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 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 SR 141716 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 marijuana by SR141716. In addition, the safety of SR 141716 when given alone to light cannabis users, or in combination with THC via inhalation and the pharmacokinetics of SR 141716 and THC are being determined. Healthy male subjects with a history of cannabis use receive placebo or active SR141716 prior to smoking placebo or active marijuana. Physiological, biochemical and behavioral measures are being monitored to evaluate pharmacodynamic effects. We are currently conducting the second phase I study of SR141716 utilizing multiple doses of the drug to reconfirm our findings and to determine if a larger blockade of marijuana's effects can be accomplished with smaller multiple doses of drug.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000415-04
Application #
6535627
Study Section
(CPTB)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2001
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lowe, Ross H; Karschner, Erin L; Schwilke, Eugene W et al. (2007) Simultaneous quantification of Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol, and 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid in human plasma using two-dimensional gas chromatography, cryofocusing, and electron impact-mass s J Chromatogr A 1163:318-27
Huestis, Marilyn A; Boyd, Susan J; Heishman, Stephen J et al. (2007) Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology (Berl) 194:505-15
Huestis, Marilyn A (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770-804
Gorelick, David A; Heishman, Stephen J; Preston, Kenzie L et al. (2006) The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J 151:754.e1-754.e5