Transcript Marijuana - Division of Social Sciences

Psych 181: Dr. Anagnostaras
Lec 10: Marijuana
Marijuana and cannabinoids
Cannabis sativa, hemp
One of earliest non-food plants cultivated
 fiber for rope, seeds for oil and birdseed
Westerm world find bioactiv.
1st archaeological evidence
of hemp use
Ritual use
in India
Use semiMedical use
Hashish use in
legal in
CA/AZ
in China
Arab world
8000 BC
2700 BC
2000 BC
1000 AD
1850s
1996
from Childers & Breivogel (1998)
Marijuana and cannabinoids
Cannabinoids
pharmacologically active compounds
 over 60 (delta-9-tetrahydrocannabinol (9THC), 8-THC, cannabinol, etc.)

CH3
OH
H 3C
H 3C
CH2
O
CH2
CH2
CH2
9-Tetrahydrocannabinol
CH3
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

C
N
O
O
CH3
CH2
N
O
WIN 55212
History

Second only to
alcohol & tobacco
History
1960
Pharmacokinetics
Absorption
very lipid soluble
 good absorption if smoked (20-37%)
THC Administration
 rapid peak
Inje ction
Sm ok ing

Blood levels
100
100
1
1
0
17.2
1
2
3
4
0
Tim e (hr)
1
2
3
4
Pharmacokinetics
Absorption
Oral
Rated “high”
Intrave nous (5 m g)
Sm ok ing (19 m g)
Oral (20 m g)
0
THC Administration
absorption with oral
120
240
Tim e (m in)
360
100
Blood levels
 slow
17.4
1
0
17.2
1
2
3
4
Tim e (hr)
5
6
Metabolism and clearance



rapid initial drop due to redistribution to fats
slower metabolism in liver
metabolites may persist for a week
Major biolgically active
compound may be metabolite
1. Primary metabolic product of 9-THC
(11-OH-9-THC) is more potent than 9-THC
2. Delay between peak plasma levels and “high”
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)

Effects on behavior
Performance decrement (s)
Psychomotor performance
1.0
Sim ple
re s pons e tim e
Re s pons e tim e
(divide d atte ntion)
0.6
0.2
2
6
12
2
Tim e (hr)
6
12
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
Tolerance
3H-CP-55,940
Chronic THC
Binding
Control
17.9
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)
Mechanisms of action
Is there a cannabinoid receptor?
Development of synthetic cannabinoids
9-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 receptor
[3H]CP-55,940 Binding
17.8
Cannabinoid receptor
Receptor localization


conserved across mammalian species
similar to cAMP distribution
 binding inhibited
by cAMP analogues
 both CB-1 and CB-2
(peripheral) receptors are
G protein coupled
 receptor density very high,
rivalling amino acid receptors
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
Others
2-arachidonyl glycerol

full agonist at CB-1 and in brain in higher
conc. than anandamide

additional unidentified compounds have been
found
CONHCH2CH2OH
Anandamide (Anandamide 20:4,n-6)
Locus of actions
Relationship between action & sites of
action not known
Speculation:
memory effects - hippocampus
 reward - mesostriatal DA system
 motor activity - basal ganglia, cerebellum
 analgesic effects - spinal cord and in
peripheral tissue (endogenous compounds

effective via non-opiate mechanism)
% change in accumbens DA
Actions on DA systems
1.0 m g/k g THC
0.5 m g/k g THC
Ve hicle
150
100
Inje ction
0
40
80
Tim e (m in)
120