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Psych 181: Dr. Anagnostaras Lec 10: Marijuana

Psych 181: Dr. Anagnostaras Lec 10: Marijuana. Westerm world find bioactiv. 1st archaeological evidence of hemp use. Ritual use in India. Use semi-legal in CA/AZ. Medical use in China. Hashish use in Arab world. 8000 BC. 2700 BC. 2000 BC. 1000 AD. 1850s. 1996.

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Psych 181: Dr. Anagnostaras Lec 10: Marijuana

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  1. Psych 181: Dr. Anagnostaras Lec 10: Marijuana

  2. Westerm world find bioactiv. 1st archaeological evidenceof hemp use Ritual usein India Use semi-legal in CA/AZ Medical usein China Hashish use inArab world 8000 BC 2700 BC 2000 BC 1000 AD 1850s 1996 Marijuana and cannabinoids Cannabis sativa, hempOne of earliest non-food plants cultivated • fiber for rope, seeds for oil and birdseed from Childers & Breivogel (1998)

  3. Marijuana and cannabinoids Cannabinoids • pharmacologically active compounds • over 60 (delta-9-tetrahydrocannabinol (9-THC), 8-THC, cannabinol, etc.)

  4. 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”

  5. 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 ~ 10-20%up to 70%

  6. Synthetic cannabinoids • Developed for research • Some very potent

  7. History • Second only toalcohol & tobacco

  8. History 1960

  9. Pharmacokinetics Absorption • very lipid soluble • good absorption if smoked (20-37%) • rapid peak THC Administration Blood levels 17.2

  10. Pharmacokinetics Absorption • slow absorption with oral THC Administration 17.4 Blood levels Rated “high” 17.2

  11. 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”

  12. 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)

  13. Effects on behavior Psychomotor performance Performance decrement (s) 17.5

  14. 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

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

  16. Repeated administration Long-term effects • Amotivational syndrome?

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

  18. 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)

  19. 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)

  20. Cannabinoid receptor [3H]CP-55,940 Binding 17.8

  21. 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

  22. 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

  23. 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

  24. 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)

  25. Actions on DA systems % change in accumbens DA

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