Association between Current and Cumulative Cannabis use and Heart Rate. The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

: Recent current cannabis use was associated with lower resting heart rate. The findings appeared to be transient, as past cumulative exposure to cannabis was not associated with heart rate. This adds to the growing body of evidence suggesting a lack of deleterious association of cannabis use at a level typical of the general population on surrogate outcomes of cardiovascular disease.

: CARDIA participants contributed to 35,654 individual exams over 30 years. At the Year 30 exam, 471/3,269 (14%) currently used cannabis. In multivariable adjusted models, compared to no current use, using cannabis five times per month was associated with lower heart rate of -0.7 bpm (95% CI: -1.0 to -0.3), and daily use with lower heart rate of -2.1 bpm (95% CI: -3.0 to -1.3, overall p<0.001). Cumulative exposure to cannabis use was not associated with heart rate.

: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a large prospective cohort of 5,115 Black and white women and men followed over 30 years. We explored the association between cannabis exposure and heart rate, adjusted for demographic factors, cardiovascular risk factors, alcohol and other illicit drug use, physical activity, and beta-blockers, in mixed longitudinal models censoring participants with cardiovascular disease.

: Resting heart rate can predict cardiovascular disease. Heart rate increases with tobacco smoking but its association with cannabis use is unclear. We studied the association between current and cumulative cannabis use and heart rate.

We set out to determine the association between heart rate and current and cumulative cannabis use in a large cohort followed over three decades, with multiple assessment of cannabis, heart rate, and a rich set of confounders.

Another important surrogate outcome is resting heart rate, which has been associated with incident heart failure and cardiovascular disease.Prospective cohort studies suggested that risk of coronary atherosclerosis,myocardial ischemia, ventricular arrhythmias, and left ventricular function continuously increase with heart rate over 60 bpm.A 2016 review on cannabis and cardiovascular disease reported an association between acute exposure to cannabis and transient increase in heart rate,but repeated exposure over a few days lowered heart rate in various studies.These studies were small and often lacked adjustment for confounders such as physical activity, multiple cardiovascular risk factors, and medication use affecting heart rate.

Association between Lifetime Marijuana use and Cognitive Function in Middle Age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade.

The current research regarding the effects of cannabis use and cardiovascular health is mixed. In the early 2000s and 2010s, case reports and small retrospective studies suggested cannabis raised the risk of myocardial infarctions. In-vitro studies of the main psychoactive agent in cannabis, Tetrahydrocannabinol (THC), tried to explain the suggested deleterious effects on smooth muscles cells and the myocardium, but found ambiguous results.On the other hand, large prospective cohort studies in the USA, Sweden, and Belgium published between the late 1990’s and the end of the 2010’s (5,000 to 65,000 participants) found no association between cannabis use and incident cardiovascular disease. These populations might have been too young, or the cannabis exposure too low to find associations with cardiovascular disease. Researchers thus studied surrogate outcomes, and found no association between cannabis and subclinical atherosclerosis, carotid intima-media thickness, or ECG abnormalities.

Association between marijuana use and electrocardiographic abnormalities by middle age The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Prognostic value of ECG findings for total, cardiovascular disease, and coronary heart disease death in men and women.

Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes: A Systematic Review. Marijuana Use and Cardiovascular Risk Factors and Outcomes.

Brief Commentary: Marijuana and Cardiovascular Disease—What Should We Tell Patients?Marijuana and Cardiovascular Disease.

French Association of the Regional A, Dependence Monitoring Centres Working Group on Cannabis C. Cannabis use: signal of increasing risk of serious cardiovascular disorders.

Cannabis is used at least once yearly by 18% of the U.S. population, and use by middle-aged people is rising.For example, twelve percent of men between 60 and 64 years of age reported to use cannabis at least once monthly.As more jurisdictions legalize its use, health care professionals, consumers, the public, and policy makers need to know if cannabis use is associated with adverse clinical or surrogate outcomes, especially the association between cannabis use and cardiovascular risk factors and outcomes, as highlighted by the 2020 statement from the American Heart Association.

Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes: A Systematic Review. Marijuana Use and Cardiovascular Risk Factors and Outcomes.

Brief Commentary: Marijuana and Cardiovascular Disease—What Should We Tell Patients?Marijuana and Cardiovascular Disease.

Prevalence of Marijuana Use Disorders in the United States Between 2001-2002 and 2012-2013.

The National Heart, Lung and Blood Institute contributed to the design and conduct of the CARDIA study. Before we submitted for publication, the CARDIA P&P committee reviewed and approved the manuscript and its scientific content.

Our sensitivity analyses included: 1. stratified analyses by sex and race; 2. using heart rate measured on ECG readings, with data available for baseline, Year 7, and Year 20; 3. analyses on participants that used cannabis in the 24 hours prior to the study visit, with data available for baseline, Year 2, 5, and 30; 4. fitting linear regressions for each clinical visit instead of pooling all the visits; 5. as positive control, models with current tobacco smoking (cigarettes per day) and cumulative tobacco use (tobacco pack-years) as main predictors; and 6. To estimate clinical significance of heart rate differences in cannabis use, exploratory models that used beta-blockers as the main exposure. Tests of statistical significance were two-tailed; alpha level was 0.05. All analyses were conducted with Stata version 14.2 (StataCorp LP, College Station, TX, USA).

First, we fitted unadjusted models with fixed effects for current cannabis use (days of cannabis use within the last month), and cumulative cannabis use (cannabis-years of exposure), separately. Second, we fitted minimally adjusted models including demographics, adding fixed effects for the covariables used in CARDIA to achieve balanced sampling (age, race, sex, study site, years of education). Third, we fitted fully adjusted models, adding fixed effects for alcohol, physical activity, serum lipids, BMI, systolic and diastolic blood pressure, beta-blockers, antidepressants, antipsychotics, and current cocaine, amphetamines, and heroin use. We censured participants with incident cardiovascular disease during follow-up, to eliminate potential bias of reversing the temporal order of predictor and outcome. We used inverse probability of censoring weights (IPCWs) to minimize potential bias by informative censoring for the main outcome heart rate.. We used last-value-carried-forward and backward imputation for missing covariables and performed sensitivity analyses using multiple imputation methods.

We used descriptive statistics to compare participants’ heart rate at different levels of current and cumulative cannabis use on every visit. To account for within-subject correlation of repeated measures and to model individual departures from the trajectories determined by the fixed effects, we used linear mixed models with correlated random subject-specific intercepts and slopes.

We used number of daily smoked tobacco cigarettes at every visit and cumulative lifetime exposure to tobacco cigarettes in pack-years.Occasional smoking was not queried in CARDIA. We estimated alcohol consumption as Education (in years) was the highest educational grade the participant reached by each exam. Physical activity was measured at every visit with questions on how much time per week the participant spent in 13 categories of leisure, occupational, and household physical activities over the past 12 months.Cardiovascular risk factor measurements included blood pressure, cholesterol levels [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides], body mass index (BMI), use of beta-blockers, antidepressants, antipsychotics, current and cumulative alcohol use (1 drink-year corresponding to 365 days/year x 1 drink/day, see online Appendix), binge drinking episodes, and current exposure to cocaine, amphetamine, and heroin. These variables were collected at each CARDIA examination.

Before assessing heart rate at every exam, participants were sitting in a quiet room for five minutes. Heart rate was then measured manually by study staff before blood pressure by palpation of the radial artery, counting the number of beats in a 30-second interval. This number was multiplied by two to get beats per minute (bpm). At Year 0, 7, and 20, heart rate was also measured with a single resting-ECG reading (ten seconds of recording time of sufficient quality).

Multiple cannabis use variables are available for all nine visits (baseline, and follow-up Years 2, 5, 7, 10, 15, 20, 25, and 30), but CARDIA did not assess modality (e.g. smoked or ingested) of cannabis use. Current cannabis use was assessed by the following survey question: “During the last 30 days, on how many days did you use cannabis?” Direct self-reported lifetime exposure was assessed by the question: “About how many times in your lifetime have you used cannabis?” We used current use and baseline lifetime use to compute cannabis-years; 1 year of exposure was equivalent to 365 days of cannabis use. We assumed that current use at each visit (the number of days of cannabis use in the month before the visit) reflected the average number of days of use during the months before and after each visit. We estimated cumulative lifetime use by totaling the number of days using cannabis during follow-up. We adjusted our estimate upwards whenever participants self-reported higher lifetime use than we computed for each visit.Cannabis use in the 24 hours before the exam was queried at baseline and Years 2, 5, and 30: “Did you use cannabis in the last 24 hours?” (See online Appendix for more information on computing cannabis exposure).

We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a cohort of 5,115 self-identified Black and white, women and men, aged between 18 and 30 years at baseline, in four study sites in the USA (Birmingham, AL, Chicago, IL, Minneapolis, MI, Oakland, CA), followed over 30 years. The study strove for equal distribution of race, sex, education, and age at each site. Participants were examined in up to nine clinical visits over the study period (1985/86 [Year 0] to 2015/2016 [Year 30]). All participants granted informed consent before entering the study and at every follow-up visit. All study protocols were approved by the institutional review boards at each site.

In a multivariable adjusted model, current use of beta-blockers was associated with lower heart rate (-4.4 bpm; 95% CI: -5.2 to -3.5) (Appendix Table 8).

At Year 30, 470 participants (14%) reported smoking tobacco. In multivariable adjusted models, mean heart rate was 67.8 bpm (95% CI: 67.6 to 68.0) in those not smoking tobacco and 70.1 bpm (95% CI: 69.7 to 70.5, overall p<0.001) in those smoking 20 cigarettes per day (Appendix Table 7). Cumulative exposure to tobacco was associated with slightly higher heart rate. The associations between tobacco smoking and heart rate as continuous outcome are presented in Appendix Figure 2.

At each clinical visit, current cannabis use was associated with lower heart rate, although results were not always statistically significant. Cumulative cannabis exposure was unassociated with heart rate in analyses stratified by visit (Appendix Table 6).

Results were similar to the main results. In multivariable adjusted models, mean heart rate was 68.6 bpm (95% CI: 67.6 to 69.6) in those not currently using cannabis and 66.4 bpm (95% CI: 65.4 to 67.4; overall p=0.01) in daily users (Appendix Table 5).

We obtained ECG measurements for a total of 11,375 participant-visits. Current cannabis use was associated with lower ECG heart rate. In multivariable adjusted models, mean ECG heart rate was 64.3 bpm (95% CI: 64.1 to 64.6) in those not currently using cannabis and 61.9 bpm (95% CI: 60.9 to 62.9, overall p<0.001) in daily users (Appendix Table 4).

Cumulative cannabis use was not associated with higher heart rate in any sex-race category (Appendix Tables 3a and 3b).

The tests for interaction terms between sex, race, or across the four sex-race strata (Black women/Black men/white women/white men) on the association between cannabis and heart rate were not statistically significant. We found no qualitative difference in the measure of association between cannabis use and heart rate in stratified analyses (Appendix Table 3a and 3b). We observed that current cannabis use was associated with lower heart rate in analyses stratified by women and men, or Black and white participants (e.g. heart rate was 68.8 bpm (68.5 to 69.1) in Black participants not using cannabis, and 65.5 bpm (64.5 to 66.5) in daily users, Appendix Table 3a). When stratifying analyses by sex and race, the association between cannabis and lower heart rate was not significant anymore in white women and white men (Appendix Table 3b).

In unadjusted models that included all participant-visits, mean heart rate was 68.4 beats per minute (bpm) (95% CI: 68.2 to 68.6) in those not using cannabis and 66.5 bpm (95% CI: 65.8 to 67.1, overall p<0.001) in daily users. Results were similar after multivariable adjustment; mean heart rate was 68.3 bpm (95% CI: 68.1 to 68.5) in those not using cannabis and 65.9 bpm (95% CI: 65.1 to 66.6, overall p<0.001) in daily users ( Table 2 ). In multivariable adjusted models, cumulative cannabis use was unassociated with heart rate ( Table 2 , Appendix Table 2 ). The associations between cannabis use and heart rate as continuous outcome are presented in Figure 1

Cumulative exposure to cannabis expressed in cannabis-years, with 1 cannabis-year of exposure equivalent to 365 days of cannabis use. Adjusted for current cannabis use.

Current exposure to cannabis assessed through the question, “During the last 30 days, on how many days did you use cannabis?”

P-values are from a Wald test. Main predictors (prolonged current cannabis use, cumualtive cannabis use) modeled flexibly. Results from multivariable adjusted mixed longitudinal models, censoring participants with incident CVD for current and future visits. Non-fatal very first event and corresponding date is captured from adjudicated morbidity data set and then linked to adjudicated death and follow up time data set to derive fatal and non-fatal outcome variables. First unadjusted, then adjusted for demographics (sex, race, age, education years, study center) and finally, for current and cumulative alcohol and tobacco use, total physical activity score, BMI, systolic and diastolic blood pressure, LDL, HDL, triglycerides, and exposure to betablockers, antidepressants and antipsychotics. Use of inverse probability of censoring weights in the multivariable adjusted model in oder to account for potential informative censoring during follow-up.

The 5,115 participants at baseline provided us with data for 35,654 participant-visits over 30 years. Of the 3,269 participants with available data on heart rate and current and cumulative cannabis use at the Year 30 follow-up exam, 1,866 (57%) were women and 1,549 (47%) were Black; 2,785 (85%) participants declared they have ever used cannabis, and 471 (14%) currently used cannabis ( Table 1 ). For participant's characteristics at baseline, see Appendix Table 1 . For distribution of cannabis use over time, see Appendix Figure 1

Results from multivariable adjusted mixed longitudinal models, using splines with three knots, and censoring participants with incident cardiovascular disease for current and future visits. Non-fatal very first event and corresponding date is captured from adjudicated morbidity data set and then linked to adjudicated death and follow up time data set to derive fatal and non-fatal outcome variables. Adjusted for demographics (sex, race, age, education years, study center), current and cumulative alcohol and tobacco use, total physical activity score, BMI, systolic and dastolic blood pressure, LDL, HDL, triglycerides, and exposure to betablockers, antidepressants and antipsychotics. Use of inverse probability of censoring weights in oder to account for potential informative censoring during follow-up. Cumulative exposure to cannabis expressed in cannabis-years, with 1 cannabis-year of exposure equivalent to 365 days of cannabis use, adjusting for current cannabis use. N included person-visits = 35,298.

Non-fatal very first event and corresponding date is captured from adjudicated morbidity data set and then linked to adjudicated death and follow up time data set to derive fatal and non-fatal outcome variables.

Physical activity measured with the CARDIA physical activity history questionnaire, which queries the amount of time per week spent in 13 categories of leisure, occupational and household physical activities over the past 12 months.3

The number of days on the illicit drug listed over the study duration was computed using current exposure (current use defined as any use within the last 30 days) at each visit and replaced by lifetime exposure when the latter was higher. Cocaine included other forms of cocaine, such as crack, powder, free base; amphetamines included speed, uppers and methamphetamines (Methods and Online Appendix, Supporting information).

Binge-drinking days defined as five or more drinks per episode (Online Appendix, Supporting information). If bingeing were to be constant over 25 years in one individual, 250 binge drinking days would correspond to 10 episodes of bingeing per year over 25 years.

Drink-years among those reporting ever drinking alcohol. A drink-year was defined as the total amount of ethanol consumed by a person who had had one alcoholic drink per day for 1 year (1drink-year = 17.24 ml of ethanol/drink × 1 drink/day × 365 days/year = 6,292.6 ml of ethanol).

Cumulative lifetime exposure to cigarettes in terms of pack-years, with 1 pack-year of exposure equivalent to 7,300 cigarettes (1 year × 365 days/year × 1 pack/days × 20 cigarettes/pack), among ever tobacco smokers.

Cumulative lifetime exposure to cannabis joints in terms of cannabis-years, with 1 cannabis-year of exposure equivalent to 365 days used cannabis (1 year × 365 days/year)2

By design, the CARDIA study sampled self-identified white men, white women, Black men and Black women in roughly equal numbers for participation in the study.1

P-values are from Kruskal-Wallis rank test for age, years of education, pack-years, number of cigarettes per day, cigarette smoking start age, drink-years, physical activity, and BMI, and from a χ2 test for race and sex, study site, current smoking status, and current alcohol use category. Values imputed for missing values.

Categories based on the answer to the questions: “Have you ever used cannabis?” and ‘During the last 30 days, on how many days did you use cannabis?’.

Characteristics of 3,269 participants with heart rate measurement and data of cannabis use at year 30 visit.

Table 1 Characteristics of 3,269 participants with heart rate measurement and data of cannabis use at year 30 visit.

Discussion and Conclusion

Current cannabis use was associated with lower resting heart rate, but cumulative cannabis exposure was not. Results were similar using ECG-measured heart rate, and after restricting to those who used cannabis within 24 hours of their visit. The association of cannabis and lower heart rate was similar between Black and white, and men and women.

37 McAlister FA WN

Ezekowitz JA

et al. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. , 38 Kovar D

Cannon CP

Bentley JH

Charlesworth A

Rogers WJ. Does initial and delayed heart rate predict mortality in patients with acute coronary syndromes?. , 39 Palatini P, Julius S. Elevated heart rate: a major risk factor for cardiovascular disease. Clinical and experimental hypertension (New York, N.Y.: 1993).2004;26:637-644. 40 Diaz A

Bourassa MG

Guertin MC

Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. In our study, we found mean resting heart rate to be around 68 bpm when counted manually, and around 64 bpm when ECG-measured. This is like resting heart rate found in other cohort studies.Differences in heart rate in current cannabis users were low (-2.1 bpm in daily users) and may not be clinically relevant compared to beta-blockers, which typically reduce heart rate by 8-15 bpm, and around 4 bpm in our exploratory models.

27 Jones RT. Cardiovascular system effects of marijuana. , 28 Schmid K

Schonlebe J

Drexler H

Mueck-Weymann M. The effects of cannabis on heart rate variability and well-being in young men. 28 Schmid K

Schonlebe J

Drexler H

Mueck-Weymann M. The effects of cannabis on heart rate variability and well-being in young men. 24 Pacher P

Bátkai S

Kunos G. Cardiovascular pharmacology of cannabinoids. 30 Bancks MP

Auer R

Carr JJ

et al. Self-reported marijuana use over 25 years and abdominal adiposity: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. 25 O'Sullivan SE Phytocannabinoids and the Cardiovascular System. Handbook of Cannabis. , 26 Kanakis Jr., C

Pouget JM

Rosen KM The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. , 27 Jones RT. Cardiovascular system effects of marijuana. , 28 Schmid K

Schonlebe J

Drexler H

Mueck-Weymann M. The effects of cannabis on heart rate variability and well-being in young men. , 29 Auer R

Vittinghoff E

Yaffe K

et al. Association between Lifetime Marijuana use and Cognitive Function in Middle Age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. , 31 Pope ZC

Gabriel KP

Whitaker KM

et al. Association between Objective Activity Intensity and Heart Rate Variability: Cardiovascular Disease Risk Factor Mediation (CARDIA). The differences in heart rate were smaller using ECG measures. Participants’ resting heart rate was lower in ECGs than in clinical measurements (overall, 64.3 bpm on ECGs vs. 68.4 bpm with clinical measures), probably because participants were supine for a few minutes during the ECG preparation, shifting autonomic nervous balance towards vagal predominance.Earlier publications suggested cannabis use alters the autonomic nervous system; the direction of the shift depends on frequency of use.A 2016 review on cannabis and cardiovascular disease reported an association between acute exposure to cannabis and transient increase in heart rate; its use may stimulate the sympathetic nervous system,but repeated exposure may lower heart rate because it reduces sympathetic and enhanced parasympathetic activity.Cannabis users may build up tolerance after a few days of use, shifting their autonomous nervous balance and reducing heart rate.

20 Nwabuo CC

Appiah D

Moreira HT

et al. Temporal Changes in Resting Heart Rate, Left Ventricular Dysfunction, Heart Failure and Cardiovascular Disease: CARDIA Study. , 22 Benowitz NL

Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. , 23 Benowitz NL

Jones RT. Prolonged delta-9-tetrahydrocannabinol ingestion. Effects of sympathomimetic amines and autonomic blockades. 12 Sidney S

Beck JE

Tekawa IS

Quesenberry CP

Friedman GD. Marijuana use and mortality. , 13 Sidney S. Cardiovascular consequences of marijuana use. , 14 Andreasson S

Allebeck P. Cannabis and mortality among young men: a longitudinal study of Swedish conscripts. , 15 Reis JP

Auer R

Bancks MP

et al. Cumulative Lifetime Marijuana Use and Incident Cardiovascular Disease in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. Prospective cohort studies suggested that risk of cardiovascular disease continuously increases with heart rate over 60 bpm.We did not find an increase in heart rate associated with cannabis use. Our findings align with epidemiological research on thousands of participants from Europe and the USA that found no association between cannabis and cardiovascular disease, mortality, or surrogate outcomes.

We found no significant interaction between sex, race, or across the four sex-race strata on the association between cannabis and heart rate. Given that CARDIA included similar proportions of self-identified Black and white women and men, we explored if the measure of associations differed by race and sex. We found no qualitative differences in the measures of associations. The non-significance of the measures of association in the analyses stratified by race and sex should be interpreted with caution given the expected lower power to detect statistically significant findings when stratifying by sub-categories in the absence of significant interaction.

Our study has limitations. While we could test the association between current exposure and heart rate, we could not test the association between hyper-acute exposure to cannabis and heart rate; we did not know the date and time of the last exposure, or the time elapsed between exposures. The number of daily cannabis users in CARDIA was limited but constant during the study period: 87/5,113 (1.7%) daily cannabis users at baseline and 82/3,358 (2.4%) at Year 30. Since few participants had high current exposure to cannabis, our results may not be representative of this population, but we found that daily cannabis users had even lower heart rates than users with fewer or no use of cannabis ( Figure 1 ). Future studies should test the effects of acute cannabis use on heart rate and stratify analyses by occasional use or repeated exposure. As we had information on use of cannabis in days per month but not on joints per day, and as we calculated cumulative cannabis exposure on data reported every two to five years, our estimates bear some uncertainties. The CARDIA questionnaire did not inquire about the modality of use of cannabis (e.g. smoked or ingested) or its type (e.g. THC content). Because cannabis use was illegal during the study, social desirability bias may have affected reporting. Also, while our results suggests that cannabis use is not associated with cardiovascular risks through higher heart rate, cardiovascular disease by other mechanisms not studied in this paper cannot be discounted and will require further studies. Finally, residual confounding due to different lifestyle potentially associated with cannabis use cannot be excluded.