The American Journal of Drug and Alcohol Abuse

Encompassing All Addictive Disorders

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Pulmonary effects of inhaled cannabis smoke

Donald P. Tashkin & Michael D. Roth

To cite this article: Donald P. Tashkin & Michael D. Roth (2019): Pulmonary effects
of inhaled cannabis smoke, The American Journal of Drug and Alcohol Abuse, DOI:
10.1080/00952990.2019.1627366

To link to this article: https://doi.org/10.1080/00952990.2019.1627366

Published online: 12 Jul 2019.

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THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE
https://doi.org/10.1080/00952990.2019.1627366

REVIEW

Pulmonary effects of inhaled cannabis smoke

Donald P. Tashkin and Michael D. Roth
Department of Medicine, Division of Pulmonary & Critical Care, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

ABSTRACT ARTICLE HISTORY

Background: The smoke generated from cannabis delivers biologically active cannabinoids and a Received 15 February 2019
number of combustion-derived toxins, both of which raise questions regarding the impact of Revised 28 May 2019
cannabis smoking on lung function, airway inflammation and smoking-related lung disease. Accepted 31 May 2019
Objectives: Review the potential effects of cannabis smoking on respiratory symptoms, lung KEYWORDS
function, histologic/molecular alterations in the bronchial mucosa, smoking-related changes in Cannabis; smoke; pulmonary
alveolar macrophage function and the potential clinical impact of cannabis smoking on chronic function; chronic obstructive
obstructive pulmonary disease, lung cancer and pulmonary infections. pulmonary disease; lung
Methods: Focused literature review. cancer
Results: The carcinogens and respiratory toxins in cannabis and tobacco smoke are similar but the
smoking topography for cannabis results in higher per-puff exposures to inhaled tar and gases. The
frequency of chronic cough, sputum and wheeze and the presence of airway mucosal inflammation,
goblet cell and vascular hyperplasia, metaplasia and cellular disorganization are similar between
cannabis smokers and tobacco smokers. Cannabis smoke has modest airway bronchodilator proper-
ties but of unclear clinical significance. While clear evidence exists for progression to obstructive lung
disease and emphysema in chronic tobacco smokers, the effects from habitual cannabis use are less
clear. Evidence suggests that alveolar macrophages from cannabis smokers have deficits in cytokine
production and antimicrobial activity not present in cells from tobacco smokers.
Conclusions: Solid conclusions regarding the respiratory consequences of regular cannabis smok-
ing are difficult to make due to a relative paucity of literature, confounding by concurrent tobacco
smoking and reports of conflicting outcomes. Additional well-controlled clinical studies on the
pulmonary consequences of habitual cannabis use are needed.

Introduction Cannabis smoking acts a simple and rapid delivery

technique for cannabinoids. In this respect, the process
Cannabis is the second most commonly smoked sub-
is very similar to conventional tobacco smoking which
stance in modern society. According to a long-standing
acts as a vehicle to deliver nicotine. In both cases, the
US national survey (1), the decline in cannabis use that
smoker inhales a combination of toxic combustion
occurred from 1990 through 2005 has been followed by
products along with the desired biologically active com-
a slow but continued rise in habitual cannabis smoking.
pounds as they puff on lit plant material. The lung
This rise is particularly significant given the steep decline
receives the highest exposure to all of these inhaled
in tobacco smoking that has occurred over the same
components. Given these similarities between cannabis
interval. As of 2017, about one in every seventeen high
and tobacco smoking there is obvious concern for the
school seniors and one in thirteen young adults (ages
impact of cannabis smoking on the development of
19–28) was a daily or near-daily cannabis smoker (1). In
airway inflammation, chronic bronchitis, emphysema
addition to conventional cannabis smoking that involves
and cancer. However, cannabinoids and nicotine are
joints, blunts, bongs and pipes, there is an emergence of
entirely unrelated compounds and cannabinoids are
vaping as an alternative approach to release and inhale
associated with a unique profile of effects on oxidative
cannabinoids from dried plant material or concentrated
stress (3), cellular energetics and survival (4–6), gene
cannabinoid extracts (in the form of waxes or oils). This
expression (7), inflammatory processes and immune
review focuses on the health effects of conventional can-
regulation (8–11). As a result, it is important to directly
nabis smoking as there is almost no available information
examine the pulmonary effects of cannabis as com-
regarding the pulmonary effects of vaped cannabis even
pared to tobacco smoking.
though it is perceived as a healthier alternative (2).

CONTACT Donald P. Tashkin dtashkin@mednet.ucla.edu Department of Medicine, Division of Pulmonary & Critical Care, David Geffen School of
Medicine at UCLA, Los Angeles, CA CHS 43-229, USA
© 2019 Taylor & Francis Group, LLC
2 D. P. TASHKIN AND M. D. ROTH

The composition of cannabis smoke and its on lung exposure and resulting toxicity. In 15 male
deposition during smoking habitual smokers of both cannabis and tobacco, Wu
et al. (17) compared the dynamics of smoking a single
Although cannabis can be consumed by several meth-
cannabis joint with that of a single filter-tipped tobacco
ods and routes, smoking remains the most common
cigarette (both of roughly the same weight). The rela-
mode and the lung represents the organ exposed first
tive burden of insoluble particulates (tar) and carbon
and foremost to the inhaled smoke. While cannabis is
monoxide that resulted from these two smoke expo-
a natural plant “product”, the smoke generated from
sures was measured. The smoking topography asso-
joints should not be considered fundamentally safe to
ciated with cannabis and tobacco smoking were
inhale. Similar to the combustion of tobacco leaf, which
different. Smoking a joint resulted in approximately
releases both nicotine and a number of toxic substances
a two-thirds larger puff volume, a one-third greater
into the smoke, the smoke generated from burning
depth of inhalation and a four-fold longer breath-hold-
cannabis delivers not only cannabinoids but an array
ing time than that observed when smoking tobacco
of other plant and combustion derived constituents.
(p < .01), differences that were little influenced by the
The volatile and particulate phase components of can-
percentage of THC in the smoke from cannabis (17). In
nabis smoke contain many of the same potent toxins
addition, as compared with tobacco, smoking cannabis
found in tobacco smoke including carbon monoxide,
was associated with a nearly five-fold greater increment
aldehydes, acrolein, phenols and carcinogenic polycyc-
in the blood carboxyhemoglobin level, an approximate
lic aromatic hydrocarbons (PAHs; 12–14). Like tobacco
three-fold increase in the amount to tar inhaled and
smoke, the PAHs generated during cannabis smoking
retention in the lung of one third more inhaled tar
induce gene expression of the cytochrome p4501A1
(p < .001) (17). The loosely-packed nature of the can-
isozyme (CYP1A1) that is involved in metabolizing
nabis joint (resulting in less rod filtration and promot-
them into proximate carcinogens (15,16). However,
ing hotter combustion) and the lack of a filter tip, in
when cannabis tar was directly examined for its impact
addition to the differences in smoking topography
on CYP1A1 gene expression it was discovered that the
noted above, likely contribute to the substantially
delta-9 tetrahydrocannabinol (THC) present within the
greater respiratory burden of carbon monoxide and
tar fraction independently activated the aryl hydrocar-
tar that occurs with cannabis smoking (18). As such,
bon receptor and induced the CYP1A1 gene in a dose-
the potential toxic smoke exposure resulting from
dependent manner. While THC levels may be relatively
a single cannabis joint might be substantially greater
low in dried cannabis leaves and buds, it is concen-
than that occurring from smoking a tobacco cigarette.
trated up to 5-fold in the tar fraction and therefore can
On the other hand, the overall smoke exposure asso-
exert potent effects on the induction of CYP1A1 (15).
ciated with cannabis use may be less due to differences
While this observation raised concern for the carcino-
in the frequency of smoking. Cannabis smoking typi-
genicity of cannabis smoke, the same study also identi-
cally involves smoking between one and a few joints
fied THC as a competitive inhibitor of CYP1A1 enzyme
per day as compared to up to 20–40 tobacco cigarettes
activity which might have the opposite effect (15). This
smoked per day.
complexity, resulting in both gene expression and com-
petitive protein inhibition is just one example of why
assumptions about the toxic consequences of tobacco
Impact of habitual cannabis use on respiratory
smoke may not directly apply to cannabis smoke. As
symptoms
already noted, the cannabinoids present in cannabis
smoke interact with different receptor pathways and Only a few studies have carefully examined the associa-
have different biologic effects compared to those tion between chronic respiratory symptoms and regular
ascribed to nicotine. Consequently, while the similari- smoking of cannabis alone as compared to (or adjusted
ties between tobacco and cannabis smoke raise real for) nonsmokers, tobacco smokers or concurrent smo-
concerns about the potentially harmful effects, the two kers of both cannabis and tobacco (19–27). Eight of the
forms of smoke exposure are not identical. At this point nine published studies in this area have shown either
in time only a limited number of studies have system- a statistically significant or numeric increase in chronic
atically examined the pulmonary effects of cannabis cough, sputum production and wheeze, while only one
smoking, the main results of which are reviewed here. study reported a numeric increase in breathlessness
In addition to differences in their active constituents, compared with nonsmokers. While one study failed to
the manner in which cannabis and tobacco cigarettes find a significant increase in symptoms consistent with
are prepared and smoked may have a significant impact chronic obstructive pulmonary disease (COPD) in

cannabis smokers (25), the same study suggested
a positive interactive effect with concomitant tobacco
smoking (cannabis and tobacco smoking group) on
respiratory symptoms. As such, there is fairly uniform
and conclusive evidence that habitual cannabis smok-
ing results in an increased frequency of cough, sputum
and wheezing. The findings by Tashkin et al. (20) were
typical. In that report, respiratory symptoms and pul-
monary function were assessed in young to middle-
aged subjects (mean age ranging 31–37 years old by
group) that included 97 nonsmokers, 144 cannabis
smokers, 170 tobacco smokers and 135 smokers of
both cannabis and tobacco. Spirometry and diffusing
capacity measurements were normal in all groups.
However, chronic cough was reported by 18–24% of
subjects from the smoking groups (including cannabis
smokers, tobacco smokers and combined cannabis and
tobacco smokers) versus only 2.9% of the nonsmokers;
sputum production was reported by 20–26% of the
smoking groups versus only 14.3% of the nonsmokers;
and wheezing was reported by 25–37% of the smoking
groups as compared to an average of 14.3% of the
nonsmokers. These differences were all statistically sig-
nificant but no significant differences were identified
between the cannabis, tobacco and combined cannabis
and tobacco smoking groups. Not surprisingly, based
on these symptoms, the frequency of at least one
exacerbation of chronic bronchitis per year was higher
in the smoking groups as compared to the nonsmokers.
While vaping is perceived as a method for reducing the
irritation and toxicity associated with cannabis smok-
ing, there are currently no studies that directly address
the impact of cannabis vaping on chronic cough, spu-
tum and wheezing. Contrary to similar expectations in
tobacco smokers, use of e-cigarettes still produced sig-
nificant bronchitis symptoms (chronic cough, phlegm
or bronchitis) when examined in a cohort of 2,086 high
school students (28).
Impact of cannabis smoking on measurements
of lung function
Acute changes in lung function and cannabis as
a potential bronchodilator
Tobacco smoking induces acute constriction of the air-
ways. This negative effect, which is relatively transient
and of modest intensity, appears to result from
a cholinergic reflex triggered by smoke-related irrita-
tion (29). It was hypothesized, therefore, that smoking
cannabis would have a comparable effect. However,
when directly measured, smoking of a single cannabis
cigarette (900 mg, 1 or 2% THC) led to an acute, dose-
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 3
dependent bronchodilator effect that lasted 1–2 hours
and was of a magnitude similar to commercially avail-
able bronchodilators (30). When cannabinoids were
removed by ethanol extraction, the bronchodilator
effect was lost. Consistent with a direct role for THC,
studies with oral THC produced similar effects
although with a delayed onset and prolonged duration
consistent with typical oral pharmacokinetics (30).
Moreover, similar findings were observed in subjects
with mild asthma in whom smoked cannabis rapidly
reversed experimentally induced bronchospasm (31,32)
and similar bronchodilator effects from THC have been
reported by others (33,34). The mechanism appears to
involve binding of THC to cannabinoid type 1 (CB1)
receptors on vagal efferent nerve endings in the bronchi
and a subsequent inhibition of acetylcholine release
(35,36). These findings provided a rationale for the
widespread use of cannabis in the 19th century as
a treatment for asthma (37). Unfortunately, enthusiasm
for smoked cannabis as an asthma therapy was ulti-
mately limited by concerns over concurrent exposure to
inhaled toxins (as already noted) and the availability of
many other relatively safe alternatives. While it is con-
ceivable that aerosolized THC (e.g., from a nebulizer,
metered dose inhaler or vaping device) may have ther-
apeutic potential, a positive outcome was not observed
when tested in asthmatic subjects exposed to THC from
a metered-dose inhaler (38). As per Tashkin et al. (38),
nebulized THC had irritating effects that resulted in
bronchospasm and cough. Moreover, a hypothesized
effect on reducing exertional dyspnea, through
a central effect, and improving exercise tolerance,
through a bronchodilator effect, was not observed in
a small randomized controlled cross-over trial in 16
adults with severe COPD (39). A single inhalation of
cannabis vapor (35 mg of cannabis containing 18.2%
THC), but not control vapor, resulted in cough in six
subjects and worsening shortness of breath in five of
these six. Consistent with the potential opposing effects
of cannabis smoke on airway irritation and bronchodi-
lation, there was no clinically meaningful positive or
negative effect on either lung function or exercise
endurance (39). At this point in time the potential
therapeutic effects of smoked cannabis or purified can-
nabinoids, especially when considered in patients who
are on other asthma or COPD medications, remains to
be proven.
Chronic changes in lung function associated with
habitual cannabis smoking
A limited number of studies have evaluated the associa-
tion of habitual cannabis smoking alone, or when
4 D. P. TASHKIN AND M. D. ROTH
adjusted for concurrent tobacco use, on different mea-
sures of lung function. The impact of habitual cannabis
smoking on spirometry was assessed in twelve studies
(19–25,40–44) which included measures of forced vital
capacity (FVC), forced expired volume in 1 sec (FEV1)
and/or the FEV1/FVC ratio. Spirometry detects airway
obstruction as observed in asthma, chronic bronchitis and
COPD. Abnormalities classically appear as an imbalance
between the measured lung volume (FVC) and the mea-
sured airflow on forced exhalation (FEV1). Analyses of
the impact of cannabis smoking on the subdivisions of
lung volume have been reported in four studies
(20,24,40,41) and included measures of total lung capacity
(TLC), functional residual volume (FRC) and/or residual
volume (RV). These measures may all be reduced in
conditions that reduce lung compliance such as lung
fibrosis or inflammatory interstitial lung disease, but
very distinctive patterns of change (e.g., increases in
TLC, FRC and/or RV) also identify the lung hyperinfla-
tion that occurs in emphysema and air-trapping that can
occur in both COPD and asthma. Plethysmographic mea-
surements of airway resistance (Raw) and specific airway
conductance (SGaw), and measurement of the single-
breath diffusing capacity of the lung for carbon monoxide
(DLCO), were reported in four studies (20,24,40,41). Raw
and SGaw may provide evidence of airways obstruction
even when spirometry is relatively normal, and abnormal
DLCO values indicate damage to the alveolar compart-
ment of the lung that is involved in gas exchange –
a characteristic sign of both emphysema and interstitial
lung disease.
In contrast to tobacco smoking, a characteristic sig-
nature of cannabis smoking as measured by lung func-
tion has been elusive. Only one of 12 spirometry studies
reported a significant decrease in FEV1 in cannabis
smokers and in this case it was observed only in former
cannabis smokers, not current, and the relevance of this
isolated finding is unclear (21). In a more recent study
in middle-aged to elderly subjects, the rate of decline in
FEV1 over time was increased in association with can-
nabis even after adjusting for tobacco smoking and
other relevant variables (44), but this has not been
a reproducible observation. Of seven studies evaluating
FVC measurements, four reported no significant differ-
ences in FVC between cannabis smokers and nonsmo-
kers, while three reported significant increases in FVC
and one other a trend toward a significant increase in
FVC in cannabis smokers. An isolated increase in FVC
is not characteristic of tobacco smoking or any other
defined lung disease and is therefore of some interest.
Of the nine studies evaluating the FEV1/FVC ratio (a
more specific measure of airflow than the FEV1), three
showed a significant decrease in this ratio in the
cannabis smokers, although in one of these three the
decrease was noted only in former cannabis smokers
and in another study an effect was observed only in the
heaviest smokers of >20 joint-years. Further, the
decreases in the FEV1/FVC ratio in this population
have been attributed to an increase in FVC rather
than a decrease in the FEV1 (as typically occurs in
tobacco smokers) and are therefore felt to be of unclear
significance (41,42). Of the four studies evaluating sub-
divisions of lung volume, one showed significant
increases in TLC, FRC and RV. The most uniform
observations occurred in studies measuring Raw and
SGaw, all four of which showed modest but statistically
significant reductions (~25%) in SGaw, findings con-
sidered indicative of airway obstruction. However, the
magnitude was of uncertain clinical importance espe-
cially in a setting where the FEV1 and the FEV1/FVC
ratio were not reduced. Finally, of the four studies that
measured DLCO (a sensitive but nonspecific indicator
of emphysema), none showed a significant decrease in
the cannabis smokers. From a clinical perspective, the
preponderance of data from these primarily cross-sec-
tional studies suggests that lung function is relatively
well preserved in habitual smokers of cannabis alone
and does not show the characteristic abnormalities in
spirometry (decreased FEV1 and related decrease in
FEV1/FVC ratio), lung volumes (increase in TLC, RV
and related RV/TLC ratio) and DLCO (decrease) that
are so well established for tobacco-related COPD. At
the same time, the consistent but subtle increase in Raw
and decrease in SGaw may identify inflammation/nar-
rowing of the central airways that is not, by itself,
a strong indicator of clinically significant obstructive
lung disease.
A controversial question is whether or not smoking
cannabis along with tobacco might result in synergistic
negative effects on lung function. Based on a random
sample survey of 878 people over age 40 years, Tan et al.
(25) reported that concurrent use of cannabis and tobacco
was associated with an increased risk of spirometrically
defined COPD (OR 2.90 95% CI 2.74) that was numeri-
cally higher than that of smoking tobacco alone (OR 2.74;
95% CI 1.66–4.52), while cannabis smoking alone was not
associated with a significantly increased risk of COPD
(OR 1.66 95% CI 0.52–5.26). While suggesting a pattern,
these differences were not statistically significant. A more
recent cross-sectional analysis of data from the
Subpopulations and Intermediate Outcomes Measures
in COPD Study (SPIROMICS) of adult smokers of
tobacco, with or without cannabis, reported
a significantly lower quantitative measurement of emphy-
sema on high resolution computerized tomography
(HRCT) scans (p = .004 and p = .03, respectively) and

higher % predicted FEV1 values (p < 001) in tobacco
smokers who were current or former cannabis smokers
compared to smokers of tobacco alone, after adjusting for
relevant covariates (43). The latter findings argue against
an additive or synergistic effect of cannabis when smoked
together with tobacco. In fact, they suggest a potential
protective effect of cannabis use on the development of
tobacco related COPD.
Four longitudinal studies measuring changes in lung
function over time in association with cannabis smoking
have been reported (21,27,44,45). Sherrill et al. (21)
reported decrements in lung function in former but not
current cannabis smokers participating in a community-
based longitudinal cohort study. Tashkin et al. (45) found
no difference in the rate of decline in FEV1 over a period
of 8 years in habitual MS compared to NS and no evi-
dence of a dose-response relationship between cannabis
use and age-related decline in lung function. In compar-
ison, within the same study, a clear dose-response rela-
tionship between the rate of decline in FEV1 and the level
of tobacco use was identified (45). In a birth cohort
followed with serial spirometry measurements from ages
18 to 32 years, Hancox et al. (27) found that cannabis use,
compared to nonsmoking, was associated with a non-
significant increase in FEV1, a greater and significant
increase in FVC and a slight but non-significant decline
in FEV1/FVC (attributed to the associated increase in
FVC). In the same study, tobacco smoking was associated
with significant decreases in FEV1 and FEV1/FVC ratio
over time. These longitudinal studies, which include
internal controls for the observed effects of tobacco smok-
ing over time, make a strong argument that despite many
similarities in the composition of the inhaled smoke, there
may be important differences between the biologic con-
sequences of cannabis and tobacco on lung structure and
pulmonary function. One caveat is that most of this data
was generated in young to middle-aged adults. Recently,
Tan et al. (44) orally presented findings regarding
a randomly recruited cohort of middle-aged to elderly
adults who were assessed at two time points (baseline
and 18 months thereafter). After adjusting for concomi-
tant tobacco smoking, these authors identified a highly
significant association between cannabis smoking and
decline in FEV1 over this time interval compared to
nonsmoking (−15.6 ml/yr; 95% CI −22.44, −6.41;
p = .0005). The effect was comparable to the association
of tobacco smoking with decline in (FEV1 − 15.8 ml/yr;
95% CI −21.2,-10.5; p < .0001). It is difficult to reconcile
the as-yet unpublished findings from this single study,
confirmation of which is required, with the largely nega-
tive findings previously reported for the association
between cannabis smoking and lung function in other
cross-sectional and longitudinal studies. It is possible
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 5
that participant age and duration of smoking might
account for the different outcomes. Age and duration of
smoking were both found to significantly contribute to
the impact of tobacco smoking on lung function in indi-
viduals with chronic obstructive pulmonary disease (46).
With the aging of cannabis smokers who started their use
in the 1960’s and 1970’s, additional population based and
longitudinal studies in older subjects may yet provide
valuable insight that was either not apparent or missed
when investigating cannabis users at earlier stages in life.
This is an important question that warrants further inves-
tigation before drawing final conclusions.
High-resolution computed tomography (HRCT)
imaging and cannabis smoking
Non-invasive lung imaging using HRCT scans has
emerged as a sensitive and highly reproducible means
for assessing the airway changes and alveolar lung
destruction that characterizes smoking-related emphy-
sema and COPD (47). Only two studies have system-
atically examined HRCT images obtained from
cannabis smokers (24,43). HRCT scans obtained in
a New Zealand community-based sample of 75 canna-
bis smokers, 92 tobacco smokers, 91 combined canna-
bis and tobacco smokers and 81 nonsmokers showed
no association of macroscopic emphysema with canna-
bis compared to non-smoking (OR 1.0; 95% CI 0.7,
1.4), in contrast to a significant association with
tobacco smoking (OR 5.7; 95% CI 2.1, 15.6) (24). The
single cannabis-only smoker with macroscopic emphy-
sema had a 437 joint-year history (defined as the num-
ber of joints of cannabis smoked per day times the
number of years smoked), suggesting a possible asso-
ciation of exceptionally heavy cannabis smoking and
emphysema. Also, the proportion of cannabis smokers
with very low levels of lung attenuation in the lung
apices (indicating enlarged air spaces) was found to be
slightly but significantly increased in the cannabis users
compared to the nonsmokers. The 196 current and
1008 former self-reported cannabis smokers participat-
ing in the US-based Subpopulations and Intermediate
Outcome Measures in COPD Study (SPIROMICS) in
whom HRCT scans were obtained actually showed sig-
nificantly less emphysema (by computer-aided quanti-
tative scoring) than never users after adjusting for age,
race, gender, FEV1% predicted, current tobacco smok-
ing status and pack-years of tobacco (43). The reason
for these unexpected findings is unexplained, but the
findings accord with the failure of any studies to find
evidence of any reduction in DLCO, a sensitive hall-
mark of smoking related emphysema.
6 D. P. TASHKIN AND M. D. ROTH

Direct inspection and biopsy of the airways in microscopy, the macrophages from both cannabis smo-
cannabis smokers kers and tobacco smokers were enlarged in size and
contained a high concentration of dense inclusion
Respiratory symptoms, lung function, and HRCT ima-
bodies and particulates consistent with engulfed tar
ging each focus on a different aspect of potential smoking-
(51). Consistent with their known exposure and sca-
related lung injury. Direct examination of the human
venger role, solvent-based extracts prepared from
airways by bronchoscopy provides yet another unique
alveolar macrophages recovered from the lungs of can-
perspective and, in addition, provides an opportunity to
nabis smokers yielded measurable levels of THC and
obtain airway mucosal biopsies. Visual identification of
THC metabolites. In addition, neutrophils were
hyperemia (an increase in microvascular prominence),
increased in all the smoking groups and their number
airway induration (identified as thickening and loss of
correlated with increased levels of interleukin-8 (49).
mucosal features) and the presence of mucoid secretions
As such, despite the relative lack of lung function
are commonly observed within the airways of habitual
abnormalities when measured by pulmonary function
tobacco smokers and correlate with the presence of
tests, these findings provide direct evidence for
chronic bronchitis (48). Bronchoscopy-based central air-
a significant inflammatory impact of cannabis smoking
way inspection and video recording was carried out in
on the lung.
a convenience sample of 10 cannabis smokers, 10 tobacco
Consistent with the impact of cannabis smoking on
smokers, 10 combined cannabis and tobacco smokers and
the visual inspection of the central airways and the
10 nonsmokers (49). Recordings were scored in a blinded
number of recovered alveolar macrophages, bronchial
manner for each parameter by two independent readers.
mucosal biopsies in the same cohort of cannabis smo-
Bronchial mucosal inflammation and injury along with
kers demonstrated significant histopathological tissue
an increase in mucoid secretions was observed in the
abnormalities. Abnormalities when comparing the can-
central airways of the cannabis smokers, tobacco smokers
nabis smoking and nonsmoking cohorts included
and combined cannabis and tobacco smoking groups as
reserve cell and goblet cell hyperplasia, squamous meta-
compared to nonsmokers, and the extent of these airway
plasia, inflammatory changes, cellular disorganization
mucosal changes were no different between the various
and increased nuclear/cytoplasmic ratio (52). Further,
smoking groups. Central airway mucosal biopsies
the extent of these abnormalities was similar to that
obtained from these subjects identified vascular hyperpla-
noted in the tobacco smoking cohort and there was
sia and ectasia, submucosal edema and mononuclear cell
a suggestion of an additive impact in the combined
infiltrates, as well as goblet cell hyperplasia that correlated
smokers of both substances (combined cannabis and
with the visual findings. The presence of visual changes
tobacco smokers). The increased numbers of mucus-
was more prominent in the central airways and dissipated
secreting surface epithelial (goblet) cells, along with the
with each bifurcation. The authors of this report specu-
replacement of ciliated epithelium by hyperplastic
lated that this central airway inflammation correlated
reserve and goblet cells and metaplastic squamous-
with the reports of cough and sputum and the finding of
type epithelial cells, implies increased mucus accumula-
abnormal measures of Raw and SGaw that have been
tion in the airways due to a combination of increased
routinely identified in cannabis smokers.
mucus secretion and impaired mucociliary clearance.
Fiberoptic bronchoscopy, broncho-alveolar lavage
In this setting, cough becomes an alternative method
(BAL) and bronchial mucosal biopsies were performed
for clearing excess mucus from the lungs and the his-
in a much larger group of participants in the University
topathology therefore suggests a possible mechanism to
of California at Los Angeles cohort study, including 40
explain the observed association of cannabis-only
cannabis smokers, 31 tobacco smokers, 44 combined
smoking with symptoms of chronic bronchitis.
cannabis and tobacco smokers and 53 nonsmokers.
In an independent bronchoscopy study carried out
BAL recovers alveolar and distal airway lining cells
to assess the impact of alcohol abuse on lung inflam-
that reside on the mucosal surface of the lung, are
mation (53), toll like receptor (TLR) gene expression
exposed directly to inhaled smoke and act as scavenger
(TLR isotypes 1–9) was measured in bronchial mucosal
cells to defend against inhaled material. Cell counts
brushings from 46 control subjects and 39 cannabis
carried out on recovered BAL fluid revealed a three-
users. As this was a sub-analysis from a study focused
fold increase in the number of alveolar macrophages in
on alcohol abuse there was substantial chronic alcohol
both the cannabis smoking and tobacco smoking
use in both of these subsets (but not meeting criteria
cohorts, as well as a six-fold increase in the combined
for a defined alcohol use disorder) and 30–35% of
cannabis and tobacco smoking group, compared to the
subjects were also tobacco smokers. As such, findings
nonsmokers (50). When examined by electron
might not relate solely to reported cannabis use. In the

collected airway mucosal brushings, mRNA expression
for TLR2, TLR 5, TLR6, TLR 7 and TLR 9 were sig-
nificantly increased in the cannabis smoking as com-
pared to control groups. These receptors provide
a mechanism for cells to detect and respond to patho-
gens including gram-positive bacteria and mycobacteria
(TLR2), bacterial flagellin (TLR5), diacyl lipoproteins
present on gram-positive bacteria (TLR-6), single
stranded ribonucleic acid (TRL7) and unmethylated
deoxyribonucleic acid (DNA) from viruses and bacteria
(TLR9). The investigators concluded that cannabis use
has a complex impact on pulmonary innate immunity
that likely predisposes to and/or reflects chronic airway
inflammation or exposure to respiratory pathogens.
Such findings would be consistent with the chronic
inflammatory state identified in the central airway
mucosa of cannabis smokers and possibly with the
history of increased episodes of bronchitis exacerba-
tions reported for this population.
In other assessments of smoking on the central airways
of habitual cannabis and tobacco smokers, Barsky et al.
(54) carried out cellular histology, immunohistology and
DNA analysis in central airway biopsies collected from
a subset of 28 nonsmokers, 12 cannabis smokers, 13
tobacco smokers and 7 combined cannabis and tobacco
smokers. The cellular histology studies focused on epithe-
lial changes associated with atypia, dysplasia and prema-
lignant transition including basal cell hyperplasia,
stratification, cell disorganization, nuclear variation,
mitotic figures, increased nuclear/cytoplasmic ratio, and
squamous cell metaplasia. When compared to the base-
line frequency observed in the nonsmoker cohort, statis-
tically-significant increases were observed in the cannabis
smoker cohort for every parameter and the changes were
similar to those observed in the biopsies from tobacco
smokers and combined cannabis and tobacco smokers.
The expression of two proteins associated with chronic
smoke exposure and pre-malignant transition, the Ki-67
proliferative antigen and epidermal growth factor recep-
tor (EGFR), were abnormally increased in a similar pat-
tern across the cannabis smoker, tobacco smokers and
combined cannabis and tobacco smoker groups. For
example, 92% of the biopsies from cannabis smokers
expressed high levels of staining for Ki-67 while expres-
sion was observed in only 29% of the nonsmokers.
Similarly, 52% of biopsies from cannabis smokers exhib-
ited high expression of the EGFR receptor while diffuse
expression was observed in only 7% of nonsmokers.
Despite the expression of these early markers, a more
proximate marker of DNA damage, abnormal DNA
ploidy, was detected in 5% of nonsmokers and 12% of
cannabis smokers (no significant difference), while
abnormal DNA ploidy was observed in 43% of tobacco
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 7
smokers (p < .01 compared to nonsmokers), suggesting
that there may be a difference in progression between the
cannabis and tobacco smoking subjects. Collectively,
these findings raise concern that cannabis smoking not
only has inflammatory effects on the central airway
mucosa but that it exerts pre-malignant changes at the
cellular and molecular level.
Impact of cannabis smoking on the protective
functions of alveolar macrophages
Alveolar macrophages line the airways and distal alveo-
lar spaces and provide an important line of defense
against inhaled antigens and pathogens, both suppres-
sing unwanted immune responses that would promote
lung inflammation and clearing inhaled materials that
might have toxic or infectious consequences. As noted
above, BAL revealed a 3-fold increase in the numbers of
alveolar macrophages in both cannabis smokers and
tobacco smokers compared to nonsmokers and
a 6-fold increase in the combined cannabis and tobacco
smoking cohort, as well as increases in neutrophil
counts in all smoking groups (50). However, despite
this common inflammatory effect that increases cell
number, ex vivo analysis has revealed functional
impairments only in alveolar macrophages collected
from cannabis users. The functional differences
between cells from cannabis smokers and tobacco smo-
kers suggest a unique biologic consequence from the
cannabinoids inhaled during cannabis smoking. THC
and other cannabinoids can directly interact with can-
nabinoid receptors-type 1 (CB-1) and type 2 (CB-2)
that are expressed by human immune cells (11,55).
When alveolar macrophages were co-cultured with sta-
phylococcus aureus (S. aureus), a common respiratory
pathogen, clear deficits in both bacterial phagocytosis
and killing were present in samples from cannabis
smokers but not those from nonsmokers or tobacco
smokers (56). Exposure of normal human immune
cells to THC in vitro can lead to the impaired produc-
tion of protective Type-1 cytokines and alter the func-
tional differentiation of human monocytes in
a cannabinoid receptor-dependent manner (10,11).
Consistent with these in vitro effects from THC, alveo-
lar macrophages recovered from cannabis smokers
were deficient in their stimulated production of tumor
necrosis factor-alpha, granulocyte-macrophage colony-
stimulating factor (GM-CSF), and interleukin-6 when
compared to cells from nonsmokers or tobacco smo-
kers (56). When examining the mechanisms responsi-
ble for deficits in antimicrobial killing, alveolar
macrophages from the cannabis smoking cohort failed
to express messenger ribonucleic acid for inducible
8 D. P. TASHKIN AND M. D. ROTH
nitric oxide synthase and supplementing these cultures
with either GM-CSF or interferon-gamma restored the
expression of inducible nitric oxide synthase and their
capacity to kill S. aureus (57,58). These investigations
provide direct evidence of a unique immune-suppres-
sing effect from cannabis smoke that can impair anti-
microbial defenses, potentially predisposing to
pneumonia (see below).
Clinical relationship between cannabis smoking
and COPD
While there is a clear relationship between cannabis
smoking and symptoms of chronic bronchitis, it is not
clear that cannabis smoking is a significant independent
risk factor for COPD. The results of both the cross-sec-
tional and longitudinal studies of lung function in smo-
kers of cannabis alone, or when adjusted for concomitant
tobacco smoking, are mixed but there is a suggestion that
particularly heavy smokers and older-aged habitual smo-
kers might be at increased risk. Clearly, further studies are
required to address this question, particularly studies that
include older and heavier smokers of cannabis. Moreover,
as pointed out by Tan and Sin (59), with the increasing
prevalence of cannabis use following its legalization in
most states, future studies of the impact of cannabis on
lung health should ideally attempt to quantify the amount
and composition of commercially available cannabis that
is consumed and examine the impact of alternative
devices for cannabis delivery.
Clinical relationship of cannabis smoking to
lung cancer
Several lines of evidence exist both for and against
a link between cannabis smoking and lung cancer.
The following evidence supports a link. First, cannabis
and tobacco smoke contain similar concentrations of
carcinogenic PAHs and other carcinogenic agents (12–
14). Second, when tar generated from cannabis cigar-
ettes was examined for its capacity to induce expression
of CYP1A1, a cytochrome P450 isozyme involved in the
activation of PAHs to proximate carcinogens, an addi-
tive effect was observed in which THC itself increased
the expression of CYP1A1 in a dose-dependent manner
(15). Third, THC has immunosuppressive properties
and animal studies suggest that THC can suppress
anti-tumor responses and promote uncontrolled lung
cancer growth (60). Fourth, while the daily consump-
tion of cannabis joints tends to be much lower than the
consumption of tobacco cigarettes, the lack of filters
and differences in packing density and smoking topo-
graphy (larger puff volume and longer breath-holding
times) can dramatically amplifying lung exposure to the
particulates (including the PAHs) within cannabis
smoke (17). Fifth, smokers of cannabis (alone or with
tobacco) exhibit widespread histopathologic alterations
in their bronchial mucosa (52), some of which (squa-
mous metaplasia, cellular disorganization, cellular aty-
pia and increased nuclea/cytoplasmic ratio) have been
shown to be precursors of the subsequent development
of lung cancer (61). Sixth, immunohistologic studies
identify molecular dysregulation in lung biopsies
obtained from cannabis smokers, including over-
expression of Ki-67 and EGFR (54). Similarly, laryngeal
cancer specimens obtained from cannabis smokers,
tobacco smokers and nonsmokers have shown
increased expression of both EGFR and downstream
onco-proteins in the specimens obtained from the can-
nabis smokers as compared to the nonsmokers (62).
Seventh, several small case series have indicated an
unusually high proportion of regular cannabis smokers
among young persons (<40–45 yrs) with lung or upper
airway cancer (63–67), consistent with a possible causal
relationship between cannabis smoking and respiratory
cancer. However, case series represent uncontrolled
observations that by themselves are not reliable indica-
tors of causality. Eighth, two older epidemiologic stu-
dies from North Africa showed a significant association
of cannabis with tobacco-related cancers (68,69).
However, as it is common in these societies to mix
tobacco with cannabis in the form of a kiff, it was not
possible to disentangle the effects of tobacco from those
of cannabis in the latter studies. Ninth, a case-control
population-based study of 79 lung cancer cases
≤55 years of age and randomly selected age-matched
controls, carried out in New Zealand, found
a significant positive association between cannabis use
and lung cancer risk but only in the heaviest tertile of
cannabis smokers after adjustment for age, gender,
ethnicity, family history of lung cancer and pack-years
of tobacco (70). These subjects had a cumulative life-
time history of >10.5 joint-years but the findings need
to be interpreted cautiously as this subgroup included
only 14 cases and 4 controls, suggesting imprecise and
possibly overinflated estimates of risk. Lastly,
a population-based cohort study of 49,321 men who
were queried regarding cannabis and/or tobacco use at
the time they were conscripted into the Swedish mili-
tary was assessed and followed for the development of
lung cancer for up to 40 years (71). A positive associa-
tion between subsequent lung cancer incidence and
a so-called “lifetime” history of smoking cannabis up
to 50 times prior to the age of conscription was identi-
fied after adjustment for tobacco use prior to that time.
However, the inability to adjust for the true lifetime

tobacco and cannabis use, especially during the up to
40 years of follow-up, represent a significant flaw in
their ability to compensate for this known cancer risk
factor.
In contrast, considerable evidence against a link
between cannabis and lung cancer also exists. First,
several investigators have demonstrated anti-tumor
effects from THC and other cannabinoids on a variety
of malignancies (lung, glioma, lymphoma, breast, pros-
tate, etc.) in both cell culture and animal models
(reviewed in 72,73). In these studies, THC and other
cannabinoids have been shown to have anti-prolifera-
tive, pro-apoptotic, anti-angiogenic, anti-mitochondrial
and a variety of other properties that underlie their
therapeutic potential. However, despite promising fea-
tures, no cannabinoid-based drug has yet demonstrated
clinical tumor-suppressive activity. Second, a large pro-
spective cohort study in Northern California of 64,855
health management plan participants (15–49 years of
age at the time of enrollment with an average follow-up
of 8.6 years) failed to find an association between self-
reported cannabis use and tobacco-related cancers (74).
Of note, the relatively young age of the subjects and
short duration of follow-up in this study may have led
to an underestimation of risk. More recently, a pooled
analysis of six well-designed case-control studies invol-
ving a total of 2159 cases and 2985 controls failed to
find a significant association between cannabis use and
risk of lung cancer (OR 0.95; 95% CI 0.66, 1.38; p = .81)
(75). Only one of the six studies included in the pooled
analysis showed a significant positive association
between cannabis smoking and lung cancer, mainly in
the heaviest cannabis use tertile (70), but, as mentioned
above, the limited number of cases and controls in this
tertile raises concerns. Overall, when the clinical studies
reporting positive vs. negative associations of cannabis
with lung cancer are compared, the weight of evidence
suggests a null effect of cannabis use with respect to
lung cancer risk. Given the very strong associations
between tobacco smoking and cancer risk, this is per-
haps one of the most striking findings associated with
cannabis smoking and supports a moderating role of
cannabinoids themselves on the known carcinogenic
effects of other components in tobacco smoke.
Clinical relationship of cannabis smoking to
pneumonia
Habitual cannabis smoking has been shown to impair
the lung’s defense against infection (56–58,76), imply-
ing that it might increase pneumonia risk. In addition,
cannabis has previously been shown to be frequently
contaminated with Aspergillus fumigatus (77) and
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 9
potentially pathogenic gram-negative bacteria (78);
pathogens that could be inhaled into the lung and
predispose to pneumonia. This possibility is supported
by case reports of Aspergillus pneumonia in cannabis
smokers who were immunocompromised by the
Acquired Immunodeficiency Syndrome (AIDS) (79),
chronic granulomatous disease (80), bone marrow
transplantation (81), renal transplantation (82) or can-
cer treated with chemotherapy (83). In addition to
issues of contamination, a few older epidemiologic stu-
dies have suggested that cannabis may be an indepen-
dent risk factor for opportunistic pneumonia in human
immunodeficiency virus (HIV) positive individuals
(84–86), but conflicting findings have been reported
(87). Lorenz et al. recently reported findings based on
an analysis of a sample of participants from the
Multicenter AIDS Cohort Study (MACS), an ongoing
prospective study of men who have sex with men and
the natural history of HIV infection, which demon-
strated a significant association of cannabis smoking
with infectious pulmonary diagnoses (mainly pneumo-
nia) in the HIV-seropositive, but not the HIV-serone-
gative, subgroup after adjustment for relevant
covariates (88). On the other hand, an as-yet unpub-
lished, oral presentation based on a multi-variate ana-
lysis of data from a larger sample of the same cohort
failed to show a significant association of cannabis
smoking in either the HIV-negative or HIV-positive
subgroup (89). Additional studies that directly assess
the possible association between regular cannabis use
and pneumonia are clearly warranted.
Clinical association of cannabis smoking with
pneumothorax, pneumomediastinium and
bullous lung disease
Several cases of pneumothorax and/or pneumomediasti-
num have been reported in association with cannabis
smoking (90–97). A hypothesized mechanism is the
deep inhalation technique followed by prolonged
breath-holding as is characteristic of cannabis smoking
topography, particularly if associated with a Valsalva or
Mueller maneuver that could predispose to alveolar rup-
ture and leakage of air into the pleural or mediastinal
space. In addition, several cases of large lung bullae have
been reported in smokers of mainly large amounts of
cannabis in addition to varying quantities of tobacco (98–
101). However, one cannot infer a causal relationship
between cannabis use and lung bullae based solely from
case series, particularly since the prevalence of bullous
lung disease in the general population is not
known (102).
10 D. P. TASHKIN AND M. D. ROTH

Summary and conclusions regarding the (e.g., pro-apoptotic, anti-proliferative, anti-angiogenic)

pulmonary consequences of habitual cannabis that might provide protection against carcinogenesis.
smoking Although THC-related impairment in the microbici-
dal activity of alveolar macrophages, a principal immune
Given the direct exposure of the lung to cannabis
effector cell residing in the lung, implicates cannabis
smoke and the combustion-related toxins that cannabis
smoking as a potential risk factor for pneumonia, good
and tobacco smoke share in common, there is under-
clinical evidence of this is lacking. Potential risk, if pre-
standable concern that regular smoking of cannabis
sent, may be in individuals with other concurrent reasons
might lead to adverse pulmonary consequences such
for immune deficiency. Several case series have suggested
as tobacco-related COPD and cancer. These concerns
an association of heavy cannabis smoking with pneu-
have recently assumed greater public health importance
mothorax, pneumomediastinum and bullous lung dis-
given the increasing legalization of cannabis for both
ease, but causality cannot be inferred from these
medicinal and recreational use and the rising preva-
uncontrolled observational reports.
lence of regular cannabis smoking.
Solid conclusions regarding the respiratory conse-
Surprisingly, and in direct contrast to tobacco smok-
quences of regular cannabis smoking cannot currently be
ing, there is a bronchodilator effect associated with can-
drawn due to the sparsity of the available literature pertain-
nabis smoking that appears dependent upon the action of
ing to this issue, confounding by combined cannabis and
THC. While intriguing, THC formulations can also
tobacco smoking and conflicting findings concerning the
induce bronchoconstriction and the net effects on airway
independent association of cannabis smoking with lung
function and symptoms have not yielded positive find-
function abnormality and both non-infectious and infec-
ings in small clinical studies. Based on a limited number
tious pulmonary disorders. Additional clinical research
of clinical investigations there is common agreement that
carried out in well-defined cannabis smoking, tobacco
cannabis smoking, either alone or adjusted for concomi-
smoking, combined cannabis and tobacco smoking and
tant tobacco use, is associated with symptoms of chronic
nonsmoking populations is needed in order to address
bronchitis (cough, phlegm and wheezing), but not
unanswered issues regarding cannabis smoking as a risk
breathlessness. Inflammatory changes in the central air-
for COPD and cancer, in particular. There is a special need
ways and on bronchial mucosal biopsies are documented
for studies in older subjects and those with long durations
as are subtle but reproducible abnormalities in airway
of cannabis use, along with better assessment regarding the
conductance and resistance. Of greater clinical impor-
amount and duration of cannabis smoked. Firm conclu-
tance, however, the overwhelming majority of cross-sec-
sions regarding the pulmonary consequences of cannabis
tional and longitudinal studies of lung function have not
smoking should await this information. Furthermore, with
identified an association between cannabis smoking and
the increasing popularity of vaping cannabis, direct inves-
an injury pattern consistent with COPD. One caveat is
tigation of this mode of cannabinoid exposure is needed.
that most existing studies were carried out in younger
smokers while COPD is a disease that manifests later in
life. A recent study of middle-aged to older smokers Funding
suggests that long-term use of cannabis “might be” asso-
The authors report no relevant financial conflicts. Work
ciated with an accelerated rate of decline of lung function supported in part by the National Institute on Drug Abuse,
similar to that found in tobacco smokers, underscoring National Institutes of Health under Grant R01 DA037102.
the need for additional studies.
There are features of cannabis smoke and cannabi-
noids that both support and argue against a link ORCID
between cannabis and cancer risk. However, the pre- Donald P. Tashkin http://orcid.org/0000-0002-5607-4872
sence of similar carcinogens in cannabis and tobacco Michael D. Roth http://orcid.org/0000-0003-2194-6578
smoke and the presence of cannabis-related pre-cancer-
ous changes in bronchial histopathology and immuno-
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