Cannabis Clinical Trial
Official title:
Antagonist-Elicited Cannabis Withdrawal
Background: Rimonabant, a CB1 receptor antagonist, blocks effects of cannabinoids and, in
dependent animals, elicits cannabinoid withdrawal. No studies have examined
rimonabantelicited cannabis withdrawal in humans.
Goals: (1) Determine the lowest single dose of oral rimonabant that elicits measurable
cannabinoid withdrawal. (2) Characterize cognitive performance, subjective state,
physiological condition, and regional brain activation (measured by functional magnetic
resonance imaging [fMRI]) during acute and chronic administration of oral delta
9-tetrahydrocannabinol (THC) and during cannabis withdrawal. (3) Characterize the
pharmacokinetics of oral THC and metabolites in body fluids and hair and of rimonabant in
plasma.
Subject Population: Up to 60 completing cannabis users aged 18-45 (up to 24 in Experiment I,
36 in Experiment II) and 18 completing non-drug-using controls (Experiment II). Enrollment
target is 82% Caucasian, 14% African American, 4% other; 9% Hispanic; 35% women.
Experimental Design and Methods: Experiment I: In this within-subject, randomized,
double-blind, dose-escalation study, six participants receive 7 days of THC (40-120 mg/day).
On Day 8, five participants receive 20 mg rimonabant; one receives placebo. If withdrawal
criteria (greater than or equal to 150% or 2.5-fold increase in selected visual-analog
scales) are not met in all five participants receiving rimonabant, separate groups of six are
similarly treated with 40, 60 or 80 mg rimonabant, if necessary. The PI and MRP will submit
all adverse events and relevant cardiovascular and scientific data to the IRB at the
completion of each rimonabant dose panel. When the extramural NIDA DSMB is in place, it will
review all data collected to date and develop and implement a monitoring plan, including
review on completion of each dose cohort. DSMB recommendations will be reviewed by the
Sponsor, Clinical Director and IRB before proceeding to the next dose cohort. In addition, if
any subject has an intolerable adverse event (ie, an adverse event leading to study
discontinuation) or serious adverse event in response to rimonabant on Day 8, the blind for
that subject will be broken, and a report sent to the Sponsor, the extramural NIDA DSMB when
in place and the IRB for discussion.
Experiment II: In this randomized, placebo-controlled, double-blind study, 36 participants
receive 7 days of THC (40-120 mg/day). On Day 8, 18 participants receive rimonabant dose
determined in Experiment I to elicit cannabis withdrawal; 18 participants receive placebo
rimonabant to evaluate spontaneous cannabis withdrawal. Cognitive, psychological,
physiological and hormonal measures are monitored to determine onset, magnitude, and duration
of THC intoxication and withdrawal and to correlate with THC and rimonabant pharmacokinetics.
Changes in blood oxygen level-dependent (BOLD) signal are determined with five fMRI scans
throughout the study. Eighteen non-drug-using controls undergo scanning and cognitive testing
at similar intervals.
Risks and Benefits: The proposed doses of THC and rimonabant have been well tolerated in
other studies. The most common side effects of oral THC are sedation, cognitive impairment,
euphoria, poor coordination, tachycardia, and hypotension. Spontaneous withdrawal from
cannabis is mild and medically benign. Experience with other drugs suggests that
antagonist-elicited cannabis withdrawal may have an earlier onset and greater intensity than
spontaneous cannabis withdrawal. There are no clinical benefits to participants. Scientific
benefits are greater understanding of cannabis intoxication, tolerance, and withdrawal and of
the role of rimonabant in eliciting cannabis withdrawal.
Background: Rimonabant, a CB1 receptor antagonist, blocks effects of cannabinoids and, in
dependent animals, elicits cannabinoid withdrawal. No studies have examined
rimonabantelicited cannabis withdrawal in humans.
Goals: (1) Determine the lowest single dose of oral rimonabant that elicits measurable
cannabinoid withdrawal. (2) Characterize cognitive performance, subjective state,
physiological condition, and regional brain activation (measured by functional magnetic
resonance imaging [fMRI]) during acute and chronic administration of oral delta
9-tetrahydrocannabinol (THC) and during cannabis withdrawal. (3) Characterize the
pharmacokinetics of oral THC and metabolites in body fluids and hair and of rimonabant in
plasma.
Subject Population: Up to 60 completing cannabis users aged 18-45 (up to 24 in Experiment I,
36 in Experiment II) and 18 completing non-drug-using controls (Experiment II). Enrollment
target is 82% Caucasian, 14% African American, 4% other; 9% Hispanic; 35% women.
Experimental Design and Methods: Experiment I: In this within-subject, randomized,
double-blind, dose-escalation study, six participants receive 7 days of THC (40-120 mg/day).
On Day 8, five participants receive 20 mg rimonabant; one receives placebo. If withdrawal
criteria (greater than or equal to 150% or 2.5-fold increase in selected visual-analog
scales) are not met in all five participants receiving rimonabant, separate groups of six are
similarly treated with 40, 60 or 80 mg rimonabant, if necessary. The PI and MRP will submit
all adverse events and relevant cardiovascular and scientific data to the IRB at the
completion of each rimonabant dose panel. When the extramural NIDA DSMB is in place, it will
review all data collected to date and develop and implement a monitoring plan, including
review on completion of each dose cohort. DSMB recommendations will be reviewed by the
Sponsor, Clinical Director and IRB before proceeding to the next dose cohort. In addition, if
any subject has an intolerable adverse event (ie, an adverse event leading to study
discontinuation) or serious adverse event in response to rimonabant on Day 8, the blind for
that subject will be broken, and a report sent to the Sponsor, the extramural NIDA DSMB when
in place and the IRB for discussion.
Experiment II: In this randomized, placebo-controlled, double-blind study, 36 participants
receive 7 days of THC (40-120 mg/day). On Day 8, 18 participants receive rimonabant dose
determined in Experiment I to elicit cannabis withdrawal; 18 participants receive placebo
rimonabant to evaluate spontaneous cannabis withdrawal. Cognitive, psychological,
physiological and hormonal measures are monitored to determine onset, magnitude, and duration
of THC intoxication and withdrawal and to correlate with THC and rimonabant pharmacokinetics.
Changes in blood oxygen level-dependent (BOLD) signal are determined with five fMRI scans
throughout the study. Eighteen non-drug-using controls undergo scanning and cognitive testing
at similar intervals.
Risks and Benefits: The proposed doses of THC and rimonabant have been well tolerated in
other studies. The most common side effects of oral THC are sedation, cognitive impairment,
euphoria, poor coordination, tachycardia, and hypotension. Spontaneous withdrawal from
cannabis is mild and medically benign. Experience with other drugs suggests that
antagonist-elicited cannabis withdrawal may have an earlier onset and greater intensity than
spontaneous cannabis withdrawal. There are no clinical benefits to participants. Scientific
benefits are greater understanding of cannabis intoxication, tolerance, and withdrawal and of
the role of rimonabant in eliciting cannabis withdrawal.
;
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