Newer Studies on the Pulmonary Consequences of Marijuana

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Three relatively large-scale, controlled observational studies of the pulmonary consequences of regular use of marijuana have been conduced since 1980. One longitudinal cohort study reported on a convenience sample of heavy habitual smokers of marijuana alone (MS; N = 144) or with tobacco (MTS; N = 134), regular smokers of

Table 1

Pulmonary Consequences of Habitual Marijuana Use

• Increased prevalence of acute and chronic bronchitis (26,28,30)

• Inconsistent evidence of mild, progressive airflow obstruction (26-31)

• Visual evidence of airway inflammation (mucosal erythema, edema, and increased secretions) that correlates with inflammatory findings on airway biopsy (5)

• Histopathological alterations in tracheobronchial epithelium and subepithelium, including squamous metaplasia, basal cell hyperplasia, goblet cell hyperplasia, loss of ciliated surface epithelium, basement membrane thickening, epithelial inflammation, cellular disorganization, and increased nuclear-to-cytoplasm ratio (35,36)

• Overexpression of epidermal growth factor receptor and Ki-67, a nuclear marker of cell proliferation, by bronchial epithelial cells suggesting dysregulated growth and a risk for progression to bronchogenic carcinoma (36)

• Epidemiological evidence of increased risk for both bacterial and opportunistic pneumonia in HIV-seropositive individuals (83-85)

tobacco alone (TS; N = 80), and nonsmokers of either substance (NS; N = 99) recruited from the greater Los Angeles area (26,27). A second cohort study reported on a random stratified sample of young residents of Tucson, AZ (28,29). The third study was a population-based approach employing a birth cohort of individuals residing in Dunedin, New Zealand (30,31). Results of these studies have revealed a number of adverse pulmonary consequences of habitual marijuana use (Table 1).

3.2.2.1. Respiratory Symptoms

All three studies reported comparable results with respect to the association between regular marijuana smoking and chronic respiratory symptoms: the prevalence of chronic cough and/or sputum and wheeze was significantly higher in the marijuana smokers than in the nonsmokers, indicating a link between regular marijuana use and symptoms of chronic bronchitis. In the Los Angeles study, the incidence of acute lower respiratory infections was also higher in both MS and TS than NS, and the prevalence of chronic respiratory symptoms was comparable between MS and TS without evidence of additive effects in those who smoked both substances (26,27). However, an additive adverse effect of combined marijuana and tobacco smoking was suggested in the Tucson study (28,29).

3.2.2.2. Lung Function

The Los Angeles study failed to reveal any association between marijuana smoking and abnormalities on pulmonary function tests including sensitive tests of small airway function, the major site of involvement in COPD, and the diffusing capacity for carbon monoxide, a sensitive physiological indicator of emphysema. Moreover, no impact of even heavy regular smoking of marijuana alone (average of three joints per day) was found on the annual rate of change in the forced expiratory volume in 1 second (FEV1), an indicator of obstructive lung disease. In contrast, TS from the same cohort study demonstrated an accelerated rate of loss of FEV1 (27), consistent with the known predisposition of tobacco smokers to the development of COPD. These findings, therefore, did not support the concept that marijuana smoking leads to the devel opment of COPD and are consistent with the results of the rat exposure experiments cited above. In contrast, both the Tucson study and the Dunedin study did find evidence of mild airflow obstruction in association with marijuana use (28,30), and the airflow obstruction progressed over time in the continuing marijuana users (29,31). In contrast to the Los Angeles study, these two reports suggest that regular use of marijuana may be a risk factor for the subsequent development of COPD.

A specialized test of lung function that serves as a measure of alveolar epithelial permeability was carried out in a subset of the participants in the Los Angeles study (32). This test measures the rate of clearance from the lung of a radiolabeled small molecule (99mTc-DTPA) after inhalation. Elimination of the 99mTc-DTPA through the normally tight junctions between adjacent alveolar epithelial cells is accelerated in the presence of epithelial cell injury. Interestingly, while the results of this test were abnormal in regular tobacco smokers, consistent with tobacco-related lung injury, findings in the regular smokers of marijuana only (MS) were similar to those in nonsmoking healthy control subjects (NS). These negative results parallel the findings of a normal diffusing capacity for carbon monoxide in the MS and provide further evidence of disparate effects of marijuana and tobacco on lung function.

Thus, the available evidence is mixed and contradictory with regard to the possible link between marijuana and COPD. Clearly, further research is required to resolve these conflicting findings.

3.2.2.3. Effects on Airway Injury and Bronchial Epithelial Pathology

A subset of MS, TS, MTS, and NS from the Los Angeles cohort underwent fiberoptic bronchoscopy during which videotapes of the tracheobronchial airway mucosa were recorded and a series of mucosal biopsies obtained. The videotapes were reviewed in a blinded manner for the presence and degree of airway injury according to a semiquantitative scoring system ("bronchitis index"; ref. 5). Visual evidence of airway injury among the MS comparable to that noted in the TS was identified with abnormal scores for mucosal erythema, swelling, and increased secretions as compared to control NS. These visual abnormalities were corroborated by histopathologi-cal alterations on the mucosal biopsies in which an increased number and size of submucosal blood vessels, submucosal edema, and hyperplasia of the mucus-secreting surface epithelial cells (goblet cells) were observed. These findings indicate that regular smoking of marijuana by young adults leads to the same frequency, type, and degree of aiway inflammation as that seen in the lungs of regular tobacco smokers, despite a marked difference in the number of cigarettes smoked for the two types of substances (~3 joints per day in the MS vs 22 tobacco cigarettes per day in the TS).

It is possible that the presence of THC in marijuana smoke directly contributes to this higher than expected degree of airway injury. During smoking, THC is concentrated in the particulate phase of the smoke and deposited onto the respiratory mucosa. To examine its potential impact on cell function, endothelial cells (ECV 304 cell line), lung tumor cells (A549 cell line), and primary human airway epithelial cells were exposed in vitro to either purified THC or to smoke from marijuana cigarettes (8,17,33,34). Exposure to whole marijuana smoke stimulated the formation of more ROS than did exposure to the same amount of tobacco smoke. Furthermore, the magnitude of ROS was directly proportional to the concentration of THC in the cigarettes

(33). Marijuana smoke exposure was also associated with a reduction in intracellular glutathione and a toxic effect on mitochondial electron transport, resulting in ATP depletion (8,33,34). Mitochondrial dysfunction was observed with both purified THC and with the tar extracts from marijuana cigarettes, but not when cells were exposed to extracts from placebo marijuana smoke (not containing THC) or regular tobacco smoke. ATP depletion may impair important energy-dependent functions, including ciliary activity, phagocytosis, and normal fluid and electrolyte transport. Another potential consequence of mitochondial toxicity is an inhibition of apoptosis and the promotion of necrotic cell death, a pattern observed when respiratory epithelial cells are exposed to THC in vitro (17,34). The shift from apoptotic to necrotic cell death has been shown in animal models to disrupt normal epithelial defenses and promote inflammation and infection. Further studies are required to determine the relevance of these toxic cellular effects of THC to the degree of lung injury observed in marijuana smokers.

Bronchial mucosal biopsies were also obtained during fiberoptic bronchoscopy from 40 MS, 31 TS, 44 MTS, and 53 NS as part of their participation in the Los Angeles study (35). Light microscopy revealed extensive histopathological abnormalities in the epithelium of the MS, including goblet cell hyperplasia, reserve cell hyperplasia, squamous metaplasia, cellular disorganization, nuclear atypia, increased mitotic index, increased nuclear/cytoplasmic ratio, and inflammatory changes. These abnormalities were comparable to those noted in the TS, and the data suggested additive changes resulting from habitual use of both substances in the MTS. Some of these histological alterations are associated with the subsequent development of bronchogenic carcinoma in tobacco smokers (36).

Immunohistology was used to examine bronchial biopsies from 52 of the previously mentioned subjects for abnormal expression of genes involved in the pathogenesis of lung cancer, including overexpression of epidermal growth factor receptor (Fig. 2), a pathway that promotes autonomous cell growth, and Ki-67, a nuclear proliferation protein involved in cell replication (36). Results of these immunohistochemical studies revealed marked overexpression of epidermal growth factor receptor and Ki-67 among the MS compared to the NS and even numerically greater expression than was noted in the TS, with the suggestion of additivity in the MTS. Together with the aforementioned light microscopic changes, these findings suggest that regular marijuana smoking damages the airway epithelium, leading to dysregulation of bronchial epithelial cell growth and potentially malignant transformation.

3.2.2.4. Effects on Alveolar Macrophages

Alveolar macrophages (AM) are key immune effector cells in the lung that protect against infection and other noxious insults. AM were recovered by bronchoalveolar lavage during the bronchoscopy studies performed on subjects studied in Los Angeles. The number of AM recovered from MS was approximately twice that from NS, whereas the yield of AM from TS and MTS was three and four times that of NS, respectively, indicating an additive effect of the two substances on either AM recruitment to, and/or replication in, the lung (Table 2; Fig. 3; refs. 37 and 38). The increased accumulation of AM in the lungs of MS may be viewed as an inflammatory response to chronic low-grade lung injury from habitual exposure to irritants, including oxyradicals, within the smoke of marijuana. Ultrastructural examination of AM

Non-Smoker

Marijuana Smoker

Fig. 2. Habitual marijuana smoking is associated with abnormal expression of epidermal growth factor receptor (EGFR), a growth factor receptor that promotes autonomous cell growth. Airway mucosal biopsies were obtained from a cohort of nonsmokers and smokers of marijuana alone, tobacco alone, or both marijuana and tobacco, and evaluated for EGFR expression by immunohistology. Compared to the limited basal staining present in normal epithelium (left panel), biopsies demonstrated diffuse and dark staining of epithelial cells in 58% of marijuana smokers (right panel) and in 89% of those who smoked both marijuana and tobacco (not shown).

• Increased number of alveolar macrophages recovered by bronchoalveolar lavage from habitual marijuana smokers compared to nonsmokers (37,38)

• Increased size of intracytoplasmic inclusions (39)

• Impaired ability to kill Candida albicans (40) and Candida pseudotropicalis (41)

• Impaired phagocytosis and killing of Staphylococcus aureus (41,42)

• Decreased respiratory burst activity (superoxide anion production) under both basal and stimulated conditions (40)

• Limited tumoricidal activity against tumor cell targets in vitro (41)

• Reduced production of proinflammatory cytokines (tumor necrosis factor-a, interleukin-6, and granulocyte macrophage-colony-stimulating factor [GM-CSF]) when stimulated by bacterial lipopolysaccharide (41)

• Inability to express inducible nitric acid synthase or produce nitric oxide upon exposure to pathogenic bacteria, largely reversed by stimulation with proinflammatory cytokines such as GM-CSF and interferon-y (42)

recovered from MS revealed large irregular-shaped cytoplasmic inclusions that most likely contain particulates from marijuana tar, possibly including metabolites of THC and other cannabinoids (39). AM from TS also show abnormal cytosolic inclusion bodies, and the number of these inclusions is dramatically increased in smokers of both marijuana and tobacco (39). It seems plausible that the presence of a large number of abnormal inclusion bodies within the cytoplasm of AM from smokers of marijuana and/or tobacco might interfere with the function of these important immune effector cells.

Table 2

Effects of Marijuana on Human Alveolar Macrophages

NS MS TS MTS

Smoking Groups

Fig. 3. The number of alveolar macrophages (AM) increases in response to smoking. Bronchoalveolar lavage was used to recover AM from the lungs of nonsmokers (NS) and smokers of marijuana alone (MS), tobacco alone (TS), or both marijuana and tobacco (MTS). The number of AM recovered from MS was approximately twice that from NS, while the yield of AM from TS and MTS was three and four times that of NS, respectively, indicating an additive effect of the two substances on the recruitment and/or replication of macrophages in the lung.

NS MS TS MTS

Smoking Groups

Fig. 3. The number of alveolar macrophages (AM) increases in response to smoking. Bronchoalveolar lavage was used to recover AM from the lungs of nonsmokers (NS) and smokers of marijuana alone (MS), tobacco alone (TS), or both marijuana and tobacco (MTS). The number of AM recovered from MS was approximately twice that from NS, while the yield of AM from TS and MTS was three and four times that of NS, respectively, indicating an additive effect of the two substances on the recruitment and/or replication of macrophages in the lung.

The function of AM recovered from a subset of MS, TS, MTS, and NS was systematically evaluated ex vivo with respect to their phagocytic and killing activity for fungi and bacteria, their production of reactive oxygen and nitrogen intermediates during incubation with fungal or bacterial microorganisms, their ability to produce pro-inflammatory cytokines when stimulated, and their cytotoxic activity against tumor cell targets. Briefly, findings from these studies showed the following: (1) an impairment in fungicidal activity against Candida albicans and Candida tropicalis when AM from both MS and TS were compared to AM collected from control NS (40,41); (2) impairment in phagocytosis and killing of the pathogenic bacterium, Staphylococcus aureus, by AM from MS but not TS (41); (3) a reduction in basal superoxide production by AM from MS (in contrast to an increase in basal superoxide generation by AM from TS) and an apparent attenuation by AM from marijuana smokers of the stimulated production of superoxide by AM from concomitant smokers of both tobacco and marijuana (40); (4) an impairment in the generation of nitric oxide by AM from MS (but not TS) that parallels their impairment in bactericidal activity (42); (5) a reduction in production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-a and granulocyte macrophage-colony-stimulating factor (GM-CSF), by AM from MS when stimulated with bacterial lipopolysaccharide (41); and (6) an impairment in tumoricidal activity by AM from MS (41). A more detailed description of the effects of marijuana and THC on the function of AM and other immune cells and the likely clinical consequences of these immunological effects is provided below.

Table 3

Evidence Supporting Carcinogenic Effects of Marijuana

• Increased concentrations of pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs), including benzo-[a]-pyrene, in the tar phase of marijuana smoke compared to tobacco smoke (3,4,7)

• Fourfold increase in lung deposition of tar from marijuana smoke as compared to tobacco smoke mainly as a result of the differences in cigarette filtration and smoking technique (6)

• Activation of the cytochrome P4501A1 gene by THC, potentially enhancing the transformation of PAHs into active carcinogens (7)

• Accelerated malignant transformation in hamster lung explants exposed to marijuana smoke for up to 2 years (43)

• Premalignant histopathological alterations in bronchial biopsies from smokers of marijuana only, including metaplastic and dysplastic changes in the bronchial epithelium (35)

• Overexpression of cell proteins associated with malignant transformation in the bronchial epithelium of habitual smokers of marijuana (36)

• Systemic administration of A9-tetrahydrocannabinol accelerates the growth of non-small-cell lung cancer cells implanted into immunocompetent mice (44)

• Case series reporting a disproportionately high percentage of chronic marijuana smokers in young patients (<45 years) diagnosed with upper airway or lung cancer (45-49)

• Conflicting case-control studies demonstrating either a significantly increased risk (51) or no increased risk (52) of upper airway cancer in association with marijuana smoking

• Evidence from a case-control study of an increased risk for developing lung cancer in association with the combined use of cannabis (hashish) and snuff (tobacco), but not with hashish alone (53)

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