Jacob Bell
New Member
Contact highs and urinary cannabinoid
excretion after passive exposure to
marijuana smoke
Five healthy men were passively exposed under pre- and postplacebo controlled conditions to sidestream
smoke from four and 16 standard marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [A-9-THC1)
for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16-cigarette exposure
conditions were similar to those observed after active smoking of one 2.8% A-9-THC marijuana cigarette.
Effects after the four-cigarette condition were less pronounced. Concurrent physiologic measurements
showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of A-
9-THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16-cigarette condition.
With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs,
urines positive per subject under the four- and 16-cigarette passive exposure conditions were 4.6 -± 2.2
and 35.2 ± 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 ± 0.8, respectively, for the EMIT 100
assay. From the results of these studies, caution is clearly indicated for individuals who might be
substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting
marijuana screening data. (QIN PHARMACOL THER 1986;40:247-56.)
Edward J. Cone, Ph.D., and Roney E. Johnson, Pharm.D. Baltimore, Md.
From the National Institute on Drug Abuse, Addiction Research
Center.
Supported in part by the United States Navy.
Received for publication Dec. II, 1985; accepted Feb. 20, 1986.
Reprint requests to: Dr. Edward J. Cone, Laboratory of Chemistry
and Drug Metabolism, Addiction Research Center, NIDA, c/o
Francis Scott Key Medical Center, Building C, 4940 Eastern Ave.,
Baltimore MD 21224.
Inhalation of psychoactive substances in marijuana
smoke is an extremely efficient means of drug delivery
to the central nervous system because of the large surface
area, abundant blood flow, and permeable nature
of lung alveolar and epithelial membranes. It has been
estimated that the major active component of marijuana
smoke, delta-9-tetrahydrocannabinol (A-9-THC), reaches the brain within 14 seconds of inhalation.' During
the actual smoking process, the rate of increase of
A-9-THC in plasma becomes maximal after about 3
minutes of smoke inhalation and declines progressively
thereafter.' Peak plasma levels of A-9-THC occur midway
through smoking a marijuana cigarette. After
smoking, the pattern of subject-rated "high" and
plasma levels of A-9-THC become quite similar to those
after intravenous injection of A-9-THC.'
Passive inhalation of sidestream marijuana smoke
also involves inhalation of A-9-THC, because a significant
portion is vaporized into room air during the
smoking of marijuana.' The question of whether a subject
can passively absorb sufficient amounts of A-9-
THC to produce a "contact high," physiologic signs,
and detectable levels of cannabinoid metabolites in
urine has arisen. Zeidenberg et al.' have reported that
a placebo-controlled subject living among chronic marijuana
users on a locked clinical ward became dizzy
and nauseated, showed tachycardia and conjunctivitis,
and excreted cannabinoid metabolites in urine. The results
of that study have been questioned.' Also, subsequent
passive inhalation studies in controlled environments
have been unable to confirm development of
a "contact high" or other subjective effects from marijuana
smoke exposure, but have found A-9-THC in
plasma and cannabinoid metabolites in urine, albeit at
low levels:7-'2 Perez-Reyes et al.'" reported a maximal
plasma level of 2.2 ng/ml and two minimally positive
urine samples for cannabinoid metabolites, both collected
from a nonsmoking subject shortly after exposure
for 1 hour to the smoke of 4 marijuana cigarettes (2.8%
A-9-THC). Seventy-eight other urine samples collected
from subjects after passive smoke exposure were negative
for cannabinoids. Law et al.' reported a complete
lack of A-9-THC in blood and <7 ng/ml of cannabinoid
metabolites in the urine of subjects exposed for approximately
1 hour to the smoke of 6 marijuana cigarettes
containing an average of 17.1 mg A-9-THC. Morland
et al.'" recently reported detection of A-9-THC in
the blood of subjects exposed to marijuana smoke in a
small closed car. Blood levels ranged from 1.3 to 6.3
ng/ml immediately after exposure. Passive inhalation
also resulted in the detection of cannabinoids in urine
by RIA and EMIT d.a.u. assay (Syva Co.).
Absorption of A-9-THC from room air in sufficient
quantity to produce detectable subjective effects,
plasma levels, and urinary metabolites would depend
on a variety of factors including duration and frequency
of smoke exposure, room air concentration of A-9-
THC, and individual sensitivity to marijuana. We assessed
the subjective and physiologic effects of passive inhalation of marijuana smoke under highly controlled
conditions, as well as the appearance of A-9-THC in
blood and the excretion of cannabinoid metabolites in
urine. Passive exposure sessions for 1 hour each day
for 6 days to the smoke of four and 16 marijuana cigarettes
simulated multiple-exposure conditions to moderate
and highly smoke-laden environments in which
marijuana is combusted.
METHODS
Subjects. Five of the subjects (A to E) were healthy,
drug-free men with a history of marijuana use and two
subjects (F and G) were healthy drug-free men from
the staff with no history of marijuana use. Subjects were
housed on a closed ward under close surveillance. The
study was conducted under guidelines for the protection
of human subjects. Characteristics of these subjects and
marijuana histories are shown in Table I.
Study protocol. Five subjects (A to E) with 14 consecutive
days of cannabinoid-free urine samples were
exposed under double-blind conditions to the smoke of
16 marijuana cigarettes (2.8% A-9-THC) for 1 hour
each day for 6 consecutive days. Marijuana cigarettes
were provided by the National Institute on Drug Abuse.
Smoke exposure was carried out at the same time each
day (8:30 to 9:30 Am). Eight marijuana cigarettes were
burned during the period 8:30 to 8:45 AM, and eight
were burned between 9 and 9:15 AM. During the entire
exposure period subjects sat quietly in assigned places
in the exposure room. Goggles were worn during exposure
to minimize eye irritation from smoke and to
prevent color discrimination between placebo and active
marijuana cigarettes. Before and after the days of marijuana
smoke exposure, subjects A to E were exposed
in a similar fashion to the smoke of 16 placebo marijuana
cigarettes for 2 days.
A second exposure study was performed with subjects
A to E with four marijuana cigarettes (2.8% A-9-
THC) for 6 days under identical conditions, but preceded
and followed by only 1 day of placebo marijuana
smoke exposure.
In a third study, subjects F and G were exposed to
the smoke of 16 marijuana cigarettes (2.8% A-9-THC)
for 6 days, but without blind conditions and placebo
marijuana smoke exposure.
General exposure conditions consisted of smoke generation
by a cigarette smoking manifold located centrally
in a small unventilated room (8.21 x 6.83 X
8.00 ft). The approximate volume of the room after
adjustment for contents and the presence of five subjects
was 12,225.8 L. The rate of cigarette burn was controlled
by a pneumatic valve located outside the room and adjusted for an average burn time of 12 minutes.
The manifold was capable of smoking up to 10 cigarettes
simultaneously. Only sidestream smoke was released
into the exposure room; mainstream smoke was
removed from the manifold through tubing to traps located
outside the room. After each burn session (0 to
12 minutes and 30 to 42 minutes), the cigarette butts
were removed by the subjects with tweezers and placed
in a holding tray on the smoking manifold. The subjects
then loaded the remaining cigarettes and lit them at the
designated time. Throughout the exposure session, subjects
were visually monitored through a plexiglass wall.
Room air samples were withdrawn at times intervals
through a wall port for A-9-THC determination.
Subjects A to E also participated in an active marijuana
smoking study in which each subject smoked
two cigarettes (two placebo cigarettes or one placebo
and one marijuana [2.8% A-9-THC] cigarette) in
a double-blind, crossover procedure. The smoking experiment
was performed in an open ventilated room.
Cigarettes were presented in random order. The first
cigarette was smoked at 8:30 AM and the second was
smoked at 9 AM. The same measurements at equivalent
times were made as in the passive inhalation study to
compare effects under passive inhalation and active
smoking conditions.
Subjective and physiologic measures. Subjective
and physiologic effects were assessed at 1 hour (7:30
AM) and 0.5 hours (8 Am) before smoke exposure and
thereafter at 9:30, 10:30, and 11:30 AM and 12:30 PM.
Subjective effects were measured with subscales of the
Addiction Research Center Inventory (MAR 15, MBG,
LSD, PCAG)," single-dose questionnaire (Feel Drug,
Drug Identification, Symptoms, Liking),' and a visual
analog scale (VAS). The latter scale consisted of a 200
mm line on which subjects rated the "high" or positive
effects and "bad" or negative effects of the test conditions.
A rating mark in the center of the line designated
neutral or no effect, whereas rating marks to the
left of center indicated graded negative effects and rating
marks to the right indicated graded positive effects.
Physiologic measures at similar times were made of
pupillary diameter, respiration rate, and standing and
supine pulse, systolic blood pressure, and diastolic
blood pressure.
Biologic fluids. All urine specimens were collected
from the subjects during their participation in the smoke
exposure and active smoking studies. Samples were
collected ad libitum; in addition, subjects A to E were
asked daily to urinate at 8 AM, 4 PM, and midnight to
complete the collection period. Specimens were collected
in subject-coded polypropylene beakers. Time,
date, subject code, and approximate volume of each
specimen were recorded by a nurse at the time of collection;
the specimens then were removed for chemical
analysis.
Venous blood samples were collected 30 minutes before
and 20 to 30 minutes after each smoke exposure
session. Samples were collected in heparinized tubes
and centrifuged, and plasma was removed and frozen
until analysis.
Analytic measures. Urine specimens were analyzed
daily for cannabinoids with an EMIT assay.' All urine
samples were screened with the EMIT d.a.u. cannabinoid
20 assay with a 20 ng/ml low calibrator. Samples
with absorbance rates equal or greater than the 20 ng/
ml calibrator were redetermined. If the average rate of
duplicates minus background rate was greater than the
20 ng/ml calibration standard, the sample was designated
"positive" for cannabinoids (EMIT 20 assay).
Specimens with rates greater than that of the medium
calibrator (75 ng/ml) were assayed by the EMIT d.a.u.
cannabinoid assay, which uses a 100 ng/ml low calibrator.
Samples with rates equal or greater than that of the 100 ng/ml calibration standard were redetermined.
If the average rate of the duplicates exceeded the rate
of the low calibrator, the sample was designated "positive"
for cannabinoids (EMIT 100 assay). Urinary cannabinoids
were also determined by RIA and the metabolite,
A-9-THC carboxylic acid, was measured by
GC/MS. The results of these latter assays will be published
elsewhere. Plasma levels of A-9-THC were measured by RIA.I6
Air concentrations of A-9-THC: were measured by gas
chromatography.
Data analysis and statistical methods. Subjective
and physiologic responses were analyzed as differences
between responses after smoke exposure and the mean
of two control responses before smoke exposure. The
AUC for the response over time was calculated by the
trapezoidal rule. If ANOVA of the AUC between study
days was significant (P < 0.05), a Tukey test was applied
to determine if significant differences in mean
responses occurred on marijuana smoke exposure days
vs. placebo marijuana smoke exposure days. The placebo
marijuana smoke exposure day immediately before
the first marijuana smoke exposure day was arbitrarily
chosen for statistical comparison of differences.
RESULTS
Subjective effects of passively inhaled marijuana
smoke. After both four- and 16-marijuana cigarette
smoke exposure sessions, responses were elevated on
the MAR 15, LSD, PCAG, VAS, Feel Drug, and Liking
scales (Fig. 1) but were not changed on the MBG scale
(data not shown). Responses on these scales after exposure
to the smoke of four marijuana cigarettes were
modest and did not differ significantly from responses
to placebo marijuana smoke. Responses after exposure
to smoke from 16 marijuana cigarettes were more robust
and differed significantly from responses to exposure
to placebo marijuana smoke on the MAR 15, LSD,
VAS, Feel Drug, and Liking scales but not on the PCAG
scale. Significant differences (P < 0.05) were also found between responses on the MAR 15, VAS, Feel
Drug, and Liking scales on the first day of exposure to
the 16 marijuana cigarette condition vs. other marijuana
exposure days. There was a significant depression
(P < 0.05) of scores on the LSD scale on the ninth day
of smoke exposure (first placebo day after marijuana
smoke exposure) during the 16-cigarette study.
Responses on most scales to passive marijuana smoke
exposure were time related, with peak effects immediately
at the end of smoke exposure. An example of
the time-response relationship is shown in Fig. 2 for
responses on the VAS scale after exposure to smoke
from 16 marijuana cigarettes. On days 1 and 2, the
group mean 9:30 AM response to placebo smoke was
negative. These effects disappeared quickly and were
absent 3 hours later. The initial 9:30 AM response on
day 3, the first day of marijuana smoke exposure, also
was negative but was elevated 1 hour later. All subsequent
9:30 AM responses after marijuana smoke exposure
were highly positive. These effects also disappeared
rapidly and generally were absent 3 hours later.
Neutral responses at all times were obtained to placebo
smoke exposure on days 9 and 10.
After the passive exposure experiments, subjects A
to E participated in a placebo-controlled, crossover
study in which marijuana cigarettes were actively
smoked and measures were taken at times equivalent
to those in the passive experiments. AUC measures of
subjective responses to smoking one marijuana cigarette
were similar to those found in the 16-marijuana cigarette
passive exposure study (Fig. 1).
Physiologic effects of passively inhaled marijuana
smoke. Physiologic measures were highly variable both
in response to passive exposure to the smoke of four
and 16 marijuana cigarettes and to active smoking of
one marijuana cigarette (Fig. 3). Mean increases in the
integrated response were occasionally noted after exposure
to the smoke of 16 marijuana cigarettes for supine
and standing pulse and systolic and diastolic
blood pressures. Infrequently, some of the differences
in response between marijuana and placebo days
reached significance (P < 0.05). Significant differences
in some responses also occurred infrequently after
exposure to the smoke of four marijuana cigarettes, but
these responses (supine pulse and standing diastolic
blood pressure) were highly erratic. Occasional significant
differences occurred between marijuana test days
and placebo test days as compared with the first marijuana
test day (day 3). Pupillary diameter and respiration
rate showed no significant changes.
Chemical analysis of body fluids. Results of urine
testing of subjects A to E after exposure to the smoke
of four and 16 marijuana cigarettes, together with the
results of the marijuana-naive subjects F and G after
exposure to the smoke from 16 marijuana cigarettes,
are shown in Table II. An average of 4.6 ± 2.2 urine
samples per subject were positive for cannabinoid metabolites
by EMIT 20 assay during the 6-day period of
smoke from exposure to four marijuana cigarettes. In
the 16-cigarette smoke exposure study, the average
number of positive EMIT 20 urine samples increased
to 35.2 ± 3.8 per subject. A similar number of urine
samples tested positive for cannabinoid metabolites
from subjects F and G under the same exposure conditions.
There was considerable between-subject variability
in results obtained in the EMIT 20 assay in the
four-marijuana cigarette exposure study; the number of
urine samples positive for cannabinoid metabolites
ranged from none (subject D) to 12 (subject C). Subject
C also produced the greatest number of urine samples
positive by EMIT 20 assay in the 16-marijuana cigarette
exposure study.
During the four-marijuana cigarette exposure study,
the urine samples that were positive by EMIT 20 had
assay rates consistently below that of the medium calibration
75 ng/ml standard; consequently, none were
tested by EMIT 100 assay. During the 16-marijuana
cigarette exposure studies, all subjects except subject
G produced urine samples that had an excretion rate
exceeding that of the medium calibrator. Retesting these
samples with the EMIT 100 assay produced a total of
39 positive samples. None of these samples had rates
that exceeded the medium calibrator standard (400 ng/
m1). The samples that tested positive by EMIT 100
assay came from three subjects (C, E, and F), with
most originating from subject F.
The time course of appearance of cannabinoid metabolites
in urine after passive smoke exposure to 16
marijuana cigarettes was similar for most subjects (Fig.
4). Six of the seven subjects produced positive EMIT
20 urine samples after the first exposure session. Subject
D produced his first positive urine sample after the
second exposure session. After exposure to the smoke
of four marijuana cigarettes, the results were more variable.
Two subjects, C and D, produced positive EMIT
20 urine samples after the first exposure session; subject
B produced a positive EMIT 20 urine sample after the
second exposure session; subject A produced a positive
EMIT 20 urine sample after the third exposure session:
and subject D produced no positive EMIT 20 urine
samples throughout the 6 days of exposure, although
reaction rates for many of his samples approached the
cutoff rate for the 20 ng/ml calibration standard. In
general, assay rates appeared to be positively related to
the specific gravity of the urine specimen and usually
decreased as specific gravity decreased during the
course of the day. Urine samples that tested positive
for cannabinoids by EMIT 20 (Table II) had an overall
confirmation of the metabolite A-9-THC carboxylic
acid by GC/MS of 84.9%. Measurable plasma levels of A-9-THC were attained
during passive exposure to the smoke of four or 16
marijuana cigarettes (Fig. 4). After exposure to the
smoke of 16 marijuana cigarettes, daily mean plasma
levels ranged from 2.4 to 7.4 ng/ml for subjects A to
E. The highest mean concentration of A-9-THC occurred
on the last day (day 8) of active marijuana smoke
exposure, with an overall individual highest plasma
level of 18.8 ng/ml for subject E. Only one subject
(subject D) was eligible to provide blood during the
four-marijuana cigarette smoke exposure study. His
levels of A-9-THC were 0.8 to 2.5 ng/ml during the
course of the 6-day study.
DISCUSSION
Our results demonstrate that passive inhalation of a
substantial amount of sidestream marijuana smoke can
produce subjective effects, plasma levels of A-9-THC,
and urinary cannabinoid metabolites in subjects similar
to those found after the active smoking of marijuana.
The profile of subjective effects in five subjects after
passive exposure to the smoke of 16 marijuana cigarettes
over 1 hour was quantitatively equivalent in magnitude
to smoking one standardized marijuana cigarette
(2.8% A-9-THC) in the same subjects. Passive exposure
to four marijuana cigarettes produced a reduced but
qualitatively similar response. This lower dose of marijuana
smoke exposure is approximately equivalent to
the highest dose studied in other passive inhalation experiments.'"
It appears that the four-marijuana cigarette
condition approximates the "threshold" exposure
level necessary for the production of marijuana-like subjective
effects and cannabinoid urinary metabolites detectable
by EMIT 20 assay. Such a "threshold" level
could be expected to vary considerably between individuals,
as was seen in this study. Intersubject variability
could be influenced by a host of factors, including
differences in respiration characteristics, body
weight, age, sex, renal function, and liver function.
This threshold exposure level was clearly exceeded in
our subjects when exposure was increased to 16 marijuana
cigarettes.
Contrary to positive subjective effects, physiologic
effects were highly variable and showed no trends at
either exposure level. After active marijuana smoking,
the increase in heart rate is one of the most reliable
dose-related measures.' This effect generally peaks
shortly after smoking and declines rapidly to control
levels in a biphasic manner. Smoking a second marijuana
cigarette was shown to produce a similar psychologic
"high," but accelerated heart rate only 50%
of the rate increase from the first cigarette. It was sug-gested that the reduced response resulted from a possible
combination of acute tolerance development and
acclimatization of the subjects to environmental and
psychologic factors.' Both facts are possible contributors
in the present study to account for the lack of
significant pulse changes on marijuana exposure days.
Acclimatization to the smoke-filled room during passive
exposure was apparent in the pulse rate responses during
the first 2 study days, both of which involved exposure
to the smoke of 16 placebo marijuana cigarettes.
Pulse rates after the second exposure session (day 2)
were markedly lower than after the first session. Increases
in supine pulse rate after the exposure to smoke
of 16 marijuana cigarettes (days 4 to 6) occurred but
were not significantly different from those after exposure
to placebo smoke on day 2. Under the same exposure
conditions, standing pulse was significantly increased
(P < 0.05) on day 4, the second day of active
marijuana smoke exposure, but was not increased on
subsequent days. The development of tolerance to these
effects with multiple exposure would presumably present
a similar pattern, but its role in our studies cannot
be clearly established. In the pulse rate measures of our
subjects during active marijuana smoking experiments,
a significant increase was also not observed. This lack
of effect on pulse rate was likely a result of the time
delay before the initial observation, which ranged from
20 to 50 minutes after passive exposure or active smoking.
Most of the initial drug effect on pulse would have
dissipated by this time.
The relationship of plasma levels of A-9-THC to subjective
effects after active smoking has been the subject
of considerable scrutiny.''''" What has been found is
that the initial peak plasma level of A-9-THC precedes
subject-rated "high" by 15 minutes. After this early
distribution phase in which effects are out of sequence
with plasma levels, compartment equilibrium is reached
and the intensity of subject-rated effects becomes more
directly related to plasma levels of A-9-THC. '8 After a
smoked dose of marijuana, plasma levels of A-9-THC
may initially rise to concentrations >100 ng/ml but fall
rapidly to 10 ng/ml in 60 to 90 minutes, while subjective
effects have just begun to decline. Plasma levels
of A-9-THC and subjective effects continue to decline
and approach baseline levels in 3 to 6 hours. In subjects
passively exposed to marijuana smoke, Perez-Reyes
et al. 12 found maximal plasma levels of A-9-THC of
only 2.2 ng/ml and no observable subjective effects.
Moreland et al.' reported A-9-THC levels of 1.3 to 6.3
ng/ml in the blood of subjects passively exposed to
marijuana smoke in a small closed car; their subjects
also reported a lack of feelings of "euphoria." In the
present study the maximal plasma level of A-9-THC
measured after exposure to the smoke of 16 marijuana
cigarettes was 18.8 ng/ml at a time when subjective
effects were reported. Other subjects in this same study
reported marijuana-like subjective effects at times when
their plasma levels of A-9-THC were in the range of 1
to 8 ng/ml. Because these measures were made 15 to
30 minutes after the last marijuana cigarette was
burned, it is likely that maximal plasma levels occurred
much earlier during the course of passive smoke exposure.
Although a specific minimum blood level of A-9-
THC associated with impairment has not been defined,
Barnett et al.' found a significant correlation between
human performance decrements in tests to assess perceptual
motor performance related to driving and A-9-
THC plasma levels over the range of 5 to 25 ng/ml for 2 hours after marijuana smoking. Mason and McBay'
suggested that an arbitrary limit of d-9-THC of 10 ng/
ml in serum and 5 ng/ml in blood be established as
evidence of functional impairment. By these conservative
standards, our subjects were generally near or
below this level when tested, but were likely to have
exceeded this limit during the course of exposure to the
smoke of 16 marijuana cigarettes. Two complicating
factors in the definition of an arbitrary blood limit for
A-9-THC are development of tolerance and drug accumulation
after chronic dosing. Tolerance is considered
to develop to the effects of marijuana when high
doses are used over an extended period of time."."-"
The finding of accumulation of A-9-THC in the blood
of heavy smokers of marijuana could also interfere with
the definition of a blood level of A-9-THC indicating
functional impairment. At present, definitive studies on
these issues regarding the chronic use of marijuana have
not been performed.
Accumulation of marijuana between passive exposure
sessions was initially suspected in our present study
because of the significant increase in subjective effects
observed on day 4 vs. day 3 (Fig. 1, lower panels).
This was generally ruled out by chemical analyses of
the remaining marijuana after burning and room air
concentrations of A-9-THC to which the subjects were
exposed. The total marijuana cigarette weight burned
was 10% less on day 3 than on subsequent test days.
Furthermore, room air concentrations of A-9-THC on
day 3 were generally less than half those of subsequent
days, possibly a result of initial adsorption on room
surfaces. Thus it appears that the five subjects were
exposed to less smoke generated from active drug on
day 3 than on subsequent days, and accumulation of
A-9-THC was not likely the cause of increased subjective
effects on day 4. However, this does not rule out
the possibility of accumulation occurring after multiple
passive inhalation sessions, because the terminal phase t, for A-9-THC in human plasma ranges from 25 to
36 hours.'
The excretion of cannabinoid metabolites in urine
after passive marijuana smoke exposure increased as a
function of the number of marijuana cigarettes burned.
After one or more passive exposure sessions to the
smoke of 16 marijuana cigarettes, the percent of urine
samples positive for cannabinoids was nearly equivalent
to that after active smoking of one marijuana cigarette.
Exposure to the smoke of four marijuana cigarettes
produced positive EMIT 20 assay results for cannabinoids
in urine from four of five subjects and appeared
to be near the minimal smoke exposure level for these
subjects. Although the presence of cannabinoid metabolites
in urine is not generally correlated with the appearance
of subjective effects, the excretion of high
urinary cannabinoid concentrations by the five subjects
after high smoke exposure in our present study is entirely
consistent with the magnitude of their reported
subjective effects.
The excretion of cannabinoid metabolites in urine
after passive marijuana smoke exposure has been reported,
with the suggestion that the conditions used for
smoke exposure were the maximum tolerable limits for
their subjects." Irritation to the smoke of the 16-
marijuana cigarette condition was partially alleviated
by our subjects wearing colored eye goggles. Most subjects
preferred to wear them, but some spent part of
their exposure time without their goggles. Also, although
the subjects were free to leave the smoke-filled
room at any time, none left during any of the 18 1-hour
passive exposure sessions. Only minor throat irritation
was reported during and after these exposure sessions,
not unlike those effects reported after active marijuana
smoking. From these studies, it appears that somewhat
higher tolerable limits of marijuana smoke exposure are
possible than were originally considered.
Passive ingestion of A-9-THC adsorbed from smoke
onto foodstuffs and liquids was prevented in our studies
by not allowing food and water ingestion during the
smoke exposure sessions. The potential for ingestion
of marijuana adsorbed onto food and other surfaces is
obvious, but nothing is known concerning the possible
contribution of this mode of passive ingestion to observable
drug effects. The amount of orally ingested
A-9-THC needed to produce measurable subjective effects
would be quite large in comparison with a smoked
dose of marijuana, because oral A-9-THC has a
systemic availability of about one third that when
smoked.' However, oral marijuana adsorbed to foodstuffs
during passive exposure might be an important
contributing factor to subsequent production of urine
samples positive for cannabinoid metabolites.
Clearly, societal and legal implications arise if a subject
can develop marijuana-like subjective effects and
test positive for urinary cannabinoid metabolites as a
result of passive inhalation. A positive urine test for
marijuana when confirmed by specific analytic assay is
perceived as evidence for recent active use or abuse. A
second unvalidated assumption often made on the basis
of positive urine results is that performance impairment
occurred in the recent past for that individual, although
no correlation is generally made with current behavior.
Our present results suggest caution both to individuals
who might be passively exposed to heavy marijuana
smoke and to those who interpret marijuana screening
data, because with sufficient time and high marijuana
smoke exposure conditions, it becomes difficult to distinguish
between active smoking and passive inhalation.
Special thanks to Drs. D. Blank and R. E. Willette for
their advice and consultation, to Dr. R. Hawks, Research
Technology Branch, National Institute on Drug Abuse, for
marijuana supplies, and to P. Welch, LPN 11, for technical
assistance.
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Source: Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke
excretion after passive exposure to
marijuana smoke
Five healthy men were passively exposed under pre- and postplacebo controlled conditions to sidestream
smoke from four and 16 standard marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [A-9-THC1)
for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16-cigarette exposure
conditions were similar to those observed after active smoking of one 2.8% A-9-THC marijuana cigarette.
Effects after the four-cigarette condition were less pronounced. Concurrent physiologic measurements
showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of A-
9-THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16-cigarette condition.
With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs,
urines positive per subject under the four- and 16-cigarette passive exposure conditions were 4.6 -± 2.2
and 35.2 ± 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 ± 0.8, respectively, for the EMIT 100
assay. From the results of these studies, caution is clearly indicated for individuals who might be
substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting
marijuana screening data. (QIN PHARMACOL THER 1986;40:247-56.)
Edward J. Cone, Ph.D., and Roney E. Johnson, Pharm.D. Baltimore, Md.
From the National Institute on Drug Abuse, Addiction Research
Center.
Supported in part by the United States Navy.
Received for publication Dec. II, 1985; accepted Feb. 20, 1986.
Reprint requests to: Dr. Edward J. Cone, Laboratory of Chemistry
and Drug Metabolism, Addiction Research Center, NIDA, c/o
Francis Scott Key Medical Center, Building C, 4940 Eastern Ave.,
Baltimore MD 21224.
Inhalation of psychoactive substances in marijuana
smoke is an extremely efficient means of drug delivery
to the central nervous system because of the large surface
area, abundant blood flow, and permeable nature
of lung alveolar and epithelial membranes. It has been
estimated that the major active component of marijuana
smoke, delta-9-tetrahydrocannabinol (A-9-THC), reaches the brain within 14 seconds of inhalation.' During
the actual smoking process, the rate of increase of
A-9-THC in plasma becomes maximal after about 3
minutes of smoke inhalation and declines progressively
thereafter.' Peak plasma levels of A-9-THC occur midway
through smoking a marijuana cigarette. After
smoking, the pattern of subject-rated "high" and
plasma levels of A-9-THC become quite similar to those
after intravenous injection of A-9-THC.'
Passive inhalation of sidestream marijuana smoke
also involves inhalation of A-9-THC, because a significant
portion is vaporized into room air during the
smoking of marijuana.' The question of whether a subject
can passively absorb sufficient amounts of A-9-
THC to produce a "contact high," physiologic signs,
and detectable levels of cannabinoid metabolites in
urine has arisen. Zeidenberg et al.' have reported that
a placebo-controlled subject living among chronic marijuana
users on a locked clinical ward became dizzy
and nauseated, showed tachycardia and conjunctivitis,
and excreted cannabinoid metabolites in urine. The results
of that study have been questioned.' Also, subsequent
passive inhalation studies in controlled environments
have been unable to confirm development of
a "contact high" or other subjective effects from marijuana
smoke exposure, but have found A-9-THC in
plasma and cannabinoid metabolites in urine, albeit at
low levels:7-'2 Perez-Reyes et al.'" reported a maximal
plasma level of 2.2 ng/ml and two minimally positive
urine samples for cannabinoid metabolites, both collected
from a nonsmoking subject shortly after exposure
for 1 hour to the smoke of 4 marijuana cigarettes (2.8%
A-9-THC). Seventy-eight other urine samples collected
from subjects after passive smoke exposure were negative
for cannabinoids. Law et al.' reported a complete
lack of A-9-THC in blood and <7 ng/ml of cannabinoid
metabolites in the urine of subjects exposed for approximately
1 hour to the smoke of 6 marijuana cigarettes
containing an average of 17.1 mg A-9-THC. Morland
et al.'" recently reported detection of A-9-THC in
the blood of subjects exposed to marijuana smoke in a
small closed car. Blood levels ranged from 1.3 to 6.3
ng/ml immediately after exposure. Passive inhalation
also resulted in the detection of cannabinoids in urine
by RIA and EMIT d.a.u. assay (Syva Co.).
Absorption of A-9-THC from room air in sufficient
quantity to produce detectable subjective effects,
plasma levels, and urinary metabolites would depend
on a variety of factors including duration and frequency
of smoke exposure, room air concentration of A-9-
THC, and individual sensitivity to marijuana. We assessed
the subjective and physiologic effects of passive inhalation of marijuana smoke under highly controlled
conditions, as well as the appearance of A-9-THC in
blood and the excretion of cannabinoid metabolites in
urine. Passive exposure sessions for 1 hour each day
for 6 days to the smoke of four and 16 marijuana cigarettes
simulated multiple-exposure conditions to moderate
and highly smoke-laden environments in which
marijuana is combusted.
METHODS
Subjects. Five of the subjects (A to E) were healthy,
drug-free men with a history of marijuana use and two
subjects (F and G) were healthy drug-free men from
the staff with no history of marijuana use. Subjects were
housed on a closed ward under close surveillance. The
study was conducted under guidelines for the protection
of human subjects. Characteristics of these subjects and
marijuana histories are shown in Table I.
Study protocol. Five subjects (A to E) with 14 consecutive
days of cannabinoid-free urine samples were
exposed under double-blind conditions to the smoke of
16 marijuana cigarettes (2.8% A-9-THC) for 1 hour
each day for 6 consecutive days. Marijuana cigarettes
were provided by the National Institute on Drug Abuse.
Smoke exposure was carried out at the same time each
day (8:30 to 9:30 Am). Eight marijuana cigarettes were
burned during the period 8:30 to 8:45 AM, and eight
were burned between 9 and 9:15 AM. During the entire
exposure period subjects sat quietly in assigned places
in the exposure room. Goggles were worn during exposure
to minimize eye irritation from smoke and to
prevent color discrimination between placebo and active
marijuana cigarettes. Before and after the days of marijuana
smoke exposure, subjects A to E were exposed
in a similar fashion to the smoke of 16 placebo marijuana
cigarettes for 2 days.
A second exposure study was performed with subjects
A to E with four marijuana cigarettes (2.8% A-9-
THC) for 6 days under identical conditions, but preceded
and followed by only 1 day of placebo marijuana
smoke exposure.
In a third study, subjects F and G were exposed to
the smoke of 16 marijuana cigarettes (2.8% A-9-THC)
for 6 days, but without blind conditions and placebo
marijuana smoke exposure.
General exposure conditions consisted of smoke generation
by a cigarette smoking manifold located centrally
in a small unventilated room (8.21 x 6.83 X
8.00 ft). The approximate volume of the room after
adjustment for contents and the presence of five subjects
was 12,225.8 L. The rate of cigarette burn was controlled
by a pneumatic valve located outside the room and adjusted for an average burn time of 12 minutes.
The manifold was capable of smoking up to 10 cigarettes
simultaneously. Only sidestream smoke was released
into the exposure room; mainstream smoke was
removed from the manifold through tubing to traps located
outside the room. After each burn session (0 to
12 minutes and 30 to 42 minutes), the cigarette butts
were removed by the subjects with tweezers and placed
in a holding tray on the smoking manifold. The subjects
then loaded the remaining cigarettes and lit them at the
designated time. Throughout the exposure session, subjects
were visually monitored through a plexiglass wall.
Room air samples were withdrawn at times intervals
through a wall port for A-9-THC determination.
Subjects A to E also participated in an active marijuana
smoking study in which each subject smoked
two cigarettes (two placebo cigarettes or one placebo
and one marijuana [2.8% A-9-THC] cigarette) in
a double-blind, crossover procedure. The smoking experiment
was performed in an open ventilated room.
Cigarettes were presented in random order. The first
cigarette was smoked at 8:30 AM and the second was
smoked at 9 AM. The same measurements at equivalent
times were made as in the passive inhalation study to
compare effects under passive inhalation and active
smoking conditions.
Subjective and physiologic measures. Subjective
and physiologic effects were assessed at 1 hour (7:30
AM) and 0.5 hours (8 Am) before smoke exposure and
thereafter at 9:30, 10:30, and 11:30 AM and 12:30 PM.
Subjective effects were measured with subscales of the
Addiction Research Center Inventory (MAR 15, MBG,
LSD, PCAG)," single-dose questionnaire (Feel Drug,
Drug Identification, Symptoms, Liking),' and a visual
analog scale (VAS). The latter scale consisted of a 200
mm line on which subjects rated the "high" or positive
effects and "bad" or negative effects of the test conditions.
A rating mark in the center of the line designated
neutral or no effect, whereas rating marks to the
left of center indicated graded negative effects and rating
marks to the right indicated graded positive effects.
Physiologic measures at similar times were made of
pupillary diameter, respiration rate, and standing and
supine pulse, systolic blood pressure, and diastolic
blood pressure.
Biologic fluids. All urine specimens were collected
from the subjects during their participation in the smoke
exposure and active smoking studies. Samples were
collected ad libitum; in addition, subjects A to E were
asked daily to urinate at 8 AM, 4 PM, and midnight to
complete the collection period. Specimens were collected
in subject-coded polypropylene beakers. Time,
date, subject code, and approximate volume of each
specimen were recorded by a nurse at the time of collection;
the specimens then were removed for chemical
analysis.
Venous blood samples were collected 30 minutes before
and 20 to 30 minutes after each smoke exposure
session. Samples were collected in heparinized tubes
and centrifuged, and plasma was removed and frozen
until analysis.
Analytic measures. Urine specimens were analyzed
daily for cannabinoids with an EMIT assay.' All urine
samples were screened with the EMIT d.a.u. cannabinoid
20 assay with a 20 ng/ml low calibrator. Samples
with absorbance rates equal or greater than the 20 ng/
ml calibrator were redetermined. If the average rate of
duplicates minus background rate was greater than the
20 ng/ml calibration standard, the sample was designated
"positive" for cannabinoids (EMIT 20 assay).
Specimens with rates greater than that of the medium
calibrator (75 ng/ml) were assayed by the EMIT d.a.u.
cannabinoid assay, which uses a 100 ng/ml low calibrator.
Samples with rates equal or greater than that of the 100 ng/ml calibration standard were redetermined.
If the average rate of the duplicates exceeded the rate
of the low calibrator, the sample was designated "positive"
for cannabinoids (EMIT 100 assay). Urinary cannabinoids
were also determined by RIA and the metabolite,
A-9-THC carboxylic acid, was measured by
GC/MS. The results of these latter assays will be published
elsewhere. Plasma levels of A-9-THC were measured by RIA.I6
Air concentrations of A-9-THC: were measured by gas
chromatography.
Data analysis and statistical methods. Subjective
and physiologic responses were analyzed as differences
between responses after smoke exposure and the mean
of two control responses before smoke exposure. The
AUC for the response over time was calculated by the
trapezoidal rule. If ANOVA of the AUC between study
days was significant (P < 0.05), a Tukey test was applied
to determine if significant differences in mean
responses occurred on marijuana smoke exposure days
vs. placebo marijuana smoke exposure days. The placebo
marijuana smoke exposure day immediately before
the first marijuana smoke exposure day was arbitrarily
chosen for statistical comparison of differences.
RESULTS
Subjective effects of passively inhaled marijuana
smoke. After both four- and 16-marijuana cigarette
smoke exposure sessions, responses were elevated on
the MAR 15, LSD, PCAG, VAS, Feel Drug, and Liking
scales (Fig. 1) but were not changed on the MBG scale
(data not shown). Responses on these scales after exposure
to the smoke of four marijuana cigarettes were
modest and did not differ significantly from responses
to placebo marijuana smoke. Responses after exposure
to smoke from 16 marijuana cigarettes were more robust
and differed significantly from responses to exposure
to placebo marijuana smoke on the MAR 15, LSD,
VAS, Feel Drug, and Liking scales but not on the PCAG
scale. Significant differences (P < 0.05) were also found between responses on the MAR 15, VAS, Feel
Drug, and Liking scales on the first day of exposure to
the 16 marijuana cigarette condition vs. other marijuana
exposure days. There was a significant depression
(P < 0.05) of scores on the LSD scale on the ninth day
of smoke exposure (first placebo day after marijuana
smoke exposure) during the 16-cigarette study.
Responses on most scales to passive marijuana smoke
exposure were time related, with peak effects immediately
at the end of smoke exposure. An example of
the time-response relationship is shown in Fig. 2 for
responses on the VAS scale after exposure to smoke
from 16 marijuana cigarettes. On days 1 and 2, the
group mean 9:30 AM response to placebo smoke was
negative. These effects disappeared quickly and were
absent 3 hours later. The initial 9:30 AM response on
day 3, the first day of marijuana smoke exposure, also
was negative but was elevated 1 hour later. All subsequent
9:30 AM responses after marijuana smoke exposure
were highly positive. These effects also disappeared
rapidly and generally were absent 3 hours later.
Neutral responses at all times were obtained to placebo
smoke exposure on days 9 and 10.
After the passive exposure experiments, subjects A
to E participated in a placebo-controlled, crossover
study in which marijuana cigarettes were actively
smoked and measures were taken at times equivalent
to those in the passive experiments. AUC measures of
subjective responses to smoking one marijuana cigarette
were similar to those found in the 16-marijuana cigarette
passive exposure study (Fig. 1).
Physiologic effects of passively inhaled marijuana
smoke. Physiologic measures were highly variable both
in response to passive exposure to the smoke of four
and 16 marijuana cigarettes and to active smoking of
one marijuana cigarette (Fig. 3). Mean increases in the
integrated response were occasionally noted after exposure
to the smoke of 16 marijuana cigarettes for supine
and standing pulse and systolic and diastolic
blood pressures. Infrequently, some of the differences
in response between marijuana and placebo days
reached significance (P < 0.05). Significant differences
in some responses also occurred infrequently after
exposure to the smoke of four marijuana cigarettes, but
these responses (supine pulse and standing diastolic
blood pressure) were highly erratic. Occasional significant
differences occurred between marijuana test days
and placebo test days as compared with the first marijuana
test day (day 3). Pupillary diameter and respiration
rate showed no significant changes.
Chemical analysis of body fluids. Results of urine
testing of subjects A to E after exposure to the smoke
of four and 16 marijuana cigarettes, together with the
results of the marijuana-naive subjects F and G after
exposure to the smoke from 16 marijuana cigarettes,
are shown in Table II. An average of 4.6 ± 2.2 urine
samples per subject were positive for cannabinoid metabolites
by EMIT 20 assay during the 6-day period of
smoke from exposure to four marijuana cigarettes. In
the 16-cigarette smoke exposure study, the average
number of positive EMIT 20 urine samples increased
to 35.2 ± 3.8 per subject. A similar number of urine
samples tested positive for cannabinoid metabolites
from subjects F and G under the same exposure conditions.
There was considerable between-subject variability
in results obtained in the EMIT 20 assay in the
four-marijuana cigarette exposure study; the number of
urine samples positive for cannabinoid metabolites
ranged from none (subject D) to 12 (subject C). Subject
C also produced the greatest number of urine samples
positive by EMIT 20 assay in the 16-marijuana cigarette
exposure study.
During the four-marijuana cigarette exposure study,
the urine samples that were positive by EMIT 20 had
assay rates consistently below that of the medium calibration
75 ng/ml standard; consequently, none were
tested by EMIT 100 assay. During the 16-marijuana
cigarette exposure studies, all subjects except subject
G produced urine samples that had an excretion rate
exceeding that of the medium calibrator. Retesting these
samples with the EMIT 100 assay produced a total of
39 positive samples. None of these samples had rates
that exceeded the medium calibrator standard (400 ng/
m1). The samples that tested positive by EMIT 100
assay came from three subjects (C, E, and F), with
most originating from subject F.
The time course of appearance of cannabinoid metabolites
in urine after passive smoke exposure to 16
marijuana cigarettes was similar for most subjects (Fig.
4). Six of the seven subjects produced positive EMIT
20 urine samples after the first exposure session. Subject
D produced his first positive urine sample after the
second exposure session. After exposure to the smoke
of four marijuana cigarettes, the results were more variable.
Two subjects, C and D, produced positive EMIT
20 urine samples after the first exposure session; subject
B produced a positive EMIT 20 urine sample after the
second exposure session; subject A produced a positive
EMIT 20 urine sample after the third exposure session:
and subject D produced no positive EMIT 20 urine
samples throughout the 6 days of exposure, although
reaction rates for many of his samples approached the
cutoff rate for the 20 ng/ml calibration standard. In
general, assay rates appeared to be positively related to
the specific gravity of the urine specimen and usually
decreased as specific gravity decreased during the
course of the day. Urine samples that tested positive
for cannabinoids by EMIT 20 (Table II) had an overall
confirmation of the metabolite A-9-THC carboxylic
acid by GC/MS of 84.9%. Measurable plasma levels of A-9-THC were attained
during passive exposure to the smoke of four or 16
marijuana cigarettes (Fig. 4). After exposure to the
smoke of 16 marijuana cigarettes, daily mean plasma
levels ranged from 2.4 to 7.4 ng/ml for subjects A to
E. The highest mean concentration of A-9-THC occurred
on the last day (day 8) of active marijuana smoke
exposure, with an overall individual highest plasma
level of 18.8 ng/ml for subject E. Only one subject
(subject D) was eligible to provide blood during the
four-marijuana cigarette smoke exposure study. His
levels of A-9-THC were 0.8 to 2.5 ng/ml during the
course of the 6-day study.
DISCUSSION
Our results demonstrate that passive inhalation of a
substantial amount of sidestream marijuana smoke can
produce subjective effects, plasma levels of A-9-THC,
and urinary cannabinoid metabolites in subjects similar
to those found after the active smoking of marijuana.
The profile of subjective effects in five subjects after
passive exposure to the smoke of 16 marijuana cigarettes
over 1 hour was quantitatively equivalent in magnitude
to smoking one standardized marijuana cigarette
(2.8% A-9-THC) in the same subjects. Passive exposure
to four marijuana cigarettes produced a reduced but
qualitatively similar response. This lower dose of marijuana
smoke exposure is approximately equivalent to
the highest dose studied in other passive inhalation experiments.'"
It appears that the four-marijuana cigarette
condition approximates the "threshold" exposure
level necessary for the production of marijuana-like subjective
effects and cannabinoid urinary metabolites detectable
by EMIT 20 assay. Such a "threshold" level
could be expected to vary considerably between individuals,
as was seen in this study. Intersubject variability
could be influenced by a host of factors, including
differences in respiration characteristics, body
weight, age, sex, renal function, and liver function.
This threshold exposure level was clearly exceeded in
our subjects when exposure was increased to 16 marijuana
cigarettes.
Contrary to positive subjective effects, physiologic
effects were highly variable and showed no trends at
either exposure level. After active marijuana smoking,
the increase in heart rate is one of the most reliable
dose-related measures.' This effect generally peaks
shortly after smoking and declines rapidly to control
levels in a biphasic manner. Smoking a second marijuana
cigarette was shown to produce a similar psychologic
"high," but accelerated heart rate only 50%
of the rate increase from the first cigarette. It was sug-gested that the reduced response resulted from a possible
combination of acute tolerance development and
acclimatization of the subjects to environmental and
psychologic factors.' Both facts are possible contributors
in the present study to account for the lack of
significant pulse changes on marijuana exposure days.
Acclimatization to the smoke-filled room during passive
exposure was apparent in the pulse rate responses during
the first 2 study days, both of which involved exposure
to the smoke of 16 placebo marijuana cigarettes.
Pulse rates after the second exposure session (day 2)
were markedly lower than after the first session. Increases
in supine pulse rate after the exposure to smoke
of 16 marijuana cigarettes (days 4 to 6) occurred but
were not significantly different from those after exposure
to placebo smoke on day 2. Under the same exposure
conditions, standing pulse was significantly increased
(P < 0.05) on day 4, the second day of active
marijuana smoke exposure, but was not increased on
subsequent days. The development of tolerance to these
effects with multiple exposure would presumably present
a similar pattern, but its role in our studies cannot
be clearly established. In the pulse rate measures of our
subjects during active marijuana smoking experiments,
a significant increase was also not observed. This lack
of effect on pulse rate was likely a result of the time
delay before the initial observation, which ranged from
20 to 50 minutes after passive exposure or active smoking.
Most of the initial drug effect on pulse would have
dissipated by this time.
The relationship of plasma levels of A-9-THC to subjective
effects after active smoking has been the subject
of considerable scrutiny.''''" What has been found is
that the initial peak plasma level of A-9-THC precedes
subject-rated "high" by 15 minutes. After this early
distribution phase in which effects are out of sequence
with plasma levels, compartment equilibrium is reached
and the intensity of subject-rated effects becomes more
directly related to plasma levels of A-9-THC. '8 After a
smoked dose of marijuana, plasma levels of A-9-THC
may initially rise to concentrations >100 ng/ml but fall
rapidly to 10 ng/ml in 60 to 90 minutes, while subjective
effects have just begun to decline. Plasma levels
of A-9-THC and subjective effects continue to decline
and approach baseline levels in 3 to 6 hours. In subjects
passively exposed to marijuana smoke, Perez-Reyes
et al. 12 found maximal plasma levels of A-9-THC of
only 2.2 ng/ml and no observable subjective effects.
Moreland et al.' reported A-9-THC levels of 1.3 to 6.3
ng/ml in the blood of subjects passively exposed to
marijuana smoke in a small closed car; their subjects
also reported a lack of feelings of "euphoria." In the
present study the maximal plasma level of A-9-THC
measured after exposure to the smoke of 16 marijuana
cigarettes was 18.8 ng/ml at a time when subjective
effects were reported. Other subjects in this same study
reported marijuana-like subjective effects at times when
their plasma levels of A-9-THC were in the range of 1
to 8 ng/ml. Because these measures were made 15 to
30 minutes after the last marijuana cigarette was
burned, it is likely that maximal plasma levels occurred
much earlier during the course of passive smoke exposure.
Although a specific minimum blood level of A-9-
THC associated with impairment has not been defined,
Barnett et al.' found a significant correlation between
human performance decrements in tests to assess perceptual
motor performance related to driving and A-9-
THC plasma levels over the range of 5 to 25 ng/ml for 2 hours after marijuana smoking. Mason and McBay'
suggested that an arbitrary limit of d-9-THC of 10 ng/
ml in serum and 5 ng/ml in blood be established as
evidence of functional impairment. By these conservative
standards, our subjects were generally near or
below this level when tested, but were likely to have
exceeded this limit during the course of exposure to the
smoke of 16 marijuana cigarettes. Two complicating
factors in the definition of an arbitrary blood limit for
A-9-THC are development of tolerance and drug accumulation
after chronic dosing. Tolerance is considered
to develop to the effects of marijuana when high
doses are used over an extended period of time."."-"
The finding of accumulation of A-9-THC in the blood
of heavy smokers of marijuana could also interfere with
the definition of a blood level of A-9-THC indicating
functional impairment. At present, definitive studies on
these issues regarding the chronic use of marijuana have
not been performed.
Accumulation of marijuana between passive exposure
sessions was initially suspected in our present study
because of the significant increase in subjective effects
observed on day 4 vs. day 3 (Fig. 1, lower panels).
This was generally ruled out by chemical analyses of
the remaining marijuana after burning and room air
concentrations of A-9-THC to which the subjects were
exposed. The total marijuana cigarette weight burned
was 10% less on day 3 than on subsequent test days.
Furthermore, room air concentrations of A-9-THC on
day 3 were generally less than half those of subsequent
days, possibly a result of initial adsorption on room
surfaces. Thus it appears that the five subjects were
exposed to less smoke generated from active drug on
day 3 than on subsequent days, and accumulation of
A-9-THC was not likely the cause of increased subjective
effects on day 4. However, this does not rule out
the possibility of accumulation occurring after multiple
passive inhalation sessions, because the terminal phase t, for A-9-THC in human plasma ranges from 25 to
36 hours.'
The excretion of cannabinoid metabolites in urine
after passive marijuana smoke exposure increased as a
function of the number of marijuana cigarettes burned.
After one or more passive exposure sessions to the
smoke of 16 marijuana cigarettes, the percent of urine
samples positive for cannabinoids was nearly equivalent
to that after active smoking of one marijuana cigarette.
Exposure to the smoke of four marijuana cigarettes
produced positive EMIT 20 assay results for cannabinoids
in urine from four of five subjects and appeared
to be near the minimal smoke exposure level for these
subjects. Although the presence of cannabinoid metabolites
in urine is not generally correlated with the appearance
of subjective effects, the excretion of high
urinary cannabinoid concentrations by the five subjects
after high smoke exposure in our present study is entirely
consistent with the magnitude of their reported
subjective effects.
The excretion of cannabinoid metabolites in urine
after passive marijuana smoke exposure has been reported,
with the suggestion that the conditions used for
smoke exposure were the maximum tolerable limits for
their subjects." Irritation to the smoke of the 16-
marijuana cigarette condition was partially alleviated
by our subjects wearing colored eye goggles. Most subjects
preferred to wear them, but some spent part of
their exposure time without their goggles. Also, although
the subjects were free to leave the smoke-filled
room at any time, none left during any of the 18 1-hour
passive exposure sessions. Only minor throat irritation
was reported during and after these exposure sessions,
not unlike those effects reported after active marijuana
smoking. From these studies, it appears that somewhat
higher tolerable limits of marijuana smoke exposure are
possible than were originally considered.
Passive ingestion of A-9-THC adsorbed from smoke
onto foodstuffs and liquids was prevented in our studies
by not allowing food and water ingestion during the
smoke exposure sessions. The potential for ingestion
of marijuana adsorbed onto food and other surfaces is
obvious, but nothing is known concerning the possible
contribution of this mode of passive ingestion to observable
drug effects. The amount of orally ingested
A-9-THC needed to produce measurable subjective effects
would be quite large in comparison with a smoked
dose of marijuana, because oral A-9-THC has a
systemic availability of about one third that when
smoked.' However, oral marijuana adsorbed to foodstuffs
during passive exposure might be an important
contributing factor to subsequent production of urine
samples positive for cannabinoid metabolites.
Clearly, societal and legal implications arise if a subject
can develop marijuana-like subjective effects and
test positive for urinary cannabinoid metabolites as a
result of passive inhalation. A positive urine test for
marijuana when confirmed by specific analytic assay is
perceived as evidence for recent active use or abuse. A
second unvalidated assumption often made on the basis
of positive urine results is that performance impairment
occurred in the recent past for that individual, although
no correlation is generally made with current behavior.
Our present results suggest caution both to individuals
who might be passively exposed to heavy marijuana
smoke and to those who interpret marijuana screening
data, because with sufficient time and high marijuana
smoke exposure conditions, it becomes difficult to distinguish
between active smoking and passive inhalation.
Special thanks to Drs. D. Blank and R. E. Willette for
their advice and consultation, to Dr. R. Hawks, Research
Technology Branch, National Institute on Drug Abuse, for
marijuana supplies, and to P. Welch, LPN 11, for technical
assistance.
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Source: Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke
