Cannabis for medical use
Department of Pharmacology
Leoš Landa

Cannabinoids
Group of 21 carbon terpenophenolic compounds uniquely produced by  hemp plants
Department of Pharmacology

NEED FOR A CHANGE OF THE ORIGINAL MEANING
Department of Pharmacology
Development of synthetic cannabinoids
Discovery of endogenous cannabinoids (endocannabinoids)

Cannabinoids
Phytocannabinoids
= substances contained  specifically in hemp
Endocannabinoids
= natural cannabinoids in the body of  animals and human beings
Synthetic cannabinoids
= artificially produced
Department of Pharmacology

Department of Pharmacology
11) miscellaneous types
1)cannabigerol type
2)
2)cannabichromene type
3)
3)cannabidiol type (CBD)
4)
4)∆9- trans-tetrahydrocannabinol type (THC)
5)
5)∆8-trans-tetrahydrocannabinol type
6)
6)cannabicyclol type
7)
7)cannabielsoin type
8)
8)cannabinol type
9)
9)cannabinodiol type
10)
10)cannabitriol type
Phytocannabinoids
subclasses according to Elsohly et al. (2005):

Endocannabinoids
Lumír Hanuš
William Devane
Department of Pharmacology
https://cs.wikipedia.org/wiki/Soubor:HanDev.jpg

Endocannabinoids
Department of Pharmacology
anandamide (N-arachidonoyl-ethanolamine, AEA) (Devane et al. 1992)
name based on the Sanskrit word ‘ananda’ (internal bliss)
2-arachidonoyl-glycerol (2-AG) (Mechoulam et al. 1995)  N-arachidonoyl-dopamine (NADA) (Bisogno t
al. 2000)
noladin ether (2-arachidonyl-glyceryl ether, 2-AGE) (Hanus et al. 2001)  virhodamine
(O-arachidonoyl-ethanolamine) (Porter et al. 2002)

Synthetic cannabinoids
Department of Pharmacology
Main purpose:
study of distribution and pharmacological  properties of cannabinoid receptors
HU-210 (CB1 a CB2 receptor agonist)  methanandamide (CB1 receptor agonist)  CP 55,940 (CB1 a CB2
receptor agonist)  WIN 55,212-2 (CB1 receptor agonist)
JWH 015 (CB2 receptor agonist)
AM 251 (CB1 receptor antagonist)

Cannabinoids - mechanism of action  (endocannabinoid system)
Cannabinoid receptors
Department of Pharmacology
Endocannabinoids
Enzymes  (biosyntesis/degradation)

Endocanabinoid system (ECS)
Department of Pharmacology
Cannabinoid receptors CB1 and CB2
CB1 receptors - primarily in the CNS
regions of the brain responsible for pain modulation: certain parts of the spinal cord,
periaqueductal grey (Grotenhermen 2006)
movement: basal ganglia, cerebellum
memory and learning: hippocampus, cerebral cortex
emotions: amygdala
sensory perception: thalamus (Velasco et al. 2012)
RESPONSIBLE FOR PSYCHOACTIVE EFFECTS
CB2 receptors - particularly in the periphery
on immune cells, especially B-cells and natural killer cells (Pertwee
1997), also expressed in tonsils or spleen (Galiegue et al. 1995)

Endocannabinoid system (ECS)
Department of Pharmacology
Other known cannabinoid receptors:
TRPV1 receptors
transient receptor potential cation channels subfamily V member 1
- also known as the “capsaicin receptor” and “vanilloid receptor (Ross 2003)
GPR18, GPR55, GPR119
(also called putative or non-classical cannabinoid receptors)
- structural similarity to CB1 and CB2
(Alexander et al. 2013; Zubrzycki et al. 2014)

Endocannabinoid system (ECS)
Department of Pharmacology
Synthesizing enzymes:
phospholipases
Degrading enzymes:
FAAH
(fatty acid amide hydrolase; post-synaptically)
MAGL
(monoacylglycerol lipase; pre-synaptically)
(Pertwee 2005; Muccioli 2010; Battista et al. 2012)

Endocannabinoids
- mechanism of action
Department of Pharmacology
NTs bind to their receptors →
activated postsynaptic neurons synthesize  endocannabinoid precursors
→ subsequent release of endocannabinoids
(This is generally induced by an increase in the cytosolic
concentration of free Ca2+)

Endocannabinoids
- mechanism of action (THC)
Department of Pharmacology
Endocannabinoids act as retrograde synaptic
messengers → bind to presynaptic CB1 cannabinoid receptors
→ inhibition of NTs release: glutamate and GABA (Guzman, 2003).

http://30c1be84fhhqj3xa1lmshckme-wpengine.netdna-ssl.com/wp-content/uploads/2015/09/endocannabinoid
-natur.jpg
Department of Pharmacology

Physiological functions of ECS are very complex:
Department of Pharmacology
motor coordination
memory  appetite
modulation of pain
neuroprotective effects
maintaining of homeostasis, etc. (Pacher et al., 2006).
Endocannabinoid system (ECS)

Effect of THC on dopamine release
→ dependence potential
Department of Pharmacology
THC stimulates neurons in dopamine reward system to release  (indirectly)
GABA normally suppresses amount of dopamine released in nucleus  accumbens.
GABA is blocked by THC → increase in dopamine release

Effect of THC on dopamine release
→ dependence potential
Department of Pharmacology
thebrain.mcgill.ca

Main medical purposes of use
chronic persistent pain – especially in association with cancer,
neuropathic pain, pain associated with glaucoma,
pain associated with degenerative disease of the musculoskeletal  system,
spasticity and pain in multiple sclerosis,  tremor caused by Parkinson’s disease,
nausea and vomiting particularly following cancer treatment,  stimulation of appetite in cancer and
HIV patients,
Tourette syndrome
superficial treatment of dermatosis and mucosal lesions