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Marijuana Brian J. Piper, Ph.D.

Neuropharmacology: Marijuana

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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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Page 1: Neuropharmacology: Marijuana

MarijuanaBrian J. Piper, Ph.D.

Page 2: Neuropharmacology: Marijuana

Goals

• History• Epidemiology• Pharmacokinetics• Pharmacodynamics• Medical uses

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History

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

1707-1730

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History

• 1964: structure of Δ9-tetrahydrocannabinol discovered followed by Raphael Mechoulam

1930-

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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

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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.

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CB1 Density

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Density of Cannabinoid Receptor 1 (Increased Darkness = more receptors labeled with [3H]CP-55,940)

Hekenham et al. (1991) J Neurosci, 11, 563-583.

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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

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CB1 Species Comparison

Relative Density

Julien et al. (2011). Primer of Drug Action. p. 485.

= =

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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

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History

•1990s: endogenous cannabinoids identified by Raphael Mechoulam

– Anandamide: Sanskrit for “bringer of inner bliss and tranquility”

1930-

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Backwards

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History

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

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

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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

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World Epidemiology

UN World Drug Report 2011

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MJ Daily by Grade

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Epidemiology (MtF)

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Availability

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MJ by Gender

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

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MJ by College Plans

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

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ER Visits

Drug Abuse Warning Network, 2011

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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.

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THC

O CH2CH2

9-Tetrahydrocannabinol

OH

CH3

H3C

H3C CH2 CH3CH2

Marijuana: 3%Hashish: 8%Hash oil: 50%

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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.

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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

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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

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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

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Messinis et al. (2006) Neurology, 66, 737-739

->

->

->

Total # Significant Differences 1 12 8

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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.

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Spice

• Synthetic cannabis is sold online as herbal incense

• These are often smoked but do not test result in positive drug screens for THC

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Summary

• History

• PK: ROA

• PD: CB1 (anandamide & 2-AG)

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