We present the largest retrospective analysis of indexed admission AMI outcomes in marijuana users. The major findings of this study are: (1) mean age of admission for AMI was on average 10 years younger in marijuana users vs. non-users; (2) patients with reported marijuana use had a lower likelihood of in-hospital mortality compared with patients without reported marijuana use; and (3) patients who had used marijuana were more likely to be placed on mechanical ventilation during their hospital stay when compared to non-marijuana users.

Perhaps the most striking finding of our study is that marijuana use prior to AMI was associated with decreased in-hospital mortality post AMI. Interestingly, Desai et al [13], also found a significant decrease in mortality following AMI in marijuana users (OR 0.742, CI 0.693–0.795). However, the authors report simply that there was no increase in the odds of mortality in marijuana users following AMI. The similarities between the populations studied in this analysis and the study by Desai, et al [13] are striking: the marijuana users admitted with AMI were younger, male, African American with decreased incidence of hypertension, heart failure, diabetes and arrhythmias, with an increase in COPD and tobacco use. Given the similarities in population characteristics as well as in outcome measures, we would strongly suggest that marijuana use is associated with a significant decrease in in-hospital mortality rather than no increase in mortality.

There are a few possible explanations for this result. Importantly, it is critical to consider the younger age, decreased incidence of known cardiac risk factors, and increased tobacco use within the marijuana cohort, as these are potential confounding variables. In previous studies, Mittleman demonstrated the mean age of marijuana users that experienced a myocardial infarction was 48±8 years, compared with 62±13 years for non-users [15], and Desai found mean ages of AMI patients to be 49±11 and 58±9 in marijuana users versus non-users, consistent with what we found between users and non-users (47.2 versus 57.2 respectively) in our study. However, age-specific analysis and controlling for other potential confounders did not explain these findings in either our study or the previous study [13].

The protective effect we found on short-term outcomes post AMI could also be similar to the “smoker’s paradox,” referring to the observed short-term mortality benefit in tobacco users post AMI [16, 17]. Several studies over the past 20 years have described a mortality benefit conferred in tobacco users in the 30-day period post AMI, especially with use of thrombolytic therapy for treatment [18, 19]. Additionally, a “dose response” relationship has been described in the era of thrombolytic therapy for AMI, with the in-hospital mortality rate increasing from 2.3–4.7% in smokers, to 5.2–7.6% in former smokers, and to 7.0–13.8% in non-smokers [20]. In the era of PCI, the CADILLAC trial showed that the mortality benefit for tobacco users persisted for both 30-days and 1 year post AMI, and the dose dependent relationship between mortality benefit and current, former, and never smoking status was still present [17]. However, the mortality benefit at 1 year did not persist in multivariable analysis, when all of the population baseline characteristics were taken into consideration [17], as the population that used tobacco was 10 years younger on average and had significantly decreased rates of several comorbidities that have a negative effect on prognosis. This is similar to our population, such that the marijuana users were younger and had a significantly lower percentage of several important cardiac risk factors. Thus, it is entirely possible that we are observing an effect similar to the “smoker’s paradox” seen in tobacco users.

Another possible explanation for the mortality benefit seen in this study is that marijuana use may have provided a cardioprotective effect to users. While small clinical studies have previously suggested worse AMI outcomes associated with marijuana use [12], there is evidence that marijuana could be protective in the setting of myocardial ischemia [21–23]. In a study by Montecucco, a single dose of CB2 agonist administered during ischemia reduced the infarct size following reperfusion [22]. Decreased infiltration of inflammatory cells has been observed post-MI in mice that were pretreated with low dose THC [23], and other studies have the noted protective effects of CB2 receptor agonism against reperfusion injury and ischemia induced cardiac arrhythmias [21, 24, 25]. Furthermore, exposure to cannabinoids has been shown to decrease the area of necrosis during ischemia-reperfusion [24] and decrease the incidence of ischemia-reperfusion arrhythmias [24]. The observed outcomes of lower rates of mortality, shock, and IABP placement in this analysis could be the result of cardioprotective effects of marijuana during AMI conferred by activation of CB2 receptors [21–23].

Lastly, marijuana use may be associated with an increased incidence of smaller, non-fatal AMIs (in a younger population that may not have otherwise experienced a cardiac event). In univariate analysis, marijuana use was associated with an increase incidence of NSTEMI (53%) compared to no marijuana use (51%). However, marijuana use was not significantly associated with STEMI vs. NSTEMI in multivariable analysis (OR 1.00 [0.93–1.08], p = 0.96, Fig 4). Nonetheless, we compared STEMI and NSTEMI outcomes separately (S3 Fig), and found that marijuana use was associated with significantly lower odds of death in patients admitted with STEMI (OR 0.76 [0.58–0.98]) whereas there was no association between marijuana use and mortality in the NSTEMI group. In both STEMI and NSTEMI groups, patients with marijuana use were less likely to receive PCI than patients who did not use marijuana.

Several studies have indicated that smoking marijuana is associated with a dose dependent increase in heart rate [26–28]. Additionally, smoking marijuana decreases oxygen carrying capacity in the face of an increased oxygen demand. Aronow and Cassidy [29] demonstrated that among people with stable angina, smoking one marijuana cigarette decreases the time to angina with exercise by 48% compared with a 9% decrease in subjects smoking a marijuana placebo that did not contain delta-9-tetrahydrocannabinol. In this analysis, we found that marijuana use was associated with similar risk of receiving a coronary angiogram when compared to the control group, but marijuana-use patients were significantly less likely to undergo PCI. This suggests that these marijuana-use patients did not have significant coronary artery disease or acute plaque rupture as the inciting event for their AMI. Several case reports have suggested that vasospasm or acute thrombosis may represent a primary mechanism of AMI in marijuana users [30]. Each of these details must be taken into account when considering the results of this study.

Mechanical ventilation was the only outcome that demonstrated increased risk in patients that had used marijuana prior to admission for AMI. Subgroup analysis revealed that while marijuana use alone increased risk of mechanical ventilation, concomitant use of tobacco and marijuana were correlated with a substantially increased risk in comparison. There could be a number of explanations for this association. Although there is no data available on the method by which patients used marijuana, smoking remains the most common method of use. Smoking cannabis has been shown to have similar respiratory effects as smoking crack cocaine, such as severe bullous emphysema [27]. In addition to acute respiratory insults, smoking marijuana early in life may be an important risk factor for the development of obstructive airway disease later in life [26], and a follow-up study suggested a progressive decline in FEV1/FVC ratio with continuous marijuana smoking [28]. In the present analysis, a large percentage of the marijuana cohort also reported tobacco use, a known risk factor emphysema and chronic bronchitis. Considering the increased risk of mechanical ventilation post AMI, tobacco use and marijuana use may have an additive effect in our study.