Marijuana

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Psych 181 Dr. Anagnostaras Lec 10 Marijuana
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Marijuana and cannabinoids

• Cannabis sativa, hempOne of earliest non-food
  plants cultivated
• fiber for rope, seeds for oil and birdseed

from Childers Breivogel (1998)
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Marijuana and cannabinoids

• Cannabinoids
• pharmacologically active compounds
• over 60 (delta-9-tetrahydrocannabinol (?9-THC),
  ?8-THC, cannabinol, etc.)

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Forms and preparations

• Marijuana
• mixture of leaves, stems, tops
• 1960s 1-3 THC 1990s up to 8-10

Bubble Gum
Big Bud
Dutch Northern Lights
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Forms and preparations

• Hashish
• dried resin from top of female plant
• THC usually 2-5, but up to 15
• Hash Oil
• organic extractionfrom hashish
• THC usually 10-20up to 70

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Synthetic cannabinoids

• Developed for research
• Some very potent

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History

• Second only toalcohol tobacco

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History
1960
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Pharmacokinetics

• Absorption
• very lipid soluble
• good absorption if smoked (20-37)
• rapid peak

THC Administration
Blood levels
17.2
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Pharmacokinetics

• Absorption
• slow absorption with oral

THC Administration
17.4
Blood levels
Rated high
17.2
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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
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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

Performance decrement (s)
17.5
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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

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Repeated administration
Tolerance
3H-CP-55,940 Binding
Control
Chronic THC
17.9
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Repeated administration

• Long-term effects
• Amotivational syndrome?

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Potential medical uses

• Glaucoma (increased intraocular pressure)
• Antiemetic (reduce nausea and vomiting)
• Anticonvulsant
• Enhance appetite (e.g., AIDS patients)
• Analgesic
• THC versus marijuana controversy?

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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
• ??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)

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Cannabinoid receptor
3HCP-55,940 Binding
17.8
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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

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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

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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)

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Actions on DA systems
change in accumbens DA