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As the stigma surrounding cannabis wanes and its potential medicinal value becomes more widely accepted, an increasing number of people are turning to the plant for both recreational and therapeutic purposes. However, despite its growing popularity, our understanding of how cannabis affects the human body is still limited. While a body of evidence points to the therapeutic potential of cannabis, it is important also to consider the potential risks associated with its use. A study by Holt et al. presented at the 43rd European Society of Cardiology congress last fall, for instance, suggested a possible link between cannabis use and an increased risk of cardiovascular events, bringing into question its safety.
On Medical Cannabis
Medical cannabis, also known as medical marijuana, generally refers to the Cannabis sativa plant derivatives used to alleviate symptoms caused by certain medical conditions. It is available in various formulations, containing different levels of the two main active components of cannabis: tetrahydrocannabinol (THC), which produces the psychoactive “high” associated with cannabis use, and cannabidiol (CBD), a non-psychoactive component that has received increasing attention for potential anti-epileptic and anxiolytic effects. Importantly, medical cannabis and recreational cannabis often differ in their formulations and chemical makeups, with medical cannabis products usually formulated to contain specific ratios of CBD and THC, while recreational cannabis products may contain a wider range of compounds found in the cannabis plant, such as terpenes and flavonoids, which can alter overall effects.
Technically, the U.S. Food and Drug Administration has not yet recognized the therapeutic benefits of cannabis for any medical condition. However, it has given the green light to certain cannabis-derived medications, such as cannabidiol or CBD (Epidiolex) and dronabinol (Marinol), which contains high levels of THC. In Denmark, where the study by Holt et al. was conducted, physicians can prescribe cannabis-based medication in three forms: dronabinol, cannabinoid – a formulation with a higher concentration of THC than CBD – and cannabidiol.
In the United States today, 37 states, three territories, and the District of Columbia permit the medical use of cannabis products, but at the federal level, cannabis is classified as a Schedule I substance under the Controlled Substances Act, which means it is considered to have a high potential for dependency and no accepted medical use. As a result, distributing cannabis technically remains a federal offense, though this federal policy contrasts with the legalization trends in many states. However, the federal government has designated prosecution of medical marijuana cases as a very low priority, so businesses and consumers in the medical marijuana sector enjoy a certain level of protection.
Still, the conflicting policies and continued federal prohibition likely contribute to the relative dearth of rigorous trials on the health effects of medical cannabis. The CDC has warned that marijuana may increase risk of cardiovascular disease (CVD), but as their own statement points out, evidence for this association comes primarily from observational studies of marijuana smokers, and we have every reason to suspect that this route of administration raises CVD risk independently of any effect of CBD or THC. In other words, we don’t know if approved medical cannabis products – which are formulated for oral consumption – have any impact on CV health. This is the question Holt et al. sought to address.
About the Study
Holt and colleagues conducted an observational study to examine the potential risk of cardiovascular events in 4,562 patients with chronic pain who were prescribed medical cannabis (cannabinoid, cannabidiol, or dronabinol) compared to a control group who weren’t taking the medication. Specifically, they looked at the risk of new-onset arrhythmias (abnormal heart rhythms), acute coronary syndrome (ACS, a condition caused by the sudden, reduced blood flow to the heart), and heart failure. The researchers used the Danish national registers to follow the cohort, who, importantly, did not have a history of arrhythmias, ACS, heart failure, or medical cannabis use prior to the study period (2018 to 2021). Patients from the exposed cohort were matched to controls in age group, sex, and chronic pain diagnosis.
The study found that the risk of new-onset arrhythmias was higher in the group prescribed medical cannabis compared to the control group, with a risk ratio of 1.64 (95% CI: 1.04-2.23) – a 64% relative risk increase. The 180-day absolute risks were 0.71% (95% CI: 0.47%-0.94%) for exposed subjects vs. 0.43% (95% CI: 0.37%-0.49%) for controls, indicating an absolute risk increase of 0.28% with cannabis use. This 0.28% absolute risk increase translates to one case of arrhythmia for every 360 users. However, the risk of ACS or heart failure was not elevated in the group prescribed medical cannabis compared to the control group.
A cause for alarm?
Given the lack of human data on medical cannabis and potential cardiovascular risks, these findings are certainly noteworthy. However, upon closer examination, the limitations of the study suggest that there may not yet be cause for alarm.
One potential source of selection bias in this study is the difference in comorbidities between the exposed and control groups. Comorbidities refer to the presence of health conditions that an individual may be experiencing in addition to their “main” condition or the condition of interest within the study. In this study, the exposed group had more comorbidities, including hypertension, ischemic heart disease, chronic kidney disease, and diabetes mellitus, than the control group, which could potentially affect the results if the exposed group was more vulnerable to certain adverse events due to their overall health status. For example, in patients with hypertension, the heart muscle may enlarge (a condition known as cardiac hypertrophy), which can also involve the growth of fibrous tissue and a decrease in connectivity between cells. These changes can disrupt the normal electrical properties of the heart and increase the likelihood of arrhythmias.
Another source of selection bias in this study is the fact that the exposed group had higher exposure to other medications compared to the control group. Other medications taken by the exposed group may interact with medical cannabis, altering the effects of both on the body and impacting susceptibility to CV concerns. It is also possible that other medications, if metabolized by the same enzymes in the body as CBD, could potentially interfere with the absorption, distribution, metabolism, and elimination of both substances. Notably, a significantly higher percentage of the exposed group (42.2%) were also taking opioid medications compared to the control group (12.3%). CBD has been shown to inhibit CYP2D6, an enzyme involved in the metabolism of opioids such as oxycodone, which may lead to an increase in the serum concentrations of these medications. In 2019, research by Dashi et al. revealed a link between opioid overdose and the occurrence of ischemic events, heart failure, and arrhythmias in patients hospitalized due to opioid overdose. Additionally, a review by Behzadi, Joukar, and Beik suggests that opioids can themselves trigger arrhythmias, and higher doses of these medications may exacerbate this effect.
Although the study does not provide statistical analysis as to whether the comorbidity and medication differences between the groups are statistically significant, the disparities are sufficiently large that statistical significance is at least possible for many variables and virtually certain for others, such as for chronic kidney disease (for which cannabis users exhibited nearly double the incidence rates of non-users) and opioid use, as described above. Further, the between-group differences across these variables were highly consistent in portraying the cannabis-exposed group as having poorer overall health than the control group, so even if some of the individual differences do not reach statistical significance, they are likely to represent a broader clinically significant difference between groups. From this perspective, it’s frankly remarkable that the authors didn’t report a greater discrepancy in CV events between groups, and it would even be conceivable that medical cannabis helped to mitigate the risk imparted by overall poor health. In other words, in light of the researchers’ egregious lack of effort in ensuring baseline equivalence between groups, we can make no reliable conclusions on the effects of medical cannabis based on their results.
The Bottom Line
Holt et al. showed that medical cannabis use was associated with a small increase in the risk of arrhythmias, but the presence of major confounds in this study stymies any meaningful interpretation of these findings with respect to the effects of cannabis per se. Those with pre-existing cardiovascular conditions may want to proceed with caution in light of the possibility that medical cannabis negatively impacts CV health, but ultimately, more research is needed.
Medical cannabis is legal in several Western countries and by state law across a growing portion of the U.S., and its popularity for medicinal purposes has accordingly been soaring. But legality alone is not enough. It is technically legal to concoct medieval potions of mouse urine and toad bones, but we have no scientific evidence that doing so will harm or improve health. Likewise, we seem stuck in the Middle Ages in our thinking about cannabis, relying on superstition and hearsay for justifying its use – or condemnation. We need to move past this and apply the same process of rigorous scientific evaluation to medical cannabis as we would to any other compounds showing therapeutic promise in observational studies: assessing risks and benefits through well-designed, randomized, placebo-controlled trials.
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