Endocannabinoid signaling and stress in CVS

1. Endocannabinoid signaling and stress in CVS Thangam Venkatesan, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Medical College of Wisconsin Milwaukee,WI

2. Disclosures Significant relationships

3. Objectives • Overview of the endocannabinoid system (ECS) • elucidate the role of the ECS in vomiting and stress • Discuss use of marijuana in CVS • Future direction • Cannabinoids as potential pharmacotherapy in CVS

4. Pathogenesis of CVS Genetics Stress CVS Marijuana Endocannabinoids

5. Personalized Medicine “Your DNA test shows you’re predisposed to sue doctors.”

6. Breaking bad – Viewer discretion advised !

7. Cannabis and the Gut

8. Marijuana • Used for centuries as a herbal remedy in the East • Described as the “elixir of the Gods” • Legalized in many states in the US • 40% of the CVS population uses marijuana for symptom relief (Choung et al. 2012) White DG. University of Chicago Press. 1996. (Tara Tantra )

9. Cannabis and the gut Is Cannabis the panacea of all ills?

10. What are cannabinoids ?

11. What are cannabinoids ?

12. The endocannabinoid system (ECS) • Phytocannabinoids (derived from the plant) • THC , cannabidiol and other compounds • Synthetic cannabinoids • Endocannabinoids • Anandamide (AEA) • Derived from “ananda” or bliss in sanskrit • 2- AG(2-arachidonylglycerol) • Receptors ( CB1 and CB2) • Enzymes involved in degradation of endocannabinoids Devane et al. 1992), Mechoulam et al. 1995; Sugiura et al. 1995

13. Cannabinoid receptors Pertwee, 2009 CB1 & CB2 • classical receptors for all types of CB agonists • endocannabinoids, • phytocannabinoids • synthetic CBs • Distributed in many areas in the CNS, enteric neurons, nerve fibers and terminals in the enteric nervous system • CB1 seen throughout the wall of the gut • Macrophages & plasma cells are immunoreactive for both CB1 and CB2 receptors

14. Inactivation of AEA and 2-AG Ahn et al., 2008 Duncan et al., 2008 • Fatty acid amide hydrolase (FAAH) • degradation of AEA and some 2-AG • Monoacylglycerol lipase (MAG lipase) is responsible for the degradation of 2-AG • Causes degradation of 2-AG

15. Endocannabinoid signalling Presynaptic neuron ↓Ca2+,K+ CB1 NT AEA or 2-AG mR T iR Stress Precursor + FAAH ↑Ca2+ Postsynaptic neuron Et, AA

16. Phytocannabinoids(plant derived) • Tetrahydrocannabinol (THC) , cannabidiolic acid (CBDA), cannabidiol (CBD) and other compounds • CBDA and CBD are not psychoactive • Heating the plant cause changes in chemical composition • CBDA CBD • THCA THC

17. Effects of phytocannabinoids • THCA • No psychoactive effects in rhesus monkeys up to 5 mg/kg • Reduced LiCl induced vomiting in the musk shrew,effect was reversed with rimonbant pretreatment • Reduced conditioned gaping in rats ( a surrogate marker for nausea) • CBDA • Reduced LiCl, motion and cisplatin-induced vomiting in the shrew

18. Role of endocannabinoids in health and disease

19. Role of EC’s in the gut Food intake and feeding behavior Obesity Nausea and vomiting IBD Stress Cancer