Marijuana and cannabinoids

Transcription

1 Psych 181: Dr. Anagnostaras Lec 10: Marijuana Marijuana and cannabinoids Cannabis sativa, hemp One of earliest non-food plants cultivated fiber for rope, seeds for oil and birdseed 1st archaeological evidence Westerm world find bioactiv. of hemp use Ritual use in India Use semilegal in Medical use Hashish use in in China Arab world CA/AZ 8000 BC 2700 BC 2000 BC 1000 AD 1850s 1996 from Childers & Breivogel (1998) Marijuana and cannabinoids Cannabinoids pharmacologically active compounds over 60 (delta-9-tetrahydrocannabinol (Δ9- THC), Δ8-THC, cannabinol, etc.) CH3 OH H3C CH2 CH2 H3C O CH2 CH2 CH3 Δ9-Tetrahydrocannabinol 1

2 Forms and preparations Marijuana mixture 1960 s: Bubble Gum of leaves, stems, tops 1-3% THC; 1990 s: up to 8-10% Big Bud Dutch Northern Lights Forms and preparations Hashish dried THC resin from top of female plant 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 C N O O CH 3 CH 2 N O WIN

3 History Second only to alcohol & tobacco History 1960 Pharmacokinetics Absorption very lipid soluble good absorption if smoked (20-37%) rapid peak THC Administration Injection Smoking Blood levels Time (hr) 3

4 Pharmacokinetics Absorption slow absorption with oral 17.4 THC Administration Oral Rated high Intravenous (5 mg) Smoking (19 mg) Oral (20 mg) Blood levels Time (min) Time (hr) 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 Δ9-THC (11-OH-Δ9-THC) is more potent than Δ9-THC 2. Delay between peak plasma levels and high 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) 4

5 Effects on behavior Psychomotor performance Performance decrement (s) Simple response time Time (hr) Response time (divided attention) 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 Tolerance 3 H-CP-55,940 Binding Chronic THC Control

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) 6

7 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 ( s) first binding experiments (1988) first localization (1990) CB-1 receptor cloned (1990) CB-2 cloned (1993) Cannabinoid receptor [ 3 H]CP-55,940 Binding 17.8 Cannabinoid receptor Receptor localization conserved across mammalian species similar to camp distribution binding inhibited by camp analogues both CB-1 and CB-2 (peripheral) receptors are G protein coupled receptor density very high, rivalling amino acid receptors 7

8 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 Others 2-arachidonyl glycerol full agonist at CB-1 and in brain in higher conc. than anandamide additional unidentified compounds have been found CONHCH2CH2OH Anandamide (Anandamide 20:4,n-6) 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) 8

9 Actions on DA systems % change in accumbens DA Injection 1.0 mg/kg THC 0.5 mg/kg THC Vehicle Time (min) 9