Introduction:
While the impact of marijuana use on symptoms of chronic bronchitis has been widely reported, association with lung function change over time, especially in those at risk of or with chronic obstructive pulmonary disease (COPD), has been less studied [1]. A recent longitudinal analysis of data from a subset of the CanCOLD study (2) reported that heavy current or former marijuana smoking defined by ≥20 joint-years (average number of joints smoked/day times number of years smoked) was associated with a significantly worse FEV1 decline over a mean of 5.9 years compared to never smokers of marijuana and tobacco after adjustment for tobacco pack-years (3). However, questions have been raised concerning the design of this study possibly influencing the results (4,5). To further address whether marijuana smoking impacts lung function change over time in mid-life and older persons, we performed a longitudinal analysis of the trajectory of lung function change in participants with or without COPD in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) with a tobacco smoking history of ≥20 pack-years.
Methods:
SPIROMICS is an ongoing prospective observational study initiated in 2011 which enrolled 2979 participants aged 40–80 years stratified into groups with no tobacco-smoking history/normal spirometry and those with ≥20 pack-years of tobacco smoking with or without COPD (6). The present analysis was restricted to the 1286 ever-tobacco smoking participants (≥20 pack-years) with non-missing marijuana use status at baseline (visit 1), at least 3 visits at which spirometry was performed (including visit 1) and no missing covariate information. These 1286 participants were then classified as never-marijuana smokers (NMS; n=697), former marijuana smokers (FMS; n=498) or current marijuana smokers (CMS; n=91). Since 262 of the 598 self-reported marijuana smokers did not provide a history of both their average daily amount of marijuana smoking and the number of years that they smoked marijuana, we could only calculate the cumulative lifetine history of marijuana smoking in joint years in the 336 participans who provided this information. These 336 self-reported ever-marijuana smokers were then categorized by their cumulative lifetime amount of marijuana smoked in joint-years, as follows: >0-<10 (n=204); 10-<20 (n=45); and ≥20 (n=87). The 697 never marijuana smokers (NMS) were classified as having 0 joint-years. Baseline demographic and clinical characteristics including smoking history (tobacco pack-years and marijuana joint-years) and smoking status were collected, and post-bronchodilator FEV1 and FVC were measured following 2005 ATS/ERS criteria (7). We used linear mixed effects models to assess annualized changes in post-bronchodilator FEV1 and FVC. Linear mixed models were fit including the primary predictor, marijuana smoking status (NMS, FMS, or CMS), and the following baseline covariates: age, sex, race, tobacco smoking status (current or former), tobacco pack-years and FEV1 % predicted. To assess dose-response relationships, the same models were used with the primary predictor being categorical marijuana joint-years at baseline (0, >0-<10, 10-<20 and ≥20).
Results:
Baseline characteristics
CMS, when compared with NMS, tended to be younger (60.9 vs. 65.0 years) and more often current tobacco smokers (48.4% vs. 30.0%), men (63.7% vs. 49.1%), and Black (25.3% vs. 16.0%). They also had a better post-bronchodilator FEV1 % predicted (83.4±23.2 vs. 72.6±23.9), but similar levels of respiratory symptoms compared with NMS. Directionally similar baseline findings were noted comparing FMS with NMS and those with ≥20 marijuana joint-years versus those with 0 joint-years.
Follow-up visits
Among participants with non-missing marijuana smoking status data and ≥3 spirometry visits at least one year apart (n=1286), the mean±SD number of spirometry visits was 4.0±2.0, 4.0±1.0 and 4.0±1 and the mean±SD follow-up time was 4.8±1.9, 5.2±1.7 and 5.1±1.6 years for NMS, FMS and CMS, respectively. Among the 1033 participants with data allowing calculation of joint-year history (including the 697 NMS with 0 joint years and the 336 ever-marijuana smokers with >0 joint-years), the mean±SD number of spirometry visits was 4.0±2.0, 4.0±1.0, 30±1.0 and 4.0±1.0 and the mean±number of follow-up years was 4.8±1.9, 4.9±1.7, 4.9±1.6 and 5.2±1.6 for those with 0, >0-<10, 10-<20 and ≥20 joint-years, respectively
Marijuana-smoking effect on change in lung function during follow-up
Estimated rates of change in FEV1 and FVC by baseline marijuana-smoking status and joint-year categories are shown in Table 1A and B, respectively. While numerically higher annual rates of FEV1 change (ml) were found comparing CMS with NMS, these differences were not statistically significant (Table 1A). Similar rates of change in FEV1 and FVC were found comparing FMS with NMS. Estimated rates of change in FEV1 and FVC between joint-year-based categories were very similar across all joint-year groups (Table 1B); e.g., the mean (95% CI) rates of change in FEV1 (ml/year) for those with ≥20 versus 0 joint-years was 36 (95% CI 47, 25) vs. 34 (95% CI 38, 30) with a non-significant between-group difference (2; 95% CI −14, 10; p=0.737).
Table 1.
Estimated year change in post-bronchodilator FEV1 and FVC by baseline marijuana use status (A) and joint-years (JYs) category (B)1; estimated hazard ratios for risk of developing obstruction (FEV1/FVC<0.70) by marijuana use status (C) and joint-years category (D)2
| Never n=697 |
Former n=498 |
Current n=91 |
Current vs. Never | |
|---|---|---|---|---|
| Outcomes | Coef. (95% CI) | Coef. (95% CI) | Coef. (95% CI) | Difference (95% CI) |
| FEV1 (ml/yr) | −34 (−39, −30) | −32 (−37, −27) | −44 (−56, −33) | −10 (−22, 2); p=0.117 |
| FVC (ml/yr) | −44 (−51, −38) | −42 (−49, −34) | −55 (−72, −37) | −10 (−29, 9); p=0.293 |
| 0 JYs n=697 |
>0-<10 JYs n=204 |
10-<20 JYs n=45 |
≥20 JYs n=87 |
≥20 JYs vs. 0 JYs | |
|---|---|---|---|---|---|
| Outcomes | Coef. (95% CI) | Coef. (95% CI) | Coef. (95% CI) | Coef. (95% CI) | Diff (95% CI) |
| FEV1 (ml/yr) | −34 (−38, −30) | −31 (−39, −24) | −36 (−52, −20) | −36 (−47, −25) | −2 (−14, 10); p=0.737 |
| FVC (ml/yr) | −45 (−51, −38) | −35 (−47, −23) | −53 (−78, −27) | −50 (−68, −32) | −5 (−24, 14); p=0.586 |
at average age at visit 1, average tobacco smoking pack-years at visit 1, average %predFEV1 at visit 1, and reference groups gender, white race, and not current tobacco smoker at visit 1. Models were fit using available case analysis
Discussion:
With the growing number of U.S. states legalizing marijuana for medicinal and/or recreational use along with increasing prevalence of marijuana smoking among adolescents and adults [7], we need to better understand marijuana’s impact on lung health in adult tobacco smokers in mid- and older life. Our analysis of the SPIROMICS cohort of current and former tobacco smokers with or at high risk of developing COPD examined marijuana smoking’s influence on lung function and represents an extension of a previously published cross-sectional analysis of the baseline findings in SPIROMICS [8]. Although we observed a trend toward higher rates of decline in post-bronchodilator FEV1 and FVC among CMS (but not FMS) compared with NMS, none of these differences across the three marijuana use groups were statistically significant. Similarly, comparing different categories of lifetime cumulative amounts of marijuana smoking, no significant differences were noted in rates of change in lung function, comparing even the heaviest lifetime users of marijuana (≥20 joint-years) with never marijuana smokers (0 joint-years).
Our findings contrast with the results of a study of Tan et al. [3] who reported a significantly greater rate of FEV1 decline among only the heaviest marijuana-smoking participants (≥20 joint-years) versus the never marijuana-smoking participants. Interestingly, the same study reported no difference in rates of FEV1 decline between the heaviest current versus former marijuana smokers, possibly due to the impact of continuing tobacco smoking among the marijuana quitters rather than an enduring effect of marijuana among the quitters, since nearly all marijuana smokers in CanCOLD also smoked tobacco. Moreover, while the reference group in the study of Tan et al. comprised never smokers of either substance without COPD, the reference control group in our analysis comprised never marijuana smokers with ≥20 pack-years of tobacco smoking, most of whom had COPD, providing more insight into a possible additive effect of marijuana on lung function decline among tobacco smokers.
Our study has several limitations. SPIROMICS was not specifically designed to examine the effects of marijuana smoking on lung function decline. The number of years to detect any demonstrable effect of exposure to marijuana is unknown, as is the magnitude of exposure and the possible exposure threshold, so that the power of our analysis to detect an effect on lung function of exposure to marijuana is unknown. Thus, our findings might be due to low statistical power due to the limitations of an inadequate sample size and/or a relatively short observation period and/or a true lack of association. These limiations underscore the need for further studies with a larger number of participants and a longer observation time to detect any clinically relevant effect of marijuana on the lung above and beyond that attributable to tobacco smoking. Another limitation was that marijuana use was self-reported and thus prone to recall or reporting biases. Moreover, SPIROMICS did not enroll a random sample, so our results may not be fully generalizable. In addition, marijuana is inhaled by various methods besides smoking a joint, including use of a pipe, bong, hookah, blunt, dabbing or vaping. or ingested as edibles/tinctures [9], none of which information was collected at baseline. However, the most common mode of inhalation of marijuana is via smoking a joint [10], although the amount of marijuana actually delivered with each use is highly variable and difficult to quantitate. Therefore, the metric we used for quantitating cumulative lifetime amount of marijuana smoked (joint-year) is crude. Moreover, using information collected at baseline, we did not take into account the fact that some CMS at baseline quit smoking marijuana during follow-up. However, those marijuana smokers in the ≥20 joint-years category who were current smokers at baseline but subsequently quit smoking marijuana would still remain in the same category if they indicated that they quit smoking marijuana at any post-baseline visit. Since previous authors have reported significantly greater decrements in lung function over time compared to never marijuana smokers only in those marijuana smokers with a lifetime history of ≥20 joint-years (3,11), the most relevant group of marijuana smokers in the SPIROMICS cohort would be those with ≥20 joint-years. Therefore, our findings with respect to the impact of such heavy cumulative lifetime amount of marijuana use might not be affected by any post-baseline changes in marijuana use status in this category unless quitting marijuana smoking slowed or halted subsequent declines in lung function. Since we cannot be sure that quitting marijuana smoking does indeed slow subsequent lung function decline with age, despite the findings by Tan et al. to the contrary (3), we regard this issue as a limitation.
Our study has some important strengths. Subjects were recruited and followed at twelve geographically varied sites nationwide with adequate representation of women and African-Americans, suggesting a measure of generalizability. Our data reflect on average four spirometric datapoints for each participant allowing for an adequate insight into the trajectory of lung function decline. A fairly large number of subjects had a history of current or former marijuana use with a moderate to heavy exposure (from 10 to over 20 joint-years), thereby allowing for an assessment of dose-response relationships.
Conclusions:
Among ever tobacco smokers of ≥20 pack-years with established COPD or at risk of developing COPD followed for approximately 5 years, we were unable to demonstrate that current and/or former marijuana smoking was independently associated with a significantly deleterious impact on lung function change over time. This result might be due to low statistical power due to the limitations of an inadequate sample size and/or a relatively short observation period and/or to a true lack of association, underscoring the need for further studies with a larger number of participants and with a longer exposure time for assessing any clinically relevant negative effect of marijuana on the lung.
Take home message:
In a cohort of 1863 tobacco smokers with COPD or at risk of COPD we failed to demonstrate any clinically significant association of current or former marijuana smoking of any cumulative lifetime amount with a worsening trajectory of FEV1 over an average of approximately 5 years.
Acknowledgements and Funding:
The authors thank the SPIROMICS participants and participating physicians, investigators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is at www.spiromics.org. We would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centers: Neil E Alexis, MD; Wayne H Anderson, PhD; Mehrdad Arjomandi, MD; Igor Barjaktarevic, MD, PhD; R Graham Barr, MD, DrPH; Lori A Bateman, MSc; Surya P Bhatt, MD; Eugene R Bleecker, MD; Richard C Boucher, MD; Russell P Bowler, MD, PhD; Stephanie A Christenson, MD; Alejandro P Comellas, MD; Christopher B Cooper, MD, PhD; David J Couper, PhD; Gerard J Criner, MD; Ronald G Crystal, MD; Jeffrey L Curtis, MD; Claire M Doerschuk, MD; Mark T Dransfield, MD; Brad Drummond, MD; Christine M Freeman, PhD; Craig Galban, PhD; MeiLan K Han, MD, MS; Nadia N Hansel, MD, MPH; Annette T Hastie, PhD; Eric A Hoffman, PhD; Yvonne Huang, MD; Robert J Kaner, MD; Richard E Kanner, MD; Eric C Kleerup, MD; Jerry A Krishnan, MD, PhD; Lisa M LaVange, PhD; Stephen C Lazarus, MD; Fernando J Martinez, MD, MS; Deborah A Meyers, PhD; Wendy C Moore, MD; John D Newell Jr, MD; Robert Paine, III, MD; Laura Paulin, MD, MHS; Stephen P Peters, MD, PhD; Cheryl Pirozzi, MD; Nirupama Putcha, MD, MHS; Elizabeth C Oelsner, MD, MPH; Wanda K O’Neal, PhD; Victor E Ortega, MD, PhD; Sanjeev Raman, MBBS, MD; Stephen I. Rennard, MD; Donald P Tashkin, MD; J Michael Wells, MD; Robert A Wise, MD; and Prescott G Woodruff, MD, MPH. The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Lisa Viviano, BSN; SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880 and U24 HL141762), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan.
Disclosures:
All authors report research grants support from the NIH/NHLBI, the COPD Foundation and the Foundation of the NIH related to this manuscript. Dr. Barjaktarevic reports grant support from AMGEN, Theravance and Viatris, Aerogen and GE Healthcare, and reports personal fees from Astra Zeneca, GSK, Theravance, Viatris, Verona Pharma, Aerogen, Grifols and Inhibrx all unrelated to this work. Dr Cooper reports personal consulting fees from NUVAIRA and MGC Diagnostics not related to this work. Dr. Hoffman is a founder and shareholder of VIDA Diagnostics. Dr. Drummond reports research grants support from the National Institutes of Health related to this manuscript; he reports research grants from the National Institutes of Health, Department of Defense, Boehringer-Ingelheim, Midmark and Teva unrelated to this work; he reports personal consulting fees from GlaxoSmithKline, Boehringer-Ingelheim, AstraZeneca, Teva, Midmark and Polarean unrelated to this work. Dr. Kanner has no conflicts of interest. Dr. Ohar reports consulting fees from Boehringer-Ingelheim, AstraZeneca, Verona, Sunovion and GlaxoSmithKlne unrelated to this work. Dr. Tashkin reports personal consulting fees from Viatris/Theravance Biopharma unrelated to this work.
Footnotes
Ethics Approvals: The SPIROMICS parent study was approved by the Institutional Review Boards of each individual site prior to the enrollment of participants. All participants provided informed consent.
Clinical Trial Registration: This study was registered on ClinicalTrials.gov, NCT01969344.
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