Smoking or Vaping Cannabis and Cardiovascular Function: Is Δ‐9‐Tetrahydrocannabinol the Main Culprit?

Cannabis use is increasing in the United States and in numerous regions of the world. ¹ , ² Although cannabis remains illegal across most of the world, many US states and some countries in the European Union have legalized cannabis for limited therapeutic and less commonly recreational purposes. Hoewever, research into the physiological effects of cannabis use has not kept pace with the continued decriminalization and legalization of cannabis. An area of particular interest is the relationship between cannabis use, cardiovascular function, and cardiovascular disease in general. ³ The acute cardiovascular effects of cannabis use remains an important but underexplored safety issue. ³ Few studies have prospectively assessed the mechanistic effects of cannabis on the cardiovascular system. The cardiovascular effects of cannabis are dependent on several factors including the route of administration, baseline state of the endocannabinoid system and the Δ‐9‐tetrahydrocannabinol (THC) content. ⁴ THC is the primary psychoactive component of cannabis and is a partial agonist to cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). As seen in the Figure, the CB1R receptors are located throughout the central nervous, cardiovascular, and integumentary systems, as well as in hepatic, adipose, and skeletal muscular tissues, and the CB2R can be found primary in the gastrointestinal tract and immune tissues. ¹ Cannabidiol acts as a modulator of CB2R, which in animal models has shown antioxidant and anti‐inflammatory properties and limited psychoactive effects. ⁵

Figure . Distribution of the CB1R (green) and CB2R (blue) throughout the body.

CBD indicates cannabidiol; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; and THC, Δ‐9‐tetrahydrocannabinol.

The evidence supporting the cardiovascular effects of cannabis use have been weak and relatively few if any have been prospective. Studies have been limited to observational and retrospective reports and mainly in the form of case series, ⁶ cohort studies using administrative claims data sets, ⁷ , ⁸ and population‐based cross sectional studies. ⁹ Additional limitations of these studies include short‐term follow‐up, variable cannabis exposure, no dose or product standardization, and predominantly low‐risk cohorts. ¹⁰ In a population‐based, cross‐sectional study of 2016 to 2020 data from the Behavioral Risk Factor Surveillance Survey, Jeffers et al. evaluated the association of cannabis use (number of days of cannabis use in the past 30 days) with self‐reported cardiovascular outcomes (coronary heart disease, myocardial infarction, stroke, and a composite measure of all 3, adjusting for tobacco use and other characteristics. ⁹ Among 434 104 respondents, the adjusted odds ratio for the association of daily cannabis use and coronary heart disease, myocardial infarction, stroke, and the composite outcome was 1.16 (95% CI, 0.98–1.38), 1.25 (95% CI, 1.07–1.46), 1.42 (95% CI, 1.20–1.68), and 1.28 (95% CI, 1.13–1.44), respectively, with proportionally lower log odds for days of use between 0 and 30 days per month. ⁹ However, this study also had many limitations: (1) cardiovascular outcomes were evaluated by self‐report and could be subject to recall bias; (2) poor agreement existed between self‐reported cannabis use and biochemical validation; and (3) objective measures of vital signs and physiological cardiovascular measures were not recorded. Hence this study, although well done had limitations that highlight the need for well‐done prospective cohort studies that can better examine the association of cannabis use and cardiovascular function and eventually outcomes.

In this issue of the Journal of the American Heart Association (JAHA), Cheung et al. ¹¹ aimed to investigate the acute effects of cannabis inhalation on subclinical dysfunction while controlling for the effects of THC or cannabidiol. The authors examined the acute cardiovascular effects of cannabis use on arterial stiffness, vascular endothelial responsiveness, and cardiac function as markers of cardiovascular impairment over 4 visits. Twenty‐two young, healthy, cannabis users were assessed for arterial stiffness via pulse wave velocity, vascular endothelial function via brachial artery flow mediated dilation, and cardiac function via echocardiography, before and after: (1) smoking THC predominant cannabis (S‐THC), (2) vaporizing THC‐predominant THC (V‐THC), and (3) vaporizing cannabidiol‐predominant cannabis. S‐THC and V‐THC increased the heart rate (S‐THC: Δ17±15 bpm, V‐THC: Δ16±16 bpm; P<0.0001) and mean arterial pressure (S‐THC: Δ7±6 mm Hg, V‐THC: Δ5±5 mm Hg; P<0.0001) whereas vaporizing cannabidiol‐predominant cannabis did not (Δ1±4 bpm, Δ3±4 mm Hg; P>0.05). After inhalation, pulse wave velocity increased (S‐THC: Δ0.29±0.75 m/s, V‐THC: Δ0.42±0.74 m/s, vaporizing cannabidiol‐predominant cannabis: Δ0.10±0.44 m/s; P=0.002) and diastolic function was reduced ([E/A ratio] S‐THC: Δ‐0.2±0.53, V‐THC: Δ‐0.33±58, vaporizing cannabidiol‐predominant cannabis: Δ0.01±66; P=0.03). Differences in heart rate were related to changes in pulse wave velocity (r²=0.2; P=0.0002) and diastolic function (r ²=0.26; P<0.0001). Inhalation method did not alter these cannabinoid‐dependent responses. Summarily, THC‐predominant, but not cannabidiol‐predominant cannabis elicited increase in heart rate and blood pressure irrespective of inhalation method and these changes may eventually increase arterial stiffness and reduce diastolic function. Strengths of the study include the (1) cannabis dose used is similar to the real world/typical dose of a recreational cannabis user (ie, 100 mg of dry flower, ~10%–15% THC/cannabidiol); (2) evaluation of 2 different modalities of cannabis administration—smoking and inhalation; and (3) prospective evaluation of clinically relevant surrogates of cardiovascular function—arterial stiffness, vascular endothelial function, and cardiac function. Limitations include a small sample size and lack of post hoc comparisons.

This study adds to the growing body of evidence that improve our understanding of the cardiovascular effects of cannabis. Increased heart rate, blood pressure, and arterial stiffness observed in this cohort may be a mechanism through which chronic cannabis use may contribute to systemic hypertension and elevated cardiovascular risk. The study also demonstrated that the effect of aerosolized cannabis inhalation is similar to that of cannabis smoke inhalation under real‐world conditions. The authors did not observe adverse effects of cannabis inhalation on peripheral vascular endothelial function, which was discrepant from findings of impaired endothelial function in a rodent model ¹² and different from acute cigarette use, which impairs flow mediated dilation in humans. ¹³ The discrepancy in flow mediated dilation responses between animal and human models may be explained by differences in cannabis dose relative to organism size, as human and rat experiments have used similar absolute doses of cannabis.

There were mixed findings regarding systolic and diastolic function with cannabis use. There was no difference in left ventricular systolic function after cannabis use which was different from prior studies. Markers of diastolic function septal A', A, and E/A ratio were impaired by S‐THC and V‐THC but not by vaporized cannabidiol. These markers are influenced by heart rate, which is acutely increased by THC inhalation and not cannabidiol inhalation. To this end, is THC the main culprit in adverse cardiovascular effects compared with cannabidiol? In terms of biological plausibility and based on these data, the answer would seem to be yes. Cannabidiol binds primarily to the CB2R, which is found predominately within immune tissues, thus exerting potential anti‐inflammatory and antioxidant effects compared with THC, which binds to the CB1R, which is believed to responsible for many of the negative cardiovascular effects of cannabis (Figure). ¹ However, it is important to highlight that cannabidiol products, such as the cannabidiol oil, will still have some residual THC. However, at this point, the cardiovascular safety of cannabidiol remains to be elucidated. Nonetheless, the lack of effects on diastolic and systolic function suggests that the effect of cannabis on and the development of heart failure remains an area of further research. Furthermore, the uncertain cardiovascular effects of cannabis will need to be clarified in future studies in order to better understand (1) the ambiguity regarding cannabis as a possible causal factor in developing incident heart disease, (2) effect of cannabis on preexisting heart disease, and (3) uncertainty regarding appropriate recommendations for cannabis use in patients being considered for heart transplantation. ¹⁴

Many unknowns remain with cannabis use and cardiovascular disease. The long‐term effect of cannabis use on cardiovascular mortality especially heart failure remains unknown as there are no large‐scale, long‐term, controlled studies (known cannabis composition, route, dose, and frequency of administration) with validated measures of cannabis use. The increasing marketing and use of synthetic “designer” CB1R agonist mixtures (spice variants) with very high potency THC, might increase the levels of cardiovascular morbidity with unknown effects on mortality. This is because cannabis (with increased THC and less cannabidiol content) is believed to potentially induce dangerous cardiovascular effects, probably mediated by the activation of CB1R. ¹⁵ With increasing therapeutic and recreational cannabis use and a growing burden of cardiovascular disease, there will be a greater need to understand, identify, and manage any adverse cardiovascular effects of cannabis. Future studies should consider biochemical validation of cannabis use, use standardized metrics to assess cardiovascular dysfunction where applicable and consider studies using different formulations of THC and cannabidiol. Improved funding for cannabis research can be attained by government and private entity partnerships. This may lead to improved data and data‐driven outcomes regarding cannabis and cardiovascular disease, which can better guide federal‐ and state‐level cannabis policy.

Disclosures

None.