Medical Cannabis: Cannabinoids and Immunomodulation

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1 Medical Cannabis: Cannabinoids and Immunomodulation Sasha Noe, DO, PhD Board Certified Family Physician President, Hillsborough County Osteopathic Medical Society Board of Directors, Florida Society of Cannabis Physicians

2 DISCLOSURE l interest/arrangement or affiliation with any l products or services to be discussed at thi

6 Cannabinoid Receptors (CBR s)

8 Chemical structures of Endocannabinoids 2

10 Major signaling pathways associated with cannabinoid receptor activation by agonists 2

11 Anabolic and catabolic pathways of Endocannabinoids and their most likely subcellular localization 2

12 Inhibitors of Endocannabinoid inactivation 2

13 Timeline of discoveries of cannabinoid receptors

14 Endocannabinoids in Immune cells 3

15 Receptor binding involved in controlling inflammation CB1 Cannabinoid Receptor CB2 cannabinoid receptor Adenosine A2A receptors CB2/5HT(1A) heterodimerization TRPV1 receptor GPR55 Receptor

16 Cannabinoid effects on adaptive immunity and T helper cells 3

17 Cannabinoid effects on pro-inflammatory cytokines 3

18 3

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20 4

21 The structures of CBD analogs and related substances 4

22 COX-2 at the interface of the Eicosanoid and Endocannabinoid systems

23 Main pathways of synthesis and degradation of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG)

24 Phytocannabinoids

28 Anti-inflammatory effects of cannabinoid-based drugs 2

29 Phytocannabinoids vs Disease

30 Sativex Oromucosal spray of a formulated extract of the cannabis sativa plant that contains the principal cannabinoids THC and CBD as well as specific minor cannabinoids and other noncannabinoid components.

31 Epidiolex (cannabidiol)

34 General Principles - 1 Endocannabinoids are expressed by immune cells Cannabinoid receptors (CBR s) at the surface of immune cells are activated after infection or immune stimulation The consequences of this for the immune response are not fully understood Regulation of cellular chemotaxis seems to be involved. Because CBR s are GPCR s (similar to receptors for chemokines and lipid mediators), their ligation during immune stimulation probably leads to regulation of gene products that are required for immune-cell function.

35 General Principles - 2 The main immune targets of CB-based drugs involve the suppression of cytokines and cell-mediated immunity, through CBR- dependent and - independent mechanisms. CBR-dependent - most probably involve G-protein signaling and the regulation of numerous cytokine genes. CBR-independent - in the case of endocannabinoids, their effects could be mediated through vanilloid receptors, which are known to bind these compounds, or they might result from the binding of as-yet-uncharacterized receptors. might also involve effects on lipid-raft structure and function, which are known to be important for immune-cell function

36 General Principles - 3 Involves the suppression, by CB-based drugs, of the chronic inflammatory response and the subsequent attenuation of disease processes and symptoms. These anti-inflammatory effects associated with the ability of these drugs to suppress the expression of cytokines, as well as other endogenous proinflammatory mediators. These drugs might also function by increasing the production of anti-inflammatory mediators. Further elucidation of the effect of cannabis-based drugs on pro-inflammatory and anti-inflammatory mechanisms will provide the basis for the formulation of more effective drugs for the management of chronic inflammatory diseases.

37 Case Study

38 Role of Medical Cannabis in treatment of disease: Opportunities and Challenges

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40 References 1. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature Jul 27;547(7664): doi: /nature Epub 2017 Jul The endocannabinoid system and its therapeutic exploitation. Di Marzo V1, Bifulco M, De Petrocellis L. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, Pozzuoli, Napoli, Italy. 3. Cannabinoid-based drugs as anti-inflammatory therapeutic. Thomas W. Klein. May 2005 Volume Cannabidiol (CBD) and its analogs: a review of their effects on inflammation Burstein, Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2 Xie, Xiao et al, Cannabidiol: State of the art and new challenges for therapeutic applications. Pisanti, Malfitano et al, Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. Cabral, Rogers, Lichtman,

researcher, bestselling author, speaker and medical cannabis expert. Dr.

research Text 3246655 Medicanna2018 (813)641-0007 An award-winning published researcher over the last two

41 Physicians Only! MedicalCannabisDocs Sasha Noe, DO, PhD is a dual doctorate, board-certified award winning physician, researcher, bestselling author, speaker and medical cannabis expert. Dr. Noe The only known physician in the US with a PhD in the field of molecular cannabinoid research Text Medicanna2018 (813) An award-winning published researcher over the last two decades contributing towards the advancement of the therapeutic potential for cannabis info@drsashanoe.com 6150 N. US. HWY 41 Apollo Beach, FL Has been referenced worldwide in numerous scholarly articles and books

Research on Cannabis and PD: Is there any evidence?

Research on Cannabis and PD: Is there any evidence? Benzi M. Kluger, MD, MS Associate Professor of Neurology and Psychiatry Director Movement Disorders Center University of Colorado Denver DISCLOSURES