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another one of man’s
oldest drugs!
medicinal uses
documented back to
ancient times…..
Cannabis sativa
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THC – major psychoactive ingredient in the
marijuana plant
cannibinol and cannbidiol also components
but less present in plants
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until ~ 1990 – classified as a mild sedativehypnotic agent with effects similar to low
doses of alcohol
since early 1990’s – evidence that THC binds
to specific cannabinoid receptors in brain
(CB-1) and PNS (CB-2).
THC mimics action of endogenous
cannabinoid (anandamide)
◦ exist in brain in quantities that exceed more NT
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first known written record
◦ China - Emperor Shen-Nung (2737 B.C.E),
 beriberi, constipation, "female weakness," gout,
malaria, rheumatism and absentmindedness
◦ Egypt (20th century B.C.E)
 cannabis was used to treat sore eyes
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1545 – Spaniards brought marijuana to New
World; English introduced it in Jamestown in
1611 where became a major commercial crop
(hemp for rope)
by 1890 – cotton replaced hemp as major
cash crop in southern states
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some medications contained marijuana
ingredients but % very small in comparison
with cocaine and heroin
1920’s – some historians claim its emergence
due to prohibition
◦ use mostly restricted to jazz muscians and people
in show business
◦ known as an evil and menace
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classified marijuana with heroin and LSD as a
schedule I drug (high abuse liability and no
medicinal value)
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most widely used illicit drug in US and
western hemisphere
15 million illicit users
2009 – 25% teenage Americans had smoked
marijuana in past month (Partnership for a
Drug-Free America)
Early onset of heavy use (daily) (by about 12
years of age) – is associated with more severe
psychopathology in later life
gateway drug?
15
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marijuana contains 500+ chemicals with 60 +
unique to the plant
66 chemicals called cannabinoids – unique to
cannabis plant
1964 – principle psychoactive agent identified
◦ most abundant psychoactive agent is ∆9 THC (isolated
in 1964)
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marijuana, hashish, charas, bhang, ganja,
sinsemilla
Hashish and charas – dried resinous exudates
of female flowers – most potent (THC 10 –
20%)
Ganja and Sinsemilla – dried material found in
tops of female plants (5 – 8%)
marijuana – lower grade preps taken from
dried remainder of plant (2 – 5%)
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potency can also differ based on
◦ where plant is grown
◦ times (higher potency now than 20 years ago)
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currently know about two cannabinoid
receptors
◦ CB1 – found primarily in brain
 Highest quantity in basal ganglia, hippocampus,
cerebellum, cortex and spinal cord
◦ CB2 – found primarily in periphery
 Immune system; heart, and body tissues involved in
inflamation and pain responses
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endogenous agent – endocannabinoids
Anadamide  sanskrit for “internal bliss”
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THC receptor is a specific G-protein-coupled
receptor
CB-1 receptors are primarily found on
presynaptic terminals and inhibit calcium ion
flux and facilitate potassium channels
◦ (inhibits release of other nt – primarily GLU)
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first isolated in 1992
weaker agonist than THC (also shorter ½ life)
partial agonist at hippocampal GLU releasing
neurons
produces behavioral, hypothermic, and
analgesic effects similar to cannabinoids
anandamide – activates only ~ 50% of
available receptors (THC only ~ 20%)
structurally- unlike THC
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can be smoked or ingested (oral)
◦ effects after smoking lasts 2 – 4 hours
◦ cannot be injected because resin is not water
soluble
◦ highly lipid soluble and so regular use can result in
storage in fats for weeks – shows up in urine tests
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Depends on route of administration
◦ Smoking – smoking patterns…..
◦ oral adm
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oral administration
◦ THC preparation – dronabinol (Marinol)
 available since mid 1980’s
 onset is delayed and 1st pass metabolism quite high
 taken for appetite stimulation
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smoking
◦ effects almost immediately after smoking begins;
Peak blood about 10 min after initiation
◦ within 2 hrs levels fall
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distribution particlarly to organs with fatty
material;
◦ readily crosses brain, placenta,
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Metabolized by p450 enzymes to active
metabolite which is then converted to inactive
metabolite and excreted
much of THC stored in body fat and slowly
released
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Clearing metabolites
◦ Can be as short as 2 days (for the one time user)
◦ 6 weeks (for the chronic user) following the last
dose.
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Effects on the CNS
◦ analgesic – in rodents THC is analgesic (and
blocked by CB1 antagonists)
 Sativex – used for relieving pain associated with MS
 used in UK, Canada, in Phase III clinical trials in US
 cannibas based pharmaceutical product containing THC
and cannabidiol delivered in an oromucosal spray
◦ decreases body temperature
◦ calms aggressive behavior
◦ potentiates the effects of barbiturates and other
sedatives
◦ blocks convulsions
◦ depresses reflexes
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Primate studies
◦ decreases complex behavior
◦ increase social interactions
◦ increase feeding behavior
 (CB 1 receptors in hypothalamus and limbic system)
 increase intake of sweet and fatty foods
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CNS effects of THC vary with dose, route of
administration, experience of user,
vulnerability to psychoactive effects and
setting
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Psychological – euphoria, relaxation,
sleepiness, “insight’
Perceptual – altered perception of space and
time, mood changes, more introspective,
more “creative”
◦ primates – hallucinating?
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Cognitive Effects – impairment of short term memory
(little doubt about acute – long term is more
controversial)
Attentional issues
◦ divided attention – easily distracted
 increased risk for accident correlated with blood concentrations
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Psychosis?
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fairly minimal
main manifestations of acute marijuana
intoxication
◦ tachycardia
(heart rate)
 no association with MJ use w cardiovascular disease
 peripheral CB2 receptors may be defense of heart against
ischemic attack
◦ conjunctival reddening of eyes (vasodilation)
◦ possible headache
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pulmonary
◦ Marijuana smoke contains many of the same tars and
carcinogenic compounds as cigarettes but in greater
quantity (more benzopyrene
◦ single mj may be more harmful then because……
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reproduction
◦ controversial; some data suggest reduced T
◦ alterations in female cycling
◦ offspring?
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immune system
◦ CB2 receptors play regulatory role in immune
function
◦ long-term MJ use associated with some
immunosuppression; significance??
◦ other depressant drugs do the same
◦ seem to exert antitumor effects
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Animal models – yes
Humans – less clear
tolerance appears to result from cannabinoid
induced down regualtion and desensitization
of brain CB1 receptors
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Primarily psychological dependence
Physical? - maybe with very very high
doses…..
◦ studies in late 1970’s – early 1980’s
 210 mg THC (10 – 20 joints/day) – can precipitate an
abstinence syndrome that may include irritability,
restlessness, reduced appetite, etc.
 more recent – 1999 study with 4 days – 4 joints/day
 no participants requested to stop the study
 Some recent studies (2008-2009) suggest there may be
something…..
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no evidence-based pharmacotherapies for
managing cannabis WD or craving
behavior therapies – perhaps
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medical application of MJ focus ofpublic and scientific
interest for a long time
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Nausea and Vomiting
◦ Dronabinol (Marinol) - 1986
 synthetic cannabinol
 available for medical use (Schedule III) for
chemotherapy-induced nausea
 approved in 1993 for AIDS patients –
 data not compelling that this is the best drug
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Increasing appetite
◦ Aids-related wasting disease
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brain injury?
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pain in advanced cancer (Canada)
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possibility of cannabidiol instead has beneficial effects (analgesic, antiemetic,
antitumor) but not intoxication, sedation or
tachycardia
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2007 –
“spice”, K2, “kind”
labeled as “incense” not intended for human
consumption
widely sold on internet
herbals in the prep do not activate the CB
receptors but synthetic drugs added to mix
do
so far these are undetectable in chemical
analysis fur MJ and other drugs of abuse
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some of these compounds are currently
illegal in numerous countries (and some
states in the US including KY)
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overactive CB system may contribute to
numerous diseases including
◦ obesity, nicotine dependence, obesity-related
cardiovascular disorders, etc
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would cannabinoid antagonists work?
◦ rimonabant (Acomplia)
 concern in the US about safety?
◦ other agents?