Department of Pharmacology
Cannabis for medical use
Leoš Landa
Department of Pharmacology
Cannabinoids
Group of 21 carbon terpenophenolic compounds uniquely produced by
hemp plants
Department of Pharmacology
NEED FOR A CHANGE OF THE ORIGINAL MEANING
Development of synthetic cannabinoids
Discovery of endogenous cannabinoids (endocannabinoids)
Department of Pharmacology
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
1) cannabigerol type
2) cannabichromene type
3) cannabidiol type (CBD)
4) ∆9- trans-tetrahydrocannabinol type (THC)
5) ∆8-trans-tetrahydrocannabinol type
6) cannabicyclol type
7) cannabielsoin type
8) cannabinol type
9) cannabinodiol type
10) cannabitriol type
11) miscellaneous types
Phytocannabinoids
subclasses according to Elsohly et al. (2005):
Department of Pharmacology
Endocannabinoids
Lumír Hanuš
William Devane
https://cs.wikipedia.org/wiki/Soubor:HanDev.jpg
Department of Pharmacology
Endocannabinoids
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)
Department of Pharmacology
Synthetic cannabinoids
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)
Department of Pharmacology
Cannabinoids - mechanism of action
(endocannabinoid system)
Cannabinoid receptors
Endocannabinoids
Enzymes
(biosyntesis/degradation)
Department of Pharmacology
Endocanabinoid system (ECS)
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)
Department of Pharmacology
Endocannabinoid system (ECS)
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)
Department of Pharmacology
Endocannabinoid system (ECS)
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)
Department of Pharmacology
Endocannabinoids
- mechanism of action
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+)
Department of Pharmacology
Endocannabinoids
- mechanism of action (THC)
Endocannabinoids act as retrograde synaptic
messengers → bind to presynaptic CB1 cannabinoid receptors
→ inhibition of NTs release: glutamate and GABA (Guzman, 2003).
Department of Pharmacology
http://30c1be84fhhqj3xa1lmshckme-wpengine.netdna-ssl.com/wp-content/uploads/2015/09/endocannabinoid-natur.jpg
Department of Pharmacology
Physiological functions of ECS are very complex:
motor coordination
memory
appetite
modulation of pain
neuroprotective effects
maintaining of homeostasis, etc. (Pacher et al., 2006).
Endocannabinoid system (ECS)
Department of Pharmacology
Effect of THC on dopamine release
→ dependence potential
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
Department of Pharmacology
Effect of THC on dopamine release
→ dependence potential
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