Antagonist-Elicited Cannabis Withdrawal
Condition: Cannabis; Dependence
MeSH terms: Marijuana Abuse
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): THC; Rimonobant; Rimonabant
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Rimonabant
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Other
Keywords: Rimonabant; fMRI; Alternative Matrices; Brain Imaging; THC