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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

3

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

4

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

6

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