Hemp as a plant: Research Perspective Dr. Eric Downer Assistant Professor in Human Health & Disease, Director BSc Human Health & Disease, Dept. Physiology, Trinity College Dublin, IRELAND 18 years in cannabinoid research Topics of talk *What are cannabinoids? *What are the effects of cannabinoids on the body? *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Topics of talk *What are cannabinoids? *What are the effects of cannabinoids on the body? *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Topics of talk *What are cannabinoids? *What are the effects of cannabinoids on the body? *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Topics of talk *What are cannabinoids? *What are the effects of cannabinoids on the body? *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Plant-derived (phyto) cannabinoids Tetrahydrocannabinol (THC) Cannabinoids Cannabinol (CBN) Cannabidiol (CBD) Cannabichromene (CBC) Endocannabinoids Anandamide 2-AG Terpenoids Synthetic cannabinoids Limonene R(+)WIN 55,212-2 Myrcene CP 55940 Pinene JWH 133 Linalool Terpenoids Russo, 2011 Elzinga et al., 2015 Phytocannabinoids Cannabis sativa Cannabis indica Cannabis ruderalis Male & female flowers of C. sativa Chandra et al., 2017 Trichomes Chandra et al., 2017 Biosynthesis of cannabinoids/terpenoids sesquiterpenes sesquiterpene synthases (sesqui-TPS) farnesyl diphosphate (FPP) 5-Carbon isoprenoids isopententyl diphosphate dimethylallyl diphosphate (IPP) (DMAPP) monoterpene synthases (mono-TPS) geranyl diphosphate (GPP) monoterpenes olivetolic acid geranyldiphosphate:olivetolate geranyltransferase Cannabigerolic acid (CBGA) Tetrahydrocannabinolic acid cannabidiolic acid cannabichromenic acid (THCA) (CBDA) (CBCA) Adapted from THC CBN CBD CBC Booth & Bohlmann, 2019 Cannabinoids *Cannabis contains a family of ~ 100-120 related compounds termed “cannabinoids” Canabidiol Cannabinol Tetrahydrocannabinol No psychoactivty psychoactivity Tetrahydrocannabinol (THC) * THC is the predominant psychoactive ingredient Raphael Mechoulam Cannabinoids – not just the plant Endocannabinoids O OH O OH William Devane 2-Arachidonoylglycerol (2-AG) O O H N H Anandamide Role of endogenous cannabinoids * Precise physiological role unknown * Inhibit neurotransmission * Regulation of cell signalling * Role in CNS development Topics of talk *What are cannabinoids *What are the effects of cannabinoids on the body *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Topics of talk *What are cannabinoids *What are the effects of cannabinoids on the body *Therapeutic potential of cannabinoids *What is cannabinoid research indicating How do cannabinoids act * Cannabinoid receptors Cannabinoid receptors - CB1 and CB2 NH S 2 C D C V I N K S F M N K W K Q K L extracellular K L P P N R D G F G I L Q Q S V F H P S L L K N V Y D V T A I A V D F H F L F L P L E D I M V F V V K T I A L S L Y S F L I A V L Y L L A S C F T V V G F M P M G L V I F A T A I V I W C W G L C L F T G S F S I T V G N L V T L T A M W T L I I T S N E L A D L V S C L L L V S V N V V S F I L V P L V L L S L A F L V A I F L I I L T V T L V A Y I V C H F I G I A K A Y A Y V A K S R L R D P M R L S H L R P S Y I Y R I Y D I S T M K R C H I V L Q A R D S R K W I I A M C intracellular L R I PO 4 I D L A H M H F F E P R S P R R K H A I T P G L A Y R H S S S V Q T S A T E T R R Q V G K D Q G V K 7 transmembrane domains CO O H CB1 – CB2 homology -68% sequence homology in transmembrane -44% throughout entire protein Cannabinoid receptor distribution Human exposure to THC What happens after receptor activation a) Ion channel changes b) Neurotransmission c) Signal transduction cascades Topics of talk *What are cannabinoids *What are the effects of cannabinoids on the body *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Medical use of C. sativa Emperor Chen Nung Diodorus Siculus William O’Shaughnessy Carl Linnaeus Bonini et al., 2018 Media coverage in Ireland Therapeutic options Marinol (dronabinol) Therapeutic options Cesamet (nabilone) Therapeutic options Sativex THC and canabidiol combination Treat spasticity and neuropathic pain associated with MS Therapeutic options Epidiolex Cannabidiol solution Treat early-onset, treatment-resistant epilepsy syndromes Chandra et al., 2017 Topics of talk *What are cannabinoids *What are the effects of cannabinoids on the body *Therapeutic potential of cannabinoids *What is cannabinoid research indicating Cannabinoids and tumour growth Cannabinoids and tumour growth Cannabinoids and inflammation ** 8000 6000 g/mL) + ρ 4000 IL-6 ( 2000 0 0 1 CBD (µM) 10 0.1 10 Control IL1α + TNFα Data from Prof. Maeve Caldwell lab Terpenoids and inflammation Cannabinoids and Multiple Sclerosis Spasticity Endocannabinoid dysregulation Cannabinoid research in my lab Peripheral blood mononuclear cells (PBMCs) PBMCs treated with cannabinoids PBMCs Demographics of study participants Beaumont Hospital (unpublished) EDSS Questionnaire PBMC Take home message *Large array of cannabinoids in the plant *Cannabinoids have diverse effects on the body *Therapeutic angles for cannabinoids exist *Downer lab – peripheral and central analysis Take home message *Large array of cannabinoids in the plant *Cannabinoids have diverse effects on the body *Therapeutic angles for cannabinoids exist *Downer lab – peripheral and central analysis Take home message *Large array of cannabinoids in the plant *Cannabinoids have diverse effects on the body *Therapeutic angles for cannabinoids exist *Downer lab – peripheral and central analysis Take home message *Large array of cannabinoids in the plant *Cannabinoids have diverse effects on the body *Therapeutic angles for cannabinoids exist *Downer lab – peripheral and central analysis Acknowledgements Research group Funding Current: John-Mark Fitzpatrick Sarah Duggan Dr. Sonia Pereira Dr. Johana Velasquez Industry collaborators GW Research Ltd Clinical collaborators Dr. Orla Hardiman (TCD/Beaumont) Dr. Lisa Costelloe (Beaumont) Dr. Orna O’Toole (MUH) Dr. Brian Sweeney (CUH) Dr. Aisling Ryan (CUH) Dr. Owen Cronin (CUH) Dr. Joe McKenna (CUDSH) Dr. Christine McCreary (CUDSH) Contact [email protected] @downerlab THC – blood versus high Blood THC high .