Psych 181: Dr. AnagnostarasLec 10: Marijuana

Marijuana and cannabinoidscannabinoidsMarijuana and cannabinoidscannabinoids

Cannabis sativaCannabis sativa, hemp, hempOne of earliest non-food plants cultivatedOne of earliest non-food plants cultivated fiber for rope, seeds for oil and birdseedfiber 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 in CA/AZ

from Childers & Breivogel (1998)

Marijuana and cannabinoidscannabinoidsMarijuana and cannabinoidscannabinoids

CannabinoidsCannabinoids pharmacologically active compoundspharmacologically active compounds over 60 (delta-9-tetrahydrocannabinol (over 60 (delta-9-tetrahydrocannabinol (9-9-

THC), THC), 8-THC, cannabinol, etc.)8-THC, cannabinol, etc.)

O CH2CH2

9-Tetrahydrocannabinol

OH

CH3

H3C

H3C CH2 CH3CH2

Forms and preparationsForms and preparations

MarijuanaMarijuana mixture of leaves, stems, topsmixture of leaves, stems, tops 1960’s: 1-3% THC; 1990’s: up to 8-10%1960’s: 1-3% THC; 1990’s: up to 8-10%

“Bubble Gum” “Big Bud” “Dutch Northern Lights”

Forms and preparationsForms and preparations

HashishHashish dried resin from top of female plantdried resin from top of female plant THC usually 2-5%, but up to 15%THC usually 2-5%, but up to 15%

Hash OilHash Oil organic extractionorganic extraction

from hashishfrom hashish THC usually ~ 10-20%THC usually ~ 10-20%

up to 70%up to 70%

Synthetic cannabinoidsSynthetic cannabinoids

Developed for researchDeveloped for research Some very potentSome very potent

CH2

CH3N

WIN 55212

O

C O

N

O

HistoryHistory

Second only toSecond only toalcohol & tobaccoalcohol & tobacco

HistoryHistory

1960

PharmacokineticsPharmacokinetics

AbsorptionAbsorption very lipid solublevery lipid soluble good absorption if smoked (20-37%)good absorption if smoked (20-37%) rapid peakrapid peak

100

1

100

1

0 1 2 3 4 0 1 2 3 4

Time (hr)

Injection Smoking

Blo

od

leve

ls

17.2

THC Administration

PharmacokineticsPharmacokinetics

AbsorptionAbsorption slow absorption with oralslow absorption with oral

Blo

od

leve

ls

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)

Ra

ted

“h

igh

”

17.4

Metabolism and clearanceMetabolism and clearance

rapid initial drop due to redistribution to fatsrapid initial drop due to redistribution to fats slower metabolism in liverslower metabolism in liver metabolites may persist for a weekmetabolites may persist for a week

1. Primary metabolic product of 9-THC 9-THC (11-OH- (11-OH-9-THC) is more potent than 9-THC) is more potent than 9-THC 9-THC 2. 2. Delay between peak plasma levels and “high”Delay between peak plasma levels and “high”

Major biolgically active compound may be metabolite

Effects on behaviorEffects on behavior

Low - moderate dosesLow - moderate doses disinhibition, relaxation, drowsinessdisinhibition, relaxation, drowsiness feeling of well being, exhileration, euphoriafeeling of well being, exhileration, euphoria sensory - perceptual changessensory - perceptual changes recent memory impairmentrecent memory impairment balance/stability impairedbalance/stability impaired decreased muscle strength, small tremordecreased muscle strength, small tremor poor on complex motor tasks (e.g., driving)poor on complex motor tasks (e.g., driving)

Effects on behaviorEffects on behavior

Psychomotor performancePsychomotor performance

1.0

0.6

0.2

2 6 122 6 12

Simpleresponse time

Response time (divided attention)

Time (hr)Per

form

ance

dec

rem

ent

(s)

17.5

Effects on behaviorEffects on behavior

High dosesHigh doses pseudohallucinationspseudohallucinations synesthesiassynesthesias impaired judgement, reaction timeimpaired judgement, reaction time pronounced motor impairmentpronounced motor impairment increasingly disorganized thoughts, increasingly disorganized thoughts,

confusion, paranoia, agitationconfusion, paranoia, agitation

Not lethal even at very high dosesNot lethal even at very high doses

Repeated administrationRepeated administration

Chronic THC Control

17.9

3H-CP-55,940 Binding

Tolerance

Repeated administrationRepeated administration

Long-term effects Amotivational syndrome?Amotivational syndrome?

Potential medical usesPotential medical uses

Glaucoma (increased intraocular pressure)Glaucoma (increased intraocular pressure) Antiemetic (reduce nausea and vomiting)Antiemetic (reduce nausea and vomiting) AnticonvulsantAnticonvulsant Enhance appetite (e.g., AIDS patients)Enhance appetite (e.g., AIDS patients) AnalgesicAnalgesic

THC versus marijuana controversy?THC versus marijuana controversy?

Mechanisms of actionMechanisms of action

Nonspecific?Nonspecific? e.g., membrane fluidity changese.g., membrane fluidity changes

Specific?Specific?is there a cannabinoid receptor?is there a cannabinoid receptor? small doses effectivesmall doses effective effects of d and l isomers differenteffects of d and l isomers different marked structure-function effectsmarked structure-function effects inhibits cAMP formation via G protein inhibits cAMP formation via G protein (1986)(1986)

Mechanisms of actionMechanisms of action

Is there a cannabinoid receptor?Is there a cannabinoid receptor?

Development of synthetic cannabinoidsDevelopment of synthetic cannabinoids 9-THC binds weakly and not full agonist9-THC binds weakly and not full agonist CP and WIN series of compounds andCP and WIN series of compounds and

antagonists (1986-1990s) antagonists (1986-1990s) first binding experiments (1988)first binding experiments (1988) first localization (1990)first localization (1990) CB-1 receptor cloned (1990)CB-1 receptor cloned (1990) CB-2 cloned (1993)CB-2 cloned (1993)

Cannabinoid receptorCannabinoid receptorCannabinoid receptorCannabinoid receptor

17.8[3H]CP-55,940 Binding

Cannabinoid receptorCannabinoid receptorCannabinoid receptorCannabinoid receptor

Receptor localizationReceptor localization conserved across mammalian speciesconserved across mammalian species similar to cAMP distributionsimilar to cAMP distribution

binding inhibitedbinding inhibitedby cAMP analoguesby cAMP analogues

both CB-1 and CB-2 both CB-1 and CB-2 (peripheral) receptors are(peripheral) receptors areG protein coupledG protein coupled

receptor density very high,receptor density very high,rivalling amino acid receptorsrivalling amino acid receptors

Endogenous cannabinoidsEndogenous cannabinoids

AnandamideAnandamide from Sanskrit for “bliss”from Sanskrit for “bliss” arachidonic acid derivative arachidonic acid derivative (1992)(1992)

similar actions to cannabinoidssimilar actions to cannabinoids inhibit cAMP via cannabinoid receptorinhibit cAMP via cannabinoid receptor inhibit binding of cannabinoidsinhibit binding of cannabinoids only partial agonist at CB-1only partial agonist at CB-1 decrease motor activitydecrease motor activity antinociceptive effectsantinociceptive effects

CONHCH2CH2OH

Anandamide (Anandamide 20:4,n-6)

Endogenous cannabinoidsEndogenous cannabinoids

OthersOthers

2-arachidonyl glycerol2-arachidonyl glycerol full agonist at CB-1 and in brain in higher full agonist at CB-1 and in brain in higher

conc. than anandamideconc. than anandamide

additional unidentified compounds have been additional unidentified compounds have been foundfound

CONHCH2CH2OH

Anandamide (Anandamide 20:4,n-6)

Locus of actionsLocus of actions

Relationship between action & sites of Relationship between action & sites of action not knownaction not known

Speculation:Speculation: memory effects - hippocampusmemory effects - hippocampus reward - mesostriatal DA systemreward - mesostriatal DA system motor activity - basal ganglia, cerebellummotor activity - basal ganglia, cerebellum analgesic effects - spinal cord and in analgesic effects - spinal cord and in

peripheral tissue peripheral tissue (endogenous compounds (endogenous compounds effective via non-opiate mechanism)effective via non-opiate mechanism)

Actions on DA systemsActions on DA systemsActions on DA systemsActions on DA systems

Injection

150

100

0 40Time (min)

80 120

1.0 mg/kg THC0.5 mg/kg THCVehicle

% c

han

ge

in a

ccu

mb

ens

DA