Steven G. Kinsey, PhD Associate Professor, Department of ... Endocannabinoid system.pdfCannabinoids...
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Steven G. Kinsey, PhD Associate Professor, Department of Psychology West Virginia University [email protected]
Transcript of Steven G. Kinsey, PhD Associate Professor, Department of ... Endocannabinoid system.pdfCannabinoids...
Steven G. Kinsey, PhD
Associate Professor, Department of Psychology
West Virginia University
Any opinions expressed are my own and do not
reflect any official position of WVU
beanpot.co
Cannabinoids are cannabis-like
compounds
Plant-derived
○ Marijuana, hashish, THC
Synthetic
○ Spice, K2, Buzz
Endogenous
○ i.e., endocannabinoids
○ Naturally produced in the body
solutions-recovery.com
O
O H
THC
http://forum.grasscity.com/toking-tools/402939-$$blunt-joint$$-smokin-picture-thread-5.html
Chemical classes Cannabinoids (100+) Nitrogenous cmpds (27) Amino acids(18) Proteins/ enzymes (11) Sugars (34) Hydrocarbons (50) Simple alcohols (7) Simple aldehydes (12) Simple ketones (13) Simple acids (21) Fatty acids (22) Simple esters/lactones (13) Steroids (11) Terpenes (20) Non-cannabinoid phenols (25) Flavoroids (21) Vitamins (1) Pigments (2) Elements (9) ------------------------------------- Total known compounds (483)
2700 BCE 2000 BCE 1000
Medical use
in China
Religious use
in India
Hashish use
in Arab world
Western world
learns of
bioactivity
Marijuana
Tax Act Medical use
legalized in
CA & AZ
1850’s 1937 1996 1964
∆9-THC
discovered
(Israel) CB
receptor
cloned
Rec. use
legalized in
WA & CO
2013
Endocannabinoids
discovered
Synthetics
banned by
DEA
The “high”
Mild euphoria and relaxation
Perceptual alterations
Time distortion
Impaired cognition - ↓memory recall
Altered motor function - ↓complex tasks
http://reason.com/assets/mc/mwelch/2010_09/snoop_dogg_stoned.jpg
Peripheral effects:
↑ heart rate
↑ appetite, “the munchies”
↓ emesis (vomiting)
↓ intraocular pressure
http://marijuana.cc/2013/06/25/top-5-indica-strains-in-2013/
• ↑ heart rate
• ↑ appetite
• ↓ movement
• ↓ pain sensitivity
• ↓ muscle tone
• ↑ Self-administration
• ↑ Memory disruption
http://www.finalpuff.co.uk; theragblog.blogspot.com
THC “tetrad” effects in mice
Adapted from Joy JE et al, eds. Marijuana and Medicine. 1999.
Red = abundant CB1 receptor expression Black = moderately abundant CB1 receptor expression
12
0 1 2 3
4 5
Skeletal Muscle
Whole Brain
Spleen
Stomach
Ileum
Prostate
Testis
Placenta
Uterus
Liver
Lung
Kidney
Spinal Cord
Adipose
Relative CB1 Gene Expression (AU)
Myocardium
Expression of the CB1 Receptor Gene in Human Tissue
Engeli S et al. Diabetes. 2005;54:2838-2843.
Presynaptic
Neuron
Postsynaptic
Neuron
CB1
CB1
anandamide
2-AG
Presynaptic
Neuron
Postsynaptic
Neuron
CB1
anandamide
2-AG
JWH-018
THC
JWH-018
THC
THC
JWH-018
CB1
harmreductioncenter.blogspot.com
THC withdrawal
Cannabis Use Disorder
Affects ~2-6% of users1
Disturbs sleep, GI function, emotionality
Treatment
Behavior modification
No FDA approved pharmaceutical treatment
1. Hasin et al., 2016
Acute cannabis reduces anxiety &
depression
Withdrawal:
Impairs daily activity
↑anxiety, ↑depression
↑cravings
Relapse to cannabis use
http://marisworld.co.uk/wp-content/uploads/2012/06/woman-anxious.jpg
Trexler et al., in prep
Heavy use = same respiratory
problems as tobacco use
Tar & CO 3-5x higher than tobacco
due to deep inhalation, holding in lungs,
unfiltered
Safety of edible forms untested
Herbal “incense” sold since 2002
includes synthetic cannabinoids
Legal by state, not detectable by
marijuana tests
2011: 11.4% 12th graders used “spice”
in prior 12 mo1
1 Monitoring the Future 2011 leadrecoverycenter.com
Psychological: anxiety, psychosis, paranoia
Physiological: nausea, hyperventilation,
diaphoresis, pallor, seizures, numbness,
muscle twitching
Aka, “Weaponized marijuana”
Beaconnews.ca
JWH = John W. Huffman
Chemist at Clemson
washingtonpost.com
“I thought it was sort of
hilarious at the time… then
I started hearing about
some of the bad results”
Seely et al., 2013
How can we harness the positive
effects of cannabinoids, without
their negative side effects?
No “high” = ↓abuse
http://marijuana.cc/2013/06/25/top-5-indica-strains-in-2013/
Mix of cannabinoids
Approved in Canada for pain:
Multiple sclerosis & cancer
Side effects: dizziness, fatigue
Phase III trials for neuropathic
pain in cancer in US
Rimonabant (Acomplia):
Significant reductions in
body weight!
But, suicidal ideation
Pulled from market
Increase endocannabinoids
Block the enzymes that break them down
No need to administer cannabinoids!
MAGL
FAAH
Presynaptic
Neuron
Postsynaptic
Neuron
CB1
CB1
JZL184
anandamide
2-AG
2-AG
URB597
Increase endocannabinoids
Block the enzymes that break them down
No need to administer cannabinoids!
Target other receptors
CB2 receptors, others(?)
Allosteric sites
○ e.g., alcohol, benzodiazepines
○ Do no bind directly to CB1
MAGL
FAAH
Presynaptic
Neuron
Postsynaptic
Neuron
CB1
CB1
anandamide
2-AG
2-AG
ZCZ011
ZCZ011
CB1 pos allosteric modulation
blocks neuropathic pain in mice
Ignatowska-Jankowska et al., 2015
Depression Anxiety
Eating disorders Arthritis
Epilepsy Brain injury/stroke
Fibromyalgia Cancer (Anti-tumor) Migraine
Tourette’s syndrome Neurotrauma/Neurotoxicity
Pain
Memory enhancement
Drug, Alcohol addiction
Smoking cessation
Spasticity (Multiple Sclerosis, spinal cord injury)
Neurodegenerative disorders (ALS, Parkinson’s, Alzheimer’s)
Depression Anxiety
Eating disorders Arthritis
Epilepsy Brain injury/stroke
Fibromyalgia Cancer (Anti-tumor) Migraine
Tourette’s syndrome Neurotrauma/Neurotoxicity
Pain
Memory enhancement
Drug, Alcohol addiction
Smoking cessation
Spasticity (Multiple Sclerosis, spinal cord injury)
Neurodegenerative disorders (ALS, Parkinson’s, Alzheimer’s)
Clinical use of cannabinoids
Anti-emesis
Chronic wasting
Glaucoma – intraocular eye pressure
Neuropathic pain
Epilepsy?
What about cannabidiol?
Very little is understood about CBD, a
plant-based cannabinoid
Does not bind to cannabinoid receptors
Seems to have some anti-inflammatory
effects in rodents
Effects in humans not well studied
Keep in mind all plant-based cannabinoids
are Schedule I compounds
What about cannabidiol?
Either THC or CBD attenuate
convulsions in rats
CBD may be effective as antiepileptic in
kids with Dravet syndrome
Only 1 study to date, so replication is
needed
Again, access to CBD is limited due to
Schedule I status
Take-home points
Cannabinoids act on CB1 (behavior) and CB2 (immune) receptors
Endocannabinoids are the natural ligands
Enzyme inhibitors that increase eCBs block pain and inflammation in animals, unclear how effective in people
Manipulation of different eCB system targets may have cleaner health applications than cannabis
