Cardiovascular Complications of Marijuana and Related Substances: A Review

Cannabis sativa, the plant known as the original marijuana, was likely first cultivated in Central Asia, and subsequently brought to other parts of the world. Currently, cannabis grows naturally in many countries and is also cultivated indoors through the use of hydroponic systems and artificial lighting [1, 2]. The plant has been long used as a medicinal herb or as a mood altering substance [2]. More recently, a rise in recreational use of cannabis has paralleled that of legislations that have legalized or decriminalized the possession, sales, and cultivation of the plant [3]. According to the United Nations office on drugs and crime, the global recreational use of cannabis increased by 27% from 1998 to 2009 [1]. In 2014, it was estimated that ~ 183 million people use cannabis worldwide with a steady rise since 2007 [4]. Today, cannabis is the most frequently used psychoactive substance after alcohol and tobacco [1]. The recreational cannabis “epidemic” has been accompanied by an increased number of case reports of serious cardiovascular complications from across the globe. A recent systematic review has identified 116 such cases published between January 2011 and March 2016 [5]. In the context of the rising popularity of recreational cannabis (and its synthetic analogues) we aim to review potential cardiovascular adverse events associated with the use of these substances. Furthermore, the potential pathophysiological mechanisms responsible for the most serious cardiovascular events in users of cannabis are discussed.

To prepare this literature review, we performed searches of PUBMED, MEDLINE and EMBASE databases using the phrases “marijuana”, “cannabis”, “cannabinoids”, “THC”, “Δ⁹-tetrahydrocannabinol”, “cardiovascular disease”, “cardiac disease”, “heart disease”, “stroke”, “cannabis arteritis”, “stress cardiomyopathy” and “arrhythmia”. All referenced material in selected articles were also reviewed carefully for potentially relevant reports. The results were thoroughly examined for accuracy of content. The available literature was then categorized according to both relevance and the clarity of the presented data. Care was particularly taken to avoid inclusion of studies with designs that deviated from usual manners that cannabis is used recreationally. The final count of the manuscripts and documents used was 135 that included 55 case reports, eight case series, 20 human experimental studies, 11 animal or ex vivo studies, 20 databases or guidelines as well as 22 review articles.

In general, three naturally growing strains of Cannabis (sativa, indica, and ruderalis) have been recognized although interbreeding has produced many more “hybrid” strains of the plants. These strains differ in the content and proportion of the two best recognized active ingredients, namely Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additionally, the effects of various cannabis strains may differ based on the varying concentration and composition of terpene resins [6]. The sativa strain contains the highest level of THC, the psychoactive cannabinoid that produces the euphoric effect and has a relatively low content of CBD, the cannabinoid that may mitigate the euphoric and psychotropic effects of THC. The leaves and buds of the female plants have the highest content of THC and can be dried for smoking or made into other forms of consumable cannabis including edibles, waxes, oils, liquid incense or vapor for both medical and recreational uses. Medically, cannabis has been used effectively for treatment of otherwise refractory nausea and vomiting following chemotherapy and neuropathic pain associated with advanced neurologic disorders and cancer, among others [2, 7, 8]. It is important to note that in the United States, cannabis (marijuana) is still listed by the Drug Enforcement Administration as a Schedule I substance, alongside hallucinogens and heroin, according to the section 202 of the Controlled Substances Act of 1970. Schedule I drugs are substances with high potential for abuse, no currently established medical use, and no accepted safety for use under medical supervision. Despite this, 42 states and the District of Columbia have either legalized or decriminalized medical uses of cannabis and related approved medications.

An important consideration in the uses of cannabis has been the unpredictability of the dosage of the active ingredients of variously prepared forms. Accordingly, similar amounts of dried leaves/flowers, waxes/oils, or ingestible forms of cannabis may contain vastly different quantities of active compounds. Additionally, the route of administration may influence the absorption, bioavailability and serum concentration of the active compounds. In a study of healthy volunteers, plasma THC concentration and clinical effects were similar after smoking and intravenous injection while ingestion resulted in less predictable, delayed and lower peak plasma THC concentration [9]. Similar trends have been found for the psychotropic effects of inhaled versus orally ingested THC [10]. The potential physiologic effects of THC are also affected by concomitant use of other illicit drugs, smoking tobacco, and drinking alcohol. The interaction of cannabis with medications used for prevention or treatment of cardiovascular diseases is largely unknown.

There has been an ongoing attempt to standardize the shelf life, dosage and bioavailability of the active compounds contained in naturally derived medical cannabis preparations. One such preparation, nabiximols, a botanical metered dose oral spray that contains both THC and CBD, has been approved in several countries for treatment of spasticity, pain, and urinary dysfunction in multiple sclerosis [7].

Synthetic THC compounds, dronabinol and nabilone, have been marketed as capsules in the United States since 1985 for treatment of nausea, vomiting and weight loss associated with cancer chemotherapy and acquired immunodeficiency syndrome. A liquid form of dronabinol has also been approved recently as an oral solution by the United States Food and Drug Administration for anorexia and weight loss associated with acquired immunodeficiency syndrome and refractory nausea/vomiting associated with cancer chemotherapy. Illegally manufactured synthetic cannabinoids and cannabimimetics have been also mass produced for recreational uses and have found appeal among users because they are higher in potency and conventional drug screening tests are unable to identify them. These substances include a family of more than 700 synthetic compounds made by various chemical alterations of THC to enhance its affinity for cannabinoid receptors, augment downstream signal transduction and increase its duration of action. Many synthetic compounds also have highly active metabolites [11]. Synthetic cannabinoids are commonly sprayed onto dried leaves and marketed under various names including Spice and K2.

The physiologic effects of cannabis are primarily mediated through the interaction of THC with the endocannabinoid system, an endogenous signaling network involved in a wide range of processes including endothelial function, metabolism, inflammation, and immunity. At least 2 G protein-coupled membrane cannabinoid receptors, CBR1 and CBR2, have been identified. CBR1 is extensively expressed within the central, peripheral sensory and autonomic nervous systems and is the primary target of THC. A significant proportion of the cardiovascular effects of cannabinoids are thus mediated through activation of the sympathetic nervous system, as well as inhibition of the parasympathetic autonomic nervous system [12]. Smoking cannabis results in an immediate increase in heart rate that may last more than 1 h after exposure [13]. This is followed by a substantial rise in serum norepinephrine level at 30 min [13]. Further support for the role of CBR1-mediated modulation of the autonomic nervous system in the chronotropic response to exogenous cannabinoids is provided by studies that have demonstrated effectiveness of pretreatment with propranolol, atropine, and rimonabant (an inverse agonist of CBR1) in preventing such a response [12, 14‐17]. Additionally, inhibition of the parasympathetic activity is suggested by an exaggerated heart rate response to atropine following cannabis smoking [15]. Acute exposure to cannabis may also result in elevation of supine systolic blood pressure [18, 19] and may induce atrial fibrillation [20‐22]. An epidemiological study has demonstrated an association between elevated systolic pressure and recent use of cannabis [23]. Along with tachycardia and hypertension [12, 24, 25], enhanced left ventricular systolic function as assessed by circumferential fiber shortening (primarily driven by tachycardia) has been reported following the use of cannabis [26]. The summative result of autonomic nervous system modulation by cannabis is an increase in cardiac workload and myocardial oxygen demand. For those who use cannabis by smoking, oxygen delivery to the heart and other vital organs may also be compromised by an elevation in blood carboxyhemoglobin levels [27]. The impaired myocardial oxygen demand to supply ratio following cannabis smoking has been shown to reduce the time to onset of symptoms during exercise in patients with stable angina [25, 28]. Ventricular fibrillation and appropriate implantable cardioverter defibrillator shock has been reported in a patient with ischemic cardiomyopathy shortly after smoking cannabis [29].

The direct effects of cannabis on regional and organ-level blood flow is complex and likely affected by type and dosage of cannabinoids used, duration of exposure and other external and physiological factors that affect vascular tone. Under controlled experimental conditions, cannabis is believed predominantly to cause an acute vasodilatory response possibly through activation of transient receptor potential ankyrin type-1 (TRPA1) ion channels on perivascular sensory neurons [30]. However, this arteriolar vasodilation is not universal to all vascular beds as vasoconstriction has been seen in the coronary, cerebral and peripheral arterial systems and has been directly responsible for many instances of acute myocardial infarction (AMI), stroke and peripheral arteriopathy [15, 31]. It has been shown that the contrasting effect of cannabinoids (including THC) in various vascular territories is primarily due to differing endothelial vasodilator mechanisms that exist in these vascular beds [12, 32]. With respect to coronary circulation, myocardial blood flow, as assessed by ¹³N-ammonia positron emission tomographic imaging during cold pressor test and after pharmacologic vasodilation, is shown to correlate inversely with circulating plasma levels of endocannabinoids [33]. In addition, cannabis has been shown to be a potent source of cellular oxidative stress through formation of reactive oxygen species [34]. The latter may then contribute to pathogenesis of endothelial dysfunction and promote regional arterial vasospasm through CBR1 receptor-mediated pathway while inhibition of CBR1 is associated with decreased oxidative stress and improved endothelial function [34].

More recently, it was shown that THC prolongs lipopolysaccharide-stimulated tissue factor protein expression in activated monocytes that results in a dose-dependent procoagulant effect [35]. This ex vivo observation has been supported by reports of thrombotic coronary artery occlusion in young individuals without underlying atherosclerosis [36‐38]. In addition, both CBR1 and CBR2 are present on the cell membrane of human platelets and exposure to THC is shown to increases the surface expression of glycoprotein IIb–IIIa and P selectin in a concentration-dependent manner [39]. Researchers have further established that cannabinoids exert their effects on platelets through non-receptor mediated pathways as their effect persists in the presence of cannabinoid receptor antagonists [40].

Figure 1 summarizes the cardiovascular physiologic effects of cannabinoids based on human studies and case reports of cardiovascular events observed in temporal relation to marijuana use. Individual major adverse cardiovascular events are subsequently discussed in more detail. Deviations from the scheme proposed in Fig. 1 have been shown in animal studies and in some clinical trials that have used large doses of cannabinoids often administered by unnatural routes. In addition, counter-regulatory mechanisms and tolerance to the effects of cannabinoids exist and may play a role in variable individual responses to these agents.

Adverse cardiovascular effects of cannabis have been suspected for the last 45 years while the last decade has witnessed a sharp rise in the reported incidence of such complications. Between 2006 and 2010, 2% of all cannabis related events reported to the French Addictovigilance Network were cardiovascular in nature [41]. Furthermore, the cardiovascular complication rate rose from 1.1% in 2006 to 3.6% in 2010 and the mortality rate from those complications was 25% [41]. Cannabis users presenting with cardiovascular emergencies are often young and frequently have no other risk factors for cardiovascular disease [42]. These growing concerns have lead other researchers to call for a registry in the United States similar to the efforts of the French Addictovigilance Network discussed above [43, 44]. The most commonly reported cardiovascular complications of cannabis use have ranged from acute coronary syndrome (ACS) to cardiac arrhythmias, stroke, peripheral arteriopathy, stress cardiomyopathy (SC) and sudden death (Table 1). Although these adverse events are primarily reported in recreational users of cannabis they have also been observed in those using the cannabis for medically approved reasons.

Cannabis use has rapidly reached epidemic proportions in the world. Appearance of highly potent and unregulated synthetic cannabinoids and cannabimimetics has further complicated the field. Although seriously underestimated and underreported, cardiovascular adverse events are being described at an alarming rate in users of cannabis and its related chemicals. Many of these serious events have occurred in children and young adults who are increasingly driven to use these substances due to the false notion of their safety and rapidly moving decriminalization and legalization processes. The pathophysiology of these adverse cardiovascular events in temporal relation to cannabis is far from established. Yet, the current evidence points to a major role for the endocannabinoid system and its interaction with the autonomic nervous system. Human data is generally deficient and most available studies in humans have been performed decades ago with methodology and resources of the time. While well conducted controlled studies are sorely needed in this area, current data should alert physicians and legislators across the world to the potentially harmful effects of unregulated use of cannabis in children, young adults and those with underlying cardiovascular risk factors or established heart disease.