Marijuana use is a public health concern. Withdrawal that occurs in over one-half of daily marijuana users is responsible, in part, for marijuana smoking. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). While progress has been made toward establishing receptor mechanisms underlying the behavioral effects of cannabinoids, it is not clear whether the clinically useful actions and abuse liability of cannabinoids vary as a function of pharmacologic efficacy at cannabinoid receptors. Moreover, it is not clear whether pharmacologic modulation (e.g. decreased metabolism or cellular uptake) of endogenous cannabinoid agonists (e.g. anandamide) produces therapeutic effects and less of the non-preferred effects associated with direct cannabinoid agonism. This competing continuation of an R01 examines cannabinoid and non-cannabinoid approaches for treating marijuana withdrawal. This application further examines relationships between behavioral effects, pharmacologic (agonist) efficacy, and pharmacologic manipulation of endocannabinoid levels in assays predictive of marijuana-like effects in humans.
Aim 1 uses a drug discrimination assay of rimonabant-induced cannabinoid withdrawal in rhesus monkeys to characterize the neuropharmacology of withdrawal that emerges upon discontinuation of treatment.
Aim 2 explores relationships between pharmacologic (agonist) efficacy at cannabinoid receptors and behavioral effects. Tolerance and cross-tolerance among cannabinoids that vary in efficacy will be examined in rhesus monkeys discriminating 9-tetrahydrocannabinol ( 9-THC).
This aim also establishes a discrimination assay with a high efficacy cannabinoid agonist and examines dependence to a high efficacy cannabinoid agonist, indexed by discriminative stimulus effects and overt signs of withdrawal. The 9-THC discrimination assay in rhesus monkeys was highly sensitive to exogenously administered anandamide, and this assay is used in Aim 3 to examine pharmacologic manipulation of endogenous cannabinoids and interactions between endocannabinoids and 9-THC.
Aim 3 also examines modification of cannabinoid withdrawal by anandamide and inhibitors of its metabolism (URB 597) and uptake (AM 404). This competing continuation addresses a need for understanding the neuropharmacology of cannabinoids in behavioral assays predictive of marijuana-like intoxication and dependence. Collectively, studies in this competing continuation provide a framework for developing novel pharmacotherapies of marijuana withdrawal and cannabinoid-based therapeutics that could produce fewer adverse effects (i.e. abuse and dependence liability) than marijuana.

Public Health Relevance

Marijuana use continues to be a public health concern. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). This competing continuation addresses a need to understand mechanisms at cannabinoid receptors that mediate the dependence liability of marijuana and the potential therapeutic utility of the cannabinoids.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Acri, Jane
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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Hruba, Lenka; McMahon, Lance R (2017) Apparent Affinity Estimates and Reversal of the Effects of Synthetic Cannabinoids AM-2201, CP-47,497, JWH-122, and JWH-250 by Rimonabant in Rhesus Monkeys. J Pharmacol Exp Ther 362:278-286
McMahon, Lance R (2016) Enhanced discriminative stimulus effects of ?(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys. Drug Alcohol Depend 165:87-93
Hruba, Lenka; Seillier, Alexandre; Zaki, Armia et al. (2015) Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with ?9-tetrahydrocannabinol in mice. J Pharmacol Exp Ther 353:261-8
Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song et al. (2015) Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther 354:111-20
Rodriguez, Jesse S; McMahon, Lance R (2014) JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. Eur J Pharmacol 740:151-9
Hruba, Lenka; McMahon, Lance R (2014) The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. Eur J Pharmacol 727:35-42
Ginsburg, Brett C; Hruba, Lenka; Zaki, Armia et al. (2014) Blood levels do not predict behavioral or physiological effects of ??-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure. Drug Alcohol Depend 139:1-8
Ginsburg, Brett C; Schulze, David R; Hruba, Lenka et al. (2012) JWH-018 and JWH-073: ??-tetrahydrocannabinol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 340:37-45
Ginsburg, Brett C; McMahon, Lance R; Sanchez, Jesus J et al. (2012) Purity of synthetic cannabinoids sold online for recreational use. J Anal Toxicol 36:66-8
Hruba, Lenka; Ginsburg, Brett C; McMahon, Lance R (2012) Apparent inverse relationship between cannabinoid agonist efficacy and tolerance/cross-tolerance produced by ??-tetrahydrocannabinol treatment in rhesus monkeys. J Pharmacol Exp Ther 342:843-9

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