ArticleLiterature Review

Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly

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Abstract

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

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... The most common symptoms seen in patients consuming SCBs are tachycardia, agitation, drowsiness, nausea, hallucinations, hypertension, psychosis, delusions, and seizures [8,9]. The cardiotoxicity of SCBs are well known [10,11]; they can produce severe cardiovascular, hematological, neurological, psychiatric, and renal side effects [12]. For instance, marijuana and SCB consumption increases the heart rate and alters blood pressure. ...
... For instance, marijuana and SCB consumption increases the heart rate and alters blood pressure. The cardiovascular symptoms are heterogenous and unpredictable; for example, both tachycardia and bradycardia are reported after SCB use [10][11][12][13]. ...
... More severe cardiovascular sequelae can also occur, such as arrythmias, acute coronary syndrome, myocardial infarction, congestive heart failure, and vasculopathies [11,14]. The most common arrhythmias are supraventircular arrhythmias and include sinus tachycardia, atrial fibrillation, sinus bradycardia, and supraventricular tachycardia. ...
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The serious adverse effects of synthetic cannabinoids (SCB), the lack of human pharmacological data on SCBs, and the increasing number of SCBs with diverse structures are growing public health concerns. A fatal case of myocardial ischemia after ADB-FUBINACA overdose is reported. A 41-year-old male died after consuming a brown, powder-like drug. Autopsy revealed pallor in the left ventricle of the subendocardial two-third of the myocardium, and histological examination revealed early signs of myocardial ischemia: few wavy myocardial fibers, contraction band necrosis in the subendocardial region, and patchy subendocardial complement component 9 (C9) positivity. Toxicological analysis detected a high concentration of the indazole carboxamide derivative SCB ADB-FUBINACA (peripheral blood: 105 ng/mL) and a low concentration of the synthetic cathinone (SC) derivative stimulant N-ethylpentylone (NEP). The literature concerning ADB-FUBINCA overdoses is reviewed, and the possible mechanism of death and the cardiac effects of SCBs are discussed. Effects of SCBs are unpredictable, but they are potentially cardiotoxic, capable causing arrhythmias, cardiac hypertrophies, and myocardial ischemia. The cardiotoxicity of SCBs can be attributed to vasospasms, decreased myocardial contractility, and increased cardiac workload and oxygen demand. Based on the autopsy, histology, and toxicology, it could be reasonably suggested, that ADB-FUBINACA have been a significant contributor to the myocardial ischemia seen in histology. The mechanism of death was likely fatal arrhythmia induced by the patchy myocardial ischemia. Due to the low concentration of NEP, it’s role in the fatal outcome is improbable.
... Both processes are associated with accelerated atherosclerosis. Furthermore, unstable arterial plaques are known to have higher CB1R expression [19]. Not surprisingly, CB1R inhibition leads to decreased vascular AT1R expression, improves endothelial function, slows the progression of atherosclerosis, attenuates cellular death, and reduces inflammation and adverse tissue remodeling [21,23,24] CB2 receptors are expressed predominantly outside of the central nervous system on peripheral immune cells, especially B lymphocytes [25]. ...
... Not surprisingly, CB1R inhibition leads to decreased vascular AT1R expression, improves endothelial function, slows the progression of atherosclerosis, attenuates cellular death, and reduces inflammation and adverse tissue remodeling [21,23,24] CB2 receptors are expressed predominantly outside of the central nervous system on peripheral immune cells, especially B lymphocytes [25]. Agonists of CB2R were shown to attenuate the inflammatory response by reducing cytokine production and oxidative stress and are considered cardioprotective [19,26,27]. Specifically, CB2R up-regulation has been detected in endothelial and smooth muscle cells stimulated by pro-inflammatory triggers, and in myocardium of patients with chronic heart failure [19]. ...
... Agonists of CB2R were shown to attenuate the inflammatory response by reducing cytokine production and oxidative stress and are considered cardioprotective [19,26,27]. Specifically, CB2R up-regulation has been detected in endothelial and smooth muscle cells stimulated by pro-inflammatory triggers, and in myocardium of patients with chronic heart failure [19]. In addition, CB2R activation may reduce atherosclerotic plaque formation, infarct size, ventricular arrhythmias, and collagen deposition following ischemia-reperfusion injury [28][29][30][31]. ...
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Cardiac transplantation requires the careful allocation of a limited number of precious organs. Therefore, it is critical to select candidates that will receive the greatest anticipated medical benefit but will also serve as the best stewards of the organ. Individual transplant teams have established prerequisites pertaining to recreational drug, tobacco, alcohol, and controlled substance use in potential organ recipients and post-transplantation. Legalization of cannabis and implementation of its prescription-based use for the management of patients with chronic conditions have been increasing over the past years. Center requirements regarding abstinence from recreational and medical cannabis use vary due to rapidly changing state regulations, as well as the lack of clinical safety data in this population. This is evident by the results of the multicenter survey presented in this paper. Developing uniform guidelines around cannabis use will be imperative not only for providers but also for patients.
... i) Failure of the anterior and posterior neuropores to close, resulting in encephalocele, exencephaly and spina bifida respectively; ii) Cleft lip and palate due to failure of the facial and palatal processes to properly fuse iii) Several cardiovascular defects including: As shown above shh is known to be a key morphogen directing the differentiation of the arterial tree and its inhibition can be expected to disrupt normal vasculogenic and arterial supply of key tissues. Cannabinoids are also vasoactive [123]. Both type 1 and 2 cannabinoid receptors (CB1Rs and CB2Rs) along with other receptor subtypes have been described on the vasculature [123]. ...
... Cannabinoids are also vasoactive [123]. Both type 1 and 2 cannabinoid receptors (CB1Rs and CB2Rs) along with other receptor subtypes have been described on the vasculature [123]. Cannabinoids acting at CB1Rs are often proinflammatory and vasoconstrictive [123][124][125][126][127]. Such vascular defects could be involved with the genesis of various congenital anomalies including: i) Body wall defects (gastroschisis and omphalocele)cocaine and various vasoconstrictive antihistaminic drugs are known to be associated with gastroschisis [128][129][130][131][132][133] and cannabinoids may act similarly at least in the foetal period of development ii) Gastrointestinal stenoses and atresias iii) Limb development as the developing limb anlage is highly vascular dependent any interruption of its blood supply will necessarily truncate development. ...
... Both type 1 and 2 cannabinoid receptors (CB1Rs and CB2Rs) along with other receptor subtypes have been described on the vasculature [123]. Cannabinoids acting at CB1Rs are often proinflammatory and vasoconstrictive [123][124][125][126][127]. Such vascular defects could be involved with the genesis of various congenital anomalies including: i) Body wall defects (gastroschisis and omphalocele)cocaine and various vasoconstrictive antihistaminic drugs are known to be associated with gastroschisis [128][129][130][131][132][133] and cannabinoids may act similarly at least in the foetal period of development ii) Gastrointestinal stenoses and atresias iii) Limb development as the developing limb anlage is highly vascular dependent any interruption of its blood supply will necessarily truncate development. ...
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Background Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA. Methods State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001–2005 to 2011–2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs. Results Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005–2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x10 ⁷ , 555.10, 7.53x10 ¹⁹ , 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships ( P = 2.83x10 ⁻⁶⁰ and 1.61x10 ⁻⁷¹ respectively). Conclusions Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern. These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.
... In addition, previous studies indicate that cannabinoids (marijuana or synthetic ligands) can influence cardiovascular autonomic nervous system activity via CB1 receptor activation, resulting in a wide range of acute hemodynamic effects that largely depend on the cannabinoid dose, route of administration, duration of the use, and individual sensitivity. In this context, hypotension, increased heart rate by 20-100%, and decreased myocardial contractility have been documented [68][69][70]. These effects may increase the myocardium workload, thereby increasing the cardiac oxygen demand with unmatched oxygen supply. ...
... Moreover, cannabinoid smoking increases the production of carboxyhemoglobin [71], which, along with the compromised oxygen supply, can further impair the myocardial oxygen balance. Generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction have also been reported with CB1 receptor activation [70]. Altogether, these acute effects may associate with transient ischemic/reperfusion changes with increased oxidative stress at the cardiovascular tissue levels that may, ultimately, lead to the activation of coagulative pathways causing MI in susceptible individuals. ...
... Potential mechanisms: Activation of CB1 receptors with increased oxidative stress at the cardiovascular tissue level that may ultimately lead to the activation of coagulative pathways. [63,[68][69][70][71] THC Stimulation of platelet activation via CB1/CB2-dependent mechanism through increasing fibrinogen receptor (glycoprotein IIb-IIIa) and P selectin expression. ...
Article
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Abnormal blood coagulation or coagulopathy is a common manifestation of many pathological conditions. It occurs when there is an imbalance between the activities of the coagulation system and the fibrinolytic system, leading to excessive or impaired intravascular blood clot formation, which can disturb blood flow causing ischemia or hemorrhage in the affected tissues. A growing body of evidence has demonstrated blood coagulation abnormalities in association with cannabinoid use, suggesting the involvement of the endogenous cannabinoid system (ECS) in modulating blood coagulation. However, the evidence in the literature has been controversial on whether cannabinoids promote or inhibit blood coagulation. The ECS has been extensively studied in recent years for its potential as a therapeutic target for many diseases. This review provides a brief introduction to the ECS and discusses the reported anticoagulatory and procoagulatory effects of various cannabinoids, highlighting some possible mechanisms that might underlie the observed effects. Understanding the coagulatory effects of cannabinoids and the interaction between the coagulation system and the ECS is vital for developing novel therapeutics for coagulopathies.
... However, this is not a uniform finding [206]. It seems well established that an increased risk of a cardiovascular event in the wake of cannabinoid use is present even after singular exposure [207][208][209][210]. The increase in tachycardia, which may be a culprit in excessive risk of cardiac events, maybe potentially abolished by pretreatment with clonidine or propranolol, both central sympathomimetics [211,212]. ...
... The standardization of the dosages is scant and complicated, with the concentration of 9-THC possibly being affected by 8-THC while being inversely related to CBD [77,78,83,179]. Furthermore, synthetic cannabinoids may further affect potency [10,207]. Considering the higher prevalence of other illicit drugs among cannabinoids, one must consider the possibility of multi-drug abuse with obvious implications for anesthesia management [9,200,276]. ...
... With increased consumption of cannabinoids worldwide, it is important to consider potential additives, as the patient may not be aware of them. Acute cannabinoid use seems to be related to increased blood pressure, tachycardia, and increased or decreased cardiac contractility [128,129,196,[198][199][200]202,206,207,232,[362][363][364]. The limitation of these data is that the perioperative intake of cannabinoids is difficult to standardize even within the same patient. ...
Article
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Increased usage of recreational and medically indicated cannabinoid compounds has been an undeniable reality for anesthesiologists in recent years. These compounds’ complicated pharmacology, composition, and biological effects result in challenging issues for anesthesiologists during different phases of perioperative care. Here, we review the existing formulation of cannabinoids and their biological activity to put them into the context of the anesthesia plan execution. Perioperative considerations should include a way to gauge the patient’s intake of cannabinoids, the ability to gain consent properly, and vigilance to the increased risk of pulmonary and airway problems. Intraoperative management in individuals with cannabinoid use is complicated by the effects cannabinoids have on general anesthetics and depth of anesthesia monitoring while simultaneously increasing the potential occurrence of intraoperative hemodynamic instability. Postoperative planning should involve higher vigilance to the risk of postoperative strokes and acute coronary syndromes. However, most of the data are not up to date, rending definite conclusions on the importance of perioperative cannabinoid intake on anesthesia management difficult.
... Postulated adverse effects of marijuana use may include sympathetic nervous system activation, blood pressure changes, platelet activation, and electrophysiological effects. [50][51][52] Concomitant tobacco smoking and other substance use and abuse possibly contribute to these effects, which may be short term and have been studied mostly in low-risk populations such as younger adults. These factors may explain why many longitudinal studies linking marijuana use and cardiovascular or metabolic risk factors have been negative after multivariable adjustment for unhealthy behaviors such as diet and tobacco smoking. ...
... With marijuana use, the most common acute reaction in humans is a decrease in blood pressure resulting from cannabinoid effects on the vasculature and autonomic nervous system. 52 Despite this physiological reaction, limited studies using the National Health and Nutrition Examination Survey showed a modest association of recent cannabis use with higher systolic blood pressure and higher prevalence of hypertension among current users 30 to 59 years of age. 56 Heavy users, defined as use of marijuana or hashish in >20 of the past 30 days, had higher odds of abnormal blood pressure compared with never-users. ...
... In addition, it induces endothelial dysfunction and vascular smooth muscle cell proliferation and migration. These processes have been linked to cardiac dysfunction 52 This is in contrast to the atheroprotective role associated with CB2. Acute cardiovascular events and stroke also have been reported in patients using synthetic cannabinoids. ...
Article
Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.
... Retrospective studies indicate that marijuana increases the risk of cardiovascular disease (CVD), including myocardial infarction (MI), angina, and arrhythmias (DeFilippis et al., 2018; Thomas et al., 2014). Marijuana exposure is known to induce endothelial dysfunction, atherosclerosis, cardiomyopathy, and metabolic dysfunction in animal models (Wang et al., 2016;Pacher et al., 2018). Nevertheless, the US Food and Drug Administration (FDA) has approved two synthetic cannabinoids for treating chemotherapy-induced nausea and vomiting and HIV-associated anorexia: dronabinol and nabilone (Whiting et al., 2015). ...
... Nevertheless, the US Food and Drug Administration (FDA) has approved two synthetic cannabinoids for treating chemotherapy-induced nausea and vomiting and HIV-associated anorexia: dronabinol and nabilone (Whiting et al., 2015). Synthetic cannabinoids are also associated with adverse cardiovascular effects (Pacher et al., 2018). Thus, there is a need to understand the link between marijuana and CVD. ...
... The endocannabinoid amantadine is made on-demand, unlike classical neurotransmitters (Di Marzo et al., 1994), and causes vasodilation, bradycardia, and hypotension (Movahed et al., 2005). Previous studies found that CB1 activation is proatherogenic by promoting inflammation and oxidative stress that cause endothelial dysfunction and atherosclerosis, whereas CB2 activation is anti-atherogenic (Pacher et al., 2018;Ibsen et al., 2017). CB2 agonists are in development for vascular disorder (Pacher and Mechoulam, 2011), and CB1 antagonists are anti-atherogenic (Pacher et al., 2018). ...
Article
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ⁹-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ⁹-THC. In mice, genistein blocked Δ⁹-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ⁹-THC-induced atherosclerosis.
... Subsequently, it would be possible to trace a contamination profile to establish a prognosis for this population. Thus, the nurse has the potential to carry out screening and brief intervention effectively (49)(50) , strengthening the role of this professional in mental health care (51) , regardless of the health care sector they act. In addition, nurses who work in specialized services in alcohol and other drugs must identify and intervene in risk situations that favor the infection of people by SARS-CoV-2. ...
... Regarding probable therapeutic uses, both THC and CBD have been mentioned in the literature as having an important function of modulating the immune system, acting in the inhibition of inflammatory cytokines and in the stimulation of anti-inflammatory cytokines (52) , confirmed by several studies (16,(20)(21)(30)(31)(32)(33)35) . Despite disagreements about the safety of cannabis and CB use, some regulatory agencies have allowed the use of CB-based drugs for the treatment of epilepsy and multiple sclerosis and for the relief of symptoms of chemotherapy, allowing new perspectives for future applications (51,53) . ...
... The use of CBD may also be a promising agent for patients recovering from COVID-19 due to improved pulmonary function (30) . Furthermore, the therapeutic potential in the treatment of cardiovascular pathologies has been considered in the literature (51) . Another resource would be the prevention strategy against the entry of SARS-CoV-2, through the use of mouthwashes containing Cannabis sativa with a high content of CBD (30) , which would act by modulating the expression of ACE2 expressed in the oral cavity (32) . ...
Article
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Objective: to identify and synthesize studies on the effects of cannabis use and its relation with SARS-CoV-2, as well as the therapeutic possibilities of using cannabinoids in the prevention and treatment of COVID-19. Methods: scoping review, in the BVS, PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, CAPES and ProQuest databases, with no language restriction and year limitation. Narrative synthesis was performed. Results: cannabis use causes changes in the respiratory and vascular system, it reduces the production of cytokines, which affects the users' immune system, increasing the susceptibility to infection and progression of COVID-19. However, studies have suggested the use of cannabinoids in the prophylaxis and treatment of COVID-19, due to their anti-inflammatory effect. Conclusions: the use of inhaled cannabis increases the progression and severity of the infection. On the other hand, the benefits of cannabinoids seem promising to modulate the immune system, but it needs further studies.
... and smooth muscle cells, and circulating blood cells. 101 Additionally, the CVS can be modulated by upstream effects of CBs on the peripheral nervous system. CB 1 receptors mediate CB-induced cardiovascular depressive effects such as hypotension and reduced myocardial contractility. ...
... CB 1 receptors mediate CB-induced cardiovascular depressive effects such as hypotension and reduced myocardial contractility. 99,101,102 Alternatively, CB 2 receptor agonists have less pronounced cardiovascular effects. 103 ...
Article
Cardiovascular complications from drugs of abuse are becoming more apparent due to increased usage worldwide. Substance abuse can cause both acute and chronic cardiovascular complications and is increasing in prevalence especially in young adults. These substances contribute to the development of acute coronary syndrome, type II myocardial injury, arrhythmias, cardiomyopathies and have numerous other cardiovascular complications. Although no screening guidelines exist, clinical awareness of these potential complications and their prevention, clinical presentation, diagnosis, and treatment are critically important. Management of cardiovascular disease should be coupled with appropriate social and mental health interventions to provide sustained clinical benefit. The higher the number of substances used recreationally, the greater the risk of premature heart disease. Epidemiological studies showed that 1 in 5 young adults misuse several substances and often start using at younger ages with a greater risk for adverse health outcomes over the long-term. The aim of this review is to highlight the basic epidemiology, cardiac complications, and disease-specific treatment options of commonly abused substances including methamphetamine, cocaine, alcohol, anabolic-androgenic steroids, cannabis, and tobacco.
... 3r,t). These findings could be related to vascular damage or vasoconstriction (46), which should be considered in future studies, especially, due to cardiotoxicity reported by some synthetic cannabinoids (47)whereas activation of CB(2. In this regard, anandamide and synthetic cannabinoids activating CB1 receptors are linked to hemorrhagic shock (47,48). ...
... These findings could be related to vascular damage or vasoconstriction (46), which should be considered in future studies, especially, due to cardiotoxicity reported by some synthetic cannabinoids (47)whereas activation of CB(2. In this regard, anandamide and synthetic cannabinoids activating CB1 receptors are linked to hemorrhagic shock (47,48). ...
Article
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In the present study the interaction of cannabinoid, PhAR-DBH-Me [(R,Z)-18-((1S,4S)-5-methyl-2,5-diazabi-cyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-ylphenyl-acetate] and tramadol in two neuropathy models, as well as their possible toxic effects, was analyzed. The anti-allodynic effect of PhAR-DBH-Me, tramadol, or their combination, were evaluated in neuropathic rats. Furthermore , the effective dose 35 (as the 35 % of the anti allo-dynic effect) was calculated from the maximum effect of each drug. Moreover, the isobolographic analysis was performed to determine the type of interaction between the drugs. A plasma acute toxicity study was carried out to assess the hepatic, renal, and heart functions after an individual or combined administration of the drugs, as well as histology using the hematoxylin-eosin or Masson-trichome method. PhAR-DBH-Me, tramadol, and their combination produced an antiallodynic effect on spinal nerve ligation (SNL) and cisplatin-induced neuropathic pain in rats. Moreover, PhAR-DBH-Me and tramadol combination showed a synergistic interaction in neuro-pathic pain rats induced by SNL but not for cisplatin-induced neuropathy. On the other hand, changes in renal and hepatic functions were not observed. Likewise, analysis of liver, kidney and heart histology showed no alterations compared with controls. Results show that the combination of PhAR-DBH-Me and tramadol attenuates the allodynia in SNL rats; the acute toxicology analysis suggests that this combination could be considered safe in administered doses.
... Cannabis use is an independent risk predictor of heart failure [11]. Mechanistically, this could be in part due to cannabinoid agonisms of the CB-1 receptor which has been shown to have several affects in humans including decreased myocardial contractility, endothelial dysfunction, tissue injury fibrosis and cell death [14,15]. ...
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Background In the United States, both cannabis use disorder (CUD) and opioid use disorder (OUD) have increased in prevalence. The prevalence, demographics, and costs of CUD and OUD are not well known in heart failure (HF) admissions. This study aimed to use a national database to examine the prevalence, demographics, and costs associated with CUD and OUD in HF. Methods This study used the National Inpatient Sample from 2008 to 2018 to identify all primary HF admissions with and without the co-diagnosis of OUD or CUD using International Classification for Diagnosis, diagnosis codes. Demographics, costs, and trends were examined. Results Between 2008 and 2018, we identified 11,692,995 admissions for HF of which 84,796 (0.8%) had a co-diagnosis of CUD only, and 67,137 (0.6%) had a co-diagnosis of OUD only. The proportion of HF admissions with CUD significantly increased from 0.3% in 2008 to 1.3% in 2018 (p<0.001). The proportion of HF admissions with OUD significantly increased from 0.2% in 2008 to 1.1% in 2018 (p<0.001). Patients admitted with HF and either CUD or OUD were younger, more likely to be Black, and from lower socioeconomic backgrounds (p<0.001, all). HF admissions with OUD or CUD had higher median costs compared to HF admissions without associated substance abuse diagnoses ($8,611 vs. $8,337 for CUD HF and $10,019 vs. $8,337 for OUD HF, p<0.001 for both). Conclusions Among discharge records for HF, CUD and OUD are increasing in prevalence, significantly affect underserved populations and are associated with higher costs of stay. Future research is essential to better delineate the cause of these increased costs and create interventions, particularly in underserved populations.
... Even more worrisome are the implications of long-term use, as NCs have only been in widespread use for less than 20 years. Some observed long-term implications include possible increased risk for developing psychotic disorders, depression, persistent anxiety, possible increased risk for cardiovascular disease, structural and functional CNS alterations, severe weight loss, and kidney diseases [46,47,48,49,50] . With constant modification of NCs and new compounds being developed every year, detection of compounds has also struggled to keep up with the stream. ...
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Cannabis has been cultivated and used for millennia by the human race. The original medicinal and industrial uses of cannabis were almost forgotten during the vilification during the early 20th century. However, with renewed focus, interest, and tolerance, this species has found itself in the limelight of its original purpose. Cannabinoids have become a staple in modern holistic medicine and have even found mainstream medicinal applications. Confusion has arisen over the classification of its primary compounds, cannabinoids, as well as to the presence of similar compounds in other plant species. Novel cannabinoids produced legitimately by researchers or illicitly by clandestine chemists have only added to this issue and furthered the need for unification not only in understanding, but also in terminology. This review seeks to define critical terms for cannabinoid chemistry as well provide an introduction to the variety of compounds.
... The consequences of alcohol misuse include physical health problems and poor academic performance [27,28]. For example, the health consequences of the abuse of alcohol, cannabis products and psychostimulants include alterations in the cardiocirculatory system [29][30][31], leading to tachycardia, whereby individuals with hypertension or heart failure may suffer worsening symptomatology. There are data indicating that there could be an increase in the incidence of anxiety crises, depression and psychosis due to chronic consumption of these substances among the many effects described on people's health [32,33]. ...
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Background and objectives: Drug abuse has become a major worldwide health concern among all age groups. The present study analyses substance misuse and its social and personal consequences using a population-based internet survey in Spain. Materials and Methods: Screening for drug abuse (of alcohol, marijuana/hashish and psychostimulants) and its related risks and problems was performed using the Car, Relax, Alone, Forget, Friends, Trouble (CRAFFT) score. Socio-demographic factors, depressive, anxiety and stress symptoms as well as health habits were also evaluated. We used Linear regression methods to compare each variable’s individual contribution so as to determine which one best explains the results. Results: In this population-based study, 1224 people completed and returned the online survey. Of all participants, 57% reported consuming at least one substance based on the CRAFFT scale. While increasing age reduces the probability of personal and social consequences of consumption, people who smoke receive up to three times more (OR = 3.370) recommendations from family and friends to reduce their consumption. As for the type of substance, the consumption of marijuana increases the risk of forgetting (OR = 2.33) and the consumption of other psychostimulant substances almost triples the risk of consuming alone (OR = 2.965). Combining substances can increase the rate of driving a vehicle after consumption by 3.4 times. Conclusions: Although age, smoking and the type of substances used increase the risk of suffering from social and personal consequences of the use or abuse of substances, future studies are needed to determine the influence of new variables as a potential tool for treating and minimizing the adverse consequences of drug abuse.
... These illicit products continue to have no oversight ensuring the accuracy or validity of their label claims and provide little or no guidance on proper storage, indications for use or dose titration, or information on commonly encountered adverse side effects. Thus, the effects that are produced in consumers can vary considerably, and can occasionally be debilitating and lethal, produce dependence and withdrawal, and range dramatically in intensity and duration depending upon dose and route of administration (for example, see [129][130][131][132][133]). Nevertheless, these products remain of considerable interest to individuals who pursue intoxication while enabling their chemical use to remain undetected and clear of legal regulations and criminal consequences (e.g., individuals subjected to periodic urinalysis for employment or military/civil service [134,135]). ...
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The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.
... Although the role of CB1 in atherosclerosis is less clear, evidence showed CB1 activation in primary human coronary artery endothelial cells induced ROS production and cell death [8]. Interestingly, the most vulnerable plaques were particularly rich in CB1 [67] probably due to the considerable number of accumulating activated immune cells within active plaques as they densely express CB1. ...
Article
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In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.
... Case reports and clinical studies have suggested an association between acute or chronic use of cannabis with serious adverse cardiovascular effects such as stroke, myocardial infarction, cardiomyopathy, and cardiac arrest. 133 Although there are some data on the arrhythmic effects of cannabis, there are not enough clinical studies and information available about the possible mechanisms of the arrhythmic effects of cannabis. It is suggested that cannabis affects the electrophysiologic system by decreasing mean sinoatrial conduction time, mean A-H interval (atrioventricular node conduction time) and mean atrioventricular nodal refractory period which may result in AF. 134 Recreational drug abuse should be carefully questioned by physicians and should always be kept in mind since younger patients with new-onset AF also have less known predisposing factors. ...
... Similarly, cannabis smoking has been suggested as a trigger for AMI in young individuals immediately after use Ravi et al., 2018 ). Furthermore, risks for adverse acute cardiovascular events appear to be dose-dependent, and higher in individuals with frequent use of high THC-potency cannabis ( Cohen et al., 2019 ;Pacher, Steffens, Hasko, Schindler, & Kunos, 2018 ;Yang et al., 2021 ) as well as in older PWUC and in individuals with pre-existing cardiovascular conditions Richards et al., 2020 ). ...
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Background Cannabis use is common, especially among young people, and is associated with risks for various health harms. Some jurisdictions have recently moved to legalization/regulation pursuing public health goals. Evidence-based ‘Lower Risk Cannabis Use Guidelines’ (LRCUG) and recommendations were previously developed to reduce modifiable risk factors of cannabis-related adverse health outcomes; related evidence has evolved substantially since. We aimed to review new scientific evidence and to develop comprehensively up-to-date LRCUG, including their recommendations, on this evidence basis. Methods Targeted searches for literature (since 2016) on main risk factors for cannabis-related adverse health outcomes modifiable by the user-individual were conducted. Topical areas were informed by previous LRCUG content and expanded upon current evidence. Searches preferentially focused on systematic reviews, supplemented by key individual studies. The review results were evidence-graded, topically organized and narratively summarized; recommendations were developed through an iterative scientific expert consensus development process. Results A substantial body of modifiable risk factors for cannabis use-related health harms were identified with varying evidence quality. Twelve substantive recommendation clusters and three precautionary statements were developed. In general, current evidence suggests that individuals can substantially reduce their risk for adverse health outcomes if they delay the onset of cannabis use until after adolescence, avoid the use of high-potency (THC) cannabis products and high-frequency/-intensity of use, and refrain from smoking-routes for administration. While young people are particularly vulnerable to cannabis-related harms, other sub-groups (e.g., pregnant women, drivers, older adults, those with co-morbidities) are advised to exercise particular caution with use-related risks. Legal/regulated cannabis products should be used where possible. Conclusions Cannabis use can result in adverse health outcomes, mostly among sub-groups with higher-risk use. Reducing the risk factors identified can help to reduce health harms from use. The LRCUG offer one targeted intervention component within a comprehensive public health approach for cannabis use. They require effective audience-tailoring and dissemination, regular updating as new evidence become available, and should be evaluated for their impact.
... This practice may be concerning, especially for patients with severe health conditions that could be detected during physical examination. 33,34 It is noteworthy that we conducted the survey during the Coronavirus Disease 2019 (COVID-19) pandemic when qualified physicians were allowed to use telemedicine for recertifications of already-existing patients. 35 However, as assessing the pandemic's impact was not in the survey's scope, we do not know how much of the physicians' responses can be attributed to the pandemic and its subsequent regulatory changes. ...
Article
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Background Little is known about the clinical training or practice experiences among physicians who certify patients for medical marijuana. The objective of this study was to determine information sources, factors influencing recommendations, clinical practices in patient assessment, communications, and recommendations, and priority areas for additional training among physicians who certify patients for medical marijuana. Methods A cross-sectional state-wide anonymous survey of registered medical marijuana physicians in Florida between June and October 2020 was administered. Numerical responses were quantified using counts and percentages. The frequencies for “often” and “always” responses were aggregated when appropriate. Results Among 116 respondents, the mean (standard deviation) age was 57 (12) years old, and 70% were male. The most frequently used information sources were research articles (n = 102, 95%), followed by online sources (n = 99, 93%), and discussions with other providers and dispensary staff (n = 84, 90%). Safety concerns were most influential in patient recommendations (n = 39, 39%), followed by specific conditions (n = 30, 30%) and patient preferences (n = 26, 30%). Ninety-three physicians (92%) reported they “often” or “always” perform a patient physical exam. Eighty-four (77%) physicians provided specific administration route recommendations. Half (n = 56) “often” or “always” provided specific recommendations for Δ-9-tetrahydrocannabinol: cannabidiol ratios, while 69 (62%) “often” or “always” provided specific dose recommendations. Online learning/training modules were the most preferred future training mode, with 88 (84%) physicians “likely” or “very likely” to participate. The top 3 desired topics for future training were marijuana-drug interactions (n = 84, 72%), management of specific medical conditions or symptoms (n = 83, 72%), and strategies to reduce opioids or other drugs use (n = 78, 67%). Conclusions This survey of over 100 medical marijuana physicians indicates that their clinical practices rely on a blend of research and anecdotal information sources. While physicians report clinical factors as influential during patient recommendation, patient assessment practices and treatment regimen recommendations vary substantially and rely on experimental approaches. More research is needed to inform evidence-based practice and training, especially considering details on drug interactions, risk-benefit of treatment for specific clinical conditions, and strategies to reduce opioid use.
... The endocannabinoid system is present in the cardiovascular system. It has been reported that cannabinoids (the effects mainly dependent on THC) induce changes such as tachycardia and acute coronary events in the cardiovascular system of marijuana smoking (Pacher et al. 2018). However, recently cannabinoids have been suggested to have therapeutic potential in the treatment of the cardiovascular diseases, which is connected with cardioprotective, vasodilatory, anti-inflammatory, and antioxidant properties of cannabinoids (Kicman and Toczek 2020). ...
Article
Mitochondria have the main roles in myocardial tissue homeostasis, through providing ATP for the vital enzymes in intermediate metabolism, contractile apparatus and maintaining ion homeostasis. Mitochondria-related cardiotoxicity results from the exposure with illicit drugs have previously reported. These illicit drugs interference with processes of normal mitochondrial homeostasis and lead to mitochondrial dysfunction and mitochondrial-related oxidative stress. Cannabis consumption has been shown to cause ventricular tachycardia, to increase the risk of myocardial infarction (MI) and potentially sudden death. Here, we investigated this hypothesis that delta-9-tetrahydrocannabinol (Delta-9-THC) as a main cannabinoid found in cannabis could directly cause mitochondrial dysfunction. Cardiac mitochondria were isolated with mechanical lysis and differential centrifugation form rat heart. The isolated cardiac mitochondria were treated with different concentrations of THC (1, 5, 10, 50, 100 and 500 µM) for 1 hour at 37 °C. Then succinate dehydrogenase (SDH) activity, mitochondrial swelling, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse and lipid peroxidation were measured in the treated and non-treated isolated cardiac mitochondria. Our observation showed that THC did not cause a deleterious alteration in mitochondrial functions, ROS production, MMP collapse, mitochondrial swelling, oxidative stress and lipid peroxidation in used concentrations (5-100 µM), even in several tests, toxicity showed a decreasing trend. Altogether, the results of the current study showed that THC is not directly toxic in isolated cardiac mitochondria, and even may be helpful in reducing mitochondrial toxicity.
... Marijuana can acutely increase the sympathetic activity and suppress the parasympathetic activity, leading to catecholamine's surge, tachycardia, vasodilation, increase in the cardiac output and the myocardium oxygen demand which can cause myocardial infarction [9] . Marijuana can also cause transient ischemic attacks and stroke via orthostatic hypotension, diminished circulatory response to exercise, cerebral vasoconstriction, intracranial stenosis, increased cerebrovascular resistance and reduced cerebrovascular perfusion [10] . ...
Article
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Ascending aortic is an uncommon site for arterial thrombosis and ascending aortic thrombosis is a very rare phenomenon with a high fatality rate. Marijuana is the most commonly used psychoactive drug in the United States and a few cases have been reported on the association of marijuana with vascular thromboembolism. However, the pathophysiology and exact mechanism are still not well studied. Herein, we present a case of a 44-year-old female with active marijuana use presented with ascending aortic thrombus associated with acute arterial occlusion of the right vertebral artery and bilateral renal artery. The unique part of this case is that the patient did not have the classical risk factors for vascular thromboembolic disease. The only risk factor was marijuana smoking. To our best knowledge, this is one of the unique cases of marijuana-associated with ascending aorta thrombosis.
... Clearly more studies related with the effects of use of synthetic cannabinoids "bonzai" on the CV system are needed. An in-depth review [34] has examined the CV effects of synthetic cannabinoids to conclude that further research is needed to document the regulatory measures that are needed to curb the spread of synthetic cannabinoids. It is essential to keep the risk/benefit ratio of the medicinal use of cannabis as low as possible. ...
Article
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Cannabis is currently the most consumed illicit substance in the world, and gradual legalization in the USA makes it important to understand the health consequences of the use of this substance. With growing body of evidence that some cannabis ingredients may be beneficial in various aspects of hemostasis, additional research is clearly needed in various clinical areas. In addition to understanding the efficacy, research efforts should also include studies that address any harmful effects of the compounds or administration methods that may result in adverse effects. This review is focused on the cardiometabolic effects of cannabis use. Cardiometabolic diseases are among the leading causes of death in the USA and around the world. The purpose of this review was to provide an overview of the known medicinal benefits of selected cannabis cannabinoids and the known side effects or contraindications. More importantly, we have proposed new questions and signposts in cannabis research to uncover additional medicinal benefits and identify the health hazards with focus on cardiovascular disease.
... Marijuana and the cannabinoid compound delta9-THC are associated with an elevation in heart rate and a minute increase in blood pressure during the supine position and, in rare cases, generate marked postural hypotension (Hiley and Ford, 2004;Pacher et al., 2018). It also contributes to redness in the eyes by causing swelling in the conjunctival vessels. ...
Article
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Cannabis sativa, widely known as ‘Marijuana’ poses a dilemma for being a blend of both good and bad medicinal effects. The historical use of Cannabis for both medicinal and recreational purposes suggests it to be a friendly plant. However, whether the misuse of Cannabis and the cannabinoids derived from it can hamper normal body physiology is a focus of ongoing research. On the one hand, there is enough evidence to suggest that misuse of marijuana can cause deleterious effects on various organs like the lungs, immune system, cardiovascular system, etc. and also influence fertility and cause teratogenic effects. However, on the other hand, marijuana has been found to offer a magical cure for anorexia, chronic pain, muscle spasticity, nausea, and disturbed sleep. Indeed, most recently, the United Nations has given its verdict in favour of Cannabis declaring it as a non-dangerous narcotic. This review provides insights into the various health effects of Cannabis and its specialized metabolites and indicates how wise steps can be taken to promote good use and prevent misuse of the metabolites derived from this plant.
... These clinical effects of potent cannabinoid receptor agonists used excessively may have serious consequences. The effects are mainly neurological, psychiatric, cardiovascular, cerebrovascular, and gastrointestinal, with different degrees of seriousness [32][33][34][35][36]. In this context, recognition of the signs and symptoms of patients with SCRA intoxication can help physicians to be more efficiency and prepared to diagnose and manage adolescents in case of intoxication. ...
Article
Background and aims MDMB-4en-PINACA is a synthetic cannabinoid receptor agonist (SCRA) that has recently emerged. Data regarding clinical presentations in the event of intoxication is scarce. This study presents MDMB-4en-PINACA identification in cannabis consumers with clinical and analytical descriptions. Methods Between November 2020 and March 2021, all patients with unexpected or unusually severe effects and Poisoning Severity Score (PSS) greater than or equal to 2 after cannabis consumption were included. Blood and/or urine samples were collected for toxicological analysis. When available, drug material samples were also collected for analysis. Results Between November 2020 and March 2021, 13 patients were included. All cases typically presented with altered mental status (n = 13), and nearly all had returned to a normal or quasi-normal state after around 11 h of observation. Neurological symptoms included headaches (n = 3), hallucinations (3), mydriasis (3), amnesia (2) and seizures (5). Psychiatric symptoms were paranoia (6) and anxiety (2). Digestive symptoms were nausea (2) and vomiting (6). No deaths were recorded. All patients were positive for the SCRA MDMB-4en-PINACA in urine, blood and/or drug material sample. Results from toxicology testing paired with case history showed the potential for MDMB-4en-PINACA to cause or contribute to different clinical disorders. Conclusions: This study highlights the risk of intoxication by SCRAs when taking low-THC cannabis products. Forensic scientists, public health and public safety officials, law enforcement personnel and clinicians should be aware of the impact that these emergent SCRAs may have in their work, especially MDMB-4en-PINACA.
... For example, cannabinoid receptor type 1 (CB1) activation by THC can initiate a wide array of events that may negatively impact the cardiovascular system, such as arrythmias, cardiomyopathy, and myocardial infarction due to inhibition of the parasympathetic nervous system, activation of the sympathetic nervous system, decreased myocyte contractility, activation of apoptotic pathways in myocytes and endothelium, increases in profibrotic effects and oxidative stress, etc. [36]. CBD, on the other hand, has been shown to decrease blood pressure and heart rate, and increase vasodilation in endothelial dysfunction models [37][38][39]. Therefore, while a Phase 1 DDI study generally enrolls 'healthy' cannabis users, the potential exists for cardiovascular safety events. ...
Article
Cannabis has become legal in much of the United States similarly to many other countries, for either recreational or medical use. The use of cannabis products is rapidly increasing while the body of knowledge of its myriad of effects still lags. In vitro and clinical data show that cannabis’ main constituents, delta-9-tetrahydrocannabinol and cannabidiol, can affect the pharmacokinetics (PK), safety and pharmacodynamics (PD) of other drugs. Within the context of clinical drug development, the widespread and frequent use of cannabis products has essentially created another special population; that is, the cannabis user. We propose that all clinical drug development programs include a Phase 1 study to assess the drug-drug interaction potential of cannabis as a precipitant on the PK, safety and if applicable, the PD of all new molecular entities (NMEs) in a combination of healthy adult subjects as well as frequent and infrequent cannabis users. This data should be required to inform drug labeling and aid health care providers in treating any patient, as cannabis has quickly become another common concomitant medication and cannabis users, a new special population.
... For many centuries Cannabis sp. has been used for medicinal purposes and, more recently, it has been investigated as a therapeutic agent for cardiovascular diseases (Mendizábal & Adler-Graschinsky, 2007;Pacher et al., 2018). Cannabis has several known compounds, named phytocannabinoids, including delta-9-tetrahydrocannabinol (THC), which is the most abundant and the main psychoactive ingredient, followed in amount by cannabidiol (CBD). ...
Article
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Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect several organs, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 is myocardial injury, which is associated with a high risk of mortality. Myocardial injury, caused directly or indirectly by SARS-CoV-2 infection, can be triggered by inflammatory processes that lead to damage to the heart tissue. Since one of the hallmarks of severe COVID-19 is the “cytokine storm”, strategies to control inflammation caused by SARS-CoV-2 infection have been considered. Cannabinoids are known to have anti-inflammatory properties by negatively modulating the release of pro-inflammatory cytokines. Herein, we investigated the effects of the cannabinoid agonist WIN 55,212-2 (WIN) in human iPSC-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. WIN did not modify angiotensin-converting enzyme II protein levels, nor reduced viral infection and replication in hiPSC-CMs. On the other hand, WIN reduced the levels of interleukins six, eight, 18 and tumor necrosis factor-alpha (TNF-α) released by infected cells, and attenuated cytotoxic damage measured by the release of lactate dehydrogenase (LDH). Our findings suggest that cannabinoids should be further explored as a complementary therapeutic tool for reducing inflammation in COVID-19 patients.
... This is in accordance with existing literature on SCs as, ever since their emergence on the drug market, many SCs have been widely associated with cardiovascular adverse effects, including severe outcomes. 5,29,63,[65][66][67][68] The mechanisms behind the cardiac effects of SCs are still not completely understood. 63 The often-observed higher activities of many SCs at CB1, when compared with THC, have been described as a contributing factor. ...
Article
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Since late 2019, low-THC preparations adulterated with synthetic cannabinoids (SCs) have been frequently observed in Switzerland. The unawareness of users concerning the presence of SCs and the typically higher potency and toxicity of SCs, when compared to delta-9-tetrahydrocannabinol (THC), can result in increased health risks. In Switzerland, low-THC (<1%) cannabis products, except hashish, are legal. These products can act as carrier materials for SCs. In this study, cannabis samples and user self-reports received through three drug checking services were collected and analysed, to gain deeper insight into this new phenomenon. Samples were collected from January 2020 to July 2021. Liquid chromatography coupled with high-resolution mass spectrometry was used for the qualitative screening and semi-quantification of SCs, while gas chromatography with flame ionization detector was applied for the quantification of THC and cannabidiol levels. Reported adverse effects were compared between users who consumed adulterated (SC-group) and non-adulterated (THC-group) products. Of a total 94 samples, 50% contained up to three different SCs. MDMB-4en-PINACA was most often detected. All adulterated cannabis flowers contained ≤1% THC. Adulterated hashish also typically presented low THC-levels (median: 0.8%). The SC-group was associated with higher numbers of adverse events (p = 0.041). Furthermore, psychologic (p = 0.0007) and cardiologic (p = 0.020) adverse effects were more profound in the SC-group than in the THC-group. Drug checking services enabled the timely detection and monitoring of new and potentially dangerous trends. Furthermore, due to user-reports, additional valuable information was gained on adverse events associated with the consumption of novel SCs.
... In general, antagonists of CB1R have conferred promising clinical prospects, particularly in cardiovascular protection, 37,38 whereas agonists of CB1R (e.g., marijuana and synthetic cannabinoids) have been shown to cause serious adverse cardiovascular events. 39 In this study, we found that selective CB1R antagonists AM 251 and AM 281 were protective against AP drug cardiotoxicity without causing additional toxicity to metabolic or solid organs. However, the CB1R antagonist Rimonabant was an exception that caused additional arrhythmia in mice. ...
Article
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Long-term use of antipsychotics is a common cause of myocardial injury and even sudden cardiac deaths that often lead to drug withdrawn or discontinuation. Mechanisms underlying antipsychotics cardiotoxicity remain largely unknown. Herein we performed RNA sequencing and found that NLRP3 inflammasome-mediated pyroptosis contributed predominantly to multiple antipsychotics cardiotoxicity. Pyroptosis-based small-molecule compound screen identified cannabinoid receptor 1 (CB1R) as an upstream regulator of the NLRP3 inflammasome. Mechanistically, antipsychotics competitively bond to the CB1R and led to CB1R translocation to the cytoplasm, where CB1R directly interacted with NLRP3 inflammasome via amino acid residues 177–209, rendering stabilization of the inflammasome. Knockout of Cb1r significantly alleviated antipsychotic-induced cardiomyocyte pyroptosis and cardiotoxicity. Multi-organ-based investigation revealed no additional toxicity of newer CB1R antagonists. In authentic human cases, the expression of CB1R and NLRP3 inflammasome positively correlated with antipsychotics-induced cardiotoxicity. These results suggest that CB1R is a potent regulator of the NLRP3 inflammsome-mediated pyroptosis and small-molecule inhibitors targeting the CB1R/NLRP3 signaling represent attractive approaches to rescue cardiac side effects of antipsychotics.
... Although SCs arrhythmogenic effects emerge with the sympathetic activation, they could activate parasympathetic nervous system through high quantities of consumption, which may cause bradycardia and hypotension. 8,27 It is possible to suggest that SCs may cause a disrupted conduction system of the heart through their impact on autonomic nervous system and resulting in arrhythmia, which may derive from both supraventricular and ventricular level. In addition, SCs inhibit the conductance of cardiac ions, including sodium, potassium, and calcium, and this may lead to an altered cardiac contractility, repolarization abnormalities, and finally ventricular tachyarrhythmia. ...
Article
Background: Synthetic cannabinoids (SCs) users appeared to have heightened risk for cardiac arrhythmias, however, current line of research is insufficient in terms of demonstrating both conventional and novel electrocardiographic arrhythmia risk indicators in this population. Objective(s): We aimed to investigate P-wave dispersion (Pwd), corrected QT interval (QTc), QTc dispersion (QTcd), Tpeak-Tend (Tp-e), Tp-e/QT ratio, corrected JT interval (JTc) and JTc dispersion (JTcd), which are shown among the risk factors for emergence of an arrhythmia, among SCs users, suggestive of possible adverse effects of SCs on the cardiac rhyhtm. Methods: Forty-one male SCs user patients who met DSM-5 substance use disorder criteria and 41 healthy male controls included in the study. Substance-related characteristics were recorded. Electrocardiography recordings under standardized procedure of all participants were performed and arrhythmia risk markers were calculated from electrocardiograms. Results: Age and heart rate per minute did not significantly differ between the groups. SCs user group had significantly higher Pwd, QTc, QTcd, Tp-e, Tp-e/QTc ratio, JTc and JTc dispersion values compared to controls. Among risk markers, only Pwd was significantly correlated with duration of SCs use. Conclusions: Alterations in electrocardiogram-derived markers of arrhythmia, which are acquired through an easy and cheap method, should be evaluated for the prediction and prevention of severe cardiac conditions in patients with SCs use.
... These smoking mixtures became popular rapidly, especially in countries where recreational use of cannabis was illegal or in situations where users wanted to avoid detection in routine drug screening (6). However, it also became clear from anecdotal reports that these SCs come with serious side effects, such as agitation, psychotomimetic effects, and cardiac events (7)(8)(9)(10), as well as fatalities (11,12). As a result, more and more of these SCs were added to the list of controlled substances in progressively more countries. ...
Article
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Due to differences in potency, efficacy, and affinity for CB1 receptors, similarities and differences in psychoactive effect profiles of natural cannabis and synthetic cannabinoids (SCs) cannot reliably be derived from equipotent dose comparisons. Instead, the current study proposes to compare the intrinsic psychoactive effects of natural cannabis (THC) and an SC, JWH-018, at psychotropic dose equivalence. Participants from two placebo-controlled studies were matched for their levels of subjective high to compare neurocognitive and psychotomimetic effects of THC and JWH-018. At equal subjective intoxication levels, both drugs impaired psychomotor, divided attention, and impulse control, with no significant difference between the two drugs. Both drugs also caused significant psychotomimetic effects, but dissociative effects were considerably more pronounced for JWH-018 than THC. We conclude that psychotropic dose equivalence provides a uniform approach for comparing the neurocognitive and psychotomimetic profiles of CB1 agonists, which can also be applied to other drug classes.
... Curcumin treatment effectively managed the ECG waveform and ST height elevation in diseased mice via CB2R activation in heart tissue. It is worth noting that the CB2R agonist effectively manages the acute inflammatory tissue injury related to MI [30]. The cardiac membrane is prone to insult the creatine kinase and dehydrogenase from the tissue as a cardiac injury marker into the bloodstream. ...
Article
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Molecular docking revealed curcumin as a potent CB2 cannabinoid receptor (CB2R) agonist. Since CB2R is involved in cardioprotective functions, we explored its role in ameliorative actions of curcumin against myocardial damage triggered by isoproterenol in diabetic animals. Mice were kept on a high-fat diet (HFD) throughout the experiment (30 days). Following 7 days of HFD feeding, streptozotocin was administered (150 mg/kg, intraperitoneal) to induce diabetes. From day 11 to 30, diabetic mice received either curcumin (100 or 200 mg/kg/day, oral), CB2R antagonist AM630 (1 mg/kg/day, intraperitoneal) or both, with concurrent isoproterenol (150 mg/kg, subcutaneous) administration on day 28 and 29. Diabetic mice with myocardial infarction showed an altered hemodynamic pattern and lipid profile, reduced injury markers, antioxidants with increased lipid peroxidation in the myocardium, and elevated glucose and liver enzymes in the blood. Moreover, an increased pro-inflammatory markers, histological severity, myonecrosis, and edema were observed. Curcumin compensated for hemodynamic fluctuations, restored biochemical markers, preserved antioxidant capacity, decreased cytokines levels, and restored cardiac functionality. However, the AM630 pre-treatment attenuated the effects of curcumin. The data suggest the involvement of CB2R in the actions of curcumin such as in the prevention of myocardial stress and in the improvement of the normal status of the myocardial membrane associated with diabetes.
... CB2 receptors in contrast play an important role in controlling tissue inflammation, inhibiting ROS, alleviating heart injury and overall exerts a beneficial effect on cardiomyocytes. (Moris et al., 2015;Pacher et al., 2018). ...
Article
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Cardiac dysfunction associated with cirrhosis in the absence of preexisting heart disease is a condition known as cirrhotic cardiomyopathy (CCM). Cardiac abnormalities consist of enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM may contribute to cardiovascular morbidity and mortality after liver transplantation and other major surgeries, and also to the pathogenesis of hepatorenal syndrome. The underlying mechanisms of CCM are poorly understood and as such medical therapy is an area of unmet medical need. The present review focuses on the pathogenic mechanisms responsible for development of CCM. The two major concurrent mechanistic pathways are the inflammatory phenotype due to portal hypertension, and protein/lipid synthetic/metabolic defects due to cirrhosis and liver insufficiency. The inflammatory phenotype arises from intestinal congestion due to portal hypertension, resulting in bacteria/endotoxin translocation into the systemic circulation. The cytokine storm associated with inflammation, particularly TNFα acting via NFκB depresses cardiac function. They also stimulate two evanescent gases, nitric oxide and carbon monoxide which produce cardiodepression by cGMP. Inflammation also stimulates the endocannabinoid CB-1 pathway. These systems inhibit the stimulatory beta-adrenergic contractile pathway. The liver insufficiency of cirrhosis is associated with defective synthesis or metabolism of several substances including proteins and lipids/lipoproteins. The protein defects including titin and collagen contribute to diastolic dysfunction. Other protein abnormalities such as a switch of myosin heavy chain isoforms result in systolic dysfunction. Lipid biochemical changes at the cardiac sarcolemmal plasma membrane result in increased cholesterol:phospholipid ratio and decreased membrane fluidity. Final common pathway changes involve abnormal cardiomyocyte intracellular ion kinetics, particularly calcium. In conclusion, cirrhotic cardiomyopathy is caused by two pathways of cellular and molecular dysfunction/damage due to hepatic insufficiency and portal hypertension.
... Cannabis use is associated with tachycardia, 5 increased myocardial oxygen demand and platelet activation, as well as endothelial dysfunction and oxidative stress. [6][7][8][9] Moreover, smoking cannabis (the predominant method of consumption) 10 increases blood carboxyhemoglobin concentrations, and does so at a fivefold higher level than tobacco smoke. 11,12 In studies that have compared tobacco smoke to cannabis smoke, cannabis appears to be more toxic than tobacco smoke in terms of particulate matter, toxins, and tar levels. ...
Article
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Background Evidence on the cardiovascular health effects of cannabis use is limited. We designed a prospective cohort study of older Veterans (66 to 68 years) with coronary artery disease (CAD) to understand the cardiovascular consequences of cannabis use. We describe the cohort construction, baseline characteristics, and health behaviors that were associated with smoking cannabis. Objective To understand the cardiovascular consequences of cannabis use. Design We designed a prospective cohort study of older Veterans (66 to 68 years) with CAD. Participants A total of 1,015 current cannabis smokers and 3,270 non-cannabis smokers with CAD. Main Measures Using logistic regression, we examined the association of baseline variables with smoking cannabis in the past 30 days. Results The current cannabis smokers and non-current smokers were predominantly male (97.2% vs 97.1%, p =0.96). Characteristics associated with recent cannabis use in multivariable analyses included lack of a high school education (odds ratio [OR] 2.15, 95% confidence interval [CI]: 1.10 to 4.19), financial difficulty (OR 1.47, 95% CI: 1.02 to 2.11), tobacco use (OR 3.02, 95% CI: 1.66 to 5.48), current drug use (OR 2.82, 95% CI: 1.06 to 7.46), and prior drug use (OR 2.84, 95% CI: 2.11 to 3.82). In contrast, compared to individuals with 0 to 1 comorbid conditions, those with 5 chronic conditions or more (OR 0.43, 95% CI: 0.27 to 0.70) were less likely to smoke cannabis. Conclusions In this older high-risk cohort, smoking cannabis was associated with higher social and behavioral risk, but with fewer chronic health conditions.
... Headaches, slowed speech, sweating, aggressiveness, lethargy and slowed speech have also been reported for other SCRA [220]. Cardiovascular effects as arrhythmias, cardiac arrest, cardiomyopathy, coronary thrombosis, acute myocardial infarction, and vasculitis have been reported [221][222][223][224]. A 34-year-old male died after consuming 5-Fluoro-ADB and was submitted to autopsy [225]. ...
Article
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The emergence of new psychoactive substances has earned a great deal of attention, and several reports of acute poisoning and deaths have been issued involving, for instance, synthetic opiates. In recent years, there have been profound alterations in the legislation concerning consumption, marketing, and synthesis of these compounds; rapid alert systems have also been subject to changes, and new substances and new markets, mainly through the internet, have appeared. Their effects and how they originate in consumers are still mostly unknown, primarily in what concerns chronic toxicity. This review intends to provide a detailed description of these substances from the point of view of consumption, toxicokinetics, and health consequences, including case reports on intoxications in order to help researchers and public health agents working daily in this area.
... (THC) and cannabidiol are the two major active components (and best studied cannabinoids) of cannabis [36]. The cardiovascular effects of cannabis are dependent on several factors, including the THC content and the route of administration. ...
Article
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Heart failure continues to account for millions of cases and deaths worldwide. Heart transplant is the gold standard for treatment of advanced heart failure. Unfortunately, the supply of donor hearts continues to be limited with the increase in demand for heart transplantation. In this review, we aim to explore the safety and efficacy of using hearts from donors with history of substance use. Despite the theoretical effect of cocaine and alcohol on the cardiovascular system, several studies demonstrate no difference in outcomes (overall survival, graft rejection, graft vasculopathy) when using hearts from patients with history of cocaine and alcohol use. The opioid epidemic has expanded the potential donor pool where the current studies have not shown any adverse outcomes when considering donors with history of opioid use. The currently available evidence would support the use of donor hearts from patients with history of alcohol, cocaine, opioids, and marijuana use. Further studies are needed to evaluate the safety of using donor hearts from patients with history of nicotine use.
... The underlying reasons of this effect are growing legalization (e.g., in U.S. the number of states legalizing marijuana for recreational purposes is still rising [42]); the impact of mass culture with the common occurrence of marijuana and its symbols in everyday products; and recently, the overall increase in the use of psychoactive substances during the lockdown of the COVID-19 pandemic [43][44][45]. Moreover, in 2016 the WHO reported a dramatic (about tenfold) increase in the THC content of marijuana [11]. ...
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The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.
... Tachycardia and hypertension are the most commonly reported symptoms from SC's intoxication. Repeated use of synthetic cannabinoids has been associated with adverse cardiovascular effects including arrhythmias, cardiomyopathy, stroke, myocardial infarction and heart failure [48] . ...
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Cannabis has been the most commonly used drug throughout the world for centuries. The psychoactive properties of cannabis are largely attributed to Δ9-tetrahydrocannabinol or THC, the active psychoactive ingredient in the cannabis plant. Lately, new psychoactive substances (NPS) have appeared that are mostly ruled by cathinone's and synthetic cannabinoids (SCs). SC's have emerged as drugs of abuse because of their ability to mimic the euphoric effects of THC. Sprayed on natural herb mixtures, they were initially sold as 'herbal incense' or 'herbal smoking blends' as substitutes for cannabis. These synthetic drugs became popular as 'legal highs' under brand names such as Spice, K2, Mojo and many others in the early 2000's. SC's stimulate the same CB1 and CB2 receptors as THC but they are linked to higher toxicity in terms of duration and severity than cannabis. This is because SC's act as direct agonist of cannabinoid receptors, whereas THC being a partial agonist. Reports suggest that SC's are associated with a range of undesired pulmonary, cardiovascular, gastrointestinal effects. Long term SC use is also linked to severe cognitive deficits. With the global rise in use of SC products, it is important to develop and validate the screening procedures and investigate the toxicological and pharmacological aspects and risk factors associated with its use and abuse.
... 39 Extracts of the leaves, stem, and roots of The more the decolourization of DPPH, the more the reducing ability of the extracts. 40 Figure 3 shows the DPPH radical scavenging properties of crude aqueous and methanolic extracts of leaves, stem and roots of D. arborescens and ascorbic acid (AA) standard within the tested concentrations 0.5 mg/mL-2.5 mg/mL. Activities were dosedependent as an increase in the concentration of extracts increased DPPH scavenging activities. ...
Chapter
A drug-drug interaction is a phenomenon in which the effects of a drug are altered by the presence of another drug or drugs. Drug-drug interactions can result in a change in the pharmacokinetic and/or pharmacodynamic profile of a drug and may increase or decrease the effect of a drug or result in the emergence of entirely new effects. Pharmacokinetic drug interactions are interactions that alter the absorption, distribution, metabolism and/or excretion of a drug. Pharmacodynamic interactions are characterized as interactions in which the pharmacological effect of a drug is altered when used in combination with another drug. Drug-drug interactions associated with drugs of abuse are of particular importance to forensic toxicologists as it is not uncommon for individuals who abuse drugs to use multiple drugs simultaneously. In this chapter, drug-drug interactions involving several drugs of abuse of significance to forensic toxicologists are described.
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Background : Reports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. Methods : Congenital anomaly data was from the National Birth Defects Prevention Network, drug use data was taken from the National Survey of Drug Use and Health (NSDUH), cannabinoid concentration was estimated from Federal seizure data and ethnicity and income data were from the US Census bureau. Geotemporospatial analysis was conducted in R. Results : 436 LRR datapoints were obtained. LRR was significantly associated with cannabis use and tetrahydrocannabinol (THC) exposure and demonstrated prominent cannabis-use quintile effects. A sharp increase in LRR occurred from the fourth to fifth quintiles of cannabis exposure (mean±S.E.M 3.78±0.38 to 6.66±0.56 / 10,000 live births, P=5.22 × 10⁻⁹). In final lagged geospatial models adjusted for ethnicity and income interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01 /10,000 live births, relative risk reduction = -0.15, (95%C.I. -0.25, -0.02), P=0.021). Internationally 37-63% of cases are estimated to not be born alive. Their inclusion in these analyses uniformly intensified the identified effects and the significance of the effect of the cannabis legalization paradigm rose from P=0.0256 to P=0.0146 to P=0.0048 with silent factors of 0%, 36% and 63% respectively. Conclusion : Therefore a spatiotemporal and dose-dependent association between several cannabinoids including THC and cannabigerol and LRR is reported, is robust to adjustment, is consistent with pathophysiological and preclinical studies, accords with findings elsewhere, is markedly exacerbated in higher exposure quintiles, is exacerbated by cannabis legalization and evidences dose-related intergenerational sequaelae.
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Common drugs of misuse, including cannabis, opioids, stimulants, alcohol, and anabolic steroids, have strikingly disparate acute and chronic vascular effects, leading to a wide range of clinical cardiovascular presentations. Acute cannabis smoking has been associated with increased risk for myocardial infarction and ischemic stroke in otherwise healthy young people. However, it remains uncertain if people who exclusively smoke cannabis have increased risk for accelerated atherosclerosis similar to that found in people who exclusively smoke tobacco cigarettes. Cocaine and methamphetamines, both stimulants, increase risk for stroke, myocardial infarction, aortic dissection, and accelerated atherosclerosis, but only methamphetamine use is strongly linked to pulmonary hypertension. Chronic alcohol use is strongly associated with chronic hypertension and hemorrhagic stroke, but perhaps confers a lower risk for myocardial infarction. Finally, anabolic steroid use, presumably through adverse effects on circulating lipids and the hematopoietic system, is associated with increased risk for accelerated atherosclerosis and myocardial infarction. Physicians, especially cardiologists, emergency medicine and internal medicine physicians, should be familiar with the short- and long-term vascular consequences of use of these substances, thereby ensuring appropriate, specific, and informed counseling and treatment.
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Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced oxidative/nitrative stress, activation of various pro-inflammatory, and cell death pathways are critical in the initiation and progression of the changes culminating in diabetic cardiomyopathy. Cannabinoid 2 receptor (CB2R) activation in inflammatory cells and activated endothelium attenuates the pathological changes associated with atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy. In this study, we explored the role of CB2R signaling in myocardial dysfunction, oxidative/nitrative stress, inflammation, cell death, remodeling, and fibrosis associated with diabetic cardiomyopathy in type 1 diabetic mice. Control human heart left ventricles and atrial appendages, similarly to mouse hearts, had negligible CB2R expression determine by RNA sequencing or real-time RT-PCR. Diabetic cardiomyopathy was characterized by impaired diastolic and systolic cardiac function, enhanced myocardial CB2R expression, oxidative/nitrative stress, and pro-inflammatory response (tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule 1, macrophage inflammatory protein-1, monocyte chemoattractant protein-1), macrophage infiltration, fibrosis, and cell death. Pharmacological activation of CB2R with a selective agonist attenuated diabetes-induced inflammation, oxidative/nitrative stress, fibrosis and cell demise, and consequent cardiac dysfunction without affecting hyperglycemia. In contrast, genetic deletion of CB2R aggravated myocardial pathology. Thus, selective activation of CB2R ameliorates diabetes-induced myocardial tissue injury and preserves the functional contractile capacity of the myocardium in the diabetic milieu. This is particularly encouraging, since unlike CB1R agonists, CB2R agonists do not elicit psychoactive activity and cardiovascular side effects and are potential clinical candidates in the treatment of diabetic cardiovascular and other complications.
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Cannabis is the most frequently used illegal psychoactive substance by older adults. With population aging, legalization and medicalization of cannabis, and changes in perceptions of older adults toward its use, recreational and medical cannabis use/misuse is on the rise in seniors. Although there are solid data related to the adverse events of cannabis in older adults, efficacy data are lacking. Older adults are at increased risk of developing cannabis use disorder alongside other medical and psychiatric comorbidities. We review the benefits and risks associated with cannabis use, and screening and management strategies for cannabis use disorder in older adults.
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Synthetic cannabinoids cannot be detected on a standard urine drug screen (UDS), making them a convenient drug of abuse. We report the first case of ST elevation myocardial infarction (STEMI) in a young patient due to coronary artery thrombosis secondary to synthetic cannabinoid use and concurrent COVID-19 infection. A 38-year-old previously healthy male developed severe chest pain and was found to have anterior STEMI and COVID-19 infection. Coronary angiography showed acute thrombotic occlusion of the mid-left anterior descending artery that was managed with thrombectomy and stent placement. He only required supportive care for COVID-19. A comprehensive literature search revealed 34 additional cases of STEMI with synthetic cannabinoid use; majority were males (97%) with mean age of 29 years. 29 patients (85.3%) underwent coronary angiography and majority had left anterior descending artery (LAD) involvement (55%), with 13 (44.8%) undergoing stent placement. We highlight STEMI as a potentially lethal complication of synthetic cannabinoids; prompt angiography may be lifesaving.
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Background: Quantitative (e.g. increasing recreational cannabinoid use) and qualitative (e.g. increasing availability and use of synthetic cannabinoids and cannabis preparations with increased tetrahydrocannabinol content) changes in cannabinoid use may be associated with changes in the prevalence of cannabinoid-related mental and behavioural disorders and, accordingly, changes in the need for medical care. We aimed to investigate if there are changes in the number of inpatient cases (ICs) due to cannabinoid-related disorders in Germany. Methods: Data were obtained from the Federal Statistical Office of Germany (Destatis) and comprised type and number of hospital main diagnoses (according to ICD-10) of all ICs in Germany in the period 2000-18. Linear trend analysis of absolute and relative annual frequencies (AFs) of ICs with diagnoses related to the use of cannabinoids (DRUCs), and, as controls, alcohol-related psychiatric disorders and schizophrenia-spectrum disorders was performed. Results: Absolute AFs of ICs with DRUCs increased statistically significantly (P<0.0001, trend analysis) in Germany between 2000 and 2018 and corresponding relative AFs increased considerably (4.8-fold increase when comparing 2000 and 2018). Specifically, absolute AFs of ICs with cannabinoid intoxications (P<0.0001), harmful use (P=0.0005), dependence syndrome (P< 0.0001), withdrawal state (P<0.0001), psychotic disorders (P< 0.0001) and residual and late-onset psychotic disorder (P<0.0001) statistically significantly increased. Absolute AFs of schizophrenia-spectrum disorders slightly, but statistically significantly decreased (P=0.008), and alcohol dependence did not statistically significantly change (P=0.844). Conclusions: Our evaluation demonstrates increasing numbers of ICs with mental and behavioural disorders due to use of cannabinoids in Germany and emphasizes the need for adequate prevention of such disorders.
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This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.
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In the recent decade, numerous new psychoactive substances (NPSs) have been added to the illicit drug market. These are synthetized to mimic the effects of classic drugs of abuse (i.e., cannabis, cocaine, etc.), with the purpose of bypassing substance legislations and increasing the pharmacotoxicological effects. To date, research into the acute pharmacological effects of new NPSs is ongoing and necessary in order to provide an appropriate contribution to public health. In fact, multiple examples of NPS-related acute intoxication and mortality have been recorded in the literature. Accordingly, several in vitro and in vivo studies have investigated the pharmacotoxicological profiles of these compounds, revealing that they can cause adverse effects involving various organ systems (i.e., cardiovascular, respiratory effects) and highlighting their potential increased consumption risks. In this sense, NPSs should be regarded as a complex issue that requires continuous monitoring. Moreover, knowledge of long-term NPS effects is lacking. Because genetic and environmental variables may impact NPS responses, epigenetics may aid in understanding the processes behind the harmful events induced by long-term NPS usage. Taken together, “pharmacoepigenomics” may provide a new field of combined study on genetic differences and epigenetic changes in drug reactions that might be predictive in forensic implications.
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Cannabis is widely used in the U.S. and internationally despite its illicit status, but that illicit status is changing. In the U.S., 33 states and the District of Columbia have legalized medical cannabis, and 11 states and D.C. have legalized adult use cannabis. A majority of state medical cannabis laws and all but two state adult use laws are the result of citizen ballot initiatives, but state legislatures are beginning to seriously consider adult use legislation. From a public health perspective, cannabis legalization presents a mix of potential risks and benefits, but a legislative approach offers an opportunity to improve on existing legalization models passed using the initiative process that strongly favor business interests over public health. To assess whether state legislatures are acting on this opportunity, this article examines provisions of proposed adult use cannabis legalization bills active in state legislatures as of February 2019 to evaluate the inclusion of key public health best practices based on successful tobacco and alcohol control public health policy frameworks. Given public support for legalization, further adoption of state adult use cannabis laws is likely, but legalization should not be viewed as a binary choice between total prohibition and laissez faire commercialization. The extent to which adult use cannabis laws incorporate or reject public health best practices will strongly affect their impact, and health advocates should work to influence the construction of such laws to prioritize public health and learn from past successes and failures in regulating other substances.
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We have previously shown that cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, modulate cardiostimulatory effects of isoprenaline in atria of Wistar rats. The aim of the present study was to examine whether such modulatory effects can also be observed (1) in the human atrium and (2) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Inotropic effects of isoprenaline and/or CGP12177 (that activate the high- and low-affinity site of β1-adrenoceptors, respectively) were examined in paced human atrial trabeculae and rat left atria; chronotropic effects were studied in spontaneously beating right rat atria. AM251 modified cardiostimulatory effects more strongly than AM630. Thus, AM251 (1 μM) enhanced the chronotropic effect of isoprenaline in WKY and SHR as well as inotropic action of isoprenaline in WKY and in human atria. It also increased the inotropic influence of CGP12177 in SHR. AM630 (1 μM) decreased the inotropic effect of isoprenaline and CGP12177 in WKY but enhanced the isoprenaline-induced inotropic effect in SHR and human atria. Furthermore, AM251 (0.1 and 3 μM) and AM630 (0.1 μM) reduced the inotropic action of isoprenaline in human atria. In conclusion, cannabinoid receptor antagonists have potentially harmful and beneficial effects through their amplificatory effects on β-adrenoceptor-mediated positive chronotropic and inotropic actions, respectively.
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Purpose of review: The purpose of the study was to examine the published evidence on the cardiovascular risk related to the use of cannabis-based products by performing a systematic review of recent literature. Recent findings: The World Health Organization (WHO) emphasizes that cannabis use represents a risky behavior as it may lead to many adverse effects, and in particular, cardiovascular effects. A systematic review of articles published between January 1, 2011 and May 31, 2016 was performed in agreement with the PRISMA statement. Articles presenting data on humans exposed to cannabis-based products and suffering from any cardiovascular condition were eligible for inclusion. The inclusion process was based on a search algorithm and performed in a blinded standardized manner. Overall, 826 articles were found in the literature search, 115 of which remained after performing the inclusion procedure. These were 81 case reports, 29 observational studies, 3 clinical trials, and 2 experimental studies. A total of 116 individuals was the subject of case reports. The mean age was 31 years (95%CI = 29-34), and patients were more frequently men (81.9%) than women (18.1%). They mainly suffered from ischemic strokes or myocardial infarctions. Data provided by the 29 included observational studies evidenced an association between exposure to cannabis-based products and cardiovascular disease. Currently, this evidence is stronger for ischemic strokes than for any other cardiovascular diseases. While the data are limited, there is some suggestion that cannabis use may have negative cardiovascular consequences, particularly at large doses.
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Islet inflammation promotes β-cell loss and type-2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB1R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates. Adoptive transfer of CB1R(-/-) bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy. ZDF islets contain elevated levels of CB1R, IL-1β, TNF-α, the chemokine CCL2 and interferon regulatory factor-5 (IRF5), a marker of M1 inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα-dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target.
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Cannabis use among older Americans is increasing. Although much of this growth has been attributed to the entry of a more tolerant baby boom cohort into older age, recent evidence suggests the pathways to cannabis are more complex. Some older persons have responded to changing social and legal environments and are increasingly likely to take cannabis recreationally. Other older persons are experiencing age-related health care needs, and some take cannabis for symptom management, as recommended by a medical doctor. Whether these pathways to recreational and medical cannabis are separate or somewhat tangled remains largely unknown. There have been few studies examining cannabis use among the growing population of Americans aged 65 and older. In this essay, we illuminate what is known about the intersection between cannabis and the aging American population. We review trends concerning cannabis use and apply the age-period-cohort paradigm to explicate varied pathways and outcomes. Then, after considering the public health problems posed by those who misuse or abuse cannabis, we turn our attention to how cannabis may be a viable policy alternative in terms of supporting the health and well-being of a substantial number of aging Americans. On the one hand, cannabis may be an effective substitute for prescription opioids and other misused medications; on the other hand, cannabis has emerged as an alternative for the undertreatment of pain at the end of life. As intriguing as these alternatives may be, policy makers must first address the need for empirically driven, representative research to advance the discourse.
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Background and Purpose—Current knowledge on cannabis use in relation to stroke is based almost exclusively on Clinical reports. By using a population-based cohort, we aimed to find out whether there was an association between cannabis use and early-onset stroke, when accounting for the use of tobacco and alcohol. Methods—The cohort comprises 49 321 Swedish men, born between 1949 and 1951, who were conscripted into compulsory military service between the ages of 18 and 20. All men answered 2 detailed questionnaires at conscription and were subject to examinations of physical aptitude, psychological functioning, and medical status. Information on stroke events up to ≈60 years of age was obtained from national databases; this includes strokes experienced before 45 years of age. Results—No associations between cannabis use in young adulthood and strokes experienced ≤45 years of age or beyond were found in multivariable models: cannabis use >50 times, hazard ratios=0.93 (95% confidence interval [CI], 0.34–2.57) and 0.95 (95% CI, 0.59–1.53). Although an almost doubled risk of ischemic stroke was observed in those with cannabis use >50 times, this risk was attenuated when adjusted for tobacco usage: hazards ratio=1.47 (95% CI, 0.83–2.56). Smoking ≥20 cigarettes per day was clearly associated both with strokes before 45 years of age, hazards ratio=5.04 (95% CI, 2.80–9.06), and with strokes throughout the follow-up, hazards ratio=2.15 (95% CI, 1.61–2.88). Conclusions—We found no evident association between cannabis use in young adulthood and stroke, including strokes before 45 years of age. Tobacco smoking, however, showed a clear, dose–response shaped association with stroke.
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BACKGROUND New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a “zombie” outbreak because of the appearance of the intoxicated persons. METHODS We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal “incense” product “AK-47 24 Karat Gold,” which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography–quadrupole time-of-flight mass spectrometry. RESULTS The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (±SD) concentration of 16.0±3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter. CONCLUSIONS The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the “zombielike” behavior reported in this mass intoxication. AMB-FUBINACA is an example of the emerging class of “ultrapotent” synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.
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Objective: Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. Research design and methods: In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated. Results: Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = -1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function [ETD = -44.51 points; P < 0.01]), adiponectin (ETD = -5.9 × 10(6) pg/mL; P < 0.01), and apolipoprotein A (ETD = -6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (-898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated. Conclusions: THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.
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Background Despite public awareness that tobacco secondhand smoke (SHS) is harmful, many people still assume that marijuana SHS is benign. Debates about whether smoke‐free laws should include marijuana are becoming increasingly widespread as marijuana is legalized and the cannabis industry grows. Lack of evidence for marijuana SHS causing acute cardiovascular harm is frequently mistaken for evidence that it is harmless, despite chemical and physical similarity between marijuana and tobacco smoke. We investigated whether brief exposure to marijuana SHS causes acute vascular endothelial dysfunction. Methods and Results We measured endothelial function as femoral artery flow‐mediated dilation (FMD) in rats before and after exposure to marijuana SHS at levels similar to real‐world tobacco SHS conditions. One minute of exposure to marijuana SHS impaired FMD to a comparable extent as impairment from equal concentrations of tobacco SHS, but recovery was considerably slower for marijuana. Exposure to marijuana SHS directly caused cannabinoid‐independent vasodilation that subsided within 25 minutes, whereas FMD remained impaired for at least 90 minutes. Impairment occurred even when marijuana lacked cannabinoids and rolling paper was omitted. Endothelium‐independent vasodilation by nitroglycerin administration was not impaired. FMD was not impaired by exposure to chamber air. Conclusions One minute of exposure to marijuana SHS substantially impairs endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco SHS. Impairment of FMD does not require cannabinoids, nicotine, or rolling paper smoke. Our findings in rats suggest that SHS can exert similar adverse cardiovascular effects regardless of whether it is from tobacco or marijuana.
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Activation of G protein-coupled receptors (GPCR) result in multiple waves of signaling which are mediated by heterotrimeric G proteins and the scaffolding proteins β-arrestin 1/ 2. Ligands can elicit full or subsets of cellular responses, a concept defined sometimes as ligand bias or functional selectivity. However, our current understanding of beta-arrestin mediated signaling is still very limited. Here we provide a comprehensive view of β-arrestin mediated signaling from the cannabinoid receptor 1 (CB1R). Utilizing a signaling biased receptor, we define the cascades, specific receptor kinases and molecular mechanism underlying β-arrestin mediated signaling: We identify the interaction kinetics of CB1R and β-arrestin 1 during their endocytic trafficking as directly proportional to its efficacy. Finally, we demonstrate that signaling results in the control of genes clustered around prosurvival and proapoptotic functions among others. Together, these studies constitute a comprehensive description of β-arrestin mediated signaling from CB1Rs and suggest modulation of receptor endocytic trafficking as a therapeutic approach to control β-arrestin mediated signaling.
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Objective: Recent evidence suggests that a potential harmful relationship exists between cannabis use and ischemic stroke. The purpose of this study was to determine the implications of cannabis use in intracerebral hemorrhage (ICH) patients. Methods: An analysis of an international, multicenter, observational database of consecutive patients with spontaneous ICH was conducted. We extracted the following characteristics on presentation: demographics, risk factors, antiplatelet or anticoagulant use, Glasgow Coma Scale, ICH score, neuroimaging parameters, and urine toxicology screen (UTS) results. Modified Rankin Scale (mRS) score was utilized for determination of outcome at discharge. Adjusted logistic ordinal regression was used as shift analysis to assess the impact of cannabis use on mRS score at discharge. The adjusted common OR measured the likelihood that cannabis use would lead to lower mRS scores. Results: Within a cohort of 725 spontaneous ICH patients, UTS was positive for cannabinoids in 8.6%. Cannabinoids-positive (CB+) patients were more frequently Caucasian (p < 0.001), younger (p < 0.001), and had lower median ICH scores on admission (p = 0.017) than those who were cannabinoids-negative. CB+ patients also showed a shift toward better outcome in the distribution of mRS categories, with an adjusted common OR of 0.544 (95% CI 0.330-0.895, p = 0.017). Conclusion: In this multinational cohort, cannabis use was discovered in nearly 10% of patients with spontaneous ICH. Although there was no relationship between cannabis use and specific ICH characteristics, CB+ patients had milder ICH presentation and less disability at discharge.
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Rationale: Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a non-psychoactive constituent of Marijuana which exerts antiinflammatory effects independent from classical cannabinoid receptors. Recently 80 clinical trials have been reported investigating the effects of CBD in various diseases from inflammatory bowel disease to graft-versus-host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received FDA approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Objectives: Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. Results: EAM was characterized by marked myocardial T cell-infiltration, profound inflammatory response, fibrosis (measured by qRT-PCR, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. Conclusion: CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.
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Background: The endocannabinoid 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation. Despite its high concentration in vascular tissue, the role of 2-AG in atherogenesis has not yet been examined. Methods: ApoE-deficient mice were sublethally irradiated and reconstituted with bone marrow from mice with a myeloid-specific knockout of the 2-AG synthesising enzyme diacylglycerol lipase α (Dagla) or control bone marrow with an intact 2-AG biosynthesis. After a cholesterol-rich diet for 8 weeks, plaque size and plaque morphology were examined in chimeric mice. Circulating inflammatory cells were assessed by flow cytometry. Aortic tissue and plasma levels of endocannabinoids were measured using liquid chromatography-multiple reaction monitoring. Results: Mice with Dagla-deficient bone marrow and circulating myeloid cells showed a significantly reduced plaque burden compared to controls. The reduction in plaque size was accompanied by a significantly diminished accumulation of both neutrophil granulocytes and macrophages in atherosclerotic lesions of Dagla-deficient mice. Moreover, CB2 expression and the amount of oxidised LDL within atherosclerotic lesions was significantly reduced. FACS analyses revealed that levels of circulating inflammatory cells were unaltered in Dagla-deficient mice. Conclusions: Myeloid synthesis of the endocannabinoid 2-AG appears to promote vascular inflammation and atherogenesis. Thus, myeloid-specific disruption of 2-AG synthesis may represent a potential novel therapeutic strategy against atherosclerosis.
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