ACUTE EFFECTS OF SMOKED MARIJUANA AND ORAL DELTA-9-TETRAHYDROCANNABINOL ON
SPECIFIC AIRWAY CONDUCTANCE IN ASTHMATIC SUBJECTS (1-3)

Donald P. Tashkin, Bertrand J. Shapiro, and Ira M. Frank

American Review of Respiratory Disease, Volume 109, 1974, p. 420-428

SUMMARY

The acute effects of smoked 2 per cent natural marijuana (7 mg per
kg) and 15 mg of oral delta-9-tetrahydrocannabinol (THC) on
plethysmographically determined airway resistance (Raw) and specific
airway conductance (SGaw) were compared with those of placebo in 10
subjects with stable bronchial asthma using a double-blind crossover
technique. After smoked marijuana, SGaw increased immediately and remained
significantly elevated (33 to 48 per cent above initial control values)
for at least 2 hours, whereas Sgaw did not change after placebo. The peak
bronchodilator effect of 1,250 mcg of isoproterenol was more pronounced
than that of marijuana, but the effect of marijuana lasted longer. After
ingestion of 15 mg of THC, SGaw was elevated significantly at 1 and 2
hours, and Raw was reduced significantly at 1 to 4 hours, whereas no
changes were noted after placebo. These findings indicated that in the
asthmatic subjects, both smoked marijuana and oral THC caused significant
bronchodilation of at least 2 hours' duration.

Introduction

In the nineteenth century, one of the medicinal uses of marijuana was in
the therapy of bronchial asthma (1); however, no definite evidence of its
effectiveness as a bronchodilator was adduced until recent studies
demonstrated significant airway dilatation in healthy young men after both
the smoking of marijuana (2,3) and the ingestion of its principal
psychoactive ingredient delta-9-tetrahydrocannabinol (THC) (3). Whether
similar effects could be elicited in subjects with bronchospastic disease
was of interest because the irritant effect of marijuana smoke, which is
probably responsible for the symptoms of bronchitis attributed to heavy or
chronic marijuana smoking (4,5), might outweigh the bronchodilator
properties of delta-9-THC, thereby resulting in bronchospasm in patients
with hyper-reactive airways. Consequently, the acute effects of both
inhaled marijuana smoke and oral delta-9-THC on specific airway conductance
(SGaw) were investigated in a group of patients with clinically stable
bronchial asthma.

Materials and Methods

Subjects: Five men and 5 women (from 22 to 74 years of age) with a
diagnosis of bronchial asthma according to the criteria established by the
American Thoracic Society (6) were studied. Each subject had a clinical
picture characterized by typical episodes of wheezing, cough, and dyspnea
occurring either spontaneously or in response to exposure to inhaled
allergens or nonspecific irritants, to emotional aspects, to respiratory
tract infections, and/or to exercise, and relieved by bronchodilator
medication. At the time of study, all subjects were clinically stable;
asthmatic symptoms were absent in 4 subjects and chronic and of mild to
moderate severity in the remainder. With the exception of 2 subjects (PF
and JBon), who probably had pulmonary emphysema in addition to
bronchospastic disease, there was no evidence of other significant medical
illness by history, physical examination, complete blood count, blood
chemistries (SMA-12), routine urinalysis, electrocardiogram, and chest
radiograph. Significant psychiatric illness was excluded on the basis of
interviews with one of the investigators and evaluation of performance on
lthe Minnesota Multiphasic Personality Inventory.
All subjects underwent screening pulmonary function studies,
including spirometry using a 13.5-liter water spirometer (Warren E.
Collins, Inc.), single-breath diffusing capacity for carbon monoxide
(DLCO) (7), airway resistance (Raw), and thoracic gas volume (Vtg)
using a 900-liter, variable-pressure body plethysmograph (8,9). To assess
the degree of reversible airway obstruction, spirometry was performed both
before and 10 minutes after inhalation of 0.25 ml of isoproterenol HCL
(1:200) via a DeVilbiss nebulizer connected to a positive pressure
breathing device powered by compressed air. The following technique was
used to administer the isoproterenol aerosol. Subjects were instructed
first to exhale to residual volume, then to inhale slowly from the
nebulizer to total lung capacity during a period of approximately 10
seconds, and then to resume normal breathing for several seconds. These
maneuvers were repeated until the bronchodilator solution in the nebulizer
was consumed (usually after 4 to 5 deep breaths). In addition, Raw and
Vtg were measured both 15 minutes before and immediately before inhalation
of isoproterenol, and at 5, 15, 30, and 60 minutes after the
bronchodilator. In all subjects, flows and/or SGaw (the ratio of the
reciprocal of Raw to the simultaneously measured Vtg) increased more than
25% after isoproterenol inhalation, indicating the responsiveness of the
airways to bronchodilator medication.
Seven of the 10 subjects had smoked marijuana previously, but only
sporadically (less than 1 cigarette per month). None admitted to the use
of drugs other than those prescribed for bronchial asthma, and none was a
tobacco cigarette smoker. No subject had used marijuana within 7 days
before the present study. In addition, bronchodilator medication was
withheld for at least 8 hours before the study.
Experiments were carried out with each subject on 4 separate days
beginning at 10 A.M., with at least 48 hours intervening between each study
session. The subjects were informed that they would be randomly receiving
marijuana or placebo.
Smoked marijuana: During 2 of the 4 experimental sessions,
subjects smoked 7 mg per kg of body weight of natural marijuana preparation
containing either 0.0 % delta-9-THC, serving as a placebo control, or 2.0 %
delta-9-THC according to a random, double-blind crossover design; however,
because of the potent psychotropic effects of marijuana, it was recognized
that the subjects probably had little difficulty in identifying the
marijuana. The THC content of the experimental preparation had previously
been assayed by gas-liquid chromatography. The 0 % preparation was
obtained by extraction of the active cannabinoids from the natural material
until assays for cannabinol, cannabidiol, delta-8-THC, and delta-9-THC were
all 0.0 %.
A uniform smoking technique was used in an effort to standardize
the amount of volatilized delta-9-THC delivered in the inhaled material.
Subjects inhaled the cigarette deeply for 2 to 4 seconds, held their breath
for 15 seconds, resumed normal breathing for approximately 5 seconds, and
then repeated these maneuvers until the cigarette was consumed, during a
period of approximately 10 minutes. The cigarette butt, or "roach," was
held with forceps to permit nearly complete consumption of the "roach,"
where the volatilized cannabinoids are concentrated.
The following characteristics were measured 15 minutes before and
immediately before marijuana or placebo was smoked (initial control
period) and immediately, 5, 10, 15, 30, 60, 90, 120, and 180 minutes after
completion of smoking: Raw, Vtg, respiratory rate, heart rate (determined
from the electro-cardiogram), and systolic and diastolic blood pressures.
In addition, to provide a rough assessment of the degree of intoxication;
at each interval after the smoking of marijuana and placebo, the 7 subjects
who had had prior experience with Cannabis were asked to estimate how
"high" they felt on a scale of zero to 7 in which 7 represented the
"highest" they had ever felt after smoking marijuana.
Oral delta-9-THC: During the remaining 2 study days, after an
overnight fast, according to a random double-blind design subjects ingested
either placebo or 15 mg of synthetic delta-9-THC dissolved in sesame oil
and contained in identical-gelatin capsules. Again, as in the smoked
marijuana experiments, the subjects were probably able to identify the
delta-9-THC because of the marked psychotropic effect. Measurements of the
same characteristics as those determined in the smoking studies and scoring
of subjective degrees of intoxication were carried out 30 minutes before
and immediately before oral administration of the drug (initial control
Period) and 30, 60, 90. 120. 180, 240, 300, and 360 minutes after
ingestion. The order of the smoking and oral experiments was randomized
among the study subjects.
All natural marijuana and synthetic THC preparations were obtained
from the National Institutes of Mental Health, under whose direction all
extraction, blending, assay, and synthetic procedures had previously been
performed.

Results

>From each set of measurements of Raw and Vtg, SGaw was calculated to
correct for changes in Raw secondary to changes in lung volume (10). For
each subject at each time interval after inhalation of isoproterenol or the
smoking or ingestion of the test agent, per cent change in each of the
measured characteristics was calculated from the average of the 2 control
values. Individual per cent changes were averaged for each inhaled or
ingested agent separately for all subjects at each time interval for each
type of experimental preparation. Using the Student t test, significance
of the differences between means was determined for (1) the average per
cent change in each characteristic for each experimental preparation
compared with initial control values, (2) the per cent changes that
followed smoked marijuana and oral THC compared with placebo using paired
observations, (3) the differences between the mean scores from zero for
the levels of "high" after smoked marijuana and oral delta-9-THC.
Physical characteristics and the results of the baseline pulmonary
function studies for each subject are indicated in table 1. Although
baseline forced expiratory volume in 1 second (FEV1) was greater than 80
% of the predicted value in 3 asymptomatic subjects (MA, SC, GT), in 2 of
the latter SGaw was more than 2 standard deviations below the mean
predicted value for this laboratory, and in the third subject, SGaw
increased 87 % after isoproterenol inhalation, indicting the presence of
reversible bronchospasm. There, symptoms and/or functional abnormalities
were present in all subjects.
Average initial control values for the measured characteristics
during each experimental session are indicated in table 2. There were no
significant differences between the mean baseline values obtained on
separate days.
Smoking studies: The average per cent changes in SGaw and Vtg
after smoked marijuana, smoked placebo marijuana, and inhaled isoproterenol
are shown in figures 1 and 2. After placebo, neither SGaw nor Vtg changed
significantly. After 2 per cent marijuana, average SGaw increased
immediately and remained elevated (33 to 48 per cent more than initial
control values) for at least 2 hours. These increases were significant
(P<0.05) compared both with control values and with placebo values. The
Vtg decreased slightly (4 to 13 per cent) but significantly (P<0.05)
compared with baseline and/or marijuana. Changes in Raw after marijuana
generally paralleled the changes in SGaw but were of lesser magnitude
because of the associated decreases in Vtg.
For comparison with the changes that followed marijuana smoking,
average per cent changes in SGaw and Vtg after inhalation of 1,250 mcg of
isoproterenol are also shown in figures 1 and 2. During the first 15
minutes after inhalation of isoproterenol, SGaw increased to levels greater
than those observed after 2 per cent marijuana. By 60 minutes after
isoproterenol, SGaw was elevated only slightly, and was significantly less
than the SGaw after marijuana (P<0.05). During the first 30 minutes after
isoproterenol inhalation, Vtg was significantly reduced, to a degee similar
to that noted after marijuana. By 60 minutes after isoproterenol, Vtg had
essentially returned to normal.
The average percentage changes in heart rate after smoking of
marijuana or placebo and after inhalation of isoproterenol are shown in
figure 3. Pulse rate decreased gradually after placebo to levels that were
slightly but significantly below baseline values after 30 to 120 minutes.
After 2 per cent marijuana, pulse rate increased immediately and remained
elevated for 30 minutes by amounts (7 to 22 Per cent) that were
significantly different from the changes that followed placebo (P<0.05).
Therafter, pulse rate decreased to levels that, at 90 and 120 minutes, were
significantly below initial control values (P<0.05) but were not
significantly different from the changes that followed placebo. Pulse rate
increased after isoproterenol, but the increase was not significant at
P<0.05.
No significant change in systolic or diastolic blood pressure or in
respiratory rate was observed after placebo, marijuana, or isoproterenol.
All subjects admitted to a definite feeling of intoxication after
smoking marijuana, whereas all but one subject had either no change or
minimal change in state of consciousness after placebo. The latter subject
(PF), who had not had any previous exposure to Cannabis, felt sleepy,
lightheaded, and jittery after both marijuana and placebo. The scores for
subjective degree of "high" after marijuana revealed a maximal feeling of
intoxication during the 5-minute period immediately after completion of
smoking, with a gradual decline thereafter (figure 4). By 2 hours, the
magnitude of the "high" was approximately one-third of the peak level,
and by 3 hours, the "high" had essentially dissipated.
Oral studies: The results of the oral studies are shown in figures
5 and 6. The SGaw increased modestly (14 to 19 per cent) but
significantly (P<0.05) at 60 to 120 minutes after ingestion of 15 mg of
delta-9-THC, whereas the placebo was not associated with any significant
changes. The Vtg did not change significantly after either placebo or THC.
As noted with smoked marijuana, decreases in Raw after oral THC paralleled
the increases in SGaw, except that Raw was still significantly reduced
(-10.2 + 3.6 and -12.9 + 3.3, with P<0.05) at 3 and 4 hours, respectively.
No alteration in respiratory rate, pulse rate, or systolic or
diastolic pressure was observed after oral delta-9-THC or placebo.
A subjective "high" was first experienced 1 hour after ingestion
of THC, reached a peak at 2 to 3 hours, then declined gradually, and was
gone by 6 hours (figure 4). The placebo preparation was not associated
with any significant change in consciousness.

Discussion

The significant increases in SGaw after the smoking of marijuana compared
with placebo suggested that inhaled marijuana caused airway dilatation in
asthmatic subjects and was consistent with findings previously reported in
persons without airway disease (2, 3). The dilatation was not due to an
increase in lung volume (10), because Vtg decreased significantly in
paralled with the increase in SGaw. The observed decrese in Vtg was
consistent with a reduction in air trapping secondary to the decrease in
bronchomotor tone. Also, the volume history of the lung, i.e., the deep,
sustained inhalation breathing pattern, did not explain the increase in
SGaw that followed marijuana smoking compared to placebo smoking, because
the breathing patterns were similar.
Because there was a significant correlation between the individual
increases in SGaw after marijuana and the magnitude of the subjective
"high" (r= 0.52; P< 0.01), the possibility that the observed
bronchodilatation was causally related either to the psychologic effects of
marijuana or to other effects of Cannabis on the central nervous system
deserves consideration. Despite the significant correlation between the
degree of marijuana-induced bronchodilatation and the level of
intoxication, the time sequences for these changes were somewhat different,
in that the bronchodilator effect at 2 hours was similar in magnitude to
that noted immediately after smoking (figure 1), whereas by 2 hours the
"high" had decreased to less than one half of the level experienced
immediately after smoking (figure 4); however, these temporal differences
did not exclude the possibility that the emotional changes experienced soon
after smoking triggered a chain of reactions that eventuated in a
relaxation of bronchomotor tone of longer duration than the initiating
emotional stimulus.
A cause-and-effect relationship between the psychologic and
bronchial effects of marijuana is consistent with the common clinical
observation that asthmatic attacks can be triggered by emotional factors
and by the demonstrated effectiveness of suggestion (13) and behavior
therapy (14) in the relief or prevention of bronchospasm. On the other
hand, the fact that significant bronchodilatation after 2 per cent
marijuana has also been noted in nonasthmatic persons suggests that the
dilator effect observed in our asthmatic subjects was probably at least not
predominantly of psychogenic origin, because there is no evidence that
bronchomotor tone in normal man is influenced significantly by emotional
factors. Moreover, although 3 of our subjects who had had no previous
exposure to Cannabis experienced a less euphoric "high" than the others
there was no difference in the degree of bronchodilatation observed between
these persons and those who had smoked marijuana previously, suggesting
that the pleasure associated with the "high" was probably not related to
the relaxant effect on the airways.
Although the mechanism whereby marijuana decreases bronchomotor
tone has not been studied in asthmatic patients, previous work in this
laboratory in normal subjects suggested that the bronchodilator effect is
mediated neither by stimulation of B-adrenergic receptors nor by an
atropine-like effect (15). These results make it appear unlikely that in
normal persons the bronchodilator effect of marijuana is mediated by its
effects on lthe central nervous system, and favor, instead, a direct effect
of the drug on bronchial smooth muscle. This may also be true in asthmatic
patients.
The fact that the smoking of placebo marijuana did not cause a
significant decrease in SGaw ;was surprising because the inhalation of
particulate matter in the smoke was expected to cause reflex
bronchoconstriction by analogy with tobacco cigarette smoking (16),
particularly in asthmatic subjects, whose airways are more reactive to
nonspecific irritants than those of subjects without airway disease (17).
In the present study, the failure of the airways to constrict after smoked
placebo might have been due to a balancing out of the constrictor effect of
inhaled irritants either by unidentified bronchodilator compounds in
marijuana that are not alcohol-extractable, or by a nonspecific placebo
bronchodilator response to the expectation of a pleasant experience. In a
prior study, it was shown that the airways of normal subjects also did not
constrict after the smoking of the placebo preparation but did constrict
after cigarette smoking (3). The fact that pulse rate decreased after
placebo, in contrast to the significant and expected increase (18) after
2 per cent marijuana (figure 3), suggests a placebo phenomenon rather
than a pharmacologic response to a bronchodilator substance in the
THC-extracted marijuana preparation.
Although the maximal mean change in SGaw after smoking of 2 per
cent marijuana (48 per cent) was less than that after inhalation of 1,250
mcg of isoproterenol HCL (69 per cent), the bronchodilator effect of
marijuana was more sustained than that of isoproterenol, consistent with
the metabolism of delta-9-THC to physiologically active compounds (19), in
contrast to the rapid conversion of isoproterenol to inactive metabolites
(20).
The pharmacologic bronchodilator principal in marijuana might have
been expected to produce a fractionally greater bronchodilator effect in
subjects with bronchospastic disease compared with healthy subjects by
analogy with the greater bronchodilator response to inhaled isoproterenol
in asthmatic compared with normal subjects. Our observation that marijuana
smoking resulted in a similar, rather than greater, magnitude of
bronchdilatation in asthmatic subjects compared with that previously noted
in normal persons (3) might possibly have been due to the following
reasons. Although an attempt was made to standardize the technique of
marijuana smoking, it is possible that the asthmatic subjects delivered
less THC to their airways because of relative inexperience with the smoking
technique compared with healthy chronic smokers; the bronchial irritant
effect of marijuana smoke might have tended to produce more
bronchoconstriction in subjects with hyper-reactive airways compared with
normal persons, thereby offsetting a potentially greater fractional
bronchodilator response to the pharmacologic agent (THC) in marijuana
smoke in subjects with bronchospastic disease; because repeated exposure
to marijuana is believed to lead to induction of enzymes needed to convert
delta-9-THC to the active 11-hydroxy metabolite (19), less extensive
metabolism of delta-9-THC to the active form in our asthmatic subjects with
relatively little previous marijuana experience might have accounted for a
lesser magnitude of physiologic effect than would have resulted had they
been chronic users.
The maximal average per cent increase in heart rate after marijuana
smoking in the present study was only 22 per cent as opposed to the 55 per
cent increase previously reported in healthy, experienced subjects smoking
the same quantity of THC (3). Possible explanations for this discrepancy
in the magnitude of marijuana-induced tachycardia in asthmatic subjects
compared with normal subjects include the following reasons: (1) the fact
that our asthmatic subjects were relatively inexperienced marijuana smokers
might have resulted in reduced delivery of marijuana smoke to the airways
and, consequently, reduced systemic absorption of THC; (2) more uneven
distribution of marijuana smoke and increased mucus and inflammatory
changes in the tracheobronchial tree of asthmatic patients might have
resulted in decreased or delayed absorption of THC from the airways; (3)
there might have been less conversion of delta-9-THC to the active
11-hydroxy metabolite in our relatively naive asthmatic smokers; (4)
there might be basic differences in myocardial tissue responsiveness to THC
in asthmatic subjects compared with healthy persons.
The small but significant increases in SGaw and decreases in Raw
after oral delta-9-THC indicated that this component of natural marijuana
has a systemically active bronchodilator effect in asthmatic patients
beginning 1 hour and lasting as long as 4 hours after ingestion of the
drug; however, this bronchodilator effect was fractionally smaller in
magnitude than that previously noted in normal subjects after the same dose
of THC (3). Moreover, heart rate did not increase significantly (maximal
mean increase, 9 + 5 per cent) after oral administration of 15 mg of
delta-9-THC in our asthmatic subjects in contrast with the significant
increases (19 + 7 per cent) previously noted in normal subjects (3).
These discrepancies in the responses to oral THC of normal experienced
Cannabis users and relatively inexperienced asthmatic persons might have
been due to differences in absorption of the drug from the gastrointestinal
tract, metabolism of THC to the active agent, or tissue responsiveness.
With regard to the first 2 possibilities, comparison of plasma
concentrations of delta-9-THC and its metabolites after oral administration
of the drug in both experienced and naive persons with and without asthma
would be of interest.
We can conclude that in clinically stable asthmatic subjects with
minimal to moderate bronchospasm, both smoked marijuana and oral
delta-9-THC resulted in bronchodilatation lasting as long as 2 hours and 4
hours, respectively. Further studies to evaluate the effects of smoked
marijuana and oral delta-9-THC on bronchomotor tone during spontaneous or
experimentally induced asthmatic attacks would be of interest. Because
only the acute effects of marijuana smoking on airway dynamics in subjects
with bronchospastic disease were studied, the results did not preclude the
possibility of an aggravation of existing bronchial pathology secondary to
chronic marijuana smoking in these same persons. Furthermore, the profound
psychotropic effect of marijuana and delta-9-THC, in addition to such side
effects as tachycardia and the atropine-like drying effect, might severely
limit any clinical therapeutic usefulness.

Acknowledgment

The writers are indebted to Dr. Stephen Szara, National Institutes of
Mental Health, for advice in the experimental design of the study; to Dr.
Daniel H. Simmons, for help in review of the manuscript; to Mr. Richard N.
Bleich, Senior Pharmacist, for assistance in the double-blind aspects of
the study, and to Mr. Enoch Lee and Mr. Charles Harper, for their
invaluable technical assistance.

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