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

Disclosures Significant relationships

 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

Pathogenesis of CVS CVS Stress Endocannabinoids Genetics Marijuana

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Cannabis and the Gut

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 (Tara Tantra )

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

What are cannabinoids ?

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

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

 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

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

 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)

 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

Role of endocannabinoids in health and disease

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