In 2012, Colorado voters made the pivotal decision to legalize the recreational use of cannabis (marijuana), making it the first state in the United States to do so. Several states followed suit, and currently 16 states allow adult recreational use of marijuana. The approval of regulated medical marijuana is even more prevalent, with a total of 36 states that permit publicly available medical marijuana programs.¹ These revolutionary changes in policy have impacted cannabis use patterns; young adults compose the group with greatest use.²

Despite widespread use and publicly touted potential benefits on chronic conditions such as epilepsy, multiple sclerosis, pain control, and depression, the understanding of the short- and long-term safety implications of marijuana use is limited. Furthermore, the scientific evaluation of the health effects of marijuana is hindered by its federal designation as a Schedule 1 controlled substance.³

Pharmacology and Mechanisms of Cardiovascular Disease

Cannabinoids (CB) are primarily responsible for the physiological effects of cannabis. There are over 100 active compounds; cannabidiol and delta-9-tetrahydrocannabinoid (THC) are most common.³ The effects of these compounds are mediated through the endocannabinoid system. CB receptors are widely spread throughout the body, with CB₁ receptors located primarily within the central and peripheral nervous systems, as well as on platelets, myocytes, skeletal muscle, liver, pancreas, and adipose tissue.^2,3 CB₂ receptors are found in immune cells and tissues. The psychoactive effects of THC are exerted by THC binding to CB₁ receptors, and the onset and duration of action can vary based on formulation and route of administration.^2,3

Because CB₁ receptors are located in the myocardium, aorta smooth muscle, and vascular endothelium, it is not surprising that acute effects of marijuana consumption include increases in blood pressure and heart rate. Although these short-term physiological effects are well-described, the impact of marijuana on high-risk cardiovascular outcomes such coronary atherosclerosis and myocardial infarction (MI) is less understood. Current evidence suggests an association of marijuana use with these major cardiovascular events, including stroke, arrhythmias, and vasculopathies.^2-4 Postulated mechanisms of THC-induced cardiovascular events are sympathetic nervous system activation, myocardial oxygen demand, increased catecholamine and beta-adrenergic stimulation, direct vasculotoxic effects, platelet activation, and peripheral vasoconstriction.^3,5

Pharmacological interactions between CB and cardiovascular therapies can occur through inhibition of CYP450 metabolism.⁵ These drug-drug interactions can cause increases in levels of medications including antiarrhythmics, anticoagulants, beta-blockers, and statins. The effects of marijuana on these cardiovascular drugs may have harmful clinical implications, and the potential may be overlooked if providers do not screen for marijuana use in their patients.

Current Evidence of Cardiovascular Risk

Randomized controlled trials evaluating the therapeutic use and safety of marijuana are lacking, but a growing body of evidence suggests that marijuana consumption may be associated with adverse cardiovascular risks. Data analyzed from the US National Vital Statistics System indicate that cardiac death rates have increased 2.3% in men and 1.3% in women since the legalization of marijuana, with a stronger incidence in states with more lenient approaches to cannabis dispensing.⁶

Several studies have shown a robust correlation between marijuana use and MI.^3,7,8 A study evaluating acute MI in 379,843 patients from a nationwide inpatient sample showed that acute MI admissions among cannabis users increased by 32%, with a 60% increase in hospital mortality over 4 years.⁹ A common limitation of several studies evaluating the risk of marijuana on the cardiovascular system is that tobacco use may confound marijuana's true effects. A recently published analysis addressed this concern by evaluating the association of marijuana and cardiovascular disease among 133,706 non-cigarette smokers who participated in the Behavioral Risk Factor Surveillance System from 2016 to 2018.¹⁰ Frequent marijuana smoking was associated with 88% higher odds of MI or coronary artery disease and 81% higher odds of stroke.

Furthermore, the development of acute MI has been shown to occur within hours after marijuana use. In a systematic review including published case reports, the average time of onset of acute MI symptoms was 5 hours after last marijuana use in a young population of long-term cannabis users (mean age 28 years) who were predominantly male.¹¹

Most recently, 2 separate studies demonstrated an association with marijuana use and complications post-MI or cardiac intervention. An analysis of a statewide registry of more than 113,000 patients who underwent percutaneous coronary intervention (PCI) at 48 hospitals in Michigan demonstrated that compared with non-users, marijuana users had significantly increased risk of bleeding and stroke after adjusting for differences in baseline characteristics.¹² Although there were no significant differences in the risk of death or need for blood transfusion between the 2 groups, marijuana smokers were at an approximately 50% increased risk for bleeding after PCI (5.2% vs. 3.4%; adjusted odds ratio 1.54 [1.20-1.97], p < 0.001). Another study examining the incidence and effect of marijuana use on admissions for patients with prior MI or revascularization procedures from a national inpatient sample over 7 years found an increasing trend of cannabis use with higher rates of acute MI, PCI, and coronary artery bypass grafting.¹³ Subsequent acute MI was also higher in marijuana users than non-users (67% vs. 41%). Alarmingly, marijuana users were younger and had a lower incidence of cardiac comorbidities such as hypertension, diabetes, and dyslipidemia. Limitations included lack of information on recreational versus medicinal use and dosage and mode of marijuana consumption.

Most of the available data on marijuana triggering major adverse cardiovascular events is observational and retrospective, with several limitations due to the barriers that exist in conducting randomized controlled trials with marijuana's Schedule I designation. Current evidence is insufficient to draw decisive conclusions on the effect of marijuana use on cardiovascular events. However, an estimated more than 2 million US adults who have cardiovascular disease report using marijuana, and providers must be aware of the potential risk of marijuana in precipitating cardiovascular events in those with pre-existing disease, as well as the potential of marijuana to be a contributing cause of premature events in younger patients.⁵ The cardiovascular medical community should remain committed to increasing awareness of the effect of marijuana on cardiovascular risk, screening for use in patient care settings, and advocating for the need for rigorous scientific research to truly understand marijuana's therapeutic uses and health implications in certain populations.

References

1. State Medical Marijuana Laws (National Conference of State Legislatures website). 2021. Available at https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Accessed June 1, 2021.
2. Latif Z, Garg N. The Impact of Marijuana on the Cardiovascular System: A Review of the Most Common Cardiovascular Events Associated with Marijuana Use. J Clin Med 2020;9:1925.
3. Page RL 2nd, Allen LA, Kloner RA, et al. Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association. Circulation 2020;142:e131-e152.
4. Rezkalla S, Kloner RA. Cardiovascular effects of marijuana. Trends Cardiovasc Med 2019;29:403-7.
5. DeFilippis EM, Bajaj NS, Singh A, et al. Marijuana Use in Patients With Cardiovascular Disease: JACC Review Topic of the Week. J Am Coll Cardiol 2020;75:320-32.
6. Abouk R, Adams S. Examining the relationship between medical cannabis laws and cardiovascular deaths in the US. Int J Drug Policy. 2018;53:1-7.
7. Desai R, Patel U, Sharma S, et al. Recreational Marijuana Use and Acute Myocardial Infarction: Insights from Nationwide Inpatient Sample in the United States. Cureus 2017;9:e1816.
8. Chami T, Kim CH. Cannabis Abuse and Elevated Risk of Myocardial Infarction in the Young: A Population-Based Study. Mayo Clin Proc 2019;94:1647-9.
9. Patel RS, Katta SR, Patel R, et al. Cannabis Use Disorder in Young Adults with Acute Myocardial Infarction: Trend Inpatient Study from 2010 to 2014 in the United States. Cureus 2018;10:e3241.
10. Shah S, Patel S, Paulraj S, Chaudhuri D. Association of Marijuana Use and Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Data Analysis of 133,706 US Adults. Am J Med 2021;134:614-620.e1.
11. Patel RS, Kamil SH, Bachu R, et al. Marijuana use and acute myocardial infarction: A systematic review of published cases in the literature. Trends Cardiovasc Med 2020;30:298-307.
12. Yoo SGK, Seth M, Earl T, et al. Abstract 14449: Not So Harmless: Marijuana Use and In-hospital Outcomes After Percutaneous Coronary Intervention: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Circulation 2020;142:A14449.
13. Desai R, Singh S, Gandhi ZJ, et al. Abstract 15863: Prevalence, Trends and Impact of Cannabis Use on Hospitalizations With Prior Myocardial Infarction and Revascularization. Circulation 2020;142:A15863.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Hypertension, Smoking

Keywords: Cannabis, Marijuana Smoking, Medical Marijuana, Marijuana Abuse, Cardiovascular Diseases, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cannabidiol, Controlled Substances, Controlled Substances, Endocannabinoids, Dronabinol, Blood Pressure, Cardiovascular Agents, Percutaneous Coronary Intervention, Cannabinoids, Heart Rate, Retrospective Studies, Anticoagulants, Hospital Mortality, Endothelium, Vascular, Behavioral Risk Factor Surveillance System, Receptor, Cannabinoid, CB2, Receptor, Cannabinoid, CB1, Blood Platelets, Preexisting Condition Coverage, Adrenergic Agents, Catecholamines, Vasoconstriction, Depression, Risk Factors, Myocardial Infarction, Coronary Artery Bypass, Hypertension, Diabetes Mellitus, Stroke, Registries, Arrhythmias, Cardiac, Myocardium, Myocardium, Dyslipidemias, Platelet Activation, Sympathetic Nervous System, Drug Interactions, Blood Transfusion, Muscle, Skeletal, Peripheral Nervous System, Adipose Tissue, Oxygen

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