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 . Studies on secondhand marijuana smoke have found endothelial dysfunction in rats after exposure . 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. The protocol was registered at PROSPERO at the start of our investigation. This review focuses on studies examining marijuana use and cardiovascular risk factors and outcomes; our protocol also includes searches and a review of hemodynamic changes associated with marijuana use that are not reported here. We searched several online databases for titles and abstracts between 1 January 1975 and 30 September 2017. We chose a 1975 start date because that was the year the Alaska Supreme Court ruled that the “Alaska constitution’s right to privacy protects an adult’s ability to use and possess a small amount of marijuana in the home for personal use” . We also conducted reference and author tracking to identify additional articles and searched Clinical-Trials.gov and the National Institutes of Health Research Portfolio for ongoing or completed studies not reported in the literature. For search terms and details, see Supplement 1 . All titles and abstracts were independently screened by 2 reviewers . We included observational studies and interventional studies that enrolled participants older than 12 years and were published in English. The exposure criterion was any form of marijuana .
The main outcomes of interest were cardiovascular risk factors and outcomes. We excluded case reports, case series, review articles, editorials,grow table and in vitro and animal studies. The same 2 investigators independently reviewed the full texts of selected articles to identify those that met our inclusion criteria. Disagreements regarding inclusion were resolved by a third reviewer . Inter rater reliability for the abstract selection process and the concurrent decision to include the article in the review was excellent . For the selection process, see Supplement 2 . Eleven studies provided data on 1 or more metabolic parameter outcomes, including hyperglycemia, dyslipidemia, and diabetes . Five cross-sectional studies examined the association between marijuana use and hyperglycemia, dyslipidemia, metabolic syndrome, or diabetes . Marijuana use was measured by self-report in all studies. Four studies were based on 3 different waves of the NHANES . Three of the 4 used multi-variable 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 , lower glucose levels , or higher high-density lipo-protein cholesterol concentrations . The fourth NHANES study used both regression models and an instrumental variable analysis to examine associations . 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 . The authors identified no differences between groups in glucose tolerance or fasting glucose, total cholesterol, or triglyceride levels. Three prospective studies examined the association of marijuana use with risk factors .
Two were based on the CARDIA cohort study, which examined the development and determinants of clinical and sub-clinical cardiovascular disease and its risk factors . 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 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 compared with nonusers during 15 years of follow-up . The moderate-ROB CARDIAbased study examined the association between marijuana use and diabetes and pre-diabetes . 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 . A greater risk for prediabetes was identified among participants who reported using marijuana 100 or more times during follow-up compared with nonusers. The final prospective study followed 18 000 Swedish men and women aged 18 to 84 years over 10 years but assessed marijuana exposure only once, at baseline . 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 . Two experimental studies examined the effect of cannabis-related compounds on metabolic factors . Both had small sample sizes, and neither identified a measurable effect on metabolic parameters.
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 . None of these studies found an association between marijuana use and BMI. Another cross-sectional study of 786 Inuit adults found that participants who used marijuana in the past year had a lower BMI than nonusers . 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 . Another study examined the charts of 297 women referred for weight management and found that marijuana use was associated with a lower BMI . This trial was limited by lack of adjustment for baseline characteristics and biased sample selection . One prospective cohort study found no association between marijuana use and changes in BMI . In a longitudinal pre birth study in 7223 women and their offspring , the children were administered health, sociodemo-graphic, and lifestyle questionnaires at ages 14 and 21 years . Although BMI was measured at both ages,4×8 grow table with wheels a retrospective assessment of marijuana use was conducted only at age 21. Daily cannabis users were less likely 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 , the effect of 5 mg of dronabinol on BMI was assessed at 28 days in 13 of the 19 participants who completed follow-up . No statistically significant association was found between marijuana use and BMI. The MIOS was a case-crossover study that examined marijuana use as a potential trigger for myocardial infarction . In this multi-center 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 and 124 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 . 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.Two prospective studies examined the effect of marijuana exposure on stroke and transient ischemic attack .
One study , based on CARDIA, reported that marijuana was not associated with stroke ; however, the exposure was minimal and the population was young and healthy . Another study enrolled 49 321 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 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 . A third study using a case–control design compared patients 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 ; 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 . Two prospective cohort studies involving myocardial infarction survivors enrolled in MIOS between 1989 and 1996 examined the association between marijuana use and mortality . 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 and less than once weekly 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 . 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 . Another investigation used CARDIA data to examine the association between cumulative lifetime marijuana use and cardiovascular mortality . This study measured exposure several times and had robust assessment of baseline characteristics and outcomes. It found no association between marijuana use and cardiovascular mortality . 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 . However, median cumulative marijuana exposure in the cohort was minimal . 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 under-powered to assess the association between marijuana use and cardiovascular disease. Finally, a retrospective cohort study 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 . Four studies examined the association between marijuana use and various outcomes, including peripheral arterial disease , irregular heartbeat , multi-focal intracranial stenosis , and aneurysmal subarachnoid hemorrhage . All 4 studies were rated as high ROB, primarily because their marijuana exposure assessments and adjustments for baseline risk factors were inadequate.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 . 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 of marijuana harms that identified 2 studies on the relationship between marijuana use and cardiovascular events . We included both articles in our systematic review and assessed 1 of them differently, assigning its ROB as moderate rather than high . The strength of this study lies in the minimization of confounding.The use of a case-crossover design in the study of marijuana compares each participant to him- or herself and eliminates this problem.