During the 2006–2010 period, the proportion of cardiovascular complications rose from 1.1% to 3.6% of all cannabis‐related disorders reported to the French Addictovigilance Network. They were all serious and included cardiac and extracardiac complications, mainly acute coronary syndromes and peripheral arteriopathies. In comparison to the most recently assessed number of regular cannabis users in France (1.2 million), only a small proportion of complications was reported to the French addictovigilance system.

Our results may reasonably be considered a biased (underestimated) representation because the main limitation of this system is the underreporting, although the reporting of all serious cases related to drug abuse and dependence is compulsory and regulated in the French Public Health Code.²³ Indeed, currently, the reporting rate of adverse drug reactions is estimated to be 5% in the field of pharmacovigilance.²⁶ In other words, 95% of cases are usually not captured. Consequently, the number of cardiovascular complications in cannabis users should be much higher than we describe, especially that this rate should even be lowered in the field of addictovigilance because adverse reactions related to drugs of abuse (of which cannabis) are less frequently reported than those related to other medicines and was recently estimated to be 0.4%.²⁷ We considered that these cases were too few to be extrapolated by applying the reporting rate, although it would have definitely provided a more accurate estimation.

However, despite poor exhaustiveness, it has already been shown that the spontaneous reporting (as, for example, in the field of pharmacovigilance) is the cornerstone to identify signals. In the context of our study, the increasing reporting of cardiovascular complications related to cannabis, and their extreme seriousness (with a death rate of 25.6%) could indicate cannabis as a possible risk factor for cardiovascular disease in young adults, in line with previous findings.⁸

Another possible explanation for the small number of cases is that cardiovascular disorders may hardly be connected to cannabis considering the lack of evidence‐based data in this area and especially because cannabis‐related disorders are frequently restricted to neuropsychiatric impairments. For instance, in a recent clinical review oriented to general practice in primary care that gives advice in the management of cannabis‐related disorders, the cardiovascular system is not even mentioned.²⁸

On the other hand, our work is somehow limited by the poor information available. Indeed, some cases were not exhaustively informed, and events were too few assess whether the cardiovascular events were actually due to the cannabis use rather than some other risk factors using statistical modeling. Toxicologic analyses were provided or available in only 37% of cases (13/35). More information about toxicology should have revealed odd associations of products among cases. In most of the available toxicologic analyses, which were mainly in forensic reports for unexplained deaths, cannabis was the only positive substance among all substances. History of cardiac or vascular disease and risk factors were not systematically available but were found in 46% (16/35) of patients. In particular, body mass index was assessed in only 31%. According to previous findings, cannabis use might be harmless to most young healthy users, whereas patients with preexisting cardiovascular weaknesses appear to be prone to the harmful effects of cannabis.²⁹ In our study, patients presented with these events with varied histories and ages (25% were younger than 28.3 years, median age 34.5 years, interquartile range 28.3 to 39 years).

A report of adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation was published recently.³⁰ The serious adverse events are very similar to those of the present study and include myocardial infarction, sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and cannabis arteritis. A population‐based study conducted in the area of preventive cardiology emphasized a strong association with unhealthy behaviors such as high caloric intake, tobacco smoking, and use of other illicit drugs, although it did not reveal any independent association between cannabis use and the occurrence of cardiovascular risk factors in young adults.³¹ Case reports of acute coronary syndromes have long been noted and remain numerous,^31–35 and there are reports in the literature of myocardial infarction in adolescents who had used the synthetic cannabinoid K2, the effects of which being reported as cannabis‐like after smoking.³² Cases of cannabis‐related limb ischemia possibly resulting in necrosis of the fingers or toes have also been reported.^14,33 In 2010, 70 case reports of cannabis arteritis were reported in the litterature.³⁴ In this 201‐ review, the patients were younger than our group of patients with peripheral arteriopathy, with a mean age of 28.5 years. However, patients with Buerger disease might be older, with an estimated mean age at onset of 35.0 years.³⁵

In addition, a recent study on hospitalizations linked to cannabis in a university hospital has shown a non‐negligible pproportion of cardiovascular complications, with 6.3% of all cannabis‐related hospitalizations.²¹ Among these cases, only a few were reported to the regional addictovigilance center. Therefore, a large underestimation of the cases described in the present study can be expected, especially because the reporting is low, estimated to be 0.4%.²⁷ Moreover, we are not certain that all areas were extensively and exhaustively covered in this study. Also, clinicians do not easily attribute these complications to cannabis, unless cannabis is the only product involved.

The 35 cases described must be compared with the 1.2 million regular users in France,³⁶ and to the incidence rates of cardiovascular complications in a comparable group. Yet, relevant comparable group is difficult to define because in the general population, patients with cardiovascular complications are much older than the patients in our study. Even in the event that rates of cardiovascular complications were available in the young, cannabis users would remain indistinguishable from nonusers. However, sudden unexpected cardiac death in persons younger than 35 years was assessed in Denmark from 2000 to 2006.³⁷ Many unexpected deaths remained unexplained (29%), which could result from a non‐negligible part of death in relation with drug uses, including cannabis, the most prevalent illicit drug worldwide,¹⁰ although only 9% of death with available toxicologic results had positive test for cannabinoids. In France, existing registries on coronary heart disease target only the 35‐ to 74‐year‐old population and exclude potential associated risk factors such as drug use history.³⁸ Between 2004 and 2007, average incidence rates of myocardial infarction and coronary deaths in patients aged 35 to 44 years were estimated to be 57 of 100 000 among men and 13 of 100 000 among woman: however, these data are hardly transferable to that of our study. Besides, the national Décès en Relation Avec l'abus de Medicaments et de Substances (DRAMES) study, which identifies and surveys deaths in relation to abuse, misuse, dependence, or accidental intake of psychoactive drugs, emphasized in 2011 a fair number (n=7) of cannabis‐positive analyses in deaths by unexplained cardiac arrest.³⁹ This constitutes another signal in favor of the growing set of evidence on the possible involvement of cannabis in cardiovascular outcomes. In addition, the prevalence of cannabis use is high in Europe with 14.9% of young European (15 to 24 years old) using cannabis in the actual year, and particularly in France, the third European country after the Czech Republic and Spain.⁴⁰

Under pathologic conditions (eg, imbalance of the endocannabinoid system), cannabinoids have been associated with cardiovascular dysfunctions.⁴¹ Thus, long‐term use of cannabis should be responsible for long‐lasting decreased blood pressure, heart rate and cardiac contractility; increased blood volume; and diminished circulatory responses to exercise: more generally, it is associated with decreased myocardial function. Moreover, because of these long‐ and short‐term complications, heart function is carefully controlled in subjects who take part in experimental studies with cannabis administration.⁴² These are consistent with centrally mediated, reduced sympathetic and enhanced parasympathetic activity.⁴³ The opposite can be observed in pathologic cardiovascular conditions: in animals, THC was shown to be responsible for vasoconstriction. Now, vasospasm could be a possible common origin for many of the cases we describe in the present study. Also, the direct impact of cannabinoids on factors such as nitric oxide or endothelial factors could explain the disparity of complications observed between cannabis and tobacco.⁴⁴ The latter is associated with deregulations observed after continuous exposition, which contrasts with the apparent immediacy of cannabis‐related cardiovascular disorders.

Such complications can be seen among young adults who use stimulant drugs (ie, cocaine, methamphetamine) that are known to be responsible for cardiovascular complications.^9,45 These stimulant drug users are likely to also be regular cannabis users.^46–47 Stimulant drug use may be less likely acknowledged than cannabis use for societal reasons, but that is not sufficient to exclude cannabis from being possibly linked to such outcomes. Our findings indicate that cannabis intoxication should be more systematically investigated in the medical management of cardiovascular complications observed in young adults. They lead us to recommend systematic investigation for cannabis use, through oral interviewing and urinary analysis, as also advocated by Wolff and colleagues.⁴⁸