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A man was arrested. Through risk assessment, Customs on that day inspected at the Shenzhen Bay Control Point an express parcel, which was declared as oil flow control valve, arriving in Hong Kong from South Africa via the Mainland. Upon examination, Customs officers found the batch of suspected cannabis buds therein. Customs officers subsequently mounted a controlled delivery operation yesterday December 14 and arrested a year-old man suspected to be connected with the case in Pat Heung, Yuen Long. He has been charged with one count of attempting to traffic in a dangerous drug and will appear at the Shatin Magistrates' Courts tomorrow December Customs reminds members of the public to stay alert and not to participate in drug trafficking activities for monetary return. They must not accept hiring or delegation from another party to carry controlled items into and out of Hong Kong. They are also reminded not to carry unknown items for other people, nor to release their personal data or home address to others for receiving parcels or goods. Customs will continue to maintain close contact with the logistics industries to step up action against drug trafficking through express courier channels. Under the Dangerous Drugs Ordinance, trafficking in a dangerous drug is a serious offence. Members of the public may report any suspected drug trafficking activities to Customs' hour hotline or its dedicated crime-reporting email account crimereport customs. Photo shows the suspected cannabis buds seized.

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Currently, cannabis is the most widely produced and consumed illicit drug in the world with global numbers of users approaching Similarly, it is the most widely used illicit substance among population aged 15—64 years in North America with estimated annual prevalence of A recent longitudinal study showed that It has been suggested that early cannabis use may be linked with higher possibility of chronic use in greater amounts. Medical use of cannabis is widespread and dates back to many centuries. In parallel with the widespread increase in the recreational use of cannabis worldwide, especially among young adults, there have been movements towards the decriminalization of cannabis use in various parts of the world, and in some countries, cannabis prescription is now permitted for various conditions other than the traditional cancer pain and neuropathy. Recently, several countries have approved the clinical use of cannabis for various conditions. Although the widespread recreational use of cannabis is mainly due to its well-known neurological and cognitive effects, the effects of cannabis on other organ systems remain unclear to some extent and risk perceptions associated with cannabis use seem to be widely underestimated. While the risk perception among youth is declining or remaining stable across the various states of the USA, the use of cannabis is increasing highlighting the need for public health policy changes regarding awareness of the risk to curb cannabis use among youth. Several systematic reviews, meta-analyses, randomized control trials and case—control studies have shown that the non-medicinal use of cannabis can significantly affect physical and mental health and lead to substance dependence 5 and alter the psychosocial development and mental health of adolescents 6. The common adverse effects of cannabis use besides dependence include the risk of motor vehicle accidents, respiratory dysfunction and cardiovascular events and pathology. Cannabis use or smoking has been linked with pneumomediastinum, pneumothorax, pneumopericardium, bullous lung disease, increased risk of chronic obstructive pulmonary disease, desquamated interstitial disease, and appearance of brown pigmented macrophages 7. Jouanjus et al. Thus, it is reasonable to conclude that the growing popularity of marijuana consumption for both medical and recreational purposes is associated with a parallel increase in the incidence of complications related to its use. Therefore, there is a need for a deep understanding of the effects of marijuana on the human body. We provide a review of the endocannabinoid system ECS followed by examining the effects of cannabis on the cardiovascular system, including the occurrence of arrhythmias and myocardial infarction MI and its effects on the peripheral vasculature and the cerebrovascular system. We conducted literature search from January to October from PubMed. We also briefly examine some of the important considerations related to anaesthesia in cannabis users. CB-1 receptors are expressed in the liver, muscle, fat, and brain, while CB-2 receptors are expressed in large numbers in the spleen and immune cells as well as in peripheral tissues, albeit at low levels These findings triggered a number of studies that eventually led to the discovery of the ECS. The ECS comprises the cannabinoid receptors CB-1 and CB-2 as well the endogenous counterparts of THC and endogenous ligands for both cannabinoid receptors, known as N-arachidonoyl-ethanolamine anandamide and 2-arachidonoyl-glycerol 2-AG. The ECS has been found to be involved in a number of processes, including cell fate and proliferation and differentiation of progenitors Owing to its wide representation of the ECS in the human body and its involvement in a variety of bodily processes, this system has emerged as a versatile therapeutic target. Endocannabinoids were detected in heart tissues and current evidences suggest that the ECS is involved in the regulation of heart rate HR and blood pressure in addition to being involved in various other pathological processes Experimental studies have shown redundancy in endocannabinoid signalling and in endocannabinoid targets with dualistic role of CB-1 and CB-2 receptors in the presence of pathological conditions. Cumulative evidence seems to suggest that CB-1 and CB-2 receptors may play contributory roles in modulating cardiometabolic risk, and atherogenesis, and can also have protective roles in limiting cardiomyocyte damage ECS have been found to exert vasorelaxing effects in cardiovascular system which appears to be mediated by numerous pathways. Activation of CB1 receptors in mice have been shown to produce prolonged hypotension. THC can cause vasodilatation, independent of cannabinoid receptor activation, by activating transient receptor potential ankyrin type-1 TRPA-1 channel. In addition, anandamide activates vanilloid VR1 receptors, a known alternative target of anandamide present on sensory nerves triggering the release of calcitonin gene-related peptide that binds to its receptors to cause vasodilatation The CB-2 receptors are expressed in cardiomyocytes, coronary endothelial cells and smooth muscle cells. Steffens and Pacher 14 examined the current literature on cannabinoid receptor CB-2 in cardiovascular disorders and concluded that expression of CB-2 receptors in cellular components of the cardiovascular system as well as infiltrating immune cells such as leukocytes and macrophages was possibly involved in controlling the extent of tissue inflammation and injury occurring in various cardiovascular conditions, thereby suggesting that these receptors may play a cardioprotective role. The pharmacological modulation of CB-2 receptors by CB-2 receptor agonists and antagonists therefore appears to be a promising strategy in the treatment of diseases such as stroke, atherosclerosis, restenosis, MI and heart failure. A thorough understanding of the endocannabinoid receptor system in humans would be paramount to the discovery of molecules that exert the therapeutic effects of cannabis and cannabinoids, with minimal adverse effects. This effect of cannabis on HR is thought to be due to cannabis induced vasodilation causing reflex tachycardia 15 , Consumption of higher doses of cannabis can cause postural hypotension associated with dizziness or fainting 17 , However, tolerance to the effects of cannabis develops rapidly after only a day or two of repeated exposure. Chronic marijuana use is associated with a decrease in HR, disappearance of orthostatic hypotension, increase in blood volume, and decrease in the circulatory responses to exercise which are consistent with reduced sympathetic and increased parasympathetic activity A study from Norway, on apprehended drivers, demonstrated that THC- positive drivers had higher mean pulse rate than THC-negative drivers and surprisingly, the magnitude of tachycardia was independent of blood THC concentration In a systematic review of 6 case reports, Korantzopoulos et al. They hypothesize that adrenergic stimulation reduces duration of action potential and alters the electrophysiological properties of myocardium to favour automaticity and micro-reentry thereby promoting development of atrial fibrillation in susceptible individuals. Moreover, atrial ischemia caused by detrimental effect of cannabis on coronary microcirculation could also contribute to development of atrial fibrillation Ventricular tachycardia has been reported in a year-old heart transplant patient, within the time frame of marijuana use documented by a hour Holter Monitor Casier et al. In another case, ventricular fibrillation occurred after consuming more than the usual dose of marijuana in a patient with CAD on two separate occasions. The authors speculated that excessive catecholamine release could be responsible for the arrhythmia Brugada-like ST segment abnormalities have also been reported after heavy consumption of cannabis 24 - This adverse effect of cannabis is thought to be due to its effect on shortening of action potential and hyper stimulation of vagal tone Thus, it appears that recent use of cannabis is associated with an increase in HR occurring in young individuals and potentially increasing the risk of sudden death. Since marijuana use is common among young persons in various social settings and the possibility of the combined use of marijuana with alcohol or other illicit substances is high, it is important to consider the potential additive or synergistic effects of commonly used such combinations. In a randomized, double blind, placebo controlled trial in healthy volunteers, Ballard et al. Assessed measures included psychomotor ability, simple reaction time and blood pressure and HR. In the past, risk of ischemia associated with marijuana use was considered to be low Over the last few years, several case reports and case series have been published worldwide about the occurrence of MI in otherwise healthy young marijuana abusers most of which are particularly male. Hodcroft et al. In a case series, Casier et al. Deharo et al. Regular cannabis use was found to be linked with acute coronary syndrome after excessive physical activity and has been reported to trigger MI in patients with known coronary artery disease Leblanc et al. Together, these case studies indicate that cannabis use is a risk factor for acute coronary events in young persons, especially men, who do not have any other risk factors for cardiovascular diseases besides smoking. The events also appear to be triggered by highly strenuous physical activity. This is an important consideration in youth who use marijuana in social entertainment settings since physical activity such as dancing may be common in such circumstances, which can increase the risk of precipitating acute coronary events. They found that marijuana smoking was associated with increased the risk of MI 4. Further, the annual risk of MI in daily users of cannabis was calculated to be 1. In another study from the similar cohort, patient were prospectively followed for an average of 3. The authors determined that compared to non-use, cannabis use less than a week, was associated with hazard ratio of 2. Any cannabis use was associated with hazard ratio of 1. However, in a follow study from the same cohort, Frost et al. The mechanisms by which cannabis causes acute coronary syndrome are unknown and multiple hypothesis have been proposed Table 1 , Figure 1. In many reported cases of cannabis induced AMI coronary angiography was normal so cannabis-induced transient coronary vasospasm is one of the hypothesis proposed. In one case report, patient developed ST-segment elevation MI with clean coronaries after using combination of sildenafil and cannabis Prolonged half-life of cannabis due to competitive substrate inhibition of CYP3A4 was proposed as the possible mechanism 39 , Cannabis is also known to cause reversible cerebral vasoconstriction syndrome RCVS associated with or without focal neurological deficits where neurovascular imaging improves after discontinuation of cannabis use discussed later in more detail. Another possible mechanism of AMI due to cannabis use could be increase in carboxyhemoglobin levels immediately after its inhalation which could reduce oxygen carrying capacity of blood. Aronow et al. It has also been proposed that cannabis has pro-coagulant effects. Both CB1 and CB2 receptors have been detected on platelet cell membrane. It has been shown in vitro that cannabis increases expression of glycoprotein IIb-IIIa and P-selectin in a concentration dependent manner which leads to platelets aggregation and Factor VII activation 42 Figure 2. Cannabis is also postulated to exert hemodynamic effects which could initiate plaque rupture and promote thrombosis. Increase in HR and sympathomimetic activity due to cannabis use can increase myocardial oxygen demand and could precipitate AMI. Postural hypotension and increase in blood pressure in supine position can also be precipitated by cannabis use which could trigger anginal episodes 22 , Thus, there is evidence to support the notion that cannabis use is associated with an increased risk of acute coronary events in patients with coronary artery disease as well as in those without any significant risk factors for atherosclerosis. However, some investigators believe that there is only low and transient risk of precipitating cardiovascular events associated with cannabis use considering that the reports of death among users of medical marijuana attributable to the drug are rare The effects of cannabis on peripheral vasculature have not been clinically well studied yet. Only a handful number of studies have been conducted on the relationship between blood vasomotion and cannabis and they show conflicting results. Further, their animal experiments revealed that in conduit arteries, such as the aorta, THC causes impairment of methoxamine-induced constriction under the influence of superoxide dismutase, production of hydrogen peroxide, and calcium channel inhibition. In the superior mesenteric artery, they noted that THC enhanced acetylcholine-induced vasorelaxation via increased hydrogen peroxide production. However, in isolated resistance vessels, THC augmented methoxamine-induced vasoconstriction and inhibited endothelium-dependent vasorelaxation These findings suggest that THC has variable effects on the central and peripheral vessels, depending on the functional properties of the arteries examined. Vandrey et al. In contrast, Bonnet et al. Cannabis smoking has also been shown to be associated with orthostatic hypotension which was more pronounced and longer lasting in hypertensive volunteers and is thought to be due to decreased vascular resistance THC might possess direct toxic effect on arterial vessels and could exert a synergistic effect with tobacco smoking THC induced peripheral vasoconstriction could also contribute to this phenomenon Multiple case reports of cannabis associated arteritis have been published in literature, however, the casualty has not been well established because most of these cases had other risk factors for thromboangitis obliterans 34 , In many instances, however, the worsening of the vascular disease was found to parallel the use of cannabis with halting of disease progression with abstinence from cannabis consumption Lou et al. They proposed chronic vasoconstriction, as the possible underlying mechanism by causing partial or complete vacuolization and lysis of the arterial media with deposition of fibrin at the interface between the adventitia and the media, eventually resulting in arterial rupture. There are anecdotal case reports of central retinal vein occlusion 56 , limb ischemia 57 , and acute thrombosis of aorta 58 associated with cannabis use. Thus, the effect of cannabinoids on peripheral vasculature is heterogeneous and complex. Further research in this field is required to understand the long-term effects of cannabis consumption on the peripheral vasculature and blood flow. Currently, the evidence regarding the relationship between stroke and cannabis use is not firmly established, although a temporal link has been reported in several cases of ischemic stroke with no other apparent causes Rumalla et al. They also found that the incidence of acute ischemic stroke was greater among marijuana users than among non-users. Similarly, a prospective study by Wolff et al. Cannabis-related stroke can also occur as a consequence of arterial obstruction from a post-MI left ventricular thrombus, as reported by Leblanc et al. Similarly, Tsivgoulis et al. In a systematic review of case reports on stroke and cannabis use by Hackam 63 showed that current evidences point towards a temporal relationship between ischemic stroke and cannabis use. Cannabis related ischemic stroke has been found to have predilection for posterior circulation 64 which could be due to multifocal intracranial stenosis in vertebrobasilar territory Thanvi and Treadwell 59 listed the following as possible mechanisms underlying the occurrence of stroke after cannabis consumption: vasospasm, vasculitis, hypotension with secondary impairment of regulation of cerebral flow and cerebral vasoconstriction syndrome Figure 3. Ntlholang et al. Recently, it was shown in rats that THC exposure induces cerebral mitochondrial dysfunction in dose dependent manner and increases reactive oxygen species production in the brain which could further contributes to its toxicity This apparent relationship of cannabis use and stroke notwithstanding, it should also be noted that stroke is not commonly reported in cannabis users While several reports have indicated the occurrence of ischemic stroke associated with cannabis use but occurrence of hemorrhagic stroke has been rarely reported. Ince et al. Behrouz et al. They found that about half of the cannabis positive patients developed delayed cerebral ischemia vs. Cannabis use can also cause RCVS which is characterized by recurrent strong headaches and development of neurological focal deficit with reversible vasoconstriction on repeat intravascular imaging within three months Wolf et al. It is possible that cannabis use is underdiagnosed or underreported in young adults developing ischemic and occasionally hemorrhagic stroke. Therefore, the actual magnitude of the contribution of cannabis usage to the incidence of stroke among youth may be significantly underestimated. This highlights the need for proper and thorough history taking in such cases focusing on the history use of recent or chronic use of marijuana, especially in the absence of other risk factors for stroke. A high degree of suspicion of illicit drug use, especially of cannabis, should be maintained in young patients presenting with stroke especially when no apparent cause of stroke can be found. Rarely, development of stress cardiomyopathy has been temporally related to consumption of cannabis Recurrent stress cardiomyopathy involving cardiac apical and basal cardiac regions on two separate occasions in the same patient has also been reported. A case of recurrent myopericarditis was reported in a year-old male which occurred after heavy consumption of adulterated cannabis both times. Authors could not find any obvious causative factor other than use of cannabis Synthetic cannabinoids SCs are cannabis preparations that were synthesized during the process of identifying cannabinoid receptors. JWH has stronger affinity for CB1 and CB2 receptors and produces extreme cannabinomimetic effects compared to marijuana. SCs are marketed under various other names including K2, skunk, joker, mojo, aroma, dream and black mamba etc. The rising popularity of these products has been accompanied by a significant increase in the number of emergency admissions due to SCs. There is considerable risk of toxicity from either acute or chronic use with evidence of an increase in the number of chronic or even daily users of this class of drugs and a parallel increase in cases of withdrawal complications Although widely considered harmless, several recent reports have been published on cases of serious cardiovascular events attributed to the use of SCs. The most prevalent cardiac side effect of SC consumption is tachycardia Chest pain has also been reported to occur after consumption of SCs Other reported cardiovascular events are peri-mesencephalic sub-arachnoid hemorrhage and middle cerebral artery occlusion Cases of ST-elevation MI, although rare, have been reported following the use of K2 in patients as young as 14 years old as well as in adults On the other hand, Orsini et al. They hypothesized that consumption of K2 caused transient myocardial ischemia resulting in ventricular stunning leading to acute CHF Shah et al. Development of acute ischemic strokes due to consumption of SCs has also been reported in young adults without any history of predisposing factors This highlights importance of appropriate and complete history taking when patients in this age group present to the emergency department especially with cardiovascular events. Important legal considerations relevant to the use of SCs are the lack of sufficiently reliable tests for their detection in urine, unlike those available for marijuana and the classification of these drugs as analogues of controlled substances rather than controlled substances Efforts to curb its use via the implementation of appropriate public health strategies are imperative. Cannabis users may require surgery due to injuries or accidents occurring after recent use. Cannabis has been shown to cause significant respiratory symptoms and changes in spirometry even with relatively short duration of inhalation Cannabis use has been associated with significant airway inflammation and alteration in histopathology in bronchial mucosa and these effects appears to be additive when cannabis is smoked in conjunction with tobacco In one study, it was concluded that smoking of cannabis is associated with significant airway inflammation which was similar to what encountered in tobacco smokers Because of all these physiological and histopathological changes, patients undergoing surgery should be inquired about illicit drug use including cannabis 91 , The interactions between cannabis and anaesthetic agents and the effects of these interactions are poorly understood. In a prospective, randomized, single blinded study, regular cannabis users showed variable response to induction of anaesthesia with propofol when compared to non-users, although higher doses of propofol were needed to achieve loss of consciousness, adequate jaw relaxation and depression of airway reflexes for insertion of laryngeal mask THC has also been reported to prolong the sedative effects of general anaesthesia in experimental models 94 , 95 , and has been implicated in perioperative complications such as bronchospasm due to airway irritation, tachycardia, and uvular oedema Cannabis leaves burn at higher temperature than similar quantity of tobacco causing increased direct airway irritation. Excessive respiratory burden of carbon monoxide and tar can occur with cannabis smoking when compared to smoking Cannabis use is also possibly reported to be associated with diffuse alveolar haemorrhage in post-operative period in a patient which was thought to be due to 97 negative pressure pulmonary edema and possible inhibition of thrombin-driven clot formation It is important to extract history of cannabis use as a routine part of preoperative work up. The choice of the appropriate anaesthetic agent is important in cases of cannabis users. If sedative hypnotic drugs are used in cannabis users, excessive depression of the central nervous system may occur; therefore, barbiturates, opioids, and benzodiazepines, and phenothiazines are preferably avoided. Further, recent use of cannabis can cause decrease blood pressure due to vasodilatation along with tachycardia leading to increased oxygen myocardial demand 99 , therefore drugs which are likely to increase HR, such as ketamine, atropine, and epinephrine should also be avoided It should also keep in mind that the intraoperative and immediate postoperative need of opiates for analgesia in patients with history of recent or chronic cannabis consumption may be significantly increased 92 , While the majority of published data suggest a harmful effect of cannabis and cannabinoids on the cardiovascular system, a few suggest possible beneficial effects. The use of cannabis or marijuana has been linked to increase risk of cardiac events immediately after use, although little information is available about the long-term impact of marijuana among patients with established coronary disease. An analysis carried out on around 4, MI patients from a U. Indirect beneficial effects have been demonstrated in studies showing that cannabis or marijuana use attenuates or modulates common cardiovascular disease risk factors. Preliminary data from a small double blinded placebo controlled study carried out in the U. Additionally, a number of epidemiologic studies have shown lower prevalence of obesity and diabetes mellitus among marijuana users compared with those who never used marijuana, suggesting a relationship between cannabinoids and metabolic processes. A study done on adult Americans from the National Health and Nutrition Examination Survey showed that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference Furthermore, some studies hypothesized that lower rates of obesity among habitual marijuana users are directly related to the exposure to the THC present in cannabis, and proposed its potential use for the management of obesity and its complications A recently published study on mice that tested three regimens of THC administration suggests that a pre-treatment with an ultra-low dose of THC provides a significant protection against an ischemic insult to the heart as evidenced by lower troponin levels, and reduced infarct size The fact that cannabis use has become increasingly popular among youngsters is a major cause for concern. It is important to consider a negative impact of cannabis abuse on education as well as the risk of abuse of other illicit drugs among the youth on the development of psychosis. Currently, there is a lack of consensus on what position to adopt regarding legalization of cannabis. While one view regards recreational cannabis uses as harmless, the opposing viewpoint is that it raises some serious public health concerns and that its use should continue to be discouraged by governing bodies and prohibited by law Table 2. The literature suggests the occurrence of harmful effects including fatal cardiovascular events that could be related to cannabis use. Further research and studies are needed to determine the impact of acute and especially the chronic regular use of cannabis on various organ systems, particularly the cardiovascular system. With the recent decriminalization and legalisation of cannabis use in some parts of the world and the increase in the number of conditions that cannabis can be prescribed for, there is a good possibility that physicians will encounter more cases of cardiovascular and cerebrovascular complications of cannabis use in the near future. It is necessary to increase awareness among physicians and the general public alike regarding the increased risk of cardiovascular complications associated with cannabis use. In addition, implementing effective strategies for the prudent dispersal of the drug is necessary to avoid unnecessary increases in cannabis-related complications and therefore preclude the resultant burden on public and private health services. The current evidences highlight the urgent need for a change in the mindset among cannabis users, particularly the young regarding the adverse effects of cannabis use and the risk of acute coronary events, stroke, and possibly death. Authors would like to acknowledge Dr. Amar Shere MD for creating the online versions of all figures. Table 1 Proposed pathophysiology of cannabis-induced acute myocardial infarction Depending on cardiac catheterization findings Full table. Figure 1 Proposed mechanisms for cannabis induced cardiovascular effects. Figure 2 Molecular mechanisms of interplay between cannabinoid system and platelets. Platelets and megakaryocytes have CB1 and CB2 receptors. Anandamide and 2-AG activate platelets via these receptors. Figure 3 Proposed mechanisms of cannabis induced cerebrovascular effects. Table 2 The effects of cannabis on the cardiovascular system Full table. Role of cannabis in cardiovascular disorders. J Thorac Dis ;9 7

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