LECTURE 8: CANNABIS AND

CANNABINOIDS

Oct 6th
- Genus annual herbaceous plants
- Temperate and tropical climates
- Cannabis indica (C. indica)
o Seeds hempseed oil
o Flowers
psychoactive/psychologically active
chemicals (5-15%)
To a lesser extent in seeds, stems,
and leaves
- C.sativa hemp plant
o Impractical amounts of psychoactive
chemicals
o Useful for numerous non-pharmaco
purposes
o Legal in Canada, but often associated
with its potent cousin
A plant by any other name.
- Cannabis names vary by culture,
preparation
- Marijuana
o Dried leaves and flowering tops
o Aka pot, grass, weed, ganja
- Hashish
o Resin from flowering tops and sprouts
o 10x THC conc of marijuana
- Bhang
CANNABINOIDS
- Organic substances within cannabis
species
- ~80 known cannabinoids, 2 of note:
o THC
o Cannabinol
- THC is only psychoactive constituent
- Cannabinol has some physiological
effects
o Overlap with those of THC, but limited
o Different mechanism of action?
CANNABIS PHARMACOLOGY
- Complicated by
o Different prep
Marijuana by far most prevalent
o Numerous cannabinoid compounds
THC most well-known and wellstudied
o Multiple plant strains/cross-breeds

Up to 15-fold changes in THC in

stains over last 30 years
Invalidates much of earlier (already
sparse) literature on topic
Variations in cannabinoid content
(THC: CBD ratio)

EFFECTS OF THC
Effects on mood
- Feelings of euphoria/relaxation/wellbeing
- Decreases in anxiety/tension/alertness
- Similar effects to ethanol but without
aggression
Effects on perception
- Colors/music/emotions
- Spatial/time
- Hallucinations
Cardiovascular
- Tachycardia (high HR)
- Vasodilation, particularly in conjunctiva
Others (see therapeutic effects)
THC PHARMACOKINETICS
Peak effects ~30mins after smoking (some
effects can start earlier rapid and
complete absorption)
- Eaten?
o Slower onset
o Prolonged duration of action
o Reduced bioavailability (1st pass
metabolism)
- Very lipid soluble leaves body very
slowly
o Important factor in limiting withdrawal
symptoms
p

lasma half-life of 4 hours

o tissue elimination T1/2 ~7 days

primarily excreted through biliary

route/feces
o 10-15% urinary excretion
- so soluble that it can re-enter
circulation
-

CANNABINOID PHARMACODYMANICS
First theories: general anesthetic-type
MOA?
- High lipid solubility
Was there an endogenous receptor? Yes
in 1988
Cannabinoid receptors
- Cannabinoid receptor 1 (CB1) central
(most abundance G-protein receptor in
mammalian CNS)
o Primary receptor involved in
cannabinoid-associated effects
- Cannabinoid receptor 2
o Primarily immune cells (T/B cells);
some peripheral nerves
- Similar THC affinity for both
CANNOBINOID RECEPTOR 1
Transmembrane, G-protein-coupled
receptors
- Generally inhibitory signal transduction
o Inhibition of neurotransmitter release
Central and peripheral localization
- Hippocampus, basal ganglia,
cerebellum, cerebrum
- Muscle, liver, heart, blood vessels, GI
tract, lung, pancreas
Limited distribution in brainstem or
medulla
- Does not lethally affect HR and
respiration this is why there are no
recorded deaths with direction
overdose of THC
DO WE HAVE ENDOGENOUS
CANNABINOID? b/c we have CB1/CB2
Yes
Short- and locally-acting molecules,
synthesized on demand
- Thought to help reduce pain
Significant structural differences with
respect to cannabinoid molecules BUT
specific portion of molecule is analogous
to the drug which is the receptor binding
site

CANNABIS DANGERS
- Overdose rare, making it safer than
other drugs of abuse (ethanol, opiates)
- Dysphoria in some, or at higher doses
o Anxiety/panic
o Paranoia/psychosis
o Usually affects people with predisposition to these issues
- Short-term memory loss
- Impaired coordination
- Lung cancer
o Similar non-cannabinoid constituents
to those found in tobacco
CANNABIS AND MOTIVATION
- Myth: marijuana has a direction effect
on motivation, causing an individual to
lose interest in society and personal
achievement (work, school)
- 2006 study;
o 4400 adults subjects completed online
questionnaire (small study group +
questionnaire study)
o assessed marijuana use and
depression
o daily users report less depression
(more positive affect) than abstainers
includes subset of medical marijuana
users with more depression than
abstainers but even then it helped
them have less depression
- 2014 study
o reduced dopamine levels in regular
cannabis users (not specifically in
nucleus accumbens)
o normally associated with
motivation/reward
o issues
n=19 larger cohort
is this reduction translatable to
reduced reward?
Which comes first? Cannabis or
demotivation?
CANNABIS AND LEARNING
- Myth: marijuana can lead to permanent
functional changes in the brain and or
damage to brain cells, leading to
impaired learning

o Animal studies show impairment in

learning activities however
temporary impairment (weeks)
- Connection in adolescent brains?
o 2013 study heavy users in teens
abnormal changes in brain related to
working memory, resembling those
seen in schizos
o other changes in attention, verbal
learning, processing speeds have been
published mostly reversible within 13 months of cessation
o still ongoing field of controversy: 2006
study no structural differences
between users/abstainers (ie. Cerebral
atrophy, loss of grey matter)
IS CANNABIS ADDICTIVE?
Consensus: ~10% dependence but very
low compared to other DOA
Two main arguments for:
- increase in people admitted to
treatment this is b/c of increase in
arrest and court order (not necessarily
b/c the people want to go)
- presence of withdrawal symptoms
(dependence) just because it shows
withdrawal symptoms doesnt mean its
dependent
CANNABIS AND DEPEDENCE
- animal models show withdrawal is
possible with cannabinoids, but:
o at higher doses (higher than most
humans use)
o with sudden loss of CB receptor
stimulation
use of antagonists (e.g rimonabant)
rather than normal, slow loss of
plasma conc.
Reality
- sudden cessation of CB receptor
stimulation unlikely, due to lipophilic
nature of THC
o slow release mechanism from fat
stores in body
- some symptoms are more common
than others
o irritability, sleeplessness, anger,
dysphoria
Relatively low dependence somewhere
close to caffeine in

Not like safe but I guess safer?

THERAPEUTIC CANNABIS USE
Multiple possibilities, keeping in mind the
costs of possible psychoactive side effects
some agonists, some antagonists
emesis (vomiting): prophylaxis and
treatment
o chemotherapy induced nausea and
vomiting
o other agents available, but particularly
effective against CINV
o mechanism of action unknown
possible 5-HT (serotonin) antagonism
- appetite stimulation
o counteract loss of appetite associated
with certain medical
treatment/conditions
cancer and/or treatment
AIDS
o Significant increase in feeding relative
to placebo doesnt increase weight
but prevent weight loss
o Most effective at lower doses? At
higher doses the psychoactive part
kicks in and can reduce interest in
eating
o Can this be exploited in opposite
situation?
Rimoabant (CB1 antagonist) in
obesity treatment
Stalled at Phase III clinical trials
psychiatric side effects (depression)
- Pain relief
o Historical roots in China, India
o Supported by animal studies and
clinical trials
o Chronic vs acute (better for chronic)
Neuropathic, inflammatory, MSrelated
Dont affect the intensity of the pain
but make you feel that the pain is
less unpleasant and you can less
about it
General preference of cannabinoid
treatment over placebo
- Glaucoma
o High intraocular pressure that if
untreated could lead to optic never
damage
-

o Cannabis is effective in placebocontrolled, double-blinded studies

o Cannabis reduce intraocular pressure
- Multiple Sclerosis
o Analgesia
o Animal models show reduced CNS
inflammation and improved
neurological survival
o Clinical studies ambiguous
Increases in mobility, tremors and
mood?
No changes in evaluation, but
increased subjective feeling
Reduced hospitalization, but no
change in markers (general health)
- Contraindications
o Individuals with (or prone) to severe
personality disorders higher
likelihood of experience negative
effects
o Children/adolescents (under 18) at
best no effect and at worst we dont
know about it some studies suggest
more likely to develop personality
disorders

o Pregnant/breastfeeding women its

lipophilic can get to baby
o Individuals suffering from addiction
disorders pre-disposition to addiction
causes more likely addiction
o Elderly should be cautioned due to
heightened risk of CNS/cardiovascular
side effects
Marijuana and legality
- Most used non-legal drug in western
society
- Legal alternatives available
o Dronabinol synthetic or isolated THC
o Nabilone synthetic cannabinoid
o Cannabis extract
- Herbal cannabis treatment legal in
certain conditions
- Opponents:
o Need to better understand toxicities
long term effects may not reveal
themselves for decades
o Gateway drug
- Proponents
o Safer than tobacco/ethanol
o Depriving those in medical need