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The Scientific Side of Medical Marijuana
Ken Mackie, MDIndiana UniversityBloomington, IN
December 3, 2009
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Financial disclosures
–NIH (NIDA) - research grants
–Alzheimer’s Association – research grant
–Abbott - Consulting
–Bristol Meyers Squibb – Consulting
–Cara Therapeutics - Consulting
–Sanofi - Consulting
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Outline
�Introduction to cannabis and cannabinoids
�Overview of cannabinoid pharmacology relevant to medicinal uses
�Oral Δ9THC vs cannabis: Scientific considerations
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Cannabis: A primer
–The plant: Cannabis, marijuana, etc.�Hemp vs psychoactive cannabis
–Major psychoactive component, 9THC
–However ~60 other compounds�Variability of constituents
–Preparations�Raw, dried plant (F vs. M)
�Flowers and buds
�Hashish
–Inhalation�Smoked (burned-joint, pipe, waterpipe)
�Vaporizer (heat to release volatile compounds, ~200ºC)
–Ingestion�Cooked into foods, extract 9THC into fats (butter)
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Cannabis: Cannabinoid synthesis
From GW Pharma
�CBG—cannabigerol
�CBD—cannabidiol
�THC—9tetrahydrocannabinol
�CBC—cannabichromene
�CBN—cannabinol
�“V” suffix denotes propyl instead of pentyl side chain
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Cannabinoid synthesis (overview)
CBG
THCV
CBC
THC
CBD
CBN
CBGV
Degrades
THC synthase
CBD synthase
CBC synthase
THC synt
hase
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Endocannabinoid system (ECS)
�Desire to understand the psychoactivity of cannabis contributed to a “Golden Era” of cannabinoid research during the 1980’s-1990’s
�This led to the discovery of the endocannabinoid system
�Receptors, ligands, metabolic enzymes
eCB’s
receptorsenzymes
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Endocannabinoid system (ECS)
�Endocannabinoids: 2-AG, AEA
�Major degrading enzymes: FAAH, MGL
�Receptors: CB1, CB2, GPR55, …
2-AGAEA
CB1, CB2…FAAH, MGL
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CB1 cannabinoid receptors
Stephen Eggan & David Saffen, 2004
�Discovered & cloned in late 1980’s
�Mediates most CNS actions of ∆9THC
�Richly expressed in brain, particularly in regions associated with cognition, emotion, perception, movement, etc.
�Low levels in brainstem, except emetic centers
�Lethal overdose extremely rare
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CB1 is expressed on axons and terminals
CB1-green, MAP2 (dendrites) red
DS
CB1 heavily expressed on some axons & terminals
M. Myoga
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CB1 agonists inhibit neurotransmission
CB1 receptor activation inhibits neurotransmission
Hájos
Measure GABAergic currents in CA1
record
Vc
stimulate
Typical experiment:
�Nervous tissue slice�Patch clamp recording of synaptic inputs
�Bath apply drugs
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CB1 agonists inhibit neurotransmission in the dorsal horn of the spinal cord
Modified from Farquhar-Smith, et al 2000
Modified from Morisset & Urban, 2001
CB1 agonist
CB1 agonist
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CB2 receptors
�Multiple modes of injury increase neuronal CB2 expression
�Microglia, too
14 d post ligation 7 d post hemicerebellectomyhttp://www.jneurosci.org/cgi/content/full/29/14/4564/F1
Modified from Zhang, et al 2003
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CB2 agonists as analgesics
�CB2 agonists are devoid of measurable psychoactivity
�CB2 agonists show strong efficacy in multiple pain models
�Need to consider actions of THC through CB2, too
�Inflame rat paw with carrageenan
�Treat or not with CB2 agonist (AM1241) ± CB1 or CB2
antagonist
�Measure withdrawal threshold (higher threshold = more pain relief)
Nackley et al. 2003
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CB2 receptor agonists
� Neurons and microglia
� CB2 activation decreases synaptic transmission
� Inducible—does this convey some unique therapeutic advantages?
� Preclinical studies are very promising
� Bottom line: How do they work in humans?
� Are any of the therapeutic effects of medical marijuana mediated by CB2 receptors?
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Endogenous cannabinoids
�What do endogenous cannabinoids do?
�Preformed in membrane, liberated by activation of specific lipases
�Well positioned to function as feedback regulators of neuronal function
�Produced by neurons, astrocytes, microglia
�The effects of THC will be primarily determined by its interactions with endocannabinoids
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Endocannabinoid system (ECS)
�Endocannabinoids: 2-AG, AEA
�Major degrading enzymes: FAAH, MGL
�Receptors: CB1 & CB2
2-AG
CB1 & CB2, FAAH, MGL
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Endocannabinoids inhibit neurotransmission
Bodor et al, 2005 (layer V)
�Post-synaptic neuron makes endocannabinoids that act on CB1-expressing presynaptic terminals
�Endocannabinoids are also produced by astrocytes and microglia
Postsynaptic
Presynaptic
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Ca2+
eCB
PLC
eCBACh
Glu
Ca2+
Multiple forms of eCB-mediated plasticity
DSI/DSE MSI/MSE
Slow-self inhibition (SSI)
PLC
eCB
Glu
n
Heterosynaptic eLTD
DSI = depolarization-induced suppression of inhibition
MSI = metabotropic-induced suppression of inhibition
n
Ca2+
eCB’s
K+
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Medical Marijuana
–Cannabis as a therapeutic�Old idea, much support for some efficacy�Cannabis vs synthetic 9THC
–Features to consider:�Route of administration�Complex mix of chemicals�“Rebel” nature of the act
–Most common indications�Pain (multiple, including spasticity)�Mood disorders (anxiety, depression)�GI disturbances (including appetite stimulation)�HIV-related symptoms
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Pharmacological approaches targeting cannabinoid receptors
–Dronabinol (9THC in sesame oil)
–Nabilone (Cesamet)
–Sativex (standardized cannabis extract)
–Medical marijuana
9THC Nabilone
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Medical marijuana vs dronabinol
–Components�Dronabinol, 9THC in sesame oil�Cannabis, complex (& variable) mixture of chemicals
–Pharmacokinetics�Oral
�Slow�Variable �First pass metabolism
�Inhaled�Rapid (self-titration)�Minimal first pass metabolism�Thermal isomerization
�Effects of CBD on THC metabolism
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9THC metabolism
Grotenhermen, 2003
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Inhaled vs oral route of administration
Grotenhermen, 2003
Inhaled Oral
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Variability in oral absorption between subjects (THC levels)
Grotenhermen, 2003
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Time to peak effect and duration varies with route of administration
Grotenhermen, 2003
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Inhaled vs oral route of administration
Inhaled Oral
�Rapid peak THC�Higher peak (~3 fold)�THC > 11-OH-THC�Similar peak THC-COOH
�Delayed peak THC�Lower peak (~1/3)�THC < 11-OH-THC�Similar peak THC-COOH
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Cannabidiol modifies THC effects
S. Bhattacharyya et al, 2003
� Cannabidiol (CBD) often a major component of cannabis
� CBD has no overt psychoactivity
� Multiple studies suggest CBD modulates the properties of THC
� Effects on THC metabolism
� Direct actions of CBD (e.g., blocks cue-induced reinstatement of heroin self administration)
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Summary
�Cannabis—complex mixture of compounds, including THC (acting through CB1 & CB2 receptors), as well as other compounds (e.g., CBD)
�THC produces its effects by interacting with the endocannabinoid system
�Very real differences between oral THC and medical marijuana
�Pharmacokinetics
�Additional compounds present in cannabis�Standardization
�Sativex
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Subjective high versus plasma THC
Grotenhermen, 2003
� 15 mg THC, po� Points are spaced 30 minutes apart
� Peak high occurs as plasma levels are declining