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ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 1
Medical Marijuana and Epilepsy: Separating the Myths from Reality
Michael Podell MSc, DVM, DACVIM (Neurology)MedVet Chicago
773-281-7110
Disclaimer
“We shall, by and by, want a world of hemp more for our own consumption."John Adams, 2nd U.S. President
Native American
ceremonial and medicinal
use
•1200-1400
Spain brings hemp to New World
•1545
Extract of Cannabis widely available•1800-1900
US restrictions begin
•1906
Oregon decriminalizes
•1973
Congress ends ban
on medical cannabis•2014
Historical Medicinal Use Of Cannabis
8000 BCE•Chinese
cultivation for various uses
1500 BCE to 350 CE•Middle East
medicinal use for childbirth, pain, epilepsy
Middle Ages•European
and New World
•1600’s for epilepsy
1800’s •Western
medicine: Analgesia, mood enhance-ment,epilepsy
Early 1900’s•Unregulated
use for a variety of disorders
1970-1980’s•First
controlled studies in epilepsy
1985•First
approved synthetic THC drug for nausea in US
Why Consider Medical Marijuana In The Treatment Of Epilepsy? People
High prevalence
50 million worldwide (0.71%)
2.2 million US
High Incidence
200,000 / year in US
30% in children
Increase in Drug-Resistant Epilepsy
27-34% in US
24 approved AED in the US alone
Dogs
High prevalence similar to people
0.62% to 0.8% reported
Translates to 583,100 dogs in US
Unknown incidence
Increase in Drug-Resistant Epilepsy
20-30%
Adult Control Adult DRE
Pediatric Control Pediatric DRE
United States
Regulatory Issues Related To Medical Marijuana
US: Schedule I drug
The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. lawAlice Mead, JD (2017) Epilepsy and Behav; 70: 288
ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 2
Cannabis Horticulture
Annual plant with ubiquitous growth in various climates throughout world
Rapid indoor growth in 9 weeks to optimal flowering stage
Non-cannabinoid components
Primary plant metabolites directly involved in plant growth
Cannibinoid components
Secondary plant metabolites indirectly involved in plant growth
Known as terpenophenolic compounds
Highest concentration found in unpollinated all female floral material and upper leaf foliage
Found in glandular trichomes on epidermal appendages
SPECIES
Exogenous Cannabinoids
Cannabinoids are chemical substances isolated from C. Sativa, and to its derivatives and transformation products
85 terpenophenolic compounds identified
Phytocannabinoids compounds that are plant derived, of which 11 sub-types have been defined.
Psychotropic forms, which contain ∆-9 tetrahydrocannabinol (THC)
Non-psychotropic forms, which do not contain ∆-9 THC
Global effect on body
The Unknown VariablesTHC
CBD
Other
1.16
.01
.14
ME-M 21 WEEKS
2.50
.03
.29
ME-M 25 WEEKS
Endocannabinoid System Anandamide (AEA)
2-Arachidonolyglycerol (2-AG)
CB1 receptor agonist
Ubiquitous reduction in presynaptic neurotransmission
Local effect in brain
CB1 receptor
Signal direction for neurotransmitters
Signal direction for endocannabinoids
CB2 activation
Decrease glutamate:Depolarization Induced Suppression Of Excitation(pyramidal cells)
Decrease GABA:Depolarization Induced Suppression Of Inhibition
Less likely to fire
More likely to fire
G-protein coupledcalcium influx inhibition
CB2
ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 3
Decrease Inhibition
Decrease Excitation
GLUTAMATE
GABA
DepolarizaitonThreshold
Human Endocannibinoid System
Canine Endocannibinoid System
Spatial distribution of cannabinoid receptortype 1 (CB1) in normal canine central andperipheral nervous systemJessica Freundt-Revilla1,2☯*, Kristel Kegler2,3☯¤, Wolfgang BaumgaÈrtner2,3, Andrea Tipold1,2
PLOS ONE | https://doi.org/10.1371/journal.pone.0181064 July 10, 2017
CB1 IHC staining:- Neuropil of the cerebral cortex, Cornu Ammonis (CA)
and dentate gyrus of the hippocampus, midbrain, cerebellum, medulla oblongata and
- Grey matter of the spinal cord. - Globus pallidus and substantia nigra surrounding
immunonegative neurons.- Astrocytes were constantly positive in all regions. - CB1 labelled neurons and satellite cells of the dorsal root
ganglia, and myelinating Schwann cells in the PNS.
Psychotropic Forms
CB1 receptor CB2 receptor
∆-9 THC Main constituent
Partial agonist Partial agonistInverse agonist (low dose)
∆-8 THC Partial agonist Inactive
Cannbinol Minimal partial agonist Partial agonist
∆-9 THCannabivarin Partial antagonist Partial agonist
∆-9 THC
Non-Psychotropic Forms Mechanisms Of Action:∆-9 THC And Cannabidiol (CBD)
Action/Effect ∆-9 THC CBD
Cannabinoid type 1 receptor Psychotropic Neuroprotection
Partial Agonist Indirect antagonist
Cannabinoid type 2 receptor Peripheral tissue (immune, muscle)
Partial Agonist Indirect agonistBlocks:• GPR55 receptor• ENT
5-HT receptor (serotonin) Increase serotonin Inactive Agonist
TRPA 1 cation receptor Decrease calcium flux Inactive Agonist
Glycine receptors (alpha 1 and 3)
Increase interneuroninhibition (Analgesic)
Inactive Agonist
Adenosine uptake Anti-inflammatory Inactive Inhibit
Fatty acid amide hydrolase Anti-oxidant Inactive Inhibit
ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 4
Neuroprotective Mechanisms
Cannibinoid Receptor Dependent Cannibinoid Receptor Independent
Neurons Glial cellsCB1 CB1
Unknown Factors
Feranando – Ruiz et al, 2014
CB1 Unknown Factors
Summary of Potential Anti-Convulsant Mechanisms of Action
Decrease seizure onset
Decrease glutamate mediated excitation
Decrease seizure propagation
Increase glycine mediated inhibition
Decrease intracellular calcium
Negative feedback through G-coupled receptor proteins
Potentiates endocannabinoid system
Vanilloid (TRPV1) receptor blocker
Improved therapeutic safety by reducing THC psychotropic effects
Potentiates THC anti-seizure effect
Comparison Of CBD Pharmacokinetics Between Human And Dog
Human Oral
DogOral IV
BioavailabilityHigh first pass effect through liver
6% 3 dogs: 03 dogs: 13-19
6-10
Concentration max (ug/L) 3 +/- 3.1 0 to NR 13.6
T max (hour) 2.8 +/- 1.3 0 to NR NR
Volume of distribution (L/kg) 32 0 to NR 100
Terminal elimination half-life (hour) 18-32 0 to NR 9
Primary method of metabolism Cytochrome P450 Cytochrome P450
Clearance (ml/min) 960-1560 0 to NR 265-288
Protein binding High High
Samara et al; Drug Metab, 1988
∆-9 THC Distribution
Human Canine
Higher concentration without tolerance
Liver, kidney, brain, heart and lymph nodes
46% in the brain
Cerebral and cerebellar gray matter
Mitochondria
Lower concentration after tolerance
Pituitary and putamen
Synaptic vesicles
Martin et al J Pharmacol Exp Therap 196:128-144, 1976
TOXICITY
EFFICACY TI TI
Safety: Therapeutic Index (TI)
∆-9 THC: Lower TI
Decreased psychomotor performance
Impaired glucose tolerance
Hepatotoxicity
Autonomic dysfunction: Heart, GI,vision
Decreased T-lymphocyte function
Physiologic addiction
CBD: Higher TI
Sedation primary adverse effect
Non-lethal
No other known adverse effects
CBD And Epilepsy
Historical
Laboratory: in vitro and in vivo
Anecdotal
Clinical studies
ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 5
Historical
First documentation of treatment of an drug-resistant epileptic patient
Refractory bromide therapy
Treated with C. indica extracts three times per day
“Fits ceased at once” without recurrence for 6 months when the patient discontinued treatment, but remitted once treatment was restarted
William Gowers John Russell Reynolds
Reynolds JR Therapeutic uses and toxic effects of Cannabis indica. Lancet, 1868;1:637-638
Animal Model STUDIES
Psychotropic9 STUDIES
∆-9 THC
2 positive
1 negative (dog)
∆-9 THCV
1 positive
CBN
1 positive
Synthetic CB1R
agonists
3 positive and 1
negative
Non-psychotropic
10 STUDIES
CBD
4 positive
CBDV
2 positive
Synthetic CBR1
antagonists
1 positive and 3
negative
Maximal electroshock
(MES)
PTZ or penicillin
Endocannibinoids Are Altered In Epilepsy
11.65
3.19 3.192.55
4.94
8.3
HUMAN CANINE CANINE >6 MONTHS
PMO
L/M
L
CSF ANANDAMIDE (AEA)
CONTROL EPILEPTIC
Cause? Human (n= 6) Romige et al Epilepsia 2010
Newly diagnosed, untreated patients with temporal lobe epilepsy
Hypothesis is that normal AEA needed to prevent onset of seizures
Effect? Canine (n= 40) Gesell et al BMC Vet Research 2013
Evaluation of new onset and chronic (? treated) epileptics
Hypothesis is that an increase in AEA represents a counter-regulatory process with chronic epilepsy to decrease glutamate neurotransmission
Human Studies: Anecdotal
Porter and Jacobsen Epil Behav29:574-577, 2013
N= 19
Mattern et al Epilepsia 56:1-16, 2015
n=353n=84
n=173n=642
Open Label, Randomized Clinical Studies
3 studies performed
Mechoulam and Carlini, 1978; Cunha et al, 1980; Ames and Cridland, 1986
N = 17 treated and 19 placebo
Duration: Weeks to months (all < 1 year)
Outcome: 4/17 ( 24%) reported to have reduction in seizure frequency
Detractors
Heterogeneous patient population
No details on randomization
Varying dose schedule
No reliable conclusions
Gloss and Vickrey. Cannabinoids in epilepsy. Cochrane Database Syst Review 2014
Double-Blinded, Randomized Clinical Studies
N 20 mg/kg 10 mg/kg Placebo
Lennox-Gastaut (1) 86 44* --- 22
Lennox-Gastaut (2) 73 42* 37* 17
Dravet (3) 59 39* ---- -----
Epidolex plus current AED therapy for all studiesResults are % median monthly seizure reduction; * Significant difference from placebo
1 GW Pharmaceuticals [Internet]. GW Pharmaceuticals announces positive phase 3 pivotal trial results for Epidiolex (cannabidiol) in the treatment of Lennox-Gastaut syndrome (press release June 27, 2016). Cited November 8, 2016.2. GW Pharmaceuticals [Internet]. GW Pharmaceuticals announces second positive phase 3 pivotal trial for Epidiolex (cannabidiol) in the treatment of Lennox-Gastaut syndrome (press release, September 26, 2016). Cited November 8, 2016.3. GW Pharmaceuticals [Internet]. GW Pharmaceuticals announces positive phase 3 pivotal study results for Epidiolex (cannabidiol) (press release March 14, 2016). Cited November 8, 2016.
ISVMA 2017 November, 2017
Dr. Michael Podell MedVet Chicago 6
Can Dogs Benefit From And Contribute To The Study Of Cannabis In Chronic Epilepsy?
Pro• High prevalence
unprovoked seizures• High prevalence DRE• Similar response to AED• Similar endocannabinoid
system and receptors
Con• Unknown pharmacokinetics• Unknown tolerance• Legal issues• Wide variety of
homeopathic agents
Industrial hemp
Stalk, fiber, oil and sterilized seed
Less than 0.3% THC
Claim of high concentration of CBD but no information on label
Other terpenoids and flavonoids of unknown type and concentration
No published scientific papers
No oversight in production
Issues For Veterinary Use
Unregulated use in states with legalized marijuana
100% increase in report of canine toxicity in 2 Colorado veterinary hospitals
Dogs have a low threshold for psychoactive effects
Sensationalist social medial results preys on owners desire to help their epileptic pets
Discrepancy between public perception and scientific reality
Validity issues for translational research from rodent to dog to human
Difficulty in obtaining medical grade drug to establish controlled studies in the US
Summary
CBD has a proven anticonvulsant effect in vitro and in rodent animal models
Dogs have a high first past effect of CBD through liver which limits distribution to the brain
Endocannabinoid system alterations exist in canine epilepsy that could indicate that pharmacologic manipulation of this system may be a therapeutic option
Phase II and III clinical trials in severely affected epileptic children indicates promise for future studies
Double-blinded, randomized clinical trials are extremely important to remove the placebo effect in veterinary medicine
