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Blockade of Effects of Smoked Marijuana by the CB1-Selective Cannabinoid Receptor Antagonist SR141716
Marilyn A. Huestis, PhD;
David A. Gorelick, MD, PhD;
Stephen J. Heishman, PhD;
Kenzie L. Preston, PhD;
Richard A. Nelson, MD;
Eric T. Moolchan, MD;
Richard A. Frank, MD, PhD
Arch Gen Psychiatry. 2001;58:322-328.
ABSTRACT
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Background SR141716, a recently developed CB1 cannabinoid receptor antagonist,
blocks acute effects of  -9-tetrahydrocannabinol (THC) and other CB1
cannabinoid agonists in vitro and in animals. These findings suggest that
CB1 receptors mediate many of the effects of marijuana, but this has not been
evaluated in humans.
Methods Sixty-three healthy men with a history of marijuana use were randomly
assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3,
10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo
marijuana cigarette 2 hours later. Psychological effects associated with marijuana
intoxication and heart rate were measured before and after antagonist and
marijuana administration.
Results Single oral doses of SR141716 produced a significant dose-dependent
blockade of marijuana-induced subjective intoxication and tachycardia. The
90-mg dose produced 38% to 43% reductions in visual analog scale ratings of
"How high do you feel now?" "How stoned on marijuana are you now?" and "How
strong is the drug effect you feel now?" and produced a 59% reduction in heart
rate. SR141716 alone produced no significant physiological or psychological
effects and did not affect peak THC plasma concentration or the area under
the time x concentration curve. SR141716 was well tolerated by all subjects.
Conclusions SR141716 blocked acute psychological and physiological effects of smoked
marijuana without altering THC pharmacokinetics. These findings confirm, for
the first time in humans, the central role of CB1 receptors in mediating the
effects of marijuana.
INTRODUCTION
WIDESPREAD medical, recreational, and religious uses of Cannabis sativa preparations (eg, marijuana, hashish) have occurred
throughout history.1, 2 -9-Tetrahydrocannabinol
(THC), the primary psychoactive component of marijuana, produces behavioral,
cardiovascular, analgesic, psychomotor, and cognitive effects that are mediated
through the cannabinoid CB1 receptor, a G protein–linked receptor located
primarily in the central and peripheral nervous systems.3, 4, 5
A second cannabinoid receptor subtype (CB2) seems to be concentrated in the
peripheral immune system.6, 7 The
identification of specific cannabinoid receptors has led to the discovery
of endogenous cannabinoid agonists, including the arachidonic acid derivatives
anandamide and 2-arachidonoylglycerol.8, 9
Development of SR141716, the first selective CB1 receptor antagonist,
has provided an important new tool for identifying functions of the endogenous
cannabinoid system. Acute administration of SR141716 blocks in vitro and in
vivo effects of cannabinoid agonists10, 11
and precipitates withdrawal signs in animals given THC for long periods.12 These findings suggest that CB1 receptors play an
important role in mediating the effects of THC in animals. This article reports
(for the first time in humans) the ability of SR141716 to antagonize the psychological
effects and tachycardia produced by smoked marijuana in research volunteers
with histories of marijuana use.
SUBJECTS AND METHODS
SUBJECTS
Subjects were recruited from the community according to the following
eligibility criteria: physically and psychologically healthy men aged between
21 and 45 years; marijuana use of at least 1 year; no current physical dependence
on any substance other than nicotine or caffeine; use of other drugs no more
than twice in the 2 weeks prior to study entry; regular alcohol intake of
no more than 4 standard drinks per day ( 5 days per week); no use of hallucinogens
during the past year; smoking fewer than 30 cigarettes per day; Shipley Institute
of Living estimated IQ greater than 85; and no history of seizures, head trauma
with loss of consciousness greater than 3 minutes, current major psychiatric
disorder, or lifetime non–drug-related psychosis. Current marijuana
use was verified by a positive urine cannabinoid test result at 50 ng/mL.
Health status was evaluated by medical history, physical examination, blood
chemistry, complete blood cell count, urinalysis, viral antibody screening
(hepatitis B, hepatitis C, human immunodeficiency virus), tuberculosis skin
test (with chest x-ray film as clinically indicated), electrocardiogram, electroencephalogram,
pulmonary function tests, clinical psychiatric interview, and standard psychological
tests. The study was approved by the National Institute on Drug Abuse (NIDA)
institutional review board. All subjects gave written informed consent and
were paid for their participation.
STUDY DESIGN
A randomized, placebo-controlled, double-blind, ascending dose design
was used. Sixty-three subjects were randomly assigned (within the constraints
of dose escalation) to 1 of 12 groups: placebo SR141716/placebo marijuana
(n = 10); placebo SR141716/active marijuana (n = 10); active SR141716/placebo
marijuana (n = 2 at 1, 3, 10, 30, and 90 mg SR141716); and active SR141716/active
marijuana (n = 8 at 1 mg; n = 7 at 3 mg; n = 6 at 10, 30, and 90 mg SR141716).
Randomization within each dosage group was based on computer-generated random
numbers. The original study design included 1-, 3-, and 10-mg doses. Groups
receiving 30 mg and 90 mg were added when a blinded review of data from lower
doses suggested no evidence of efficacy and the doses were well tolerated
by subjects. Subjects received a single oral dose of active or placebo SR141716
at 9 AM, then smoked an active or placebo marijuana cigarette 2 hours later.
A 2-hour interval was used to match the expected time of peak SR141716 plasma
concentration (unpublished data, Sanofi-Synthelabo Inc).
Subjects resided on the closed clinical research unit of the NIDA [National
Institute on Drug Abuse] Intramural Research Program for at least 1 day prior
to dosing and 2 days afterward. To avoid the possibility of precipitating
marijuana withdrawal, SR141716 was not administered until urine cannabinoid
concentration was below 20 ng/mL. Medical evaluations were repeated prior
to unit discharge and at a follow-up visit 1 week after dosing. Review of
adverse events and clinical laboratory data suggested no dose-dependent trends.
No subject left the study because of an adverse event attributed to SR141716.
MEDICATIONS
SR141716 and matching placebo capsules were obtained from Sanofi-Synthelabo
Inc, Malvern, Pa. Each subject took 3 capsules containing 0, 1, 10, or 30
mg of SR141716 as needed to achieve his assigned dose. Marijuana was supplied
by the NIDA Research Technology Branch in machine-rolled cigarettes, weighing
an average of 764 mg. Active cigarettes contained 2.64% THC by weight, confirmed
by gas chromatography/mass spectrometry (GC/MS) assay, and were estimated
to contain 20 mg of THC. Placebo cigarettes were identical in appearance and
smell, except that cannabinoids were removed by solvent extraction. Subjects
smoked 8 puffs at 60-second intervals beginning 110 minutes after oral dosing
with SR141716.
ASSESSMENTS
Primary outcome measures were subjective report of intoxication and
heart rate, reliable measures of acute marijuana intoxication.13, 14
Marijuana intoxication was assessed by 3 visual analog scale (VAS) questions
and the Marijuana (M) scale. Each VAS question was given separately on a video
monitor. Subjects responded by moving the cursor along a 100-mm line labeled
"Not at all" on the left and "Extremely" on the right. The 3 questions were
"How high do you feel now?" "How stoned on marijuana are you now?" and "How
strong is the drug effect you feel now?" Visual analog scale scores were analyzed
as a composite score (mean of the 3 individual scores) and as individual scores.
The M scale is a 12-item subset of the Addiction Research Center Inventory.15 Each item describes a sign or symptom commonly associated
with marijuana intoxication, to which subjects respond true or false. The
VAS questions and M scale were completed 1 hour before SR141716 dosing, 1
hour before marijuana smoking, and at 5, 10, 15, 20, 25, 55, and 65 minutes
after marijuana smoking.
Heart rate was monitored continuously during the session using a 2-lead
Passport NR Physiological Monitor (Datascope Corp, Paramus, NJ) and analyzed
in terms of average heart rate during consecutive 5-minute intervals. Heart
rate baseline was the 5-minute interval immediately preceding the start of
the smoking period.
Blood for SR141716 and THC assays was drawn from an indwelling venous
catheter in the arm 10 minutes before SR141716 dosing, 5 minutes before marijuana
smoking, and at 2, 5, 10, 15, 20, 40, 60, 80, and 100 minutes after smoking.
Heparinized plasma was stored at -20°C until analysis (SR141716
was assayed by liquid chromatography–tandem mass spectrometry with a
1-ng/mL limit of detection). -9-Tetrahydrocannabinol was assayed by
chemical ionization gas chromatography/mass spectrometry using a modification
of the method of Foltz et al,16 with a 0.5-ng/mL
limit of detection.
STATISTICAL ANALYSES
Data from the 62 randomized subjects who received SR141716 and smoked
a marijuana cigarette were used in the analysis (1 subject did not smoke marijuana
because of administrative issues and was not included in the analysis). Psychological
data from 3 subjects and heart rate data from 1 subject were not used because
they provided fewer than 4 data points during the 60 minutes following smoking.
Comparison of baseline subject characteristics across treatment groups was
conducted using 1-way analysis of variance (ANOVA) for continuous variables
and the Fisher exact test for categorical variables.
Data were expressed as peak change from baseline for heart rate and
peak effect for psychological variables for 1 hour after smoking because previous
results indicated that peak effects occurred within 1 hour after smoking marijuana.13, 14 Peak effect data from all variables
were analyzed using a 2-way ANOVA with marijuana cigarette (placebo, active)
and SR141716 dose (0, 1, 3, 10, 30, 90 mg) as factors. Planned pairwise contrasts
were used to compare the antagonism of marijuana effects by each dose of SR141716
with antagonism by placebo and to examine the effects of marijuana and SR141716
alone. Residual variances for each group were used in the analysis because
of observed group differences in variance. A secondary analysis on composite
VAS score, heart rate, and M scale was conducted using orthogonal polynomial
trend tests to examine the dose-response effect of SR141716 after active marijuana
administration. The trend tests were performed on log (SR141716 dose), replacing
the 0-mg dose with 0.01 mg. All statistical tests were 2-tailed with 
= .05.
Percent blockade at each SR141716 dose was calculated as 100 x
[(placebo SR141716/active marijuana) - (active SR141716/active marijuana)]
/ [(placebo SR141716/active marijuana) - (placebo SR141716/placebo marijuana)].
The Feiller theorem was used to calculate 95% confidence intervals (CIs) for
percent blockade. The effects of marijuana alone were evaluated by comparing
data from the placebo SR141716/placebo marijuana group (n = 10) and the placebo
SR141716/active marijuana group (n = 10). The effects of SR141716 alone were
evaluated by comparing the effects of placebo SR141716/placebo marijuana (n
= 10) with those of the combined group receiving active SR141716/placebo marijuana
(n = 10).
RESULTS
SUBJECT CHARACTERISTICS
Subjects in the 8 treatment groups differed significantly in number
of days of marijuana use in the 30 days prior to study entry (F7,55
= 2.72, P = .02), but did not differ significantly
in years of lifetime marijuana use (F7,55 = 0.87, P = .54), age (F7,55 = 0.75, P
= .63), race (Fisher exact test = 2.24, P = .98),
or body mass index (F7,55 = 0.84, P =
.56) (Table 1). The 90-mg SR141716
group had the highest recent marijuana use (25 days) and the 1-mg SR141716
group had the lowest (4.6 days).
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Characteristics of Participants According to Treatment Group*
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EFFECTS OF MARIJUANA AND SR141716 ALONE
Marijuana smoking alone produced expected physiological and psychological
effects. Marijuana significantly (t49
= 4.67, P<.001) increased heart rate, producing
a mean increase of 30 beats per minute 15 minutes after smoking (Figure 1). Marijuana also increased scores
on the composite VAS (t47 = 6.58, P<.001), individual VAS questions (t47 = 6.63, P<.001; t47 = 6.24, P<.001; and t47 = 6.61, P<.001,
for "drug high," "stoned," and "drug strength," respectively), and the M scale
(t47 = 3.85, P<.001)
(Figure 1). Peak effects occurred
within 60 minutes after smoking.
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Figure 1. Time course of SR141716 blockade
of marijuana's effects for the following treatment groups: placebo SR141716/placebo
marijuana (P-SR/P-M, n = 10), active SR141716/placebo marijuana (SR/P-M, n
= 10), placebo SR141716/active marijuana (P-SR/M, n = 10), and 90-mg SR141716/active
marijuana (SR-90/M, n = 6). Data are responses (mean ± SE) during the
60 minutes (heart rate) or 65 minutes (psychological measures) after smoking.
VAS indicates visual analog scale.
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SR141716 alone produced no significant effects on any of the outcome
measures (Figure 1) (t49 = 0.01, P = .99; t47 = 0.03, P = .98; t47 = 0.13, P = .90; t47 = 0.10, P = .92; t47 = 0.03, P = .98; and t47 = 0.22, P = .83
for heart rate, composite VAS, individual VAS questions, and M scale, respectively).
In addition, visual inspection of data collected from all subjects during
the 2 hours between SR141716 dosing and smoking (data not shown), and during
the placebo marijuana smoking session showed no evidence of any significant
changes from baseline.
BLOCKADE OF MARIJUANA EFFECTS BY SR141716
The 90-mg dose of SR141716 (compared with placebo SR141716) significantly
reduced the effects of marijuana on the composite VAS (t47 = 2.23, P = .03) and individual
VAS questions (t47 = 2.49, P = .02; t47 = 1.97, P = .05; and t47 = 2.37, P = .02, for "drug high," "stoned," and "drug strength,"
respectively) and produced a trend toward reduced tachycardia (t49 = 1.79, P = .08) and M scale
scores (t47 = 1.97, P = .06) (Figure 1). The
percent reductions (95% CI) in peak marijuana effect produced by 90-mg SR141716
(Figure 2) were heart rate, 59%
(range, -7% to 153%); composite VAS, 41% (range, 4%-85%); drug high,
43% (range, 8%-87%); stoned on marijuana, 38% (range, -1% to 86%); drug
strength, 43% (range, 6%-88%); and M scale, 75% (range, -2% to 209%).
Percent reductions of peak marijuana effects at lower doses of SR141716 were
not statistically significant. Polynomial trend tests indicated a significant
linear trend for SR141716 dose on heart rate (F1,49 = 4.03, P = .05), composite VAS (F1,47 = 5.59, P = .02), and M scale (F1,47 = 6.22, P = .02). The only nonlinear term to achieve statistical significance
was a quadratic term for the M scale (F1,47 = 6.60, P = .01).
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Figure 2. Percent blockade (mean ±
SE) of peak marijuana effects produced by single oral doses of 1 mg (n = 8),
3 mg (n = 7), 10 mg (n = 6), 30 mg (n = 6), and 90 mg (n = 6) SR141716. VAS
indicates visual analog scale; asterisk, percent blockade of marijuana effects
by 90-mg SR141716 compared with placebo SR141716 (P .05).
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PHARMACOKINETIC MEASURES
There was no significant difference in mean peak plasma THC concentration
between subjects receiving placebo SR141716 (139 ng/mL, 95% CI, 121-157) and
those receiving 90-mg SR141716 (130 ng/mL, 95% CI, 113-147). There was also
no significant difference in the THC area under the curve (0-1.8 hours after
smoking) between the placebo SR141716 (43.6 ng • h/mL, 95% CI, 38.2-49.0)
and 90-mg SR141716 (36.2 ng • h/mL, 95% CI, 30.5-41.9) treatment groups.
COMMENT
These findings of significant blockade of smoked marijuana effects after
pretreatment with the selective CB1 receptor antagonist SR141716 suggest that
in humans, many of the acute psychological and physiological effects of marijuana
are mediated, at least in part, by interaction with CB1 receptors. In particular,
the antagonism of psychological effects of acute marijuana intoxication is
consistent with animal studies showing that SR141716 blocks the discriminative
stimulus effects of THC in rats, monkeys, and pigeons,17, 18, 19, 20
suggesting that agonist activity at CB1 receptors plays an important role
in human marijuana abuse. A pharmacokinetic explanation for these findings
(ie, an SR-induced decrease in achieved concentration of THC) seems unlikely
because there were no significant differences in peak THC concentration or
THC area under the curve between subjects receiving active or placebo SR141716.
Group differences in recent marijuana use (Table 1) were also unlikely to have influenced these results. Regardless
of marijuana use in the past month, no subject was administered SR141716 until
substantially all marijuana had been eliminated from the body. Subjects spent
a mean ± SD of 6.4 ± 5.1 days on the closed NIDA research unit
prior to dosing. This monitored drug-free interval did not vary significantly
among the treatment groups (F7,55 = 0.57, P
= .77). Significant tolerance to cardiovascular (eg, tachycardia) and psychological
effects of smoked marijuana or oral THC has been reported in human experimental
studies involving repeated administration lasting from days to weeks.21, 22, 23, 24, 25
This tolerance dissipates within 2 to 7 days of abstinence for tachycardia21, 22, 23 and 4 to 7 days for
psychological effects.21, 22, 23, 24, 25
Thus, differences among treatment groups in persisting tolerance to marijuana
effects were unlikely to account for the observed blockade in marijuana effects
after administration of SR141716.
In THC-naive rodents, SR141716 sometimes produced behavioral effects
including stimulation of locomotor activity, increased wakefulness, improved
memory, hyperalgesia, suppression of sucrose and alcohol ingestion, and defensive
behavior.26, 27, 28, 29, 30, 31
Most of these actions are opposite to those expected from a CB1 receptor agonist
or from marijuana. It is not clear to what extent these SR141716 effects are
due to blockade of endogenous cannabinoid "tone" or to potential inverse agonist
action of SR141716. Recent studies with human CB1 receptors expressed in isolated
cell cultures suggest that SR141716 can act as an inverse agonist at the G-protein
level.32, 33, 34 There
was no evidence for an inverse agonist effect of SR141716 in humans in this
study because SR141716 alone produced no significant effect on any measure.
Thus, the observed blockade of acute marijuana effects probably was not due
to opposing SR141716 effects partially masking the pure agonist effects of
marijuana.
The mechanism of marijuana-induced tachycardia in humans remains unclear,
in part because there is no good animal model (the acute effect of marijuana
in animals is bradycardia).35 Limited human
data suggest that the tachycardia may be related to increased sympathetic
and decreased parasympathetic autonomic activity.35, 36
Regardless of whether these actions are centrally or peripherally mediated,
the finding of this study that a CB1 receptor antagonist partially blocked
marijuana-induced tachycardia suggests that CB1 receptors play an important
role in the cardiovascular effects of marijuana.
This study has several limitations. Subjects received a single dose
of SR141716, achieving only 40% to 75% reductions in acute marijuana effects
at the highest dose (90 mg). Thus, the maximum possible blockade of marijuana
effects by CB1 receptor antagonism remains unknown, leaving uncertain the
degree to which mechanisms other than CB1 action (such as CB2 receptor agonism)
might mediate the acute effects of marijuana in humans. Future studies with
higher single doses or multiple doses of SR141716 (whose long half-life would
lead to accumulation of the drug) could better define maximal blockade of
CB1 receptors by the antagonist. To avoid possible precipitation of acute
marijuana withdrawal, SR141716 was not administered until subjects' urine
cannabinoid concentrations were below 20 ng/mL. Administration of SR141716
closer to the time of last marijuana use, with higher blood (and brain) cannabinoid
concentrations, might produce different results. Finally, all subjects were
healthy men aged 21 to 45 years. The generalizability of these findings to
a more representative, heterogeneous population of both sexes, varying ages,
and with medical and psychiatric comorbidities remains unknown.
The findings of this study have significant implications for understanding
the neurobiology of the endogenous cannabinoid system in humans and its potential
role in the pathophysiology and treatment of a variety of clinical disorders.
High densities of CB1 receptors in the human cortex, hippocampus, anterior
cingulate, basal ganglia, and cerebellum suggest a role for the endogenous
cannabinoid system in attention, cognition, and motor control.37, 38, 39
Animal studies have shown that CB1 receptor agonists impaired learning and
memory31, 40 and increased appetite
and food intake,41 whereas CB1 receptor antagonists
enhanced learning and memory31, 40
and reduced food intake.26 Cannabinoid systems
may play a role in psychotic disorders,42 as
suggested by the recent finding of increased anandamide concentrations in
the cerebrospinal fluid of schizophrenic patients.43
The results of the present study support the importance of these roles by
demonstrating, for the first time in humans, blockade of well-characterized
physiological and psychological effects of smoked marijuana by the selective
CB1 receptor antagonist SR141716. Further research into the role of CB1 receptors
and the pharmacology of marijuana may lead to improved treatment for disorders
related to dysfunction of the endogenous cannabinoid system and to the development
of novel therapeutic agents.
AUTHOR INFORMATION
Accepted for publication November 17, 2000.
This study was supported by NIDA intramural funds, Baltimore, Md, and
Sanofi-Synthelabo Inc, Malvern, Pa.
We thank Edward Cone, PhD, Harry Haverkos, MD, Linda Jefferson, RN,
PhD, and Nicholas Carriero, PhD, from the NIDA Intramural Research Program
for clinical, technical, and logistical support, and Keith Lasher, BS, John
Newton, PhD, and Ramin Ebrahimi, MS, from Sanofi-Synthelabo Inc for technical
support.
From the Clinical Pharmacology and Therapeutics Branch, Intramural
Research Program, National Institute on Drug Abuse, National Institutes of
Health, Baltimore, Md (Drs Huestis, Gorelick, Heishman, Preston, Nelson, and
Moolchan); and Sanofi-Synthelabo Inc, Malvern, Pa (Dr Frank).
Corresponding author and reprints: Marilyn A. Huestis, PhD, National
Institute on Drug Abuse Intramural Research Program, 5500 Nathan Shock Dr,
Baltimore, MD 21224 (e-mail: mhuestis{at}intra.nida.nih.gov).
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