Pharmacology of Cannabinoids

Pharmacology of Cannabinoids
Chuthamanee C. Suthisisang BPharm, PhD

Department of Pharmacology
Faculty of Pharmacy
Mahidol University
Printed with FinePrint trial version - purchase at www.fineprint.com

Endocannabinoid system in pre-
and postsynaptic neurons
EMT, endocannabinoid membrane transporter;

MAGL, monoacylglyceride lipase;
DAGL, DAG lipase; AEA, anandamide; NArPE, N-
arachidonyl phosphatidylethanolamine;
NAT, N-acyltransferase
2
Pharmacol Rev. 2006; 58(3): 389–462

Chemical structure and pharmacological
activity of endogenous cannabinoids
3
Pharmacol Rev 2006; 58(3): 389–462

Important features of
endocannabinoids
Synthesized on demand eg. brain trauma

Act locally (paracrine or autocrine)
Quickly degraded after their action
Act as retrograde neurotransmitters in the
nervous system
Inhibit neurotransmitter release
Derived from lipid precursors
4 Devane et al 1992; Sugiura et al 1995; Schmid 2000; Howlett et al 2004; Hillard et al 2000; Alger 2002

5

Pharmacology of cannabinoids
Phytocannabinoids
Endocannabinoids

More than 400 compounds in Cannabis
Cannabis
~480 pharmacologic entities
Combustion
~2000 chemicals
Cannabinoids Non-
Other
(~66-100) cannabinoid
psychoactive (hundreds)
components Cannabis
Monoterpenoids/sesquiterpenoids
(~20-40+)
The composition of cannabis varies depending upon species

(C. sativa, C. indica, C. ruderalis),geography,locations and
7
growth manipulations

Chemical structure and pharmacological
activity of phytocannabinoids
8
Pharmacol Rev 2006; 58(3): 389–462

Not all cannabinoids are
psychoactive
Cannabinoids
Psychoactive Not Psychoactive
• Cannabinol (CBN) • Cannabigerols (CBG)
• Cannabinodiol (CBDL) • Cannabichromenes
• delta – 9 –/delta-8 (CBC)
tetrahydrocannabinol • Cannabidiols (CBD)
(THC)
9
http://learnaboutmarijuanawa.org/factsheets/cannabinoids.htm

Cannabinoids pharmacological
actions
THC CBD CBN

(delta-9- (Cannabidiol) (Cannabinol)
tetrahydro-
cannabinol)
Psychoactive √ √
Anti-emetic √
Appetite stimulant √
Analgesic √ √
Anti-inflammatory √ √
Anti-seizure √√ √
Anti-spasmodic √
Neuroprotective √
10

Molecular mechanisms of
phytocannabinoids
• Activity at cannabinoid receptors
• Cannabinoid receptor independent activity
11

12

Location of cannabinoid receptors
Location Structure Function
CB1 receptors
CNS Hippocampus Memory storage
Cerebellum Coordination of motor function, posture, balance
Basal ganglia Movement control
Hypothalamus Thermal regulation, neuroendocrine release, appetite
Spinal cord Pain
Vomiting center/ N tractus solitarius Emesis
Periphery Lymphoid organs Cell-mediated and innate immunity
Vascular smooth muscle cells Control of blood pressure
Duodenum, ileum, myenteric plexus Control of emesis
Lung smooth muscle cells Bronchodilation
Eye ciliary body Intraocular pressure
CB2 receptors
Periphery Lymphoid tissue Cell-mediated and innate immunity
Peripheral nerve terminals Peripheral nervous system
Retina Intraocular pressure
CNS Cerebellar granule cells mRNA Coordination of motor function
13 Croxford, JL. CNS Drugs 2003; 17(3)

Major signaling pathways initiated from
activation of the cannabinoid CB1 and
CB2 receptors
14 http://dx.doi.org/10.1016/B978-0-12-800756-3.00068-5

CB1 receptor signal transduction
CB1 receptor inhibits N/P/Q-type voltage-gated Ca2+ channels and activates A-

15
type and G-protein-coupled inwardly-rectifying K+ channels (GIRK)

Selectivity of some endogenous,
plant-derived and synthetic
cannabinoids
16
Brain and Neuroscience Advances 2018; 2: 1–8

Some Ki values of (-)-D9-THC and
certain other phytocannabinoids
17
British Journal of Pharmacology 2008; 153, 199–215

CB1 receptor effects
Physiologic effects
• CNS depressant effects (drowsiness, decrease

alertness, slow reaction, impair short term memory,
decreased accuracy of psychomotor task
performance, motor coordination and muscle tone
Psychologic effects
• Low dose: Elation, euphoria, decrease anxiety,
increased appetite, heightened perception
• High dose: Dysphoria, increase anxiety, irritability,
impaired short term memory, hallucination, panic
reaction, paranoia, sensory distortions
18
Baron EP. Headache. June 2015

Chronic Effects
• CNS
– Cognitive and executive decline: poor
memory, vagueness of thought, decreased
verbal fluency, learning deficits
– daily high doses can cause chronic

intoxication syndrome (apathy), confusion,
depression, paranoia
– cannabis dependence (DSM-V criteria)
19

CB1 receptor distribution
Cerebral
cortex
Higher cognitive and
emotional functions
Hypothalamus
Medulla appetite
oblongata Spinal cord

nausea/vomiting centre peripheral sensation
chemoreceptor trigger pain sensitivity
zone
20

delta -9 - tetrahydrocannabinol
(THC) – Sites of Action
• THC activates CB1 receptors all over the brain
• Some possible sites of action

– Cerebral cortex/ Hippocampus - memory impairment
– Nucleus accumbens - euphoria/psychosis (increased
DA release)
– Hypothalamus - stimulation of appetite
– Vomiting center – antiemetic action
– Spinal cord – analgesic effect
21

Effect of THC on DA release at
NAcc
GABA
interneurons
GABAA
GABA GABA
VTA release
CB1
11-OH THC
DA
THC
DA release
D2
Nabilone
NAcc THC induced psychosis
22

Cannabis induced-psychotic disorder
23

Cannabis- induced psychosis:
Research questions
24

SENSATIONS
INPUTS
REFLEXES
25

C-fiber
C-fiber
α2 5-HT 3
δ
µ 5-HT2
CB1
Glu
SP SP
Glu
Ca ++ Na +
µ δ α2 NMDA AMPA GABAB GABAA 5-HT 3 5-HT2
Increase Dorsal horn

Dorsal horn
Increase Na+ influx
26 Ca++ influx

C-fiber
Dexmedetomidine
THC
α2 5-HT 3
δ
µ 5-HT 2
CB1
Glu
SP SP
Glu
Morphine
Fentanyl
Ca++
x x Na+
µ δ α2 NMDA AMPA GABAB GABAA 5-HT 3 5-HT2
Ketamine
Increase
Na+ influx Dorsal horn
Increase
27 Ca++ influx

THC action independent of CB1
and CB2 receptors
• At < 1 uM THC can activate GPR18, GPR55,
PPARγ, TRPV2 and TRPA1 receptor
• THC block the activity of 5-HT3 receptors

(antiemetic effects) and TRPM8 receptors at
concentration < 1 uM
28

CBD pharmacology: “Multitarget”
• Cannabidiol has low affinity for both cannabinoid CB1 and
CB2 receptors (negative allosteric moderator of CB1)
• CBD has agonist effect at the 5-HT1A receptor, the α3
and α1 glycine receptors and TRPV1
• Moderately inhibit cellular reuptake of anandamide
• Moderate inhibitor of anandamide hydrolysis by FAAH
• At low micromolar to sub-micromolar concentrations, CBD
is a blocker of the equilibrative nucleoside transporter
(ENT), the orphan G-protein-coupled receptor GPR55,
and the transient receptor potential of melastatin type 8
(TRPM8) channel
• Potent antioxidant
29
Rambam Maimonides Med J 2013;4 (4):e0022. doi:10.5041/RMMJ.10129; Epilepsia, 55(6):791–802, 2014

CBD pharmacology: “Multitarget”
• Negative allosteric moderator of CB1: reduce
unwanted effect of THC
• 5-HT1A receptor agonist: anxiolytic effect,

analgesic effect
• Glycine receptors agonist: anti-seizure,

antispasmodic
• Increase anandamide: anxiolytic effect, analgesic

effect, anti-seizure
30
•
CBD has anti-inflammatory effects
• Increase adenosine stimulation at A1A and A2A

adenosine receptors via the inhibition of adenosine
uptake by equilibrative nucleoside transporter
(ENT1)
• Activation of strychnine-sensitive α1 and α1β glycine

receptors
• CBD dose-dependently suppressed the production

and secretion of both IL-17 and of IL-6, a key factor in
Th17 induction
Eur J Pain 2018; 22: 471-84

31
J Basic Clin Physiol Pharmacol 2016; 27(3): 181–7

Physiological Effects of Δ9-THC and CBD
32
Canadian Journal of Kidney Health and Disease 2019; 6: 1–14

Adverse Effects and Precautions With
Cannabis Use
33
Canadian Journal of Kidney Health and Disease 2019; 6: 1–14

Average reduction in hippocampal volumes
found amongst heavy, long-term adult
cannabis users
34

Potential impact of cannabis on
brain development
35

Unlike neuronal tissues, white matter
structures show a decrease in CB1 receptor
expression as the brain matures
36

Proposed pathophysiology of
cannabinoid hyperemesis syndrome
37
ACG Case Rep J 2018;5:e3

Reported adverse cardiovascular events associated
with cannabis, synthetic cannabinoids and
cannabimimetics
38
Cardiol Ther 2018; 7:45–59

Arrhythmogenic properties of
cannabis
• One of the most consistent effects of cannabis smoking on
heart is 20% to 100% increase in HR which can last up to
2–3 hours
• This effect of cannabis on HR is thought to be due to

cannabis induced increased in noradrenaline within 15-30
min and followed with vasodilation causing reflex
tachycardia and increased in sympathetic activity
• Regular cannabis use was found to be linked with acute

coronary syndrome after excessive physical activity and has
been reported to trigger MI in patients with known coronary
artery disease
39

Pathophysiologic pathways to common major
adverse cardiovascular eventsreported in users
of cannabis and related chemicals
40
Cardiol Ther 2018; 7:45–59

Molecular mechanisms of interplay between
cannabinoid system and platelets
41
J Thorac Dis 2017;9(7):2079-92

Proposed mechanisms of cannabis
induced cerebrovascular effects
42
J Thorac Dis 2017;9(7):2079-92

Cannabinoid pharmacokinetics
Pharmacokinetic Clinical Implications
parameters
• Very lipophilic • Distributes into tissues
• THC: Vd = ~10L/kg • Long duration of effect
• Safety concerns in pregnancy
and lactation
• Hepatic metabolism • High first pass effect
(THC:CYP3A4, 2C9, 2C19, 2D6) • Genetic variability
(CBD: CYP2C19, 3A4 major) • Many drug interactions eg;
fluoxetine, clarithromycin
• Long half-life and many active • Long duration of effect
metabolites (THC: ~25-36h; • Natural taper when discontinued
tissue 5-7d) • Prolonged exposure to toxins
• Elimination over days to weeks, • Affects timing of monitoring
hundreds of metabolites, via
urine and feces
43

THC/CBD drug interactions
• THC induce CYP12 and inhibit CYP2C9,

CYP2D6, CYP3A4 and p-glycoprotein
• CBD potently inhibit CYP1A2, CYP2B6,

CYP2C9, CYP2D6, CYP3A4 and p-glycoprotein
• Enhance CNS depressant effects when

coadministration with other CNS depressant
drugs
44 Medicines 2019;;6:3;doi:10.3390/medicines6010003

Cannabis products in the market
Products can vary greatly in active

45
substances and their concentration

Pharmaceutical products
GW Pharmaceuticals (UK)
Bedrocan BV (NT)
AbbVie Inc. (USA)
Sativex: THC:CBD extract

Prescription medicine
Admin: sublingual spray
Bedrocan: GMP cannabis flos
Prescribed medicine (NL) Marinol: synthetic THC
Admin: vaporization (Dronabinol)
(oral dose forms also
Admin: oral dose
available)
Valeant Pharma. Int. (USA)
Cesamet: synthetic THC
(Nabilone)
Epidiolex: CBD Admin: oral dose
Admin: oral dose
46

Cannabinoids in palliative care setting
• Reduce pain
• Relaxation
• Increase appetite
• Reduce vomiting & nausea
Cannabis cannot reduce dyspnea
Cannabis should be avoided in patients with hepatic and renal insufficiency
Patients with CKD who use cannabis may experience a more rapid decline in renal
function than non-users (Rein JL, Texter LJ, Wurfel MM, et al. Marijuana use and kidney
outcomes in the ASSESS-AKI Cohort. Data presented at the American Society of Nephrology’s
2018 Kidney Week conference in San Diego, Oct. 23-28. Abstract FR-PO233)
Cannabis should be avoided in patient with cardiac diseases

47

Cannabis – the Israeli perspective
• Not all medical conditions can be treated with the same

ratio of cannabis constituents or with pure compounds.
• In epilepsy, pure CBD is apparently preferable than a
mixture
• CBD is not available as a pure compound. Children with
epilepsies are administered medical cannabis with a ratio of
CBD:THC of about 20:1 or less
• CBD is a nontoxic molecule which
does not seem to cause side effects.
However,the doses needed are high due to
low bioavailability
• Clinical trials are badly needed
48
Raphael Mechoulam. J Basic Clin Physiol Pharmacol 2016; 27(3): 181–7

Pharmacology of Cannabinoids

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pharmacology of Cannabinoids

Uploaded by

Copyright:

Available Formats

Pharmacology of Cannabinoids

Chuthamanee C. Suthisisang BPharm, PhD

Printed with FinePrint trial version - purchase at www.fineprint.com

EMT, endocannabinoid membrane transporter;

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Synthesized on demand eg. brain trauma

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

The composition of cannabis varies depending upon species

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

THC CBD CBN

Printed with FinePrint trial version - purchase at www.fineprint.com

• Activity at cannabinoid receptors

• Cannabinoid receptor independent activity

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

13 Croxford, JL. CNS Drugs 2003; 17(3)

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

CB1 receptor inhibits N/P/Q-type voltage-gated Ca2+ channels and activates A-

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

• CNS depressant effects (drowsiness, decrease

Printed with FinePrint trial version - purchase at www.fineprint.com

– daily high doses can cause chronic

– cannabis dependence (DSM-V criteria)

Printed with FinePrint trial version - purchase at www.fineprint.com

oblongata Spinal cord

Printed with FinePrint trial version - purchase at www.fineprint.com

• THC activates CB1 receptors all over the brain

• Some possible sites of action

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

µ δ α2 NMDA AMPA GABAB GABAA 5-HT 3 5-HT2

Increase Dorsal horn

Printed with FinePrint trial version - purchase at www.fineprint.com

µ δ α2 NMDA AMPA GABAB GABAA 5-HT 3 5-HT2

Printed with FinePrint trial version - purchase at www.fineprint.com

• THC block the activity of 5-HT3 receptors

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

• 5-HT1A receptor agonist: anxiolytic effect,

• Glycine receptors agonist: anti-seizure,

• Increase anandamide: anxiolytic effect, analgesic

• Increase adenosine stimulation at A1A and A2A

• Activation of strychnine-sensitive α1 and α1β glycine

• CBD dose-dependently suppressed the production

Eur J Pain 2018; 22: 471-84

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com

Printed with FinePrint trial version - purchase at www.fineprint.com