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Lecture 16 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University. Covers pharmacokinetics, pharmacodynamics, and epidemiology.
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MarijuanaBrian J. Piper, Ph.D.
Goals
• History• Epidemiology• Pharmacokinetics• Pharmacodynamics• Medical uses
History
• 8,000 BC: archeological records of hemp• 1753 AD: Carl Linnaeus labels Cannabis sativa• 1930s: anti-marijuana propaganda scare tactics
1707-1730
History
• 1964: structure of Δ9-tetrahydrocannabinol discovered followed by Raphael Mechoulam
1930-
Pharmacokinetics
THC Bloodlevels
100
1
Time (hr)0 1 2 3 4 5 6
Oral
Route of administration influences THC pharmacokinetics, left = 5 mg i.v. injection,center = smoking 13.0 mg, or right =consuming cookie with 20 mg (Agurell et al. 1986).
100
1
100
1
0 1 2 3 4 0 1 2 3 4Time (hr)
Injection Smoking
0 120 240 360Time (min)
Intravenous (5 mg) Smoking (19 mg) Oral (20 mg)
Rated“high”
0
10
Agurell et al. (1986) Pharmacol Review 38, 21-43.
CB1 Density
Density of Cannabinoid Receptor 1 (Increased Darkness = more receptors labeled with [3H]CP-55,940)
Hekenham et al. (1991) J Neurosci, 11, 563-583.
Infusion of THC into the dorsal (A) or ventral (B) hippocampus increased errors in the radial arm maze. Egashira et al. Brain Research 952(2), 239-245.
Spatial Memory
CB1 Species Comparison
Relative Density
Julien et al. (2011). Primer of Drug Action. p. 485.
= =
Effects of THC on dopamine
Injection
150
100
0 40Time (min)
80 120
1.0 mg/kg THC0.5 mg/kg THCVehicle
% change in accumbens DA
History
•1990s: endogenous cannabinoids identified by Raphael Mechoulam
– Anandamide: Sanskrit for “bringer of inner bliss and tranquility”
1930-
Backwards
History
• 1970: Controlled Substances Act lists MJ as I (marinol as III)• 1996- present: Medical marijuana legalized in 15 states
Medical marijuana (8), decriminalized possession laws (7)Both medical marijuana & decriminalized possession (5)
Medical Medical MarijuanaMarijuana
• 1998 IOM report concluded that there is scientific evidence for the medical use of marijuana– Analgesic – Peripheral and central– Anti-emetic– Anti-spastic– Appetite Stimulant– Glaucoma
World Epidemiology
UN World Drug Report 2011
MJ Daily by Grade
Epidemiology (MtF)
Availability
MJ by Gender
Monitoring the Future (2005) Paper 63 http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
MJ by College Plans
Monitoring the Future (2005) Paper 63 http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
ER Visits
Drug Abuse Warning Network, 2011
Drug Education
• Comparison of 3 types:– D.A.R.E.– Noninteractive: expert– Interactive: peer to peer
d = (Meanprogram – Meanno program) / SD
0.00 = no effect
0.20 small effect
0.50 moderate effect
0.80 large effect
Ennett et al. (1994). American Journal of Public Health, 84(9), 1394-1401.
THC
O CH2CH2
9-Tetrahydrocannabinol
OH
CH3
H3C
H3C CH2 CH3CH2
Marijuana: 3%Hashish: 8%Hash oil: 50%
Repeated Administration
Vehicle 14 Days of THC
[3H]CP-55,940 binding following 14 days of 10 mg/kg THC or vehicle to rats. Oviedo et al. (1993) Brain Res, 616, 293-302.
Subtle Neuropsychological Impairment?
• Subjects:– 20 Heavy/Long-term MJ users (4+ joints/week for 10 years)– 20 Heavy/Short-term MJ users (4+ joints/week for 5-9 years)– 24 Control subjects
• Tests (24 hours MJ free):– Rey Auditory Verbal Learning Test (RAVLT): verbal learning/memory
– Trail Making Test (TMT): Motor speed/attention
– Beck Depression Inventory (BDI)
Messinis et al. (2006) Neurology, 66, 737-739.
http://portal.wpspublish.com/portal/page?_pageid=53,70251&_dad=portal&_schema=PORTAL
Trail Making Test
Part B: Draw line connecting # -> letter -> #1-A-2-B-3-C
Part A: Draw line connecting #’s 1-2-3-4
Trail Making Test
Mean (SEM) Trail Making Test: A
Control Short MJ Long MJ0
10
20
30
40
50
60 * *
Sec
on
ds
Mean (SEM) Trail Making Test: B
Control Short MJ Long MJ0
25
50
75
100
125* *
Sec
on
ds
Messinis et al. (2006) Neurology, 66, 737-739
Messinis et al. (2006) Neurology, 66, 737-739
->
->
->
Total # Significant Differences 1 12 8
Withdrawal from MJ?
• Long-term MJ (N=7) users (6 days/week, 4 joints/day) lived in a laboratory
• The 5-HT/NE reuptake inhibitor Nefazodone was adminstered. Days
Haney (2002). J Clinical Pharmacology, 42, 34S-40S.
Spice
• Synthetic cannabis is sold online as herbal incense
• These are often smoked but do not test result in positive drug screens for THC
Summary
• History
• PK: ROA
• PD: CB1 (anandamide & 2-AG)
Pollan, Michael (2009). The botany of desire. 0:00 to 4:50, 55:50-1:23:30 http://www.youtube.com/watch?v=AHUKC8ovPzE