Hemp as a plant: Research PerspectiveHemp as a plant: Research Perspective Dr. Eric Downer Assistant Professor in Human Health & Disease, Director BSc Human Health & Disease, Dept.

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





Topics of talk





Topics of talk





Cannabinoids Plant-derived (phyto) cannabinoids

Tetrahydrocannabinol (THC)

Cannabinol (CBN)

Cannabidiol (CBD)

Cannabichromene (CBC)

Endocannabinoids

R(+)WIN 55,212-2

CP 55940

JWH 133

Anandamide

2-AG

Synthetic cannabinoids Terpenoids

Limonene

Myrcene

Pinene

Linalool

Elzinga et al., 2015

Russo, 2011

Terpenoids

Cannabis sativa Cannabis indica Cannabis ruderalis

Phytocannabinoids

Male & female flowers of C. sativa

Chandra et al., 2017


Trichomes

Biosynthesis of cannabinoids/terpenoids

5-Carbon isoprenoids

isopententyl diphosphate (IPP)

dimethylallyl diphosphate (DMAPP)

Adapted from Booth & Bohlmann,

2019

olivetolic acid

farnesyl diphosphate (FPP)

geranyl diphosphate (GPP)

geranyldiphosphate:olivetolate geranyltransferase

Cannabigerolic acid (CBGA)

monoterpene synthases (mono-TPS)

monoterpenes

sesquiterpene synthases (sesqui-TPS)

sesquiterpenes

Tetrahydrocannabinolic acid (THCA)

cannabidiolic acid (CBDA)

cannabichromenic acid (CBCA)

CBC CBD THC CBN

Cannabinoids

*Cannabis contains a family of ~ 100-120 related compounds termed “cannabinoids”

psychoactivity No psychoactivty

Tetrahydrocannabinol Canabidiol Cannabinol

* THC is the predominant psychoactive ingredient

Raphael Mechoulam

Tetrahydrocannabinol (THC)

Cannabinoids – not just the plant

William Devane

2-Arachidonoylglycerol (2-AG)

O OH OH

O

N H

O O H

Anandamide

Endocannabinoids

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



Topics of talk





How do cannabinoids act

* Cannabinoid receptors

Cannabinoid receptors - CB1 and CB2

7 transmembrane domains

CB1 – CB2 homology -68% sequence homology in transmembrane -44% throughout entire protein

extracellular

intracellular

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Cannabinoid receptor distribution

Human exposure to THC

a) Ion channel changes

What happens after receptor activation

b) Neurotransmission

c) Signal transduction cascades

Topics of talk





Bonini et al., 2018

Emperor Chen Nung Diodorus Siculus

Carl Linnaeus

William O’Shaughnessy

Medical use of C. sativa

Media coverage in Ireland

Marinol (dronabinol)

Therapeutic options

Cesamet (nabilone)

Therapeutic options

Sativex

THC and canabidiol combination Treat spasticity and neuropathic pain associated with MS

Therapeutic options

Epidiolex Therapeutic options

Cannabidiol solution Treat early-onset, treatment-resistant epilepsy syndromes


Topics of talk





Cannabinoids and tumour growth

Cannabinoids and tumour growth

Cannabinoids and inflammation

Contro

l 10 0 0.1 1 10

0

2000

4000

6000

8000

CBD (µM)

IL1α + TNFα

**

+

IL-6

( ρg/

mL)

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

(unpublished)

Beaumont Hospital

Questionnaire EDSS PBMC

Demographics of study participants

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





Take home message





Take home message





Research group 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

Funding

Acknowledgements

Blood THC

high

THC – blood versus high

Hemp as a plant: Research PerspectiveHemp as a plant: Research Perspective Dr. Eric Downer Assistant Professor in Human Health & Disease, Director BSc Human Health & Disease, Dept.

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