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Canadian Journal of Cardiology

Managing Cannabis Use in Patients With Cardiovascular Disease

  • Neal L. Benowitz
    Correspondence
    Corresponding author: Dr Neal L. Benowitz, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, California 94143-1220, USA. Tel.: +1-415-206-8324; fax: +1-415-206-4956.
    Affiliations
    Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, Departments of Medicine, and Biopharmaceutical Sciences; Center for Tobacco Control Research and Education, University of California, San Francisco, California, USA
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Published:December 28, 2018DOI:https://doi.org/10.1016/j.cjca.2018.12.033
      In the context of widespread legalization of cannabis use for both medical and recreational purposes, health care providers need to understand and manage cannabis use and its complications in older patients, particularly in those with cardiovascular disease (CVD). The report by Drs Saunders and Stevenson in this issue of the Canadian Journal of Cardiology
      • Saunders A.
      • Stevenson R.S.
      Marijuana lollipop-induced myocardial ischemia.
      illustrates some of the cardiovascular (CV) problems that may occur with cannabis use in such patients.
      The relevant clinical features of this case include an older man with stable coronary artery disease (CAD), taking appropriate cardiac medications, who consumed a large dose of delta-9-tetrahydrocannabinol (THC) orally for the treatment of pain and to aid sleep. The patient had smoked marijuana in his youth, but had not used since then. The ingestion resulted in extreme discomfort, which included anxiety and fearful hallucinations, associated with intense sympathetic neural stimulation and a non–ST-segment elevation myocardial infarction. Initial vital signs included tachycardia and hypertension, despite taking substantial doses of metoprolol and a calcium channel blocker. After resolution of the hallucinations, the chest pain resolved. A number of prior case reports, as well as epidemiologic studies, have described the association between cannabis use and acute CV adverse events, including myocardial infarction, stroke, arrhythmias, and sudden death.
      • Goyal H.
      • Awad H.H.
      • Ghali J.K.
      Role of cannabis in cardiovascular disorders.
      • Pacher P.
      • Steffens S.
      • Hasko G.
      • Schindler T.H.
      • Kunos G.
      Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      In considering the toxicity of medical cannabis use broadly, one needs to appreciate the main cannabinoid constituents. Cannabis products may contain THC, the main psychoactive and cardioactive chemical, and/or cannabidiol (CBD), a cannabinoid with minimal psychoactivity and no cardioactivity. The latter is widely used for relief of pain and anxiety and to aid sleep. Products may contain mostly THC, mostly or only CBD, or varying proportions of the 2. Thus, an important question the provider needs to address is what constituents are being consumed by the patient. For the remainder of this editorial, the focus will be primarily on THC-containing cannabis products.

      CV Toxicity of Marijuana

      CV toxicity of marijuana can be viewed as a consequence of 1 or more of the following: (1) inhalation of combustion products of marijuana, (2) direct CV effects of THC, and (3) indirect effects of THC related to acute anxiety, hallucination, and/or psychosis.
      Aside from one containing THC and the other nicotine, the composition and toxicity of marijuana smoke is qualitatively similar to that of cigarette smoke. Marijuana smoke exposes the smoker to even more of some toxicants such as ammonia and cyanide than cigarette smoking.
      • Moir D.
      • Rickert W.S.
      • Levasseur G.
      • et al.
      A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions.
      Smoke exposes the smoker to high levels of oxidants, particulates, numerous toxic volatile organic chemicals, and carbon monoxide. Adverse CV effects of smoke include oxidant damage, inflammation, endothelial dysfunction, induction of a prothrombotic state, and reduction of oxygen-carrying capacity of red blood cells. These toxic effects can translate into plaque rupture, acute thrombosis, and/or vasoconstriction with reduced coronary blood flow, resulting in an increased risk of acute coronary syndrome, stroke, and sudden cardiac death (Fig. 1). Although these mechanisms and adverse events are most extensively described in active regular cigarette smokers, the same acute CV effects are also seen acutely in people who smoke only occasionally and in the context of second-hand cigarette smoke exposure. A case-crossover study supports the idea that smoking a single marijuana cigarette can acutely trigger myocardial infarction.
      • Mittleman M.A.
      • Lewis R.A.
      • Maclure M.
      • Sherwood J.B.
      • Muller J.E.
      Triggering myocardial infarction by marijuana.
      Figure thumbnail gr1
      Figure 1Overview of mechanisms by which marijuana smoke might cause acute cardiovascular events. THC, tetrahydrocannabinol.
      THC, acting on the cannabinoid receptor 1, primarily via central nervous system pathways, increases sympathetic nervous system activity, resulting in a dose-related tachycardia, (20% to 100%), increased myocardial contractility, supine hypertension, and systemic catecholamine release.
      • Gash A.
      • Karliner J.S.
      • Janowsky D.
      • Lake C.R.
      Effects of smoking marihuana on left ventricular performance and plasma norepinephrine: studies in normal men.
      Coronary blood flow may be reduced because of catecholamine effects to constrict coronary vessels and/or activate platelets. The net effect is a substantial increase in myocardial work and oxygen demand combined with an impairment in the expected and necessary compensatory increase in coronary blood flow. Marijuana was shown many years ago to markedly reduce exercise tolerance in patients with stable angina pectoris, a consequence of increased myocardial work and reduced coronary blood supply.
      • Aronow W.S.
      • Cassidy J.
      Effect of marihuana and placebo-marihuana smoking on angina pectoris.
      Increases in sympathetic tone can trigger supraventricular or ventricular arrhythmias and increase ventricular response rate in atrial fibrillation. Paradoxically, THC can also cause orthostatic hypotension, believed to be due to impaired venoconstriction, which may aggravate myocardial ischemia in the context of CAD or precipitate stroke. In the elderly, orthostatic hypotension also increases the risks of syncope or falls with concomitant injury.

      Central Nervous System Toxicity

      Another aspect of THC toxicity, as seen in the patient described in this issue’s case report is the onset of acute anxiety, paranoia, hallucination, and panic. Such effects are typically seen with high doses of THC and with the use of synthetic cannabinoids, but are also observed with smaller therapeutic doses in older people, such as in patients with cancer taking THC to manage nausea and vomiting and for appetite stimulation. Many such individuals who are THC naïve and are not used to taking any mind-altering drugs can become highly distressed by impaired cognition and feelings of loss of control produced by THC. In the case of the patient in the case report, the dose of THC consumed was approximately 70 mg, an extremely large dose for a THC-naïve person. This compares with the recommended starting dose of dronabinol (Marinol), a synthetic THC marketed for nausea and vomiting and appetite stimulation in patients undergoing cancer chemotherapy or with AIDS, of 2.5 mg for an older patient. The maximal recommended dose for any patient is 20 mg per day. Extreme emotional responses in the context of THC psychiatric toxicity are associated with surges of catecholamines, which can have adverse acute CV effects.

      Considerations in Cannabis Toxicity

      Important considerations with respect to cannabis toxicity are the pattern of use, dose, route of administration, and degree of tolerance. Some people take a couple of puffs of marijuana before bedtime for sleep, in which case toxicity is likely to be low. Others use cannabis products all day. Smoking or vaping cannabis results in a rapid increase in arterial blood THC levels, which peak soon after inhalation; and inhaled THC has a duration of action for 4 to 6 hours.
      • Huestis M.A.
      • Henningfield J.E.
      • Cone E.J.
      Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana.
      Inhaled doses can be relatively small because the rapid absorption of small doses delivers high concentrations to the brain, facilitating titration of dosing to the desired effect. On the other hand, oral ingestion of cannabis results in slow and erratic absorption with blood THC levels peaking at 4 hours or longer, and with a duration of action that can be 24 hours or more.
      • Vandrey R.
      • Herrmann E.S.
      • Mitchell J.M.
      • et al.
      Pharmacokinetic profile of oral cannabis in humans: blood and oral fluid disposition and relation to pharmacodynamic outcomes.
      Because of slow absorption, the psychoactive effects of oral THC are delayed, leading to consumption of large doses before effects are felt, which may then lead to protracted exposure to high levels and toxicity. Although the oral bioavailability of THC is relatively low (10% to 20%), THC is metabolized to 11-hydroxy-THC, which is also highly psychoactive.
      Tolerance is an important determinant of toxicity. With regular use, a high degree of tolerance can develop to both psychological and CV effects. Conversely, as discussed above, even a moderate dose of THC in a naïve user, particularly in older adults, can produce significant toxicity.

      Practical Considerations Regarding Cannabis Use in Patients With CVD in an Era of Expanded Legalization

      How should health care providers manage patients with CVD who are using or would like to use cannabis products? Many patients would like to use or are using cannabis to manage anxiety, chronic pain, and/or to aid sleep, as was the case for the patient described in the case report.
      • Saunders A.
      • Stevenson R.S.
      Marijuana lollipop-induced myocardial ischemia.
      Particularly vulnerable to the adverse effects of cannabis are patients with coronary artery or cerebrovascular disease, heart failure, and arrhythmias, including atrial fibrillation, paroxysmal supraventricular arrhythmias, and ventricular tachycardia.
      No empirical evidence is available to guide management of cannabis use in older patients and/or patients with cardiovascular disease. I suggest an approach as follows: for the CV patient at high risk, the use of THC should be discouraged. The concern about THC is greater for those who use THC throughout the day as opposed to those who use small doses before sleep. For patients who want to use cannabis, one can recommend the use of CBD rather than THC for relief of pain and to aid sleep. For patients who are smoking marijuana for the effects of THC and who are unwilling to stop, it is advisable to switch to a noncombusted delivery system, such as vaporizer. This will at least avoid the harmful effects of marijuana smoke. Because the toxic effects of THC are dose related, patients should be advised to use the smallest doses that provide the desired beneficial effects. THC is often packaged and sold in a way that it is difficult for the consumer to evaluate an appropriate dose. Some edible products, such as brownies for example, may contain several “servings” of THC, but the patient may not know that. In the case of a 90 mg THC lollipop, such as was purchased by the patient in this case report, an appropriate starting dose might be a few licks or a small piece. Understanding appropriate dosing would likely have prevented the toxicity suffered by the patient. Patients may need counselling as to what constitutes a low dose, and how that compares with the amount of THC in products they may have purchased; and the health care providers may be called on to provide guidance.
      Another management question relates to the selection of medications in CV patients using THC-containing cannabis products. Again, there are no empirical data, and the following represents my approach: selection of medications will depend on a number of factors, including the dosing pattern, coexisting medical conditions, and medications. The logical target of medication in THC users is control of tachycardia, which can aggravate CAD and arrhythmias. Patients on β-blockers may need higher doses. Others may need to have β-blockers started. With coexisting hypertension, which may be aggravated by the effects of THC, a β-blocker with α-blocking activity such as carvedilol, or a β-blocker and calcium-blocker combination are reasonable options. At the same time, the likelihood of orthostatic hypotension needs to be considered. Patients should be warned that the consumption of THC, especially at bedtime, may result in dizziness while standing up with an increased risk of falling at night, and this risk would be expected to be even higher in a patient taking α-blockers for prostate disease. Counselling may include sitting on the side of the bed for a minute or 2 until dizziness resolves and avoidance of prolonged standing.
      The legalization of cannabis has considerable public support, but also raises public health concerns. Some users may benefit from the social and medical effects, but others will be at risk for adverse health outcomes. Little information has been disseminated to patients or health care providers about cannabis use in older patients, and in particular those with CVD. For better or worse, providing advice and care to such patients who are using cannabis is now necessary for the provision of optimal medical care to such patients.

      Acknowledgements

      I thank Dr Craig Smollin for critical review of the manuscript and Newton Addo for editorial assistance.

      Disclosures

      N.L. Benowitz has been a consultant to Pfizer and GlaxoSmithKline, pharmaceutical companies that market medications to aid smoking cessation and has served as a paid expert witness in litigation against tobacco companies.

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