Lecture 16 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Covers pharmacokinetics, pharmacodynamics, and epidemiology.

1. Marijuana
Brian J. Piper, Ph.D.

2. Goals
• History
• Epidemiology
• Pharmacokinetics
• Pharmacodynamics
• Medical uses

3. History
• 8,000 BC: archeological records of hemp
• 1753 AD: Carl Linnaeus labels Cannabis sativa 1707-1730
• 1930s: anti-marijuana propaganda scare tactics

4. History
1930-
• 1964: structure of Δ9-tetrahydrocannabinol discovered followed
by Raphael Mechoulam

5. Pharmacokinetics
Injection Smoking Oral
100 100 100
THC
Blood
levels
1 1 1
0 1 2 3 4 0 1 2 3 4
0 1 2 3 4 5 6
Time (hr)
Time (hr)
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).

6. 10
Intravenous (5 mg)
Smoking (19 mg)
Oral (20 mg)
Rated
“high”
0 120 240 360
0
Time (min)
Agurell et al. (1986) Pharmacol Review 38, 21-43.

7. CB1 Density

8. Density of Cannabinoid Receptor 1 (Increased
Darkness = more receptors labeled with [3H]CP-55,940)
Hekenham et al. (1991) J Neurosci, 11, 563-583.

9. Spatial Memory
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.

10. CB1 Species Comparison
= =
Relative Density
Julien et al. (2011). Primer of Drug Action. p. 485.

11. Effects of THC on dopamine
1.0 mg/kg THC
0.5 mg/kg THC
150 Vehicle
% change in
accumbens DA
100
Injection
0 40 80 120
Time (min)

12. History
1930-
•1990s: endogenous cannabinoids identified by Raphael
Mechoulam
– Anandamide: Sanskrit for “bringer of inner bliss and tranquility”

13. Backwards

14. History
• 1970: Controlled Substances Act lists MJ as I (marinol as III)
• 1996- present: Medical marijuana legalized in 15 states

15. Medical marijuana (8), decriminalized possession laws (7)
Both medical marijuana & decriminalized possession (5)

16. Medical
Marijuana
• 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

17. World Epidemiology
UN World Drug Report 2011

19. MJ Daily by Grade

20. Epidemiology (MtF)

21. Availability

22. MJ by Gender
Monitoring the Future (2005) Paper 63
http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

23. MJ by College Plans
Monitoring the Future (2005) Paper 63
http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

24. ER Visits
Drug Abuse Warning Network, 2011

25. 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
Ennett et al. (1994). American Journal of Public Health, 84(9), 1394-1401.

26. THC
CH 3
OH
H 3C
CH 2 CH 2
H 3C O CH 2 CH 2 CH 3
∆ 9-Tetrahydrocannabinol
Marijuana: 3%
Hashish: 8%
Hash oil: 50%

27. 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.

28. 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

29. Trail Making Test
Part A: Draw line connecting #’s Part B: Draw line connecting # -> letter -> #
1-2-3-4 1-A-2-B-3-C

30. Trail Making Test
Mean (SEM) Trail Making Test: A Mean (SEM) Trail Making Test: B
60 125
* * *
*
50 100
40
Seconds
75
Seconds
30
50
20
10 25
0 0
Control Short MJ Long MJ Control Short MJ Long MJ
Messinis et al. (2006) Neurology, 66, 737-739

31. ->
->
->
Messinis et al. (2006) Neurology, 66, 737-739 Total # Significant Differences 1 12 8

32. 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.

33. Spice
• Synthetic cannabis is sold online as herbal
incense
• These are often smoked but do not test
result in positive drug screens for THC

34. Summary
• History
• PK: ROA
• PD: CB1 (anandamide & 2-AG)

35. Pollan, Michael (2009). The botany of desire. 0:00 to 4:50, 55:50-1:23:30
http://www.youtube.com/watch?v=AHUKC8ovPzE