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Marijuana / Cardiovascular Disease
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Download the PDF here
Marijuana use impacts midlife cardiovascular events in HIV-infected men - (05/17/17)
from Jules: looks like this review may have missed this study in HIV
23 January 2018
Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes: A Systematic Review
"Evidence that marijuana use either increases or decreases most cardiovascular risk factors is insufficient, as is evidence regarding any association between marijuana use and adverse cardiovascular outcomes (Table). The current available literature is limited by a preponderance of cross-sectional study designs. Although the literature includes several long-term prospective studies, they are limited by recall bias, a lack of robust longitudinal assessment of marijuana use, participants with infrequent marijuana use, and the relative youth of some of the cohorts.
As more states legalize the sale and consumption of marijuana, the number of Americans using it continues to rise (1,2). This increase in the use of marijuana highlights the need for a better understanding of its risks and benefits. One area of importance is its effect on cardiovascular disease, the number one cause of morbidity and mortality worldwide (3).
Marijuana may affect cardiovascular health in several ways. Like other psychoactive drugs, it may have hemodynamic effects that can precipitate events (4). The active ingredient in marijuana is Δ9-tetrahydrocannabinol (THC) (5), which is responsible for the psychoactive effects of marijuana through its interaction with cannabinoid receptors. These receptors are ubiquitous in the brain and its vasculature and present throughout the body, including the myocardium, coronary endothelium, and smooth muscle cells (6,7). In vitro and animal studies have reported that THC can modulate cannabinoid receptors on human cardiomyocytes and vascular smooth muscles, resulting in ischemia (7,8). In vitro studies also have demonstrated that THC influences the regulation of glucose and lipid metabolism, suggesting a possible effect on vascular risk factors (9,10). At the cellular level, THC may cause inflammatory cytokine release, alteration in lipid metabolism (11,12), and reactive oxygen species formation (13). These effects may potentiate the progression of vascular disease. Marijuana smoking, the predominant method of use, causes a 5-fold increase in the blood carboxyhemoglobin level and a 3-fold increment in the quantity of tar inhaled compared with tobacco (14). Studies on secondhand marijuana smoke have found endothelial dysfunction in rats after exposure (15).
Given the myriad ways in which marijuana might potentiate vascular disease, we conducted a systematic review to assess the effect of regular marijuana use on cardiovascular outcomes and their associated risk factors.
An important consideration in our understanding of marijuana effects relates to the standards of evidence necessary to identify harms. Using experimental trials to study marijuana harms is unethical; only observational studies are feasible, despite their inherent biases.Further, the greatest clinical uncertainty concerns older patients at higher risk for cardiovascular disease (such as those with hypertension and diabetes) who use marijuana regularly over long periods. Therefore, the best possible study to assess the effect of marijuana use on cardiovascular outcomes would be a prospective cohort study among higher-risk participants, with several exposure assessments during follow-up and a robust evaluation of baseline characteristics and outcomes. The best evidence currently available, in contrast, is from the MIOS and CARDIA cohorts, although both have serious flaws (26,28,34,35). Whereas MIOS assessed marijuana exposure only once and was limited by recall bias, CARDIA made several assessments of marijuana exposure, but the overall exposure in the cohort was minimal and the cohort was young and likely underpowered to assess the outcomes of stroke and cardiovascular mortality."
Annals of Int Med - Divya Ravi, MD, MPH; Mehrnaz Ghasemiesfe, MD; Deborah Korenstein, MD; Thomas Cascino, MD;and Salomeh Keyhani, MD, MPH
Abstract
Background:
Marijuana use is increasing in the United States, and its effect on cardiovascular health is unknown.
Purpose:
To review harms and benefits of marijuana use in relation to cardiovascular risk factors and clinical outcomes.
Data Sources:
PubMed, MEDLINE, EMBASE, PsycINFO, and the Cochrane Library between 1 January 1975 and 30 September 2017.
Study Selection:
Observational studies that were published in English, enrolled adults using any form of marijuana, and reported on vascular risk factors (hyperglycemia, diabetes, dyslipidemia, and obesity) or on outcomes (stroke, myocardial infarction, cardiovascular mortality, and all-cause mortality in cardiovascular cohorts).
Data Extraction:
Study characteristics and quality were assessed by 4 reviewers independently; strength of evidence for each outcome was graded by consensus.
Data Synthesis:
13 and 11 studies examined associations between marijuana use and cardiovascular risk factors and clinical outcomes, respectively. Although 6 studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and were not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, dyslipidemia, acute myocardial infarction, stroke, or cardiovascular and all-cause mortality was insufficient. Although the current literature includes several long-term prospective studies, they are limited by recall bias, inadequate exposure assessment, minimal marijuana exposure, and a predominance of low-risk cohorts.
Limitation:
Poor- or moderate-quality data, inadequate assessment of marijuana exposure and minimal exposure in the populations studied, and variation in study design.
Conclusion:
Evidence examining the effect of marijuana on cardiovascular risk factors and outcomes, including stroke and myocardial infarction, is insufficient.
Primary Funding Source:
National Heart, Lung, and Blood Institute. (PROSPERO: CRD42016051297)
As more states legalize the sale and consumption of marijuana, the number of Americans using it continues to rise (1, 2). This increase in the use of marijuana highlights the need for a better understanding of its risks and benefits. One area of importance is its effect on cardiovascular disease, the number one cause of morbidity and mortality worldwide (3).
Marijuana may affect cardiovascular health in several ways. Like other psychoactive drugs, it may have hemodynamic effects that can precipitate events (4). The active ingredient in marijuana is Δ9-tetrahydrocannabinol (THC) (5), which is responsible for the psychoactive effects of marijuana through its interaction with cannabinoid receptors. These receptors are ubiquitous in the brain and its vasculature and present throughout the body, including the myocardium, coronary endothelium, and smooth muscle cells (6, 7). In vitro and animal studies have reported that THC can modulate cannabinoid receptors on human cardiomyocytes and vascular smooth muscles, resulting in ischemia (7, 8). In vitro studies also have demonstrated that THC influences the regulation of glucose and lipid metabolism, suggesting a possible effect on vascular risk factors (9, 10). At the cellular level, THC may cause inflammatory cytokine release, alteration in lipid metabolism (11, 12), and reactive oxygen species formation (13). These effects may potentiate the progression of vascular disease. Marijuana smoking, the predominant method of use, causes a 5-fold increase in the blood carboxyhemoglobin level and a 3-fold increment in the quantity of tar inhaled compared with tobacco (14). Studies on secondhand marijuana smoke have found endothelial dysfunction in rats after exposure (15).
Given the myriad ways in which marijuana might potentiate vascular disease, we conducted a systematic review to assess the effect of regular marijuana use on cardiovascular outcomes and their associated risk factors.
Discussion
Evidence that marijuana use either increases or decreases most cardiovascular risk factors is insufficient, as is evidence regarding any association between marijuana use and adverse cardiovascular outcomes (Table). The current available literature is limited by a preponderance of cross-sectional study designs. Although the literature includes several long-term prospective studies, they are limited by recall bias, a lack of robust longitudinal assessment of marijuana use, participants with infrequent marijuana use, and the relative youth of some of the cohorts.
A MEDLINE search revealed a recent systematic review (46) of marijuana harms that identified 2 studies (rated as high ROB in the review) on the relationship between marijuana use and cardiovascular events (34, 39). We included both articles in our systematic review and assessed 1 of them differently, assigning its ROB as moderate rather than high (34). The strength of this study lies in the minimization of confounding. Marijuana users also engage in other behaviors that are associated with poor outcomes. The use of a case-crossover design in the study of marijuana compares each participant to him- or herself and eliminates this problem. The study was limited by recall bias related to the marijuana use assessment; otherwise, it was well-designed.
Although some cross-sectional studies in this review suggested that marijuana has metabolic benefits (21, 22, 25, 31-33), those with more robust analytic designs found no evidence of benefit (23), and other prospective studies found potentially harmful effects (28). These findings are of particular interest. Many articles in the lay press have suggested to the public that marijuana use has cardiovascular benefits, reduces blood pressure, stabilizes blood sugar levels, or improves cholesterol profiles (47, 48). Our review found insufficient evidence to support these claims. Given public opinion that marijuana is safe or even beneficial, the insufficiency of the literature is concerning (49). An active research agenda in this area is needed to provide the public with accurate information. Finally, despite the popular belief that marijuana use causes “the munchies” (50), we found no evidence that it is associated with weight gain or obesity.
An important consideration in our understanding of marijuana effects relates to the standards of evidence necessary to identify harms. Using experimental trials to study marijuana harms is unethical; only observational studies are feasible, despite their inherent biases. Further, the greatest clinical uncertainty concerns older patients at higher risk for cardiovascular disease (such as those with hypertension and diabetes) who use marijuana regularly over long periods. Therefore, the best possible study to assess the effect of marijuana use on cardiovascular outcomes would be a prospective cohort study among higher-risk participants, with several exposure assessments during follow-up and a robust evaluation of baseline characteristics and outcomes. The best evidence currently available, in contrast, is from the MIOS and CARDIA cohorts, although both have serious flaws (26, 28, 34, 35). Whereas MIOS assessed marijuana exposure only once and was limited by recall bias, CARDIA made several assessments of marijuana exposure, but the overall exposure in the cohort was minimal and the cohort was young and likely underpowered to assess the outcomes of stroke and cardiovascular mortality.
Our systematic review also highlights other important evidence gaps. First, most studies failed to capture current and lifetime marijuana use adequately. More robust exposure assessment tools are necessary to allow evaluation of the acute and long-term health effects of marijuana (51). Second, almost a quarter of the studies failed to report the specific route of cannabis use and the chemical constitution of the cannabis examined. The number of marijuana users, as well as the variety of routes (for example, vaping, dabbing, ingesting, topical application), is increasing; therefore, collection of data regarding use must be more standardized, because the various forms may differ in toxic effects. In particular, high-quality safety data on the effects of edible marijuana on the cardiovascular system are lacking. The effects of THC persist in the body longer after oral administration than inhalation. Prospective studies examining the effects of edible marijuana on other cardiovascular events, such as acute myocardial infarction and stroke, are necessary, especially because use of edible forms is increasing among older adults, who are at higher risk for cardiovascular disease (52).
Our study has several limitations that deserve comment. We excluded articles not published in English; thus, we may have overlooked relevant studies. The diverse representation of outcomes across studies, variation in study design, and frequent lack of effect size reporting precluded a meta-analysis. In addition, most studies inadequately assessed marijuana exposure. Finally, most studies in this review were rated as high ROB, so their results should be interpreted with caution.
In summary, although several studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, hyperlipidemia, acute myocardial infarction, stroke, and cardiovascular mortality was insufficient. Adequately powered prospective studies are needed to determine the effect of chronic marijuana use on cardiovascular health.
Results
Literature Search
Our search yielded 3006 abstracts, 1669 of which were selected for further evaluation. Among these, 140 were selected for full-text review. Another 7 articles were added via author and reference tracking. Of these 147 papers, 24 met our inclusion criteria (Figure).
Study Characteristics
The evidence included 9 prospective cohort studies, 3 retrospective cohort studies, 2 case-control studies, 2 interventional studies (1 experimental study and 1 randomized trial), 7 cross-sectional studies, and 1 case-crossover study. Thirteen studies assessed cardiovascular risk factors, and 11 examined cardiovascular diseases. Most studies (n= 16; 66.7%) did not report the chemical constitution (for example, THC vs. cannabidiol) of the marijuana used in the study. Among articles that specified the form of marijuana used, the plant-based form was predominant (n= 7). Among those that specified the route of exposure, smoking was predominant (n= 11), followed by oral use (n= 2). Eleven papers did not report the specific route or form of marijuana administration (such as edible or smoked). Tables 1 to 4 of Supplement 3 detail the quality assessments for individual studies.
Cardiovascular Risk Factors
Metabolic Parameters: Lipid and Glucose Levels and Diabetes
Eleven studies provided data on 1 or more metabolic parameter outcomes, including hyperglycemia, dyslipidemia, and diabetes (Appendix Table 1).
Five cross-sectional studies (3 low and 2 high ROB) examined the association between marijuana use and hyperglycemia, dyslipidemia, metabolic syndrome, or diabetes (21-25). Marijuana use was measured by self-report in all studies. Four studies were based on 3 different waves of the NHANES (National Health and Nutrition Examination Survey; 1988 to 1994, 2005 to 2010, and 2005 to 2012) (21-23, 25). Three of the 4 used multivariable analysis to examine the association between marijuana use and metabolic parameters after adjustment for baseline characteristics. All 3 studies reported that marijuana use had different favorable associations, including a lower prevalence of diabetes (22), lower glucose levels (25), or higher high-density lipoprotein cholesterol concentrations (21, 22, 25). The fourth NHANES study (2005 to 2012) used both regression models and an instrumental variable analysis to examine associations (23). Marijuana use was associated with a beneficial metabolic effect in the regression model evaluation; no such effect was seen in the instrumental variable analysis. The final cross-sectional study was an exploratory analysis based on a small sample of 30 persons who were heavy marijuana users and 30 control participants matched for age, sex, ethnicity, and body mass index (BMI) (24). The authors identified no differences between groups in glucose tolerance or fasting glucose, total cholesterol, or triglyceride levels.
Three prospective studies (1 low, 1 moderate, and 1 high ROB) examined the association of marijuana use with risk factors (26-28). Two were based on the CARDIA (Coronary Artery Risk Development in Young Adults) cohort study, which examined the development and determinants of clinical and subclinical cardiovascular disease and its risk factors (26, 28). The CARDIA study began in 1985 to 1986 with 5113 black and white men and women aged 18 to 30 years. It included comprehensive in-person baseline and outcome data (sociodemographic characteristics; fasting glucose levels; BMI; diet and physical activity; and use of tobacco, alcohol, and other substances) and several exposure assessments during a long follow-up. Questions pertaining to marijuana use lacked detail on the form used, and exposure was quantified differently in each study. The low-ROB CARDIA-based study reported no associations between marijuana use and changes in glucose, high-density lipoprotein cholesterol, or triglyceride levels among heavy users (>1800 days of use) compared with nonusers during 15 years of follow-up (26). The moderate-ROB CARDIA-based study examined the association between marijuana use and diabetes and prediabetes (28). Marijuana use was ascertained in year 7 of the prospective cohort, and exposure was very limited: The highest category of use was a lifetime frequency of more than 100 times. Incidence of diabetes and prediabetes assessed at 4 subsequent follow-up examinations over 18 years was based on laboratory assessment (oral glucose tolerance or glycosylated hemoglobin test). A greater risk for prediabetes (hazard ratio [HR], 1.39 [95% CI, 1.13 to 1.71]) was identified among participants who reported using marijuana 100 or more times during follow-up compared with nonusers. The final prospective study (high ROB) followed 18000 Swedish men and women aged 18 to 84 years over 10 years but assessed marijuana exposure only once, at baseline (27). Measures of socioeconomic factors, diet, or other drug use at baseline were limited. No definite relationship was found between marijuana use and diabetes; CIs around the risk estimate were wide and compatible with either increased or decreased risk for diabetes with marijuana use (adjusted odds ratio, 0.94 [CI, 0.63 to 1.42]).
Two experimental studies (high ROB) examined the effect of cannabis-related compounds on metabolic factors (29, 30). Both had small sample sizes, and neither identified a measurable effect on metabolic parameters.
Obesity
The association between marijuana use and obesity was evaluated in 1 prospective study; 1 retrospective study; 1 randomized controlled trial; and 4 cross-sectional studies, 2 of which were based on NHANES (both low ROB) (21, 23). None of these studies found an association between marijuana use and BMI. Another cross-sectional study of 786 Inuit adults (moderate ROB) found that participants who used marijuana in the past year had a lower BMI than nonusers (odds ratio, 0.56 [CI, 0.37 to 0.84]). Although this study included important baseline characteristics, such as physical activity and dietary intake, the marijuana exposure assessment that divided the population into ever- and never-users was inadequate (31). Another study (high ROB) examined the charts of 297 women referred for weight management and found that marijuana use was associated with a lower BMI (R2, 0.96; P= 0.0173). This trial was limited by lack of adjustment for baseline characteristics and biased sample selection (32).
One prospective cohort study (low ROB) found no association between marijuana use and changes in BMI (mean [SE] adjusted BMI among nonusers, 28.9±0.3 kg/m2; mean [SE] BMI among frequent users, 28.9±0.3 kg/m2) (26). In a longitudinal pre birth study (the Mater-University of Queensland Study of Pregnancy) in 7223 women and their offspring (high ROB), the children were administered health, sociodemographic, and lifestyle questionnaires at ages 14 and 21 years (33). Although BMI was measured at both ages, a retrospective assessment of marijuana use was conducted only at age 21. Daily cannabis users were less likely (odds ratio, 0.2 [CI, 0.1 to 0.4]) to have a BMI greater than 25 kg/m2 than were never-users. This study was limited by inadequate baseline data on the children.
In a small double-blind placebo-controlled randomized trial (high ROB), the effect of 5 mg of dronabinol on BMI was assessed at 28 days in 13 of the 19 participants who completed follow-up (30). No statistically significant association was found between marijuana use and BMI.
Clinical Outcomes
Details of described studies are available in Appendix Table 2.
Acute Myocardial Infarction
The MIOS (Determinants of Myocardial Infarction Onset Study) was a case-crossover study that examined marijuana use as a potential trigger for myocardial infarction (34). In this multicenter trial, 3882 patients with acute myocardial infarction were interviewed, on average within 4 days of their infarction, about their history, timing, and frequency of marijuana smoking. Marijuana use in the 1 hour immediately preceding the onset of myocardial infarction symptoms was then compared with its expected frequency on the basis of self-reported use during the previous year. Of the 3882 patients, 9 (0.2%) and 124 (3.2%) reported smoking marijuana within 1 hour of the onset of myocardial infarction symptoms and in the previous year, respectively. The myocardial infarction risk in the first hour after smoking was greater than that expected among users (relative risk, 4.8 [CI, 2.4 to 9.5]). That individuals served as their own control helped limit confounding from other behaviors that may be associated with marijuana use. The study, however, was assessed as moderate ROB, primarily because of recall bias.
Stroke
Two prospective studies examined the effect of marijuana exposure on stroke and transient ischemic attack (35, 36). One study (moderate ROB), based on CARDIA, reported that marijuana was not associated with stroke (adjusted HR, 0.65 [CI, 0.16 to 2.66]; P= 0.76); however, the exposure was minimal (median lifetime of 0.51 marijuana-years or 50 times) and the population was young and healthy (35). Another study (high ROB) enrolled 49321 Swedish men conscripted into compulsory military service between the ages of 18 and 20 years. They were followed until age 59 to assess the initial occurrence of stroke. No association between cannabis use and stroke (HR, 0.93 [CI, 0.34 to 2.57]) was identified, but the study was limited by potential misclassification of the exposure, given that it was not reassessed over 25 years of follow-up and adjustment for baseline characteristics was inadequate (36).
A third study (high ROB) using a case-control design compared patients (aged 18 to 55 years) admitted to the hospital for stroke or transient ischemic attack with other, matched hospitalized patients. It found no association between stroke and plant-based marijuana use (adjusted odds ratio, 1.59 [CI, 0.71 to 3.70]); however, the study was limited because it measured use with urine toxicology screens, and although all case participants were screened, it is unclear why the control participants underwent screening. The urine drug screen may have misclassified exposure, because results may remain positive for up to 10 weeks (37).
Cardiovascular Mortality and All-Cause Mortality
Two prospective cohort studies (both high ROB) involving myocardial infarction survivors enrolled in MIOS between 1989 and 1996 examined the association between marijuana use and mortality (38, 39). Marijuana use in the year before the first myocardial infarction was self-reported at baseline and was not evaluated again. Cause of death was assessed by physician review of death certificates. In the study that followed patients for a median of 3.8 years, baseline use of marijuana once weekly or more (HR, 4.2 [CI, 1.2 to 14.3]) and less than once weekly (HR, 2.5 [CI, 0.9 to 7.3]) was associated with an increased risk for cardiovascular mortality compared with nonuse. This study also found an association between marijuana use and an increased risk for all-cause mortality (HR, 3.0 [CI, 1.3 to 7.0]; P= 0.009) (38). In the other MIOS-based study, which followed patients for a median of 12.7 years, any marijuana use was associated with an increased risk for all-cause mortality compared with nonuse, although the finding was not statistically significant (HR, 1.29 [CI, 0.81 to 2.05]; P= 0.28) (39).
Another investigation (moderate ROB) used CARDIA data to examine the association between cumulative lifetime marijuana use and cardiovascular mortality (35). This study measured exposure several times and had robust assessment of baseline characteristics and outcomes. It found no association between marijuana use (cumulative ≥5 years and recent) and cardiovascular mortality (adjusted HR, 0.95 [CI, 0.2 to 4.59]). The study also included a composite outcome of cardiovascular mortality, stroke, and coronary heart disease and, again, found no association between 5 or more years of marijuana use and this combined outcome (adjusted HR, 0.72 [CI, 0.35 to 1.50]). However, median cumulative marijuana exposure in the cohort was minimal (0.51 marijuana-years over 26 years). Further, although participants were followed for 26 years, the median age at recruitment was 18 to 30 years. Because of these factors, the study probably was underpowered to assess the association between marijuana use and cardiovascular disease. Finally, a retrospective cohort study (high ROB) linking NHANES to the National Center for Health Statistics survey found that users were at higher risk than nonusers for “hypertension-related” mortality. However, the marijuana exposure assessment was flawed, the outcome definition unclear, and the adjustment for baseline differences inadequate (40).
Other Cardiovascular Outcomes
Four studies examined the association between marijuana use and various outcomes, including peripheral arterial disease (41), irregular heartbeat (42), multifocal intracranial stenosis (43), and aneurysmal subarachnoid hemorrhage (44). All 4 studies were rated as high ROB, primarily because their marijuana exposure assessments and adjustments for baseline risk factors were inadequate.
Ongoing Studies
We found no relevant ongoing or completed studies at ClinicalTrials.gov (Supplement 1). Our search of NIH RePORTER revealed a prospective cohort study funded by the NIH in 2017 called Impact of Marijuana on Adherence, Risk Factor Control and Cardiovascular Outcomes (45). This project is evaluating the association between smoking marijuana in the past 30 days and the composite outcome of acute myocardial infarction, stroke, and revascularization in elderly patients with coronary artery disease.
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