Effects of marijuana on the lung and its immune defenses
P. Tashkin, M.D.,
UCLA School of Medicine
Youth Substance Abuse Prevention Intiative: Resource Papers, March 1997, Center
for Substance Abuse Prevention, pp. 33-51.
Habitual marijuana use may lead to the following effects on the lung:
- acute and chronic bronchitis;
- extensive microscopic abnormalities in the cells lining the bronchial passages (bronchial epithelium), some of which may be premalignant;
- overexpression of genetic markers of progression to lung cancer in bronchial tissue;
- abnormally increased accumulation of inflammatory cells (alveolar macrophages) in the lung; and
- impairment in the function of these immune-effector cells (reduced ability to kill microorganisms and tumor cells) and in their ability to produce protective inflammatory cytokines.
Clinically, the major pulmonary consequences that may ensue from regular marijuana use (approximately one "joint" per day on the average) are pulmonary infections and respiratory cancer. Infections of the lung are more likely in marijuana users due to a combination of smoking-related damage to the ciliated cells in the bronchial passages (the lung's first line of defense against inhaled microorganisms) and marijuana-related impairment in the function of alveolar macrophages (the principal immune cells in the lung responsible for defending it against infection). Patients with preexisting immune deficits due to AIDS or cancer chemotherapy might be expected to be particularly vulnerable to marijuana-related pulmonary infections. Finally, biochemical, cellular, genetic, animal, and human studies all suggest that marijuana is an important risk factor for the development of respiratory cancer. However, proof that habitual use of marijuana does in fact lead to respiratory cancer must await the results of well-designed case-control epidemiologic studies. Such studies should now be feasible after the passage of 30 years since the initiation of widespread marijuana use among young individuals in our society in the mid-1960s.
Marijuana is the second most widely smoked substance in our society after tobacco (Johnston et al. 1995, 1996). Since marijuana is smoked, the lung is exposed to higher concentrations of the inhaled smoke constituents than any other tissue, causing concern about possible harmful effects of marijuana on the lung by analogy with the wellknown detrimental effects of tobacco on the lung (U.S. Department of Health, Education, and Welfare 1979). Pulmonary consequences of regular tobacco smoking include (1) lung cancer; (2) chronic obstructive pulmonary disease (COPD), which consists of chronic bronchitis and emphysema; and (3) an increased incidence of respiratory tract infection due to smoking-related impairment in the lung's host defenses. The importance to public health of these pulmonary consequences of tobacco is underscored by the fact that lung cancer accounts for over 125,000 deaths each year in the United States; COPD causes approximately 90,000 deaths per year and more chronic disability than any other medical illness; and respiratory tract infection (acute bronchitis and pneumonia) is a frequent cause of impairment in activities of daily living, increased utilization of health care resources, and even mortality. In this report, the evidence concerning the potential for habitual use of marijuana to produce adverse effects on the lung comparable to those caused by tobacco will be reviewed.
Smoke Contents of Marijuana and Tobacco
Analysis of the smoke contents of marijuana and tobacco reveals much the same gas phase constituents, including chemicals known to be toxic to respiratory tissue (Hoffmann et al. 1975; Novotny et al. 1982). Moreover, these gas phase components are present in somewhat similar concentrations in the smoke generated from the same quantity of marijuana and tobacco. The particulate phase (tar) constituents of marijuana and tobacco smoke are also generally similar, with the major exception that marijuana contains tekahydrocannabinol (THC) and scores of other llIC-like (cannabinoid) compounds not found in tobacco, while tobacco tar contains nicotine not found in marijuana. With regard to the carcinogenic potential of marijuana, it is noteworthy that the tar phase of marijuana smoke contains many of the same carcinogenic compounds contained in tobacco smoke, including polycyclic aromatic hydrocarbons, such as benz[a]pyrene, which was recently identified as a key factor promoting human lung cancer (Denissenko et al. 1996).
Animal and human studies provide the biologic evidence that regular exposure of the lung to the noxious components in marijuana smoke is, in fact, injurious to lung tissue. Studies in animals exposed to varying doses of marijuana smoke for from 12 to 30 months have shown extensive damage in dogs (Roy et al.1976) and monkeys (Fligiel et al. 1991) to the smaller airways, which are the major site of injury due to tobacco-related COPD, as well as acute and chronic pneumonia in rats (Fleischman et al. 1979; Rosenkrantz and Pleischman 1979) and monkeys (Fligiel et al. 1991). On the other hand, rats exposed for 1 year to increasing doses of marijuana smoke failed to demonstrate any anatomic or functional evidence of emphysema, whereas such evidence was apparent in tobacco-exposed rats (Huber and Mahajan 1988).
Early human studies yielded mixed results: some reported an association between regular marijuana use and chronic bronchitis and emphysema (Chopra 1973; Hall 1975), while others failed to find such a relationship (Boulougouris et al. 1976; Rubin and Comitas 1975). These studies may be criticized because of deficiencies in experimental design, including (1) failure to control for the important confounding variable of tobacco, (2) only small numbers of participants, and (3) probable selection biases.
Chronic respiratory symptoms
Subsequently, Tashkin and colleagues (1987) reported the following findings in a large sample of volunteers recruited from the LosAngeles area, including 144 heavy, habitual smokers of marijuana only (MS) and 135 smokers of marijuana plus tobacco (MTS), as well as 70 smokers of tobacco only (TS) and 97 nonsmokers (NS). Compared to NS, a significantly higher proportion of MS (15-20 percent) acknowledged symptoms of chronic bronchitis (chronic cough and phlegm production). While 20-25 percent of TS also reported symptoms of chronic bronchitis, the proportion of symptomatic TS did not differ significantly from that of symptomatic MS (despite a marked disparity in the amount of each substance smoked per day: 3 joints of marijuana vs. more than 20 cigarettes of tobacco), and no additive effects of marijuana and tobacco were noted. Similar findings were reported by Bloom and coworkers (1987) in a randomly stratified sample of young individuals (15 40 years of age) residing in the Tucson area' with the exception that these investigators noted an additive effect of marijuana and tobacco that was not observed in the Los Angeles study.
In the Tucson study (Bloom et al. 1987), regular marijuana use (approximately 1 joint/day on the average) by young persons was associated with significant impairment in measurements that reflect the function of the small airwaysthe major site of COPD. These changes were even greater than those noted in young regular tobacco smokers, and the effects of both marijuana and tobacco appeared to be additive. The authors concluded that regular marijuana smoking was a risk factor for the development of COPD, which, in its advanced stages, is characterized by disabling shortness of breath. In contrast, the Los Angeles study (Tashkin et al. 1987) failed to find any impairment in small airways function in association with even heavier regular use of marijuana (3 - joints per day), although mild, statistically significant narrowing of large, central airways was noted in the marijuana users. Recently, a longitudinal analysis of the lung function results obtained in Los Angeles (Tashkin et al. 1997) revealed an accelerated rate of decline in lung function with age (as is characteristic of tobacco smokers who are destined to develop symptomatic COPD) in the tobacco-smoking participants but failed to find such an effect in the marijuana smokers. The mixed findings from these two studies leave open the question as to whether habitual smoking of marijuana, in the absence of tobacco, can lead to COPD.
Bronchoscopic findings: visual appearance and microscopic alterations in bronchial wall biopsies
Bronchoscopy was performed in 53 NS, 40 MS, 31 IS, and 44 MTS who participated in the LosAngeles study (Fligiel et al. in press; Gong et al. 1987) to ascertain whether regular smoking of marijuana with or without tobacco might cause damage to the airways and lung that might not be reflected by abnormalities in lung function. Visual inspection of the appearance of the large, central airways showed that a large proportion of smokers of marijuana or tobacco alone (but rarely nonsmokers) showed evidence of increased redness (erythema) and swelling (edema) of the airway tissues and increased mucous secretions, and the findings in the combined smokers of both marijuana and tobacco appeared additive (Roth et al. 1996). These visual findings were correlated with microscopic evidence of increased numbers and size of small blood vessels in the bronchial wall, tissue edema, and replacement of the normal ciliated surface lining cells (ciliated columnar epithelial cells) by mucus-secreting goblet cells. These observations may explain the relatively high proportion of marijuana smokers who complain of chronic cough and phlegm. Overproduction of mucus by the increased numbers of mucus-secreting cells in the face of diminished numbers of ciliated cells (cells with hair-like projections) that normally function to transport the mucus toward the mouth by rapid ciliary motion might leave cough as the only mechanism to remove mucus from the airways.
Microscopic findings in biopsies of the bronchial mucosa (superficial layer of cells) revealed that a much higher proportion of MS than NS (and a proportion comparable to, if not greater than, that of IS) exhibited a variety of cellular abnormalities. The latter included abnormal proliferation of cells (reserve cells, goblet cells), transformation of normal ciliated cells into abnormal cells resembling skin (squamous metaplasia), accumulation of inflammatory cells, and abnormalities in the cell nuclei (Fligiel et al. in press; Gong et al. 1987). Some of these changes (e.g., nuclear alterations and squamous metaplasia) have been described as precursors to the subsequent development of lung cancer in tobacco smokers (Auerbach et al. 1961) and thus may be considered to be premalignant. Smokers of both marijuana and tobacco exhibited these microscopic cellular abnormalities to the greatest extent, suggesting an additive injurious effect of marijuana and tobacco on airway tissue. These findings in healthy, largely nonsymptomatic, young marijuana smokers confirm and extend previous bronchoscopic observations of Tennant (1980) in symptomatic U.S. servicemen who smoked cannabis (in the form of hashish) heavily.
Genetic markers of precancer progression
A specific combination of genes (oncogenes, tumor suppressor genes) that are responsible for regulating cell growth must be activated and/ or mutated for lung cells to transform into cancerous cells. Bronchoscopic biopsies from 63 participants in the Los Angeles study (12 MS, 9 MTS, 14 TS, and 28 NS), none of whom used crack cocaine, were examined for alterations in some of the genes known to be involved in the development of lung cancer. Immunohistology was used to detect the overexpression of the protein products of these genes by epithelial cells in the bronchial biopsies (Roth et al. 1996). Protein products for two of the three genes examined were markedly overexpressed in the biopsies from MS compared to NS (and even to a greater extent than in the biopsies from TS), and the effects of marijuana and tobacco were additive. Expression of the third gene, the p53 oncogene, which may play a role in as many as 75 percent of all lung cancers, was found only in a smoker of marijuana plus tobacco, as well as in one of 12 combined smokers of marijuana, cocaine, and tobacco who were also examined. These results indicate genetic evidence of extensive growth dysregulation in these relatively young smokers of marijuana alone and, particularly, in the combined smokers of marijuana and tobacco, implying an important role of marijuana use in progression to lung cancer.
Structure and function of alveolar macrophages
Alveolar macrophages are the principal immune-effector (inflammatory) cells in the lung and are primarily responsible for protecting the lung against infectious microorganisms. A saline (salt water) rinse was used in participants in the Los Angeles study at the time of bronchoscopy to harvest cells from the air spaces in the lung (over 90 percent of which are alveolar macrophages). Approximately two and three times as many alveolar macrophages were obtained from the lungs of marijuana or tobacco smokers, respectively, as from nonsmokers, and the effects of smoking both substances were additive (Barbers et al. 1987). These observations indicate that regular marijuana use produces an inflammatory response, i.e., an accumulation of increased numbers of alveolar macrophages, in the lung. Under the electron microscope, alveolar macrophages from marijuana or tobacco smokers showed a striking increase in size and complexity of inclusion bodies in their cytoplasm (probably due to ingestion by these cells of particulate material in the smoke), and macrophages from combined smokers of marijuana and tobacco were nearly completely filled by these inclusions (Bears et al. 1989). It might be expected that the padding of these important cells with large inclusion bodies would interfere with their function.
Various aspects of alveolar macrophage function have been evaluated by contributing researchers in the Los Angeles study. Compared to NS, alveolar macrophages of both MS and IS showed a significantly reduced ability to kill a common fungal organism (Candida albicans) (Sherman et al. 1991). Moreover, alveolar macrophages of MS, but not IS, showed a significant impairment in (1) their ability to ingest and kill an important bacterial pathogen (Staphylococcus aureus); (2) their ability to kill tumor cell targets; and (3) their ability to produce a variety of proinflammatory cytokines, which play a key role in immunologic responses to infection and malignancy (Baldwin et al. 1996).
Role of Marijuana in Cancer
The following lines of evidence suggest that marijuana may play an important role in the development of respiratory cancer.
- The tar phase of marijuana smoke, as already noted, contains many of the same carcinogenic compounds contained in tobacco smoke, induding nitrosamines, reactive aldehydes, and up to a 50 percent higher concentration of carcinogenic polycydic hydrocarbons, induding benz[a]pyrene (Hoffmann et al. 1975). Benz[a]pyrene, which has recently been shown to promote mutations in the p53 oncogene (Denissenko et al. 1996), is believed to play an important role in human cancer.
- One marijuana cigarette was shown by Wu and colleagues (1988) to deposit four times as much tar in the lung as a single filtered tobacco cigarette of approximately the same weight. The higher content of carcinogenic polycyclic hydrocarbons in marijuana tar and the greater deposition of marijuana tar in the lung act together to amplify exposure of the marijuana smoker to the carcinogens in the tar phase.
- Painting tar from marijuana smoke on the skin of mice produced lesions correlated with malignancy (Cottrell et al. 1973).
- Marijuana tar induced comparable numbers of mutations to those produced by tar from the same quantity of tobacco in a common bacterial assay for mutagenicity (Wehner et al. 1980).
- Exposure of hamster lung cell cultures to marijuana or tobacco smoke over a period of 2 years led to accelerated malignant transformation within 3-6 months of marijuana exposure compared to control (unexposed) cell cultures. Moreover, the changes in the cells exposed to marijuana smoke were more impressive than those in the tobacco-exposed cells (Leuchtenberger and Leuchtenberger 1976).
- Biopsies of bronchial lining tissue of habitual marijuana smokers demonstrated extensive cellular alterations, some of which may be considered premalignant. Effects of smoking both marijuana and tobacco on these cellular changes appeared to be additive (Fligiel et al. in press).
- Bronchial immunohistology revealed overexpression of genetic markers of lung tumor progression in smokers of marijuana (Roth et al. 1996).
- Preliminary findings suggest that marijuana smoke activates cytochrome P4501A1, the enzyme that converts polycyclic hydrocarbons, such as benz[a]pyrene, into active carcinogens (Roth preliminary data).
- Alveolar macrophages from marijuana-only smokers have reduced ability to kill tumor cell targets (Baldwin et al. 1996).
- Pretreatment of mice with THC for 2 weeks prior to implanting Lewis lung cancer cells (a non-small-cell immunogenic carcinoma) into the animals caused larger, faster-growing tumors, a finding that was correlated with the increased immunosuppressive cytokine produced by the tumor cells, transforming growth factor-beta (Zhu et al. 1997). These findings suggest a THC-related impairment in immune responsiveness to tumor antigens.
- Several case-series reports indicate an unexpectedly large proportion of marijuana users among cases of lung cancer (Sridhar et al. 1994; Taylor 1988) and upper aerodigestive tract cancers (cancers of the oral cavity, pharynx, and larynx); (Donald 1991; Endicott et al. 1993; Taylor 1988) that occurred before age 45 years. These case-series reports suggest that marijuana may play a role in the development of human respiratory cancer. Without a control group, however, the effect of marijuana use on cancer risk cannot be estimated, nor can the potentially confounding effect of tobacco and other risk factors be controlled.
Taken together, the observations from a number of biochemical, cellular, genetic, tissue, animal, and clinical studies provide a biologically plausible basis for the hypothesis that marijuana is a risk factor for human cancer. What is lacking is epidemiologic evidence that marijuana indeed increases the risk of developing respiratory cancer. Because of the long period of time (latency period) required for induction of human carcinomas and the infrequent use of marijuana in the general U.S. population prior to 1966, there are currently no published epidemiologic studies that examine the association between marijuana and cancer. However, at the present time, epidemiologic investigation of this association may have become feasible since approximately 30 years have elapsed since the start of widespread marijuana use in the United States among teenagers and young adults, who are currently reaching an age when respiratory cancers are more common.
Effects of Marijuana on the Immune System
In vitro and animal studies
The recent finding of cannabinoid receptors (to which THC binds) on white blood cells (Bouaboula et al.1993) is consistent with observations that THC is capable of influencing immune responses. In vitro and animal studies suggest that THC has a general immunosuppressive effect on a variety of immune cells, induding rnacrophages, natural killer cells, and T cells (Burnette Curley and Cabral 1995; Huber et al. 1975, 1980; Klein et al. 1991; Kusher et al. 1994). Mice exposed to D9THC were unable to develop protective immunity against lung infection by Legionella pneumophilia, an opportunistic pathogen (Newton et al. 1994).
Immune deficits in marijuana smokers
As noted above, alveolar macrophages from the lungs of healthy, habitual marijuana smokers were suppressed in their ability to kill fungaland bacterial organisms, as well as tumor cells. Moreover, the same cells were suppressed in their ability to release proinflarnmatory cytokines. These findings suggest that marijuana is an immunosuppressant with clinically significant effects on host defense, which could have potentially serious health consequences in patients with preexisting immune deficits due to AIDS, organ transplantation (receiving immunosuppressive therapy to prevent rejection of the transplant), or cancer (receiving immunosuppressive chemotherapy). The latter possibility is supported by reports of fungal and bacterial pneumonias in patients with AIDS or organ transplantation who used marijuana (Caiaffa et al. 1994; Denning et al. 1991). Moreover, among HIV-positive individuals, active marijuana use has been found to be a significant risk factor for rapid progression from HIV infection toAIDS and acquisition of opportunistic infections and/or Kaposi's sarcoma (Tindall et al. 1988).
The evidence for the harmful consequences of marijuana smoking is preliminary and requires long-term study. In the interim, prudent advice must serve where substantial clinical evidence is lacking. Habitual marijuana use, as often as one joint per day, may result in serious pulmonary consequences. In the short term, breathing may be restricted, coughing may be increased, and resistance may be lowered to opportunistic infections of the lungs such as pneumonia. Respiratory cancer is a likely result in the long term. Heavier use of marijuana is likely to have more potent, adverse health consequences.
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