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.  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 Objectives

4. Pathogenesis of CVS CVS Stress Endocannabinoids Genetics Marijuana

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

10. 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. 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 Cannabinoid receptors Pertwee, 2009

14.  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 Inactivation of AEA and 2-AG Ahn et al., 2008 Duncan et al., 2008

15. AEA or 2-AG Stress iR mR FAAH Precursor T ↑ Ca 2+ Et, AA + Postsynaptic neuron ↓ Ca 2+,K + Presynaptic neuron CB 1 NT Endocannabinoid signalling

16.  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 Phytocannabinoids(plant derived)

17.  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 Effects of phytocannabinoids

18. Role of endocannabinoids in health and disease

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