judgement due to circulation [76]. These observations have been drug use or to the analgesic effect of cannabis corroborated by other investigators [77, 78]. that may mask symptoms [67]. Although atherosclerosis may be responsible for stroke in some cannabis users, the primary mechanism of stroke in this setting has been Cerebrovascular Disease reversible cerebrovascular spasm (RCVS) [79, 80]. RCVS is characterized by severe head- Reports of acute neurovascular events related to ache often associated with nausea, vomiting, cannabis use have appeared as early as 1964 photophobia, confusion and blurred vision and [68]. A recent systemic review of the literature a ‘‘string and beads’’ appearance of cerebral has firmly concluded that although cannabis arteries on angiography [81]. In a prospective 52 Cardiol Ther (2018) 7:45–59 study of 67 consecutive patients with angio- mellitus, hypertension, CAD, tobacco use, and graphically confirmed RCVS, 32% showed pos- alcohol use [97]. An association between can- itive toxicology for cannabis [81]. In another nabis use and SC has been shown in case reports prospective study of acute ischemic stroke, [92, 98] and in hospitalized patients [99]. multifocal narrowing of cerebral arteries (pre- Among the latter, cannabis use was found to be dominantly in posterior circulation) was highly an independent predictor of SC, particularly predictive of cannabis use [82]. Reversibility of among younger men, after adjustment for other cerebral vasoconstriction has been demon- known risk factors for the disease [96]. Impor- strated by angiography within days to months tantly, cannabis users with SC frequently suf- after cessation of cannabis use [82, 83]. It should fered from serious adverse events including be noted that similar to AMI, vasospasm is not cardiac arrest [99]. the sole etiology of ischemic stroke in cannabis The pathophysiology of SC in cannabis users users. Transcranial Doppler has demonstrated remains poorly defined although the associated persistently elevated cerebral vascular resistance catecholamine surge may be largely responsible in cannabis users even long after monitored for the association. However, evidence for a abstinence [84]. In a study of 334 of young primary role of the endocannabinoid system in (age\45 years) patients admitted with canna- pathogenesis of stress cardiomyopathy has been bis related stroke, intracranial arterial stenosis mounting. As discussed previously, cannabi- was demonstrated in 45% [85]. The etiology of noids exert cardiovascular effects and a hyper- stroke in the remaining patients was deter- adrenergic state through receptor-mediated and mined to be cardio-embolic (14%), presumed receptor-independent mechanisms paradoxical embolism through an isolated [12, 95, 100]. Endogenous cannabinoids have a patent foramen ovale (3%), carotid artery dis- CBR1-mediated negative inotropic effect on section or atherosclerosis (10%), hypercoagula- cardiac muscle [93] and inhibition of CBR1 with ble state (3%) or small vessel disease (2%) while rimonabant results in prevention of myocardial the etiology of stroke remained undetermined dysfunction and myocyte apoptosis after expo- in nearly one-fourth of the patients [85]. Other sure to doxorubicin [94]. It should be noted that potential causes of stroke in cannabis users are the presence of pre-existing myocardial dys- cardioembolic events associates with AMI or function may particularly predispose individu- atrial fibrillation [86, 87]. Left ventricular apical als to deterioration of left ventricular systolic thrombus has been reported as the etiology of function particularly with the use of potent stroke in a young patient with AMI following synthetic cannabinoids [101]. synthetic cannabinoid use [88]. Rhythm Disturbances and Sudden Cardiac Left Ventricular Systolic Dysfunction Death The endocannabinoid system is implicated in An association between cannabis use and pal- myocardial stunning associated with acute pitation was suggested by an epidemiologic neurological events, stress (takotsubo) car- study reported nearly three decades ago [102]. A diomyopathy, sepsis and hemorrhagic shock multitude of case reports have also documented [89–92]. Cannabinoids are also shown to reduce a range of rhythm abnormalities in cannabis myocardial contractility through CBR1-medi- users from sinus tachycardia to ectopic atrial or ated effects [93, 94]. Myocardial dysfunction ventricular rhythms, and atrial or ventricular may also result from persistent tachycardia, fibrillation [20–22, 29, 103–110]. Logically, atrial fibrillation or induction of ischemia in these cardiac tachyarrhythmias are explainable those with pre-existing CAD [12, 21, 25, 95, 96]. by the presence of a hyperadrenergic state fol- Cannabis use is shown to be an independent lowing exposure to cannabis and related sub- predictor of hospitalization with heart failure stances. In fact, electrophysiology study after after adjustment for age, gender, diabetes cannabis use has demonstrated increased Cardiol Ther (2018) 7:45–59 53 burden of inducible premature ventricular and cannabimimetics has further complicated contractions [111]. Myocardial ischemia caused the field. Although seriously underestimated by microvascular spasm, AMI, or pre-existing and underreported, cardiovascular adverse CAD may accompany serious ventricular events are being described at an alarming rate in arrhythmias and may result in dizziness, syn- users of cannabis and its related chemicals. cope, cardiac arrest or sudden cardiac death Many of these serious events have occurred in [29, 103–110, 112]. children and young adults who are increasingly Atrial fibrillation has been reported in can- driven to use these substances due to the false nabis users as young as 14 years old and without notion of their safety and rapidly moving structural heart disease shortly after smoking decriminalization and legalization processes. cannabis [22, 113]. Cannabis use may also be The pathophysiology of these adverse cardio- the sole precipitating factor for atrial fibrillation vascular events in temporal relation to cannabis in the younger (\45 years old) individuals and is far from established. Yet, the current evidence recurrence may occur upon repeated exposure points to a major role for the endocannabinoid [114]. Atrial fibrillation following cannabis use system and its interaction with the autonomic may be complicated by adverse events due to nervous system. Human data is generally defi- delayed recognition of the condition in young, cient and most available studies in humans otherwise healthy, individuals with altered have been performed decades ago with mental status [114]. methodology and resources of the time. While well conducted controlled studies are sorely needed in this area, current data should alert Cannabis Arteritis physicians and legislators across the world to the potentially harmful effects of unregulated Cannabis vasculopathy was first described use of cannabis in children, young adults and nearly seven decades ago [115]. Since then, a those with underlying cardiovascular risk fac- large number of cases [116–119] and two com- tors or established heart disease. prehensive reviews [120, 121] have appeared in the literature. The disease is clinically indistin- guishable from thromboangiitis obliterans ACKNOWLEDGEMENTS [122–127], but tends to occur at an earlier age in those who use both cannabis and tobacco [128]. The typical angiographic appearance is that of Funding. No funding or sponsorship was segmental narrowing of distal arteries with received for this study or publication of this minimal if any collateral vessels [127–129]. article. Subacute and progressive ischemia of upper and lower extremities affected by arteritis may then Authorship. All named authors meet the lead to serious complications including tissue International Committee of Medical Journal necrosis and gangrene with worsening during Editors (ICMJE) criteria for authorship for this periods of heavy cannabis use [130]. Other manuscript, take responsibility for the integrity vascular complications of cannabis use have of the work as a whole, and have given final included migratory thrombophlebitis [131] and approval for the version to be published. renal artery dissection [132]. A rare form of vasculopathy involving occlusion of the central Disclosures. A Singh, S. Saluja, A. Kumar, S. retinal vein has also been reported [133]. Agrawal, M. Thind, S. Nanda and J. Shirani have nothing to disclose. CONCLUSIONS Compliance with Ethics Guidelines. 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Cardiovascular Complications of Marijuana and Related Substances: A Review

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Cardiol Ther (2018) 7:45–59 https://doi.org/10.1007/s40119-017-0102-x REVIEW Cardiovascular Complications of Marijuana and Related Substances: A Review . . . . Amitoj Singh Sajeev Saluja Akshat Kumar Sahil Agrawal . . Munveer Thind Sudip Nanda Jamshid Shirani Received: August 21, 2017 / Published online: December 7, 2017 The Author(s) 2017. This article is an open access publication established cardiovascular disease are at even ABSTRACT higher danger of such events following expo- sure to cannabis. The pathophysiological basis The recreational use of cannabis has sharply of these events is not fully understood and increased in recent years in parallel with its likely encompasses a complex interaction legalization and decriminalization in several between the active ingredients (particularly the countries. Commonly, the traditional cannabis major cannabinoid, D -tetrahydrocannabinol), has been replaced by potent synthetic and the endo-cannabinoid system, autonomic cannabinoids and cannabimimetics in various nervous system, as well as other receptor and forms. Despite overwhelming public perception non-receptor mediated pathways. Other com- of the safety of these substances, an increasing plicating factors include opposing physiologic number of serious cardiovascular adverse events effects of other cannabinoids (predominantly have been reported in temporal relation to cannabidiol), presence of regulatory proteins recreational cannabis use. These have included that act as metabolizing enzymes, binding sudden cardiac death, vascular (coronary, cere- molecules, or ligands, as well as functional bral and peripheral) events, arrhythmias and polymorphisms of target receptors. Tolerance to stress cardiomyopathy among others. Many of the effects of cannabis may also develop on the victims of these events are relatively young repeated exposures at least in part due to men with few if any cardiovascular risk factors. receptor downregulation or desensitization. However, there are reasons to believe that older Moreover, effects of cannabis may be enhanced individuals and those with risk factors for or or altered by concomitant use of other illicit drugs or medications used for treatment of Enhanced content To view enhanced content for this established cardiovascular diseases. Regardless article go to http://www.medengine.com/Redeem/ of these considerations, it is expected that the 68FCF06068C10492. current cannabis epidemic would add signifi- Electronic supplementary material The online cantly to the universal burden of cardiovascular version of this article (https://doi.org/10.1007/s40119- diseases. 017-0102-x) contains supplementary material, which is available to authorized users. A. Singh  S. Saluja  A. Kumar  S. Agrawal Keywords: Autonomic nervous system; M. Thind  S. Nanda  J. Shirani (&) Cannabis; Endocannabinoid system; Department of Cardiology, St. Luke’s University Marijuana; Myocardial infarction; Stress Health Network, Bethlehem, PA, USA e-mail: jamshid.shirani@sluhn.org 46 Cardiol Ther (2018) 7:45–59 cardiomyopathy; Stroke; Tetrahydrocannabinol; arteritis’’, ‘‘stress cardiomyopathy’’ and ‘‘ar- Vasculopathy rhythmia’’. All referenced material in selected articles were also reviewed carefully for poten- tially relevant reports. The results were thor- INTRODUCTION oughly examined for accuracy of content. The available literature was then categorized Cannabis sativa, the plant known as the original according to both relevance and the clarity of marijuana, was likely first cultivated in Central the presented data. Care was particularly taken Asia, and subsequently brought to other parts of to avoid inclusion of studies with designs that the world. Currently, cannabis grows naturally deviated from usual manners that cannabis is in many countries and is also cultivated indoors used recreationally. The final count of the through the use of hydroponic systems and manuscripts and documents used was 135 that artificial lighting [1, 2]. The plant has been long included 55 case reports, eight case series, 20 used as a medicinal herb or as a mood altering human experimental studies, 11 animal or substance [2]. More recently, a rise in recre- ex vivo studies, 20 databases or guidelines as ational use of cannabis has paralleled that of well as 22 review articles. legislations that have legalized or decriminal- ized the possession, sales, and cultivation of the Compliance with Ethics Guidelines plant [3]. According to the United Nations office on drugs and crime, the global recre- This article does not contain any new studies ational use of cannabis increased by 27% from with human or animal subjects performed by 1998 to 2009 [1]. In 2014, it was estimated that any of the authors. * 183 million people use cannabis worldwide with a steady rise since 2007 [4]. Today, can- nabis is the most frequently used psychoactive NATURAL FORMS OF CANNABIS substance after alcohol and tobacco [1]. The recreational cannabis ‘‘epidemic’’ has been In general, three naturally growing strains of accompanied by an increased number of case Cannabis (sativa, indica, and ruderalis) have been reports of serious cardiovascular complications recognized although interbreeding has pro- from across the globe. A recent systematic duced many more ‘‘hybrid’’ strains of the plants. review has identified 116 such cases published These strains differ in the content and propor- between January 2011 and March 2016 [5]. In tion of the two best recognized active ingredi- the context of the rising popularity of recre- ents, namely D -tetrahydrocannabinol (THC) ational cannabis (and its synthetic analogues) and cannabidiol (CBD). Additionally, the effects we aim to review potential cardiovascular of various cannabis strains may differ based on adverse events associated with the use of these the varying concentration and composition of substances. Furthermore, the potential patho- terpene resins [6]. The sativa strain contains the physiological mechanisms responsible for the highest level of THC, the psychoactive most serious cardiovascular events in users of cannabinoid that produces the euphoric effect cannabis are discussed. and has a relatively low content of CBD, the cannabinoid that may mitigate the euphoric and psychotropic effects of THC. The leaves and METHODS buds of the female plants have the highest content of THC and can be dried for smoking or To prepare this literature review, we performed made into other forms of consumable cannabis searches of PUBMED, MEDLINE and EMBASE including edibles, waxes, oils, liquid incense or databases using the phrases ‘‘marijuana’’, ‘‘can- vapor for both medical and recreational uses. nabis’’, ‘‘cannabinoids’’, ‘‘THC’’, ‘‘D -tetrahydro- Medically, cannabis has been used effectively cannabinol’’, ‘‘cardiovascular disease’’, ‘‘cardiac for treatment of otherwise refractory nausea disease’’, ‘‘heart disease’’, ‘‘stroke’’, ‘‘cannabis and vomiting following chemotherapy and Cardiol Ther (2018) 7:45–59 47 neuropathic pain associated with advanced SYNTHETIC CANNABINOIDS neurologic disorders and cancer, among others AND CANNABIMIMETICS [2, 7, 8]. It is important to note that in the United States, cannabis (marijuana) is still listed Synthetic THC compounds, dronabinol and by the Drug Enforcement Administration as a nabilone, have been marketed as capsules in the Schedule I substance, alongside hallucinogens United States since 1985 for treatment of nau- and heroin, according to the section 202 of the sea, vomiting and weight loss associated with Controlled Substances Act of 1970. Schedule I cancer chemotherapy and acquired immunod- drugs are substances with high potential for eficiency syndrome. A liquid form of dronabi- abuse, no currently established medical use, and nol has also been approved recently as an oral no accepted safety for use under medical solution by the United States Food and Drug supervision. Despite this, 42 states and the Administration for anorexia and weight loss District of Columbia have either legalized or associated with acquired immunodeficiency decriminalized medical uses of cannabis and syndrome and refractory nausea/vomiting related approved medications. associated with cancer chemotherapy. Illegally An important consideration in the uses of manufactured synthetic cannabinoids and cannabis has been the unpredictability of the cannabimimetics have been also mass produced dosage of the active ingredients of variously for recreational uses and have found appeal prepared forms. Accordingly, similar amounts among users because they are higher in potency of dried leaves/flowers, waxes/oils, or ingestible and conventional drug screening tests are forms of cannabis may contain vastly different unable to identify them. These substances quantities of active compounds. Additionally, include a family of more than 700 synthetic the route of administration may influence the compounds made by various chemical alter- absorption, bioavailability and serum concen- ations of THC to enhance its affinity for tration of the active compounds. In a study of cannabinoid receptors, augment downstream healthy volunteers, plasma THC concentration signal transduction and increase its duration of and clinical effects were similar after smoking action. Many synthetic compounds also have and intravenous injection while ingestion highly active metabolites [11]. Synthetic resulted in less predictable, delayed and lower cannabinoids are commonly sprayed onto dried peak plasma THC concentration [9]. Similar leaves and marketed under various names trends have been found for the psychotropic including Spice and K2. effects of inhaled versus orally ingested THC [10]. The potential physiologic effects of THC are also affected by concomitant use of other CARDIOVASCULAR PHYSIOLOGIC illicit drugs, smoking tobacco, and drinking EFFECTS OF CANNABINOIDS alcohol. The interaction of cannabis with med- ications used for prevention or treatment of The physiologic effects of cannabis are primarily cardiovascular diseases is largely unknown. mediated through the interaction of THC with There has been an ongoing attempt to stan- the endocannabinoid system, an endogenous dardize the shelf life, dosage and bioavailability signaling network involved in a wide range of of the active compounds contained in naturally processes including endothelial function, derived medical cannabis preparations. One metabolism, inflammation, and immunity. At such preparation, nabiximols, a botanical least 2 G protein-coupled membrane cannabi- metered dose oral spray that contains both THC noid receptors, CBR1 and CBR2, have been and CBD, has been approved in several coun- identified. CBR1 is extensively expressed within tries for treatment of spasticity, pain, and uri- the central, peripheral sensory and autonomic nary dysfunction in multiple sclerosis [7]. nervous systems and is the primary target of 48 Cardiol Ther (2018) 7:45–59 THC. A significant proportion of the cardiovas- cannabinoids used, duration of exposure and cular effects of cannabinoids are thus mediated other external and physiological factors that through activation of the sympathetic nervous affect vascular tone. Under controlled experi- system, as well as inhibition of the parasympa- mental conditions, cannabis is believed pre- thetic autonomic nervous system [12]. Smoking dominantly to cause an acute vasodilatory cannabis results in an immediate increase in response possibly through activation of tran- heart rate that may last more than 1 h after sient receptor potential ankyrin type-1 exposure [13]. This is followed by a substantial (TRPA1) ion channels on perivascular sensory rise in serum norepinephrine level at 30 min neurons [30]. However, this arteriolar vasodi- [13]. Further support for the role of CBR1-me- lation is not universal to all vascular beds as diated modulation of the autonomic nervous vasoconstriction has been seen in the coro- system in the chronotropic response to exoge- nary, cerebral and peripheral arterial systems nous cannabinoids is provided by studies that and has been directly responsible for many have demonstrated effectiveness of pretreat- instances of acute myocardial infarction (AMI), ment with propranolol, atropine, and rimona- stroke and peripheral arteriopathy [15, 31]. It bant (an inverse agonist of CBR1) in preventing has been shown that the contrasting effect of such a response [12, 14–17]. Additionally, cannabinoids (including THC) in various vas- inhibition of the parasympathetic activity is cular territories is primarily due to differing suggested by an exaggerated heart rate response endothelial vasodilator mechanisms that exist to atropine following cannabis smoking [15]. in these vascular beds [12, 32]. With respect to Acute exposure to cannabis may also result in coronary circulation, myocardial blood flow, as elevation of supine systolic blood pressure assessed by N-ammonia positron emission [18, 19] and may induce atrial fibrillation tomographic imaging during cold pressor test [20–22]. An epidemiological study has demon- and after pharmacologic vasodilation, is strated an association between elevated systolic shown to correlate inversely with circulating pressure and recent use of cannabis [23]. Along plasma levels of endocannabinoids [33]. In with tachycardia and hypertension [12, 24, 25], addition, cannabis has been shown to be a enhanced left ventricular systolic function as potent source of cellular oxidative stress assessed by circumferential fiber shortening through formation of reactive oxygen species (primarily driven by tachycardia) has been [34]. The latter may then contribute to reported following the use of cannabis [26]. The pathogenesis of endothelial dysfunction and summative result of autonomic nervous system promote regional arterial vasospasm through modulation by cannabis is an increase in car- CBR1 receptor-mediated pathway while inhi- diac workload and myocardial oxygen demand. bition of CBR1 is associated with decreased For those who use cannabis by smoking, oxygen oxidative stress and improved endothelial delivery to the heart and other vital organs may function [34]. also be compromised by an elevation in blood More recently, it was shown that THC carboxyhemoglobin levels [27]. The impaired prolongs lipopolysaccharide-stimulated tissue myocardial oxygen demand to supply ratio fol- factor protein expression in activated mono- lowing cannabis smoking has been shown to cytes that results in a dose-dependent proco- reduce the time to onset of symptoms during agulant effect [35]. This ex vivo observation exercise in patients with stable angina [25, 28]. has been supported by reports of thrombotic Ventricular fibrillation and appropriate coronary artery occlusion in young individuals implantable cardioverter defibrillator shock has without underlying atherosclerosis [36–38]. In been reported in a patient with ischemic car- addition, both CBR1 and CBR2 are present on diomyopathy shortly after smoking cannabis the cell membrane of human platelets and [29]. exposure to THC is shown to increases the The direct effects of cannabis on regional surface expression of glycoprotein IIb–IIIa and and organ-level blood flow is complex and P selectin in a concentration-dependent man- likely affected by type and dosage of ner [39]. Researchers have further established Cardiol Ther (2018) 7:45–59 49 Fig. 1 Flow diagram demonstrating pathophysiologic negative inotropic effect on cardiomyocytes and together pathways to common major adverse cardiovascular events with catecholamine surge may precipitate stress cardiomy- reported in users of cannabis and related chemicals. opathy. For those individuals who use cannabis by Although non-receptor and non-endocannabinoid recep- smoking, elevation of blood carboxyhemoglobin levels tor-mediated pathways have been identified, most patho- may contribute to reduction in oxygen supply to vital logic effects of cannabis are mediated through CBR1. organs including the heart. AMI acute myocardial infarc- Autonomic nervous system is a major contributor to the tion; CBR1 cannabinoid receptor 1, CVA cerebrovascular pathogenesis of most complications while oxidative stress, accident, MVO myocardial oxygen consumption (de- hypercoagulability and increased platelet aggregation mand), O oxygen, ROS reactive oxygen species potentiate such effects. CBR1 activation also has a direct that cannabinoids exert their effects on pla- CARDIOVASCULAR telets through non-receptor mediated path- COMPLICATIONS ways as their effect persists in the presence of OF CANNABINOID USE cannabinoid receptor antagonists [40]. Figure 1 summarizes the cardiovascular Adverse cardiovascular effects of cannabis have physiologic effects of cannabinoids based on been suspected for the last 45 years while the human studies and case reports of cardiovascu- last decade has witnessed a sharp rise in the lar events observed in temporal relation to reported incidence of such complications. marijuana use. Individual major adverse car- Between 2006 and 2010, 2% of all cannabis diovascular events are subsequently discussed in related events reported to the French Addic- more detail. Deviations from the scheme pro- tovigilance Network were cardiovascular in posed in Fig. 1 have been shown in animal nature [41]. Furthermore, the cardiovascular studies and in some clinical trials that have used complication rate rose from 1.1% in 2006 to large doses of cannabinoids often administered 3.6% in 2010 and the mortality rate from those by unnatural routes. In addition, counter-regu- complications was 25% [41]. Cannabis users latory mechanisms and tolerance to the effects presenting with cardiovascular emergencies are of cannabinoids exist and may play a role in often young and frequently have no other risk variable individual responses to these agents. factors for cardiovascular disease [42]. These 50 Cardiol Ther (2018) 7:45–59 Table 1 Reported adverse cardiovascular events associated Table 1 continued with cannabis, synthetic cannabinoids and Vasculopathy cannabimimetics S54–S57 Cannabis arteritis Acute coronary syndrome S58 Migratory thrombophlebitis S1–S3 Coronary thrombosis without atherosclerosis S59 Renal artery dissection S4 Recurrent coronary thrombosis S60 Central retinal vein occlusion Acute myocardial infarction Fetal cardiovascular complications S5–S8 Non-fatal S61 Maternal use and single ventricle physiology S4 Fatal S62 Maternal use and transposition of great arteries S10–S12 Worsening of stable angina Paternal use and membranous ventricular septal S13–S18 Coronary vasospasm S63 defects S19 Recurrent coronary vasospasm S64 Intra-uterine growth retardation S20,S21 Coronary no reflow Miscellaneous Cerebrovascular disease S65 Rhabdomyolysis S22–S28 Ischemic stroke Superscript notations refer to references listed in Supple- S29 Recurrent stroke with re-challenge mentary Appendix 1 S30, S31 Stroke with posterior circulation predilection S32–S33 growing concerns have lead other researchers to Cerebral vasospasm call for a registry in the United States similar to S34, S35 Reversible cerebral vasoconstriction syndrome the efforts of the French Addictovigilance Net- work discussed above [43, 44]. The most com- Synthetic cannabinoid and acute cerebrovascular S36 monly reported cardiovascular complications of event cannabis use have ranged from acute coronary Congestive heart failure syndrome (ACS) to cardiac arrhythmias, stroke, S37, S38 peripheral arteriopathy, stress cardiomyopathy Transient left ventricular regional ballooning (SC) and sudden death (Table 1). Although S39 Acute congestive heart failure these adverse events are primarily reported in recreational users of cannabis they have also Synthetic cannabinoids and acute congestive heart S40, S41 been observed in those using the cannabis for failure medically approved reasons. S42 Diastolic dysfunction Rhythm disturbances Acute Coronary Syndrome S43 Asystole and atrioventricular block The risk of AMI increases nearly fivefold within S44 Increase in premature ventricular contractions an hour of exposure to cannabis compared to S45 nonusers [45]. The population-attributable fac- Ectopic atrial rhythm tor for triggering an AMI by cannabis was found S46, S47 Atrial fibrillation to be relatively low in a meta-analysis of epi- S48 Ventricular tachycardia demiological studies published between 1960 S49 and 2010 [46]. However, the growing burden of Ventricular fibrillation cannabis use and availability of potent syn- S50–S53 Sudden cardiacdeath thetic cannabis will likely impact the overall risk of AMI attributable to cannabis. Cardiol Ther (2018) 7:45–59 51 Over the last four decades many case reports use has been linked to several adverse cardio- have temporally linked cannabis use to devel- vascular events, the evidence is strongest for opment of AMI [5]. In some instances, reintro- ischemic stroke [5]. Neurological symptoms duction of marijuana has also been associated were the most common reasons (44%) for hos- with recurrence of myocardial ischemia [47]. pitalization of cannabis users in French health- Many, but not all, cannabis users presenting care facilities from 2004 to 2007 [69]. with AMI have been young men with no pre- Additionally, ischemic stroke is the most com- existing coronary artery disease (CAD) and have monly reported adverse cardiovascular effect of had normal coronary angiograms [5, 48]. Toxi- cannabis use [5]. In a study of young individuals cology in such cases has often been positive for (age 18–44 years) admitted with stroke and cannabis only [31, 47–56], although routine substance abuse, cannabis was associated with urine toxicology may be negative in those using ischemic but not hemorrhagic events, while synthetic cannabinoids [57–59]. The latter may amphetamines were associated with predomi- have led to significant underestimation of the nantly hemorrhagic events [70]. A general cannabinoid associated AMI in the young. The population survey of Australians aged pathophysiology of marijuana induced coro- 20–64 years (n = 7455), past year cannabis use nary events is shown in Fig. 1 and involves a was associated with a 2.3-fold higher risk of series of interactions that lead to increased cerebrovascular ischemic events after adjust- myocardial oxygen demand [60–64], reduced ment for covariates related to stroke including oxygen supply [28, 61, 64], and a pro-coagulant tobacco smoking [71]. The risk was increased to [35] or pro-thrombotic [36–39] state. In many 4.7-fold if the participant used cannabis weekly instances, microvascular [54, 62] or epicardial or more often [71]. Similar results were reported coronary artery spasm [55, 56, 63] in the from the United States Nationwide Inpatient absence of atherosclerotic coronary artery dis- Sample, where cannabis use was found to be an ease have been described. In other cases, acute independent predictor of acute stroke and coronary thrombosis in the absence of angio- associated with a 2.26-fold increased likelihood graphic atherosclerosis as confirmed by of hospitalization with acute Ischemic stroke intravascular ultrasonography has been among those aged 25–34 years [72]. responsible for AMI [36, 37]. An extreme case of Further support for a causal relationship thrombotic total occlusion of the left main between cannabis use and ischemic stroke requiring emergent coronary artery bypass graft comes from numerous case reports over the last surgery has also been reported [38]. The three decades [73–75]. A recent series has threshold for precipitation of acute myocardial described 17 cases (age 15–63 years) of ischemic ischemia is likely lower in cannabis users with stroke temporally related to cannabis use [76]. established atherosclerotic CAD [28, 64, 65]. In Among the latter, five individuals had recur- general, AMI in cannabis users may be associ- rence of cerebrovascular ischemic symptoms on ated with higher short-term mortality [66]. The resuming cannabis use after hospital discharge latter may in part be related to the potential [76]. Interestingly, the ischemic strokes showed delay in seeking medical attention in young a predilection (53%) for the posterior cerebral individuals with impaired judgement due to circulation [76]. These observations have been drug use or to the analgesic effect of cannabis corroborated by other investigators [77, 78]. that may mask symptoms [67]. Although atherosclerosis may be responsible for stroke in some cannabis users, the primary mechanism of stroke in this setting has been Cerebrovascular Disease reversible cerebrovascular spasm (RCVS) [79, 80]. RCVS is characterized by severe head- Reports of acute neurovascular events related to ache often associated with nausea, vomiting, cannabis use have appeared as early as 1964 photophobia, confusion and blurred vision and [68]. A recent systemic review of the literature a ‘‘string and beads’’ appearance of cerebral has firmly concluded that although cannabis arteries on angiography [81]. In a prospective 52 Cardiol Ther (2018) 7:45–59 study of 67 consecutive patients with angio- mellitus, hypertension, CAD, tobacco use, and graphically confirmed RCVS, 32% showed pos- alcohol use [97]. An association between can- itive toxicology for cannabis [81]. In another nabis use and SC has been shown in case reports prospective study of acute ischemic stroke, [92, 98] and in hospitalized patients [99]. multifocal narrowing of cerebral arteries (pre- Among the latter, cannabis use was found to be dominantly in posterior circulation) was highly an independent predictor of SC, particularly predictive of cannabis use [82]. Reversibility of among younger men, after adjustment for other cerebral vasoconstriction has been demon- known risk factors for the disease [96]. Impor- strated by angiography within days to months tantly, cannabis users with SC frequently suf- after cessation of cannabis use [82, 83]. It should fered from serious adverse events including be noted that similar to AMI, vasospasm is not cardiac arrest [99]. the sole etiology of ischemic stroke in cannabis The pathophysiology of SC in cannabis users users. Transcranial Doppler has demonstrated remains poorly defined although the associated persistently elevated cerebral vascular resistance catecholamine surge may be largely responsible in cannabis users even long after monitored for the association. However, evidence for a abstinence [84]. In a study of 334 of young primary role of the endocannabinoid system in (age\45 years) patients admitted with canna- pathogenesis of stress cardiomyopathy has been bis related stroke, intracranial arterial stenosis mounting. As discussed previously, cannabi- was demonstrated in 45% [85]. The etiology of noids exert cardiovascular effects and a hyper- stroke in the remaining patients was deter- adrenergic state through receptor-mediated and mined to be cardio-embolic (14%), presumed receptor-independent mechanisms paradoxical embolism through an isolated [12, 95, 100]. Endogenous cannabinoids have a patent foramen ovale (3%), carotid artery dis- CBR1-mediated negative inotropic effect on section or atherosclerosis (10%), hypercoagula- cardiac muscle [93] and inhibition of CBR1 with ble state (3%) or small vessel disease (2%) while rimonabant results in prevention of myocardial the etiology of stroke remained undetermined dysfunction and myocyte apoptosis after expo- in nearly one-fourth of the patients [85]. Other sure to doxorubicin [94]. It should be noted that potential causes of stroke in cannabis users are the presence of pre-existing myocardial dys- cardioembolic events associates with AMI or function may particularly predispose individu- atrial fibrillation [86, 87]. Left ventricular apical als to deterioration of left ventricular systolic thrombus has been reported as the etiology of function particularly with the use of potent stroke in a young patient with AMI following synthetic cannabinoids [101]. synthetic cannabinoid use [88]. Rhythm Disturbances and Sudden Cardiac Left Ventricular Systolic Dysfunction Death The endocannabinoid system is implicated in An association between cannabis use and pal- myocardial stunning associated with acute pitation was suggested by an epidemiologic neurological events, stress (takotsubo) car- study reported nearly three decades ago [102]. A diomyopathy, sepsis and hemorrhagic shock multitude of case reports have also documented [89–92]. Cannabinoids are also shown to reduce a range of rhythm abnormalities in cannabis myocardial contractility through CBR1-medi- users from sinus tachycardia to ectopic atrial or ated effects [93, 94]. Myocardial dysfunction ventricular rhythms, and atrial or ventricular may also result from persistent tachycardia, fibrillation [20–22, 29, 103–110]. Logically, atrial fibrillation or induction of ischemia in these cardiac tachyarrhythmias are explainable those with pre-existing CAD [12, 21, 25, 95, 96]. by the presence of a hyperadrenergic state fol- Cannabis use is shown to be an independent lowing exposure to cannabis and related sub- predictor of hospitalization with heart failure stances. In fact, electrophysiology study after after adjustment for age, gender, diabetes cannabis use has demonstrated increased Cardiol Ther (2018) 7:45–59 53 burden of inducible premature ventricular and cannabimimetics has further complicated contractions [111]. Myocardial ischemia caused the field. Although seriously underestimated by microvascular spasm, AMI, or pre-existing and underreported, cardiovascular adverse CAD may accompany serious ventricular events are being described at an alarming rate in arrhythmias and may result in dizziness, syn- users of cannabis and its related chemicals. cope, cardiac arrest or sudden cardiac death Many of these serious events have occurred in [29, 103–110, 112]. children and young adults who are increasingly Atrial fibrillation has been reported in can- driven to use these substances due to the false nabis users as young as 14 years old and without notion of their safety and rapidly moving structural heart disease shortly after smoking decriminalization and legalization processes. cannabis [22, 113]. Cannabis use may also be The pathophysiology of these adverse cardio- the sole precipitating factor for atrial fibrillation vascular events in temporal relation to cannabis in the younger (\45 years old) individuals and is far from established. Yet, the current evidence recurrence may occur upon repeated exposure points to a major role for the endocannabinoid [114]. Atrial fibrillation following cannabis use system and its interaction with the autonomic may be complicated by adverse events due to nervous system. Human data is generally defi- delayed recognition of the condition in young, cient and most available studies in humans otherwise healthy, individuals with altered have been performed decades ago with mental status [114]. methodology and resources of the time. While well conducted controlled studies are sorely needed in this area, current data should alert Cannabis Arteritis physicians and legislators across the world to the potentially harmful effects of unregulated Cannabis vasculopathy was first described use of cannabis in children, young adults and nearly seven decades ago [115]. Since then, a those with underlying cardiovascular risk fac- large number of cases [116–119] and two com- tors or established heart disease. prehensive reviews [120, 121] have appeared in the literature. The disease is clinically indistin- guishable from thromboangiitis obliterans ACKNOWLEDGEMENTS [122–127], but tends to occur at an earlier age in those who use both cannabis and tobacco [128]. The typical angiographic appearance is that of Funding. No funding or sponsorship was segmental narrowing of distal arteries with received for this study or publication of this minimal if any collateral vessels [127–129]. article. Subacute and progressive ischemia of upper and lower extremities affected by arteritis may then Authorship. All named authors meet the lead to serious complications including tissue International Committee of Medical Journal necrosis and gangrene with worsening during Editors (ICMJE) criteria for authorship for this periods of heavy cannabis use [130]. Other manuscript, take responsibility for the integrity vascular complications of cannabis use have of the work as a whole, and have given final included migratory thrombophlebitis [131] and approval for the version to be published. renal artery dissection [132]. A rare form of vasculopathy involving occlusion of the central Disclosures. A Singh, S. Saluja, A. Kumar, S. retinal vein has also been reported [133]. Agrawal, M. Thind, S. Nanda and J. Shirani have nothing to disclose. CONCLUSIONS Compliance with Ethics Guidelines. This article does not contain any new studies with Cannabis use has rapidly reached epidemic human or animal subjects performed by any of proportions in the world. Appearance of highly the authors. potent and unregulated synthetic cannabinoids 54 Cardiol Ther (2018) 7:45–59 clinical effects after oral and intravenous adminis- Open Access. This article is distributed tration and smoking. Clin Pharmacol Ther. under the terms of the Creative Commons 1980;28:409–16. Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ 10. Grotenhermen F. Pharmacokinetics and pharma- codynamics of cannabinoids. Clin Pharmacokinet. by-nc/4.0/), which permits any noncommer- 2003;42:327–60. cial use, distribution, and reproduction in any medium, provided you give appropriate credit 11. Gurney SMR, Scott KS, Kacinko SL, Presley BC, to the original author(s) and the source, provide Logan BK. Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs. 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Cardiology and TherapySpringer Journals

Published: Dec 7, 2017

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