marijuana and cannabinoids
TRANSCRIPT
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Psych 181: Dr. AnagnostarasLec 10: Marijuana
Marijuana and cannabinoids
Cannabis sativa, hempOne of earliest non-food plants cultivated fiber for rope, seeds for oil and birdseed
8000 BC 2700 BC 2000 BC 1000 AD 1850s 1996
1st archaeological evidenceof hemp use
Medical usein China
Ritual usein India
Hashish use inArab world
Westerm world find bioactiv.
Use semi-legal inCA/AZ
from Childers & Breivogel (1998)
Marijuana and cannabinoids
Cannabinoids pharmacologically active compounds over 60 (delta-9-tetrahydrocannabinol (Δ9-
THC), Δ8-THC, cannabinol, etc.)
O CH2CH2
Δ9-Tetrahydrocannabinol
OH
CH3
H3CH3C CH2 CH3
CH2
2
Forms and preparations
Marijuana mixture of leaves, stems, tops 1960’s: 1-3% THC; 1990’s: up to 8-10%
“Bubble Gum” “Big Bud” “Dutch Northern Lights”
Forms and preparations
Hashish dried resin from top of female plant THC usually 2-5%, but up to 15%
Hash Oil organic extraction
from hashish THC usually ~ 10-20%
up to 70%
Synthetic cannabinoids
Developed for research Some very potent
CH2
CH3N
WIN 55212
O
C O
N
O
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History
Second only toalcohol & tobacco
History
1960
Pharmacokinetics
Absorption very lipid soluble good absorption if smoked (20-37%) rapid peak
100�
1
100�
1
0 1 2 3 4 0 1 2 3 4Time (hr)
Injection Smoking
Bloo
d le
vels
17.2
THC Administration
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Pharmacokinetics
Absorption slow absorption with oral
Bloo
d le
vels
100�
1
Time (hr)0 1 2 3 4 5 6
Oral
17.2
THC Administration
0 120 240 360Time (min)
Intravenous (5 mg) Smoking (19 mg) Oral (20 mg)
Rate
d “ h
igh”
17.4
Metabolism and clearance
rapid initial drop due to redistribution to fats slower metabolism in liver metabolites may persist for a week
1. Primary metabolic product of Δ9-THC (11-OH-Δ9-THC) is more potent than Δ9-THC 2. Delay between peak plasma levels and “high”
Major biolgically active compound may be metabolite
Effects on behavior
Low - moderate doses disinhibition, relaxation, drowsiness feeling of well being, exhileration, euphoria sensory - perceptual changes recent memory impairment balance/stability impaired decreased muscle strength, small tremor poor on complex motor tasks (e.g., driving)
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Effects on behavior
Psychomotor performance
1.0
0.6
0.2
2 6 122 6 12
Simpleresponse time
Response time (divided attention)
Time (hr)Perfo
rman
ce d
ecre
men
t (s)
17.5
Effects on behavior
High doses pseudohallucinations synesthesias impaired judgement, reaction time pronounced motor impairment increasingly disorganized thoughts,
confusion, paranoia, agitation
Not lethal even at very high doses
Repeated administration
Chronic THC Control
17.9
3H-CP-55,940 Binding
Tolerance
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Repeated administration
Long-term effects Amotivational syndrome?
Potential medical uses
Glaucoma (increased intraocular pressure) Antiemetic (reduce nausea and vomiting) Anticonvulsant Enhance appetite (e.g., AIDS patients) Analgesic
THC versus marijuana controversy?
Mechanisms of action
Nonspecific? e.g., membrane fluidity changes
Specific?is there a cannabinoid receptor? small doses effective effects of d and l isomers different marked structure-function effects inhibits cAMP formation via G protein (1986)
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Mechanisms of action
Is there a cannabinoid receptor?Development of synthetic cannabinoids Δ9-THC binds weakly and not full agonist CP and WIN series of compounds and
antagonists (1986-1990s) first binding experiments (1988) first localization (1990) CB-1 receptor cloned (1990) CB-2 cloned (1993)
Cannabinoid receptor17.8[3H]CP-55,940 Binding
Cannabinoid receptor
Receptor localization conserved across mammalian species similar to cAMP distribution
binding inhibitedby cAMP analogues
both CB-1 and CB-2(peripheral) receptors areG protein coupled
receptor density very high,rivalling amino acid receptors
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Endogenous cannabinoids
Anandamide from Sanskrit for “bliss” arachidonic acid derivative (1992)
similar actions to cannabinoids inhibit cAMP via cannabinoid receptor inhibit binding of cannabinoids only partial agonist at CB-1 decrease motor activity antinociceptive effects
CONHCH2CH2OH
Anandamide (Anandamide 20:4,n-6)
Endogenous cannabinoids
Others2-arachidonyl glycerol full agonist at CB-1 and in brain in higher
conc. than anandamide
additional unidentified compounds have beenfound
CONHCH2CH2OH
Anandamide (Anandamide 20:4,n-6)
Locus of actions
Relationship between action & sites ofaction not known
Speculation: memory effects - hippocampus reward - mesostriatal DA system motor activity - basal ganglia, cerebellum analgesic effects - spinal cord and in
peripheral tissue (endogenous compoundseffective via non-opiate mechanism)
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Actions on DA systems
Injection
150
100
0 40Time (min)
80 120
1.0 mg/kg THC0.5 mg/kg THCVehicle
% c
hang
e in
acc
umbe
ns D
A