Delta-9- tetrahydrocannabinol (THC), the primary psychoactive cannabinoid, exerts the majority of its central nervous system effects through interaction with the G-protein linked cannabinoid CB1 receptor. A second cannabinoid-binding seven-transmembrane spanning receptor subtype, termed CB2, has been cloned and appears to be involved with regulation of immunological functions. SR 141716 or Rimonabant is the first antagonist of the central cannabinoid receptor CB1 to be identified. It antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylcyclase activity in rat brain membranes. Availability of a pure cannabinoid receptor antagonist has helped to assess the role of the endogenous cannabinoid system. The potential therapeutic utility of this antagonist in modulating the large number of brain systems that appear to express cannabinoid CB1 receptors is especially interesting. Cannabinoid effects on """"""""reward"""""""" systems could be mediated through moderate receptor densities in ventral tegmental area and the nucleus accumbens. We have shown for the first time the ability of Rimonabant to block the acute effects of THC in humans, thus confirming the parallelism of effects in humans and animals. We conducted a phase I clinical trial of the antagonism of the subjective and cardiovascular effects of smoked cannabis by Rimonabant. In addition, the safety of Rimonabant when given alone to light cannabis users, or in combination with THC via inhalation and the pharmacokinetics of Rimonabant and THC are being determined. Healthy male subjects with a history of cannabis use receive placebo or active Rimonabant prior to smoking placebo or active cannabis. Physiological, biochemical and behavioral measures are being monitored to evaluate pharmacodynamic effects. We conducted a second phase I study of Rimonabant utilizing multiple doses to show that blockade a cannabis's effects were accomplished with smaller multiple doses of drug.

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2010
Total Cost
$190,573
Indirect Cost
Name
National Institute on Drug Abuse
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Type
DUNS #
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Warren, Kimberly R; Buchanan, Robert W; Feldman, Stephanie et al. (2013) Effects of the cannabinoid-1 receptor antagonist/inverse agonist rimonabant on satiety signaling in overweight people with schizophrenia: a randomized, double-blind, pilot study. J Clin Psychopharmacol 33:118-20
Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene et al. (2013) Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers. Am J Addict 22:510-4
Goodwin, Robert S; Baumann, Michael H; Gorelick, David A et al. (2012) CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men. Am J Drug Alcohol Abuse 38:114-9
Boggs, Douglas L; Kelly, Deanna L; McMahon, Robert P et al. (2012) Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial. Schizophr Res 134:207-10
Karschner, Erin L; Schwope, David M; Schwilke, Eugene W et al. (2012) Predictive model accuracy in estimating last ?9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC. Drug Alcohol Depend 125:313-9
Schwilke, Eugene W; Gullberg, Rod G; Darwin, William D et al. (2011) Differentiating new cannabis use from residual urinary cannabinoid excretion in chronic, daily cannabis users. Addiction 106:499-506
Milman, Garry; Schwope, David M; Schwilke, Eugene W et al. (2011) Oral fluid and plasma cannabinoid ratios after around-the-clock controlled oral ?(9)-tetrahydrocannabinol administration. Clin Chem 57:1597-606
Milman, Garry; Barnes, Allan J; Schwope, David M et al. (2011) Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration. Anal Bioanal Chem 401:599-607
Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene et al. (2011) Antagonist-elicited cannabis withdrawal in humans. J Clin Psychopharmacol 31:603-12
Kelly, Deanna L; Gorelick, David A; Conley, Robert R et al. (2011) Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study. J Clin Psychopharmacol 31:86-91

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