effects of smoked marijuana and oral delta-9-tetrahydrocannabinol on specific
airway conductance in asthmatic subjects
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Review of Respiratory Disease, Volume 109, 1974, p. 420-428
Donald P. Tashkin, Bertrand J. Shapiro, and Ira M. Frank
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.
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'
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.
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.
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.
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.
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.
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 %.
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.
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.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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
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.
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).
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.
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.
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).
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.
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
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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