bs_bs_banner
EDITORIAL
Increasing cannabis use: What we still need to know about its effects on the lung Key words: chronic obstructive pulmonary disease, lung cancer, marijuana, pneumonia, respiratory risk. Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expired volume in 1 s; FVC, forced vital capacity.
Following a period of rapidly increasing cannabis use from the mid-1960s through the end of the following decade, cannabis use gradually declined but has more recently risen again, presumably due to changing attitudes concerning medicinal applications as well as recreational use. This new cannabis ‘epidemic’ has renewed concerns regarding the public health implications of the increasingly widespread use of this substance. Since the major route of cannabis administration is through smoking and because the contents of both the volatile and particulate phases of cannabis smoke are at least qualitatively similar to those of tobacco,1 there is naturally concern that habitual smoking of cannabis could lead to deleterious respiratory consequences similar in nature to those from regular tobacco smoking. The pulmonary effects of tobacco use have been amply documented, especially chronic obstructive pulmonary disease (COPD) and lung cancer, both of which are leading causes of morbidity and death worldwide. Unlike tobacco smoking, however, the respiratory risks of cannabis use have not been extensively studied, resulting in serious gaps in our knowledge concerning the true impact of cannabis on respiratory health. The article by Gates et al.2 in the current issue of Respirology provides a timely review of the knowledge gained from the comparatively sparse published literature in this area, the results of which reveal some important inconsistencies. The most consistent finding from the limited number of studies conducted to date, as reviewed by Gates et al.,2 is that chronic cannabis use (after adjustment for tobacco) is uniformly associated with an increased prevalence of symptoms of chronic bronchitis.3–8 This association is compatible with the finding by one group of investigators of widespread endoscopic and microscopic evidence of injury and inflammation involving the central airways of habitual smokers of cannabis without tobacco, including loss of ciliated epithelium and replacement by mucus-secreting goblet cells, the frequency and severity of which were comparable to that of smokers of tobacco alone.9,10 What is less clear, however, is the impact of chronic cannabis use on lung function, some studies showing little differences from nonsmoking controls,3,6,11 others revealing evi© 2014 Asian Pacific Society of Respirology
dence of mild airflow obstruction4,5 and another12 showing a non-significant trend towards decreases in forced expired volume in 1 s (FEV1) over a 20-year follow-up period only in the heaviest smokers, who, however, comprised only a minute fraction of the total cohort. Some of this inconsistency could be due to differences in the populations studied (including the age of the subjects), differences in the cumulative lifetime quantity duration of cannabis smoked and failure to take into account the effect of cannabisassociated increases in forced vital capacity (FVC)11 (possibly due to stretching of the lung by the repeated deep inhalations and prolonged breathhold times typical of cannabis smoking topography) on the FEV1/ FVC ratio, which is the preferred metric for identifying airflow obstruction. Since COPD is generally not diagnosed in individuals under age 40 years and its prevalence increases with age, there is also a need to include older subjects in future studies of the potential impact of cannabis, since failure to do so could underestimate the potential influence of cannabis on the development of this disease. The relationship of cannabis use to lung cancer is also contentious. While the presence of known carcinogens in cannabis smoke1 and histologic and immunopathologic evidence of potentially precancerous changes in the bronchial epithelium of smokers of cannabis without tobacco10,13 suggest a possible link to lung cancer, again the evidence from epidemiologic studies is mixed. While three of these studies suggest a positive association,14–16 all three have serious limitations, including (i) confounding by tobacco admixed with cannabis,14 (ii) small sample size leading to imprecise estimates of risk,15 and (iii) failure to account for the quantity duration of cannabis and tobacco during the follow-up period.16 On the other hand, two studies have notably failed to find a positive association with cannabis. One of these was a large retrospective cohort study of enrollees in a health maintenance organization (n = 64 855) but was limited by the relatively young age of the participants in relation to the age of highest tobacco-related cancer incidence and the short period of follow-up.17 The other was a large case–control study involving 611 lung cancer cases and 1040 matched controls which failed to find any positive association even in the heaviest users or any trend towards a dose– response relationship.18 The results of latter study, however, require replication, particularly in view of the conflicting results from other studies. Another area of uncertainty regarding the respiratory effects of cannabis is its possible association with Respirology (2014) doi: 10.1111/resp.12308
2 an increased risk of pneumonia. The combination of the potent immunosuppressive effect of delta-9 tetrahydrocannabinol on alveolar macrophage function19 and the cannabis-related loss of ciliated bronchial epithelium and its replacement by hyperplastic mucus-secreting bronchial epithelial cells10 would be expected to impair the lung’s defenses against infection, potentially predisposing to pneumonia, including tuberculosis. Moreover, cannabis has been reported to be contaminated with fungal and bacterial pathogens. While isolated case series and a few older epidemiologic studies in immunocompromised subjects suggest a possible link to pneumonia, additional, well-designed studies are required to establish a causal association. Finally, several cases of pneumothorax/ pneumomediastinum and bullous lung disease have been reported in mostly heavy smokers of cannabis along with variable amounts of tobacco. However, the prevalence of these abnormalities in the general population has not been studied, so that a cause-andeffect relationship cannot be inferred from these isolated case reports. Future research is urgently needed to resolve the inconsistencies in the published literature concerning the respiratory risks of regular cannabis use. In particular, studies relating to effects on lung function should include older individuals who are at higher risk for COPD and, when possible, incorporate a longitudinal study design to capture any progressive rate of lung function loss that is a characteristic of COPD. Further investigation of the potential risks for respiratory cancer should include well-designed case– control studies that contain sufficient numbers of heavy users whose cumulative lifetime use of cannabis has been recorded for reliable assessment of dose– response relationships, as well as large cohort studies of sufficient length of follow-up to encompass the age range in which cancer is most prevalent. Knowledge of the true impact of cannabis on lung and overall health is essential for credibly informing the public of the real health hazards of cannabis. Donald P. Tashkin, MD Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
REFERENCES 1 Moir LD, Rickert WS, Levasseur G, Larose Y, Maertens R, White P, Desjardins S. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem. Res. Toxicol. 2008; 21: 494– 502. 2 Gates P, Jaffe A, Copeland J. Cannabis smoking and respiratory health: consideration of the literature. Respirology 2014; 19: ••–••.
Respirology (2014)
Editorial 3 Tashkin DP, Coulson AH, Clark VA, Simmons M, Bourque LB, Duann S, Spivey GH, Gong H. Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am. Rev. Respir. Dis. 1987; 135: 209–16. 4 Bloom JW, Kaltenborn WT, Paoletti P, Camilli A, Lebowitz MD. Respiratory effects of non-tobacco cigarettes. Br. Med. J. 1987; 295: 1516–18. 5 Taylor DR, Poulton R, Moffitt TE, Ramankutty P, Sears M. The respiratory effects of cannabis dependence in young adults. Addiction 2000; 95: 1669–77. 6 Aldington S, Williams M, Nowitz M, Weatherall M, Pritchard A, NcNaughton A, Robinson G, Beasley R. Effects of cannabis on pulmonary structure, function and symptoms. Thorax 2007; 62: 1058–63. 7 Tan WC, Lo C, Jong A, Xing L, FitzGerald MJ, Vollmer WM, Buist SA, Sin DD. Marijuana and chronic obstructive lung disease—a population-based study. CMAJ 2009; 180: 814–20. 8 Moore BA, Augustson EM, Moser RP, Budney AJ. Respiratory effects of marijuana and tobacco use in a U.S. sample. J. Gen. Intern. Med. 2004; 20: 33–7. 9 Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP. Airway inflammation in young marijuana and tobacco smokers. Am. J. Respir. Crit. Care Med. 1998; 157: 928–37. 10 Fligiel SEG, Roth MD, Kleerup EC, Barsky SH, Simmons MS, Tashkin DP. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 1997; 112: 319–26. 11 Hancox RJ, Poulton R, Ely M, Welch D, Taylor DR, Machlan CR, Greene JM, Moffitt TE, Caspi A, Sears MR. Effects of cannabis on lung function: a population-based cohort study. Eur. Respir. J. 2010; 35: 42–7. 12 Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S. Association between marijuana exposure and pulmonary function over 20 years. JAMA 2012; 307: 173–81. 13 Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine and/or tobacco. J. Natl Cancer Inst. 1998; 90: 1198–200. 14 Berthiller J, Straif K, Boniol M, Voirin N, Benhaim-Luzon V, Ben Ayoub W, Dari I, Laouamri S, Hamdi-Cherif M, Bartal M et al. Cannabis smoking and risk of lung cancer in men. A pooled analysis of three studies in Maghreb. J. Thorac. Oncol. 2008; 3: 1398–403. 15 Aldington S, Harwood M, Cox B, Weatherall M, Beckert L, Hansell A, Pritchard A, Robinson G, Beasley R. Cannabis use and risk of lung cancer: a case-control study. Eur. Respir. J. 2008; 31: 280–6. 16 Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of lung cancer: a 40-year cohort study. Cancer Causes Control 2013; 24: 1811–20. 17 Sidney S, Quesenberry CP Jr, Friedman GD, Tekawa IS. Marijuana use and cancer incidence (California, United States). Cancer Causes Control 1997; 8: 722–8. 18 Baldwin GC, Tashkin DP, Buckley DM, Park AN, Dubinett SM, Roth MD. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am. J. Respir. Crit. Care Med. 1997; 156: 1606–13. 19 Shay AH, Choi R, Whittaker K, Salehi K, Kitchen CMR, Tashkin DP, Roth MD, Baldwin GC. Impairment of antimicrobial activity and nitric oxide production in alveolar macrophages from smokers of marijuana and cocaine. J. Infect. Dis. 2003; 187: 700–4.
© 2014 Asian Pacific Society of Respirology
EDITORIAL
Increasing cannabis use: What we still need to know about its effects on the lung Key words: chronic obstructive pulmonary disease, lung cancer, marijuana, pneumonia, respiratory risk. Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expired volume in 1 s; FVC, forced vital capacity.
Following a period of rapidly increasing cannabis use from the mid-1960s through the end of the following decade, cannabis use gradually declined but has more recently risen again, presumably due to changing attitudes concerning medicinal applications as well as recreational use. This new cannabis ‘epidemic’ has renewed concerns regarding the public health implications of the increasingly widespread use of this substance. Since the major route of cannabis administration is through smoking and because the contents of both the volatile and particulate phases of cannabis smoke are at least qualitatively similar to those of tobacco,1 there is naturally concern that habitual smoking of cannabis could lead to deleterious respiratory consequences similar in nature to those from regular tobacco smoking. The pulmonary effects of tobacco use have been amply documented, especially chronic obstructive pulmonary disease (COPD) and lung cancer, both of which are leading causes of morbidity and death worldwide. Unlike tobacco smoking, however, the respiratory risks of cannabis use have not been extensively studied, resulting in serious gaps in our knowledge concerning the true impact of cannabis on respiratory health. The article by Gates et al.2 in the current issue of Respirology provides a timely review of the knowledge gained from the comparatively sparse published literature in this area, the results of which reveal some important inconsistencies. The most consistent finding from the limited number of studies conducted to date, as reviewed by Gates et al.,2 is that chronic cannabis use (after adjustment for tobacco) is uniformly associated with an increased prevalence of symptoms of chronic bronchitis.3–8 This association is compatible with the finding by one group of investigators of widespread endoscopic and microscopic evidence of injury and inflammation involving the central airways of habitual smokers of cannabis without tobacco, including loss of ciliated epithelium and replacement by mucus-secreting goblet cells, the frequency and severity of which were comparable to that of smokers of tobacco alone.9,10 What is less clear, however, is the impact of chronic cannabis use on lung function, some studies showing little differences from nonsmoking controls,3,6,11 others revealing evi© 2014 Asian Pacific Society of Respirology
dence of mild airflow obstruction4,5 and another12 showing a non-significant trend towards decreases in forced expired volume in 1 s (FEV1) over a 20-year follow-up period only in the heaviest smokers, who, however, comprised only a minute fraction of the total cohort. Some of this inconsistency could be due to differences in the populations studied (including the age of the subjects), differences in the cumulative lifetime quantity duration of cannabis smoked and failure to take into account the effect of cannabisassociated increases in forced vital capacity (FVC)11 (possibly due to stretching of the lung by the repeated deep inhalations and prolonged breathhold times typical of cannabis smoking topography) on the FEV1/ FVC ratio, which is the preferred metric for identifying airflow obstruction. Since COPD is generally not diagnosed in individuals under age 40 years and its prevalence increases with age, there is also a need to include older subjects in future studies of the potential impact of cannabis, since failure to do so could underestimate the potential influence of cannabis on the development of this disease. The relationship of cannabis use to lung cancer is also contentious. While the presence of known carcinogens in cannabis smoke1 and histologic and immunopathologic evidence of potentially precancerous changes in the bronchial epithelium of smokers of cannabis without tobacco10,13 suggest a possible link to lung cancer, again the evidence from epidemiologic studies is mixed. While three of these studies suggest a positive association,14–16 all three have serious limitations, including (i) confounding by tobacco admixed with cannabis,14 (ii) small sample size leading to imprecise estimates of risk,15 and (iii) failure to account for the quantity duration of cannabis and tobacco during the follow-up period.16 On the other hand, two studies have notably failed to find a positive association with cannabis. One of these was a large retrospective cohort study of enrollees in a health maintenance organization (n = 64 855) but was limited by the relatively young age of the participants in relation to the age of highest tobacco-related cancer incidence and the short period of follow-up.17 The other was a large case–control study involving 611 lung cancer cases and 1040 matched controls which failed to find any positive association even in the heaviest users or any trend towards a dose– response relationship.18 The results of latter study, however, require replication, particularly in view of the conflicting results from other studies. Another area of uncertainty regarding the respiratory effects of cannabis is its possible association with Respirology (2014) doi: 10.1111/resp.12308
2 an increased risk of pneumonia. The combination of the potent immunosuppressive effect of delta-9 tetrahydrocannabinol on alveolar macrophage function19 and the cannabis-related loss of ciliated bronchial epithelium and its replacement by hyperplastic mucus-secreting bronchial epithelial cells10 would be expected to impair the lung’s defenses against infection, potentially predisposing to pneumonia, including tuberculosis. Moreover, cannabis has been reported to be contaminated with fungal and bacterial pathogens. While isolated case series and a few older epidemiologic studies in immunocompromised subjects suggest a possible link to pneumonia, additional, well-designed studies are required to establish a causal association. Finally, several cases of pneumothorax/ pneumomediastinum and bullous lung disease have been reported in mostly heavy smokers of cannabis along with variable amounts of tobacco. However, the prevalence of these abnormalities in the general population has not been studied, so that a cause-andeffect relationship cannot be inferred from these isolated case reports. Future research is urgently needed to resolve the inconsistencies in the published literature concerning the respiratory risks of regular cannabis use. In particular, studies relating to effects on lung function should include older individuals who are at higher risk for COPD and, when possible, incorporate a longitudinal study design to capture any progressive rate of lung function loss that is a characteristic of COPD. Further investigation of the potential risks for respiratory cancer should include well-designed case– control studies that contain sufficient numbers of heavy users whose cumulative lifetime use of cannabis has been recorded for reliable assessment of dose– response relationships, as well as large cohort studies of sufficient length of follow-up to encompass the age range in which cancer is most prevalent. Knowledge of the true impact of cannabis on lung and overall health is essential for credibly informing the public of the real health hazards of cannabis. Donald P. Tashkin, MD Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
REFERENCES 1 Moir LD, Rickert WS, Levasseur G, Larose Y, Maertens R, White P, Desjardins S. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem. Res. Toxicol. 2008; 21: 494– 502. 2 Gates P, Jaffe A, Copeland J. Cannabis smoking and respiratory health: consideration of the literature. Respirology 2014; 19: ••–••.
Respirology (2014)
Editorial 3 Tashkin DP, Coulson AH, Clark VA, Simmons M, Bourque LB, Duann S, Spivey GH, Gong H. Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am. Rev. Respir. Dis. 1987; 135: 209–16. 4 Bloom JW, Kaltenborn WT, Paoletti P, Camilli A, Lebowitz MD. Respiratory effects of non-tobacco cigarettes. Br. Med. J. 1987; 295: 1516–18. 5 Taylor DR, Poulton R, Moffitt TE, Ramankutty P, Sears M. The respiratory effects of cannabis dependence in young adults. Addiction 2000; 95: 1669–77. 6 Aldington S, Williams M, Nowitz M, Weatherall M, Pritchard A, NcNaughton A, Robinson G, Beasley R. Effects of cannabis on pulmonary structure, function and symptoms. Thorax 2007; 62: 1058–63. 7 Tan WC, Lo C, Jong A, Xing L, FitzGerald MJ, Vollmer WM, Buist SA, Sin DD. Marijuana and chronic obstructive lung disease—a population-based study. CMAJ 2009; 180: 814–20. 8 Moore BA, Augustson EM, Moser RP, Budney AJ. Respiratory effects of marijuana and tobacco use in a U.S. sample. J. Gen. Intern. Med. 2004; 20: 33–7. 9 Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP. Airway inflammation in young marijuana and tobacco smokers. Am. J. Respir. Crit. Care Med. 1998; 157: 928–37. 10 Fligiel SEG, Roth MD, Kleerup EC, Barsky SH, Simmons MS, Tashkin DP. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 1997; 112: 319–26. 11 Hancox RJ, Poulton R, Ely M, Welch D, Taylor DR, Machlan CR, Greene JM, Moffitt TE, Caspi A, Sears MR. Effects of cannabis on lung function: a population-based cohort study. Eur. Respir. J. 2010; 35: 42–7. 12 Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S. Association between marijuana exposure and pulmonary function over 20 years. JAMA 2012; 307: 173–81. 13 Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine and/or tobacco. J. Natl Cancer Inst. 1998; 90: 1198–200. 14 Berthiller J, Straif K, Boniol M, Voirin N, Benhaim-Luzon V, Ben Ayoub W, Dari I, Laouamri S, Hamdi-Cherif M, Bartal M et al. Cannabis smoking and risk of lung cancer in men. A pooled analysis of three studies in Maghreb. J. Thorac. Oncol. 2008; 3: 1398–403. 15 Aldington S, Harwood M, Cox B, Weatherall M, Beckert L, Hansell A, Pritchard A, Robinson G, Beasley R. Cannabis use and risk of lung cancer: a case-control study. Eur. Respir. J. 2008; 31: 280–6. 16 Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of lung cancer: a 40-year cohort study. Cancer Causes Control 2013; 24: 1811–20. 17 Sidney S, Quesenberry CP Jr, Friedman GD, Tekawa IS. Marijuana use and cancer incidence (California, United States). Cancer Causes Control 1997; 8: 722–8. 18 Baldwin GC, Tashkin DP, Buckley DM, Park AN, Dubinett SM, Roth MD. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am. J. Respir. Crit. Care Med. 1997; 156: 1606–13. 19 Shay AH, Choi R, Whittaker K, Salehi K, Kitchen CMR, Tashkin DP, Roth MD, Baldwin GC. Impairment of antimicrobial activity and nitric oxide production in alveolar macrophages from smokers of marijuana and cocaine. J. Infect. Dis. 2003; 187: 700–4.
© 2014 Asian Pacific Society of Respirology
