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

2. cannabinoids Marijuana and cannabinoids Cannabis sativa, hemp One of earliest non-food plants cultivated fiber for rope, seeds for oil and birdseed fiber for rope, seeds for oil and birdseed 8000 BC2700 BC2000 BC1000 AD1850s1996 1st archaeological evidence of hemp use Medical use in China Ritual use in India Hashish use in Arab world Westerm world find bioactiv. Use semi- legal in CA/AZ from Childers & Breivogel (1998)

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

4. Forms and preparations Marijuana mixture of leaves, stems, tops mixture 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”

5. Forms and preparations Hashish dried resin from top of female plant dried resin from top of female plant THC usually 2-5%, but up to 15% THC usually 2-5%, but up to 15% Hash Oil organic extraction from hashish organic extraction from hashish THC usually ~ 10-20% up to 70% THC usually ~ 10-20% up to 70%

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

7. History Second only to alcohol & tobacco Second only to alcohol & tobacco

8. History 1960

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

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

11. Metabolism and clearance rapid initial drop due to redistribution to fats rapid initial drop due to redistribution to fats slower metabolism in liver slower metabolism in liver metabolites may persist for a week metabolites may persist for a week  9-THC (11-OH-  9-THC) is more potent than  9-THC 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” 2. Delay between peak plasma levels and “high” Major biolgically active compound may be metabolite

12. Effects on behavior Low - moderate doses disinhibition, relaxation, drowsiness disinhibition, relaxation, drowsiness feeling of well being, exhileration, euphoria feeling of well being, exhileration, euphoria sensory - perceptual changes sensory - perceptual changes recent memory impairment recent memory impairment balance/stability impaired balance/stability impaired decreased muscle strength, small tremor decreased muscle strength, small tremor poor on complex motor tasks (e.g., driving) 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 pseudohallucinations synesthesias synesthesias impaired judgement, reaction time impaired judgement, reaction time pronounced motor impairment pronounced motor impairment increasingly disorganized thoughts, confusion, paranoia, agitation increasingly disorganized thoughts, confusion, paranoia, agitation Not lethal even at very high doses

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

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

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

18. Mechanisms of action Nonspecific? e.g., membrane fluidity changes e.g., membrane fluidity changes Specific? is there a cannabinoid receptor? small doses effective small doses effective effects of d and l isomers different effects of d and l isomers different marked structure-function effects marked structure-function effects inhibits cAMP formation via G protein (1986) inhibits cAMP formation via G protein (1986)

19. Mechanisms of action Is there a cannabinoid receptor? Is there a cannabinoid receptor? Development of synthetic cannabinoids  9-THC binds weakly and not full agonist  9-THC binds weakly and not full agonist CP and WIN series of compounds and antagonists (1986-1990s) CP and WIN series of compounds and 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)

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

21. Cannabinoid receptor Receptor localization conserved across mammalian species conserved across mammalian species similar to cAMP distribution similar to cAMP distribution binding inhibited by cAMP analogues binding inhibited by cAMP analogues both CB-1 and CB-2 (peripheral) receptors are G protein coupled both CB-1 and CB-2 (peripheral) receptors are G protein coupled receptor density very high, rivalling amino acid receptors receptor density very high, rivalling amino acid receptors

22. Endogenous cannabinoids Anandamide from Sanskrit for “bliss” from Sanskrit for “bliss” arachidonic acid derivative (1992) arachidonic acid derivative (1992) similar actions to cannabinoids similar actions to cannabinoids inhibit cAMP via cannabinoid receptor inhibit cAMP via cannabinoid receptor inhibit binding of cannabinoids inhibit binding of cannabinoids only partial agonist at CB-1 only partial agonist at CB-1 decrease motor activity decrease motor activity antinociceptive effects antinociceptive effects

23. Endogenous cannabinoids Others 2-arachidonyl glycerol full agonist at CB-1 and in brain in higher conc. than anandamide full agonist at CB-1 and in brain in higher conc. than anandamide additional unidentified compounds have been found additional unidentified compounds have been found

24. Locus of actions Relationship between action & sites of action not known Speculation: memory effects - hippocampus memory effects - hippocampus reward - mesostriatal DA system reward - mesostriatal DA system motor activity - basal ganglia, cerebellum motor activity - basal ganglia, cerebellum analgesic effects - spinal cord and in peripheral tissue (endogenous compounds effective via non-opiate mechanism) analgesic effects - spinal cord and in peripheral tissue (endogenous compounds effective via non-opiate mechanism)

25. Actions on DA systems % change in accumbens DA