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.
marijuana use may lead to the following effects on the lung:
and chronic bronchitis;
microscopic abnormalities in the cells lining the bronchial passages (bronchial
epithelium), some of which may be premalignant;
of genetic markers of progression to lung cancer in bronchial tissue;
increased accumulation of inflammatory cells (alveolar macrophages) in the lung;
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.
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.
Contents of Marijuana and Tobacco
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).
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).
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
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
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.
findings: visual appearance and microscopic alterations in bronchial wall biopsies
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.
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.
markers of precancer progression
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.
and function of alveolar macrophages
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.
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).
of Marijuana in Cancer
following lines of evidence suggest that marijuana may play an important role
in the development of respiratory cancer.
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.
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.
tar from marijuana smoke on the skin of mice produced lesions correlated with
malignancy (Cottrell et al. 1973).
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).
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).
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).
immunohistology revealed overexpression of genetic markers of lung tumor progression
in smokers of marijuana (Roth et al. 1996).
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).
macrophages from marijuana-only smokers have reduced ability to kill tumor cell
targets (Baldwin et al. 1996).
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.
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
vitro and animal studies
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).
deficits in marijuana smokers
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).
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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