Cannabis biology

1. William B.
O'Shaughnessy
400 Cannabis cultivated for the first time in England
at Old Buckeham Mare.
1563: Elizabeth I orders people with more than 60
acres of land to grow cannabis/hemp or be fined
1841: W.B. O’Shaughnessy an Irish medic working for
British Army in India introduces cannabis to
western medicine
1928. The Dangerous Drugs Act 1925 becomes
law and Cannabis is made illegal in UK,
1971: Misuse of Drugs Act 1971. “Cannabis has no
medical use!” and is removed for UK
pharmacopeia. Cannabis a Schedule B Drug
2004: Cannabis Rescheduled to Class C
(2 years unlimited fine/up to 14 years for supply)
2009: Cannabis Rescheduled to Class B
(5 years unlimited fine/up to 14 years for supply)
2010: Sativex medical cannabis licensed in UK
HISTORY OF (MEDICAL) CANNABIS IN UK

2. MEDICAL CANNABIS
PwMS Tell us that Cannabis Helps
Alleviate Symptoms (Pain
& Spasticity) of Multiple Sclerosis:
Evidence from Understanding the
Biology of Cannabis and the Disease
2. BIOLOGY
1. ANECDOTE
Why should we think about using
Cannabis to treat Multiple Sclerosis?

3. UCL-INSTITUTE OF NEUROLOGY
Queen Square BIOLOGY OF MULTIPLE SCLEROSIS
SYMPTOMS OF MULTIPLE SCLEROSIS
BLINDNESS
NYSTAGMUS
FATIGUE
PAIN
TREMOR
SPASMS & SPASTICITY
BLADDER PROBLEMS
INCONTINENCE
SEXUAL PROBLEMS
COGNITIVE DEFICITS
MOTOR (MOVEMENT) DEFICITS
NEUROTRANSMISSION
PROBLEMS
Conduction Block
Demyelination
Loss of Axons and Neurons
Loss of Synaptic Plasticity
THE NATURE OF THE SYMPTOMS DEPEND ON THE LOCATION OF LESIONS
WITHIN THE NEURAL CIRCUITARY

4. TOO MUCH NERVE EXCITATION
TOO LITTLE NERVE INHIBITION
SPASTICITY= MUSCLE STIFFNESS
Damage due to Multiple Sclerosis causes:
Treatment = Boost Inhibitory Signals
Baclofen (Arbaclofen)
GABApentin
Benzodiazepines
SIDE-EFFECTS= SEDATION
Treatment = Block Excitatory Signals
Nabiximols (Sativex)
Tizanidine
Anti-Convulsants
SIDE-EFFECTS= SEDATION
Inhibitory
Nerve
Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBIOLOGY OF CANNABINOID SYSTEM

5. BaclofenDantrolene
Corticospinal
Tract
Benzodiazepine
TizanidineInhibitory Interneuron
Muscle
CONTROL
Of SPASMS
Action Potential
GABA
α2
α2
Motor
Neuron
AMPA
GABA A
GABA B
UCL-INSTITUTE OF NEUROLOGY
Queen Square BIOLOGY OF MULTIPLE SCLEROSIS

6. CANNABIS (Cannabis sativa)
Some varieties (HEMP) used for making: rope, paper, cloth (canvas) & oil
Other varieties (described as dope, marijuana, weed, grass, hashish,
resin) used as a medical and more importantly a recreational drug.
Cannabis Sativa
MALE
Cannabis Sativa
FEMALE
Bract
Glandular
BIOLOGY OF CANNABINOID SYSTEM

7. Cannabinol
(CBN)
Cannabigerol (CBG)
Cannabidiol
(CBD)
Epidiolex
Tetrahydrocannabinol
(THC)
Cannabis plant can contains
over 113 cannabinoid chemicals
Major Psychoactive
Ingredient
Major Non-Psychoactive
Ingredient
BIOLOGY OF CANNABINOID SYSTEM

8. E
LL
M
*
CB1 Receptor
CB2 Receptor
Immune System
PMN B cells Monocytes
Spleen Tonsils
CB2CB1
Brain Adipose
Tissue
Muscle Liver GI
Tract
Pancreas
Nervous System
OH
O
THC
Plant Cannabinoids
N
H
OH
O
Anandamide:
Endocannabinoids
BIOLOGY OF CANNABINOID SYSTEM
O
OH
O
2-Arachidonoyl Glycerol

9. Red = abundant CB1 receptors Black = moderately abundant CB1 receptors
The Function of the Brain Area where the Cannabis Receptor is located
Will Determine the Effect That occurs Following Cannabis Use
BIOLOGY OF CANNABINOID SYSTEM
CB1R Imaging
Hippocampus
Learning, Memory
Amygdala
Emotion, Fear
Cerebellum
Movement
Striatum
Globus Pallidus
Substantia Nigra
Caudate Nucleus
Putamen
Balance & Movement
Cerebral Cortex
Cognitive Functions

10. Cannabinoid control of Nerve Impulse Transmission
Glu=Glutamate Ca2+ = calcium Ion
MS
Health
Synapse
Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBIOLOGY OF CANNABINOID SYSTEM

11. Time Post-Injection (Min)
0 10 20 30 40 50 60 70 80 90 100 110 120
ChangeinHindlimbStiffness(%)±SEM
-50
-40
-30
-20
-10
0
10
20
Sativex
Vehicle
CB RECEPTOR STIMULATION CAN
INHIBIT TREMOR & SPASTICITY IN
MODEL OF MS
Cannabis +
THC +
CB1R Stimulators +
THC-free Cannabis -
CB BLOCKADE TRANSIENTLY
WORSENS SPASTICITY
Stimulators of +
Endocannabinoids
Sativex® Biological Drug Substances
inhibits Experimental Spasticity
P<0.001 compared to baseline
BIOLOGY OF CANNABINOIDS

12. CHANGES OF SPASTICITY SCORES
-0.4
-0.2
0
0.2
0.4
0.6
0.8
W
eek
0
W
eek
1
W
eek
2
W
eek
3
W
eek
4
W
eek
5
W
eek
6
W
eek
7
W
eek
8
W
eek
9
W
eek
10
W
eek
11W
eek
12
LO
C
F
Sativex
Placebo
P<0.0002
DeteriorationinSpasticityScore
Placebo
Sativex
CANNABINOIDS IN THE CLINIC
Novotna et al. 2011

13. CANNABINOIDS IN THE CLINIC
Nabiximols (Sativex®) is Mix of
Botanical Cannabis containing
Tetrahydrocannabinol and Cannabidiol
Licensed for
the treatment of MS
Neuropathic Pain in Canada
Licensed for the treatment
of MS Spasticity
in United Kingdom
Spain, Germany
Denmark & Sweden
Italy, Austria & Czech Republic
Poland
Sativex® Sublingual
(under the Tongue)
Spray

14. Prohibited
Nabiximols not approved
in USA
Medicinal Use
29 States Legalised
D
Nabiximols approved in Canada
Recreational & Medical Use
Medical Use
Medical Use with limited THC content
Decriminalised
MEDICAL MARIJUANA
CANNABINOIDS IN THE CLINIC
Despite stare legalisation Cannabis is Illegal based on Federal Law
Foreigners caught in possession in USA can be banned for life

15. Tolerated
Illegal but decimalized
Illegal but often unenforced
Illegal
Nabiximols approved
in European Union
Nabiximols not approved
NHS England
RECREATIONAL MARIJUANA
Medical Cannabis
Germany
The Netherlands
Israel
Ireland
CANNABINOIDS IN THE CLINIC

16. Diazepam
Baclofen
Gabapentin
Nabiximols
(Sativex)
Potassium Ion (K+) expelled
(Inside of cell more negative)
MECHANISM OF ACTION
SPASTICITY
BIOLOGY OF CANNABINOIDS
Chloride Ion (Cl-) Influx
(Inside of cell more negative)

17. SELECTION OF MARIJUANA
>3%
THC CONTENT
1970s
>3%
2010s
>16%
>20%
CANNABINOIDS IN THE STREET

18. Price $8-$12/g
MEDICAL MARIJUANA OR STONER FOOD
SELECTION OF MARIJUANA
CANNABINOIDS IN THE STREET

19. • HERB-MARSH MELLOW PLANT
• SYNTHETIC CANNABINOID (NOT CONSISTENT)
• SCENT (OPTIONAL)
• NOT FOR HUMAN CONSUMPTION LABEL
Psychoactive Substances Act 2016.
Laws criminalising the production, distribution, sale
and supply of psychoactive substances
Offenders face up to seven years in prison
CANNABINOIDS IN THE STREET

20. Anandamide (Ki values of 89nM)
Tetrahydrocannabinol (Ki values of
10nM)
JWH-018 (Ki values of 10nM)
CP55, 950 (Ki values of 0.58nM)
HU-210 (Ki values are 0.061nM)
Anandamide
JWH-018
HU-210
THC
SPICE CONTENTS (>180 synthetics found)
CANNABINOIDS IN THE STREET

21. LACKS THE CANNABIS SMELL
PRISONER APPEAL
VULNERABLE PEOPLE
HOMELESS PEOPLE
PRISONERS
VERY POTENT
CANNABIS HIGH + OTHERS
CAUSES DEATH
CHEAP
Increase Rate Heart Rate
Blood Pressure Fluctuations
Chest Pain
Headache
Vomiting
Inability to Speak or move
Unconsciousness
Extreme Paranoias
Memory Loss
Seizures
CANNABINOIDS IN THE STREET

22. ANTIDOTE: SOCIETAL-DEAL WITH THE SOCIAL PROBLEM
ANTIDOTE: MEDICAL-NONE PROVEN
MONITOR & KEEP SAFE
MANAGE ADVERSE EVENTS
UNTIL EFFECTS WEAR-OFF
Smoked cannabis 1-3h
Ingested several hours
Synthetic cannabinoid hours longer
CANNABINOID RECEPTOR INVERSE AGONIST
SHOWN IN ANIMALS (CURRENTLY NON-AVAILABLE)
Rimonabant/Acomplia
CB1 Receptor Antagonist
Anti-Obesity Drug Licensed 2006
October 2008 EMEA issued warning
Risks outweigh Benefits
SEVERE DEPRESSION &
SUICIDAL TENDENCIES
Licence withdrawn January 2009
CANNABINOIDS IN THE STREET