are in Research
of Smoked Marijuana in Experimentally Induced Asthma
P. TASHKIN, BERTRAND J. SHAPIRO, Y. ENOCH LEE, and CHARLES E. HARPER
REVIEW OF RESPIRATORY DISEASE, VOLUME 112, 1975
in original form February 20, 1975 and in revised form June 19, 1975 )
From the Division of Pulmonary Disease, Department of Medicine, UCLA School of
Medicine, Los Angeles, Calif. 90024.
Supported by U. S. Public Health Service Grant no. HSM 42-71-89.
induction of acute bronchospasm in 8 subjects with clinically stable bronchial
asthma, effects of 500 mg of smoked marijuana (2.0 per cent Delta 9-tetrahydrodrocannabinol)
on specific airway conductance and thoracic gas volume were compared with those
of 500 mg of smoked placebo marijuana (0.0 per cent Delta 9-tetrahydrocannabinol),
0.25 ml of aerosolized saline, and 0.25 ml of aerosolized isoproterenol (1,250
ug). Bronchospasm was induced on 4 separate occasions, by inhalation of methacholine
and, on four other occasions, by exercise on a bicycle ergometer or treadmill.
Methacholine and exercise caused average decreases in specific airway conductance
of 40 to 55 per cent and 30 to 39 per cent, respectively, and average increases
in thoracic gas volume of 35 to 43 per cent and 25 to 35 per cent, respectively.
After methacholine-induced bronchospasm, placebo marijuana and saline inhalation
produced minimal changes in specific airway conductance and thoracic gas volume,
whereas 2.0 per cent marijuana and isoproterenol each caused a prompt correction
of the bronchospasm and associated hyperinflation. After exercise-induced bronchospasm,
placebo marijuana and saline were followed by gradual recovery during 30 to 60
min, whereas 2.0 per cent marijuana and isoproterenol caused an immediate reversal
of exercise-induced asthma and hyperinflation.
studies have demonstrated significant, acute bronchodilatation in healthy young
men after both smoked marijuana (1, 2) and oral Delta 9-tetrahydrocannabinol (Delta
9-THC), the principal psychoactive ingredient in marijuana (2). More recently,
the smoking of marijuana and ingestion of Delta 9-THC by subjects with chronic,
clinically stable, bronchial asthma of minimal to moderate severity has been shown
to produce airway dilatation of a magnitude similar to that previously noted in
healthy subjects (3). Although these findings appear to support the benefit ascribed
to the use of cannabis in the last century for the treatment of bronchial asthma
(4), they do not provide any direct evidence for a bronchodilator effect of marijuana
during an acute asthmatic attack. In the present study, the effects of smoked
marijuana on bronchomotor tone were evaluated in asthmatic subjects after acute
bronchospasm was induced either by inhalation of methacholine or by exercise.
patients with bronchial asthma characterized by typical attacks of wheezing, breathlessness,
and cough at least partially relieved by bronchodilator medication and without
other significant medical illness were selected for study. All subjects were clinically
stable at the time of the study. Three subjects had participated in previous studies
to evaluate the acute bronchial effects of smoked marijuana and oral Delta 9-THC
in stable asthma (3). Five subjects had smoked marijuana previously. Of these
5 subjects, one had smoked marijuana only in connection with the previous study
(3), 3 had smoked infrequently (less than 1 joint per month), and one had smoked
regularly, but mildly (I joint per week).
subject had used marijuana within 7 days of the study. No subject was a tobacco
cigarette smoker. The schedule of screening, preliminary, and experimental studies
is indicated in table 1. Days on which studies were performed were generally separated
by 1 week or less. All oral bronchodilator drugs were withheld for at least 8
hours; inhaled bronchodilator drugs were withheld for at least 4 hours before
the beginning of each morning or afternoon study session. Screening studies were
performed on day 1 and consisted of spirometry using a 13.5-liter, water-seal
spirometer (Warren E. Collins, Inc.), and measurement of single-breath diffusing
capacity for CO (DLco) (5), airway resistance (Raw), and thoracic gas volume (Vtg)
using a 900-liter, variable-pressure, body plethysmograph (6, 7). The Vtg and
Raw were measured at or near the volume of resting end -expiration. The average
slope of the inspiratory and expiratory pressure-flow loops at flows of + 0.5
liter per sec was used in the calculation of Raw. Plethysmographic measurements
were made in quintuplicate, and the results were averaged. Plethysmographic and
spirometric measurements were performed before and 5 to 10 min after inhalation
of 1,250 mg of isoproterenol hydrochloride as previously described (3) to establish
the presence of reversible bronchospasm.
studies were performed in the morning (9 A.M.) and afternoon (1:30 P.M.) of day
2 to determine the type, duration, and severity of exercise and the dose of methacholine
required to produce the required degree of bronchospasm. (see below). During the
morning session, two sets of control measurements of Raw and Vtg were obtained
15 min apart, after which bronchospasm was induced by exercise either oil a bicycle
ergometer (3 subjects) or on a treadmill (4 subjects). Treadmill exercise was
used if a subject felt uncomfortable riding a bicycle or if previous exhaustive
exercise on a bicycle ergometer failed to produce the requisite degree of bronchoconstriction.
Each subject performed stead), exercise for 6 to 10 min using incremental work
loads of 200 to 650 kilopond-m (bicycle ergometer) or 1 to 3.5 mph at a 0 to 10
per cent grade (treadmill) until specific airway conductance (SGaw = 1Raw/Vtg)
determined within 10 min of completion of the exercise decreased by at least 20
per cent from the mean of that subject's control values. When this degree of bronchoconstriction
was not achieved, exercise was repeated at the next higher work load after a rest
of at least 15 min and after plethysmographic measurements had returned to initial
control values. In one subject (JB), bronchospasm could not be provoked despite
exhaustive treadmill exercise. During the afternoon session, after plethysmographic
measurements of Raw and Vtg had returned to values similar to those obtained during
the control period of the morning session, each subject inhaled graded doses of
methacholine (62.5 to 625 ug in 0.25 to 0.5 ml of saline) until SGaw determined
within 5 min of methacholine inhalation decreased by at least 25 per cent from
that subject's control value. The methacholine solution, were nebulized via a
DeVilbiss nebulizer connected to a positive- pressure breathing device powered
by compressed air. Subjects inhaled the aerosol using slow, deep inspirations
followed by several seconds of end-expiratory breath-holding. When the requisite
degree of bronchospasm did not develop within 5 min after one dose of methacholine,
the next higher dose was not administered until at least 15 min after the previous
dose and after SGaw had returned to initial values.
the morning and afternoon of days 3 and 4 (a total of 4 experimental sessions),
2 sets of control measurements of Raw and Vtg were obtained. Bronchospasm was
then induced in each subject by inhalation of the same dose of methacholine that
been shown in the preliminary studies to reduce SGaw in that subject by at least
25 per cent. During the morning sessions, approximately 8 to 9 min after induction
of bronchospasm, subjects inhaled 0.25 ml of either saline or 0.5 per cent isoproterenol
(Iso) in a randomly ordered, single blind fashion using the same nebulization
and inhalation techniques that had been used to administer the methacholine solution.
Serial plethysmographic measurements were performed within 1 to 2 min ("zero"
time), and at 5, 10, 15, 30, and 60 min after saline or Iso inhalation. During
the afternoon sessions, experimental bronchospasm was induced only after plethysmographic
measurements had returned to the baseline values recorded at the beginning of
the morning session of the same day. Immediately after the development of bronchospasm,
subjects smoked a joint containing 500 mg of marijuana assayed at either 2.0 per
cent Delta 9-THC or 0.0 per cent Delta 9-THC (placebo) according to a randomly
ordered, single blind protocol joints were smoked during a 10-min period using
a standard deep-inhalation technique (2). Marijuana. and placebo marijuana preparations
were obtained from the National Institute on Drug Abuse, under whose direction
extraction, assay, and blending procedures were performed. Immediately after completion
of smoking, serial plethysmographic measurements were repeated at the same intervals
the morning and afternoon of days 5 and 6 (4 experimental sessions), after control
measurements were made, bronchospasm was induced in each subject by the type,
duration, and degree of exercise that had been demonstrated during preliminary
studies to reduce SGaw in that subject by at least 20 per cent. Afternoon exercise
was begun only after measurements had returned to the control values determined
during the same morning. Using a randomly ordered, single blind protocol, in morning
sessions, subjects inhaled Iso or saline 8 to 9 min after the development of bronchospasm,
and in afternoon sessions, subjects smoked 2.0 per cent marijuana or placebo during
a period of 10 min immediately after the induction of bronchospasm. Serial measurements
of Raw and Vtg were performed at the same intervals after inhalation or smoking
of the test preparations, as indicated for the methacholine experiments.
order of the experiments in which bronchospasm was induced by either methacholine
inhalation or exercise was randomized among the subject population.
SGaw was calculated from each set of measurements of Raw and Vtg to correct for
changes in Raw secondary to changes in lung volume (8). For each subject at each
time interval during each experimental protocol, per cent changes in SGaw and
Vtg were calculated from the average of the 2 pre-methacholine or pre-exercise
At each time interval for each type of experiment, the individual per cent changes
in SGaw and Vtg were averaged for all subjects, thereby minimizing the factor
of intersubject variability of control values. The significance of the average
per cent changes in SGaw and Vtg from initial control values, of the per cent
changes that followed marijuana, compared with placebo or saline, and that followed
isoproterenol, compared with saline or marijuana, was determined using "Student's"
t test (paired observations). In addition, the average individual differences
in control values among the various types of experiments were tested for significance
using the t test (paired observations) to ascertain whether all experiments were
performed under comparable conditions.
characteristics of each subject and the results of baseline pulmonary function
studies are given in table 2. Three men and 5 women from 19 to 59 years of age
were studied. The ratio of 1-sec forced expiratory volume (FEV1 ) to
forced vital capacity ranged between 49 and 79 per cent of the predicted value,
indicating the presence of minimal to moderately severe airway obstruction. Inhalation
of Iso resulted in mild to moderate increases in FEV1 and SGaw, indicating
the presence of reversible bronchospasm. The DLco was normal or greater than normal,
consistent with bronchial asthma (13).
mean initial control values of SGaw and Vtg during each experimental session before
induction of bronchospasm with methacholine or exercise are shown in table 3.
The average individual differences in control values for each measured variable,
comparing any one session with any other, were not significantly different from
mean per cent changes in SGaw and Vtg after smoked marijuana or placebo, or inhaled
Iso or saline after methacholine-induced bronchospasm are shown in figures 1 and
2. Methacholine inhalation promptly caused significant bronchoconstriction, with
average decreases in SGaw of 40 to 55 per cent, and significant hyperinflation,
with mean increases in Vtg of 35 to 43 per cent. After subsequent placebo marijuana
smoking or saline inhalation, SGaw increased only modestly, remaining significantly
less than initial control values for 30 to 60 min, and Vtg decreased only gradually,
remaining significantly increased for 15 min. On the other hand, 2 per cent marijuana
and Iso each resulted in a prompt return of SGaw and Vtg to control values, which
were significantly different from values after placebo and saline. Although the
mean values for SGaw after Iso were greater than both initial control values and
those after smoked marijuana, these differences were not significant.
average per cent changes in SGaw and Vtg that followed each test preparation after
exercise-induced bronchospasm are shown in figures 3 and 4. Exercise resulted
in average decreases in SGaw of 30 to 39 per cent and average increases in Vtg
of 25 to 35 per cent. There was a gradual return to control values during 30 to
60 min after placebo and saline. After marijuana, on the other hand, SGaw and
Vtg returned promptly to pre-exercise values, which were significantly different
from values after placebo and saline for 15 to 60 min. The Iso caused a prompt
return of Vtg to baseline values and an immediate increase in SGaw to values that
significantly exceeded initial control values and remained significantly greater
than values after saline and marijuana for as long as 60 min.
4 subjects who had previously used cannabis experienced emotional changes after
smoking marijuana that were generally pleasant, whereas no "high" developed after
placebo marijuana. Because these subjects were able to distinguish between real
and placebo marijuana, these experiments were not truly blind. The 4 subjects
with essentially no previous cannabis experience either admitted to no central
changes or experienced mild somnolence or light-headedness after marijuana.
40 to 50 per cent decrease in SGaw after inhalation of < 625 ug of methacholine
noted in our subjects is consistent with the known bronchial hyper-reactivity
of asthmatic subjects to muscarinic stimulation (14). In our laboratory, normal
subjects require more than 5 times these doses of methacholine to develop a comparable
degree of bronchoconstriction. The associated increase in Vtg observed in our
asthmatic subjects was probably related to the increase in expiratory flow resistance.
was a relatively small and nonsignificant (P > 0.05) average individual difference
in the magnitude of the methacholine-induced decrease in SGaw when any one of
the 4 experimental sessions was compared with any other, and a very small difference
when the marijuana and placebo marijuana sessions were compared with each other
(1.4 + 4.8 per cent SE). These findings indicate a reasonable degree of reproducibility
of airway constriction after inhalation of the same dose of methacholine by individual
subjects from one session to the next, thereby permitting a reliable comparison
of the effects of marijuana, placebo, Iso, and saline on methacholine-induced
of placebo marijuana smoking and saline inhalation showed negligible differences
in the magnitude or duration of methacholine-induced bronchoconstriction (figure
hyperinflation (figure 2) after these two preparations. This suggests that any
bronchial irritant effect of marijuana smoke was not sufficient to aggravate or
perpetuate existing acute bronchospasm to an extent greater than that which might
result from an irritant effect of inhaled saline. Comparison of the magnitude
and time course of changes in SGaw and Vtg immediately after marijuana smoking
to those after placebo marijuana and saline indicate that inhaled Delta 9-THC
causes a prompt, complete, and sustained reversal of methacholine-induced bronchospasm
and correction of the associated hyperinflation. These effects were not significantly
different from those observed after Iso, although there was a tendency toward
a greater degree of bronchodilatation after the latter.
30 to 39 per cent average decrease in SGaw and 25 to 35 per cent average increase
in Vtg after mild to heavy exercise for 6 to 10 min in 7 of the 8 asthmatic subjects
tested are consistent with previous reports of bronchospasm (15) and hyperinflation
(16) after exercise. The average individual difference in exercise-related decrease
in SGaw when any of the 4 study periods was compared with any other was small
and nonsignificant (P > 0-2), so that the effects of smoked and inhaled test
preparations on exercise-induced bronchospasm. could be validly compared.
appropriateness of comparing effects of various drugs on bronchospasm provoked
by exercise twice on the same day might be questioned, because McNeill and associates
(17) found partial to complete loss of exercise-induced bronchoconstriction in
3 of 4 asthmatic subjects after repeated periods of exercise throughout one day.
In our subjects, however, there were no consistent differences between the per
cent decrease in SGaw after exercise during afternoon sessions and that observed
in the same subjects during morning sessions. The mean + SE morning-to-afternoon
difference was -1.7 + 3.1 per cent (P > 0.5). Our findings are more in agreement
with those of Godfrey and co-workers (18) and Silverman and Anderson (19). They
showed a reproducible magnitude of postexercise bronchospasm in individual asthmatic
children after a similar type and severity of exercise when repeat tests were
performed either on separate days within 1 week or 2 hours apart within the same
day. These investigators found more variability after bicycle ergometer than treadmill
occurrence of the most marked changes in SGaw and Vtg during the first 10 min
after induction of bronchospasm, with a gradual return to control values during
30 to 60 min after placebo or saline is characteristic of the time course of exercise-induced
asthma (15, 16). The prompt return of SGaw and Vtg to pre-exercise values after
smoked marijuana contrasts with the delayed recovery that followed placebo and
saline, indicating the efficacy of inhaled Delta 9-THC in the correction of exercise-induced
asthma. Comparison of the response to 1,250 ug of Iso with that to 2 per cent
marijuana (10 mg of Delta 9-THC), however, revealed that the former caused a significantly
greater degree of bronchodilatation in the doses used.
effects of smoked marijuana on acute, experimentally induced bronchoconstriction
and hyperinflation noted in the present study extend our previous observations
of significant bronchodilatation and reduction in hyperinflation in resting patients
with stable bronchial asthma (3).
suggestion and other psychological factors probably play an important role in
the response of asthmatic patients to inhalants (20), the lack of response to
Delta 9-THC-extracted marijuana in the present study suggests that a placebo effect
was not responsible for the reversal of experimentally induced asthma observed
to follow smoking of natural. marijuana. Moreover, it is unlikely that pleasant
emotional sensations after marijuana contributed significantly to the bronchodilatation.
Although the 4 subjects with no or negligible prior cannabis experience did not
admit to a feeling of tranquility or euphoria after smoking marijuana, they did
demonstrate a degree of correction of experimentally induced bronchospasm comparable
to that observed in the subjects who had used cannabis previously. Although the
mechanism of Delta 9-THC-induced bronchodilatation has not been completely determined,
previous studies have demonstrated that this effect is not mediated by B-adrenergic
stimulation or inhibition of muscarinic receptors (21). A vagolytic mechanism
proximal to the muscarinic receptor site is suggested by correlative studies involving
the dog salivary gland (22) and guinea pig ileum (23).
present findings and those previously reported (1-3) demonstrated acute airway
dilatation after smoked marijuana. In contrast, mild, but significant, reductions
in forced expiratory flows and SGaw after chronic, heavy marijuana smoking were
recently reported (24), suggesting airway obstruction secondary to a chronic irritant
effect of the smoke. An acute, deleterious effect of the gas phase of marijuana
smoke on alveolar macrophages has also been demonstrated in vitro (25). Consequently,
smoking would not appear to be an appropriate long-term method for administration
of bronchodilator cannabinoid compounds for potential therapeutic purposes. Although
ingestion of Delta 9-THC in a sesame oil vehicle has produced bronchodilatation
in asthmatic patients (3), less dilatation was noted than that after smaller doses
of Delta 9-THC delivered by smoking (3). In preliminary studies in our laboratory,
aerosolization of an ethanol solution of Delta 9-THC using a Freon® propellant
resulted in mean peak increase in SGaw of 88 per cent in 4 normal subjects, but
unwanted psychological effects were not circumvented. Regardless of its route
of administration, Delta 9-THC does not appear to be a suitable bronchodilator
for therapeutic use because of its systemic psychotropic and possible undesirable
endocrine, immunologic, and cytogenetic effects (26). Related cannabinoid compounds,
however, such as cannabinol and cannabidiol, do not produce the central nervous
system effects or tachycardia characteristic of cannabis (27), but appear to share
another and potentially useful property with D-THC. reduction of intraocular pressure
(28). These compounds should be further investigated for possible bronchodilator
activity and therapeutic utility.
writers are indebted to Dr. Daniel H. Simmons for help in review of the manuscript.
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