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