Transcript Afternoon Keynote Address

Cannabidiols & Epilepsy
Orrin Devinsky, M.D.
Department of Neurology
NYU Langone School of Medicine
Cannibas in
History
• Cannibas sativa – ? ~8,000 bce in China - rope
• Cultivated, used for garments, bowstrings,
paper and medicine in China
• 2700 bce – cannibas (ma) for menstruation,
gout, rheumatism, malaria, constipation, and
absentmindedness (Abel, 1980)
• 1st Century AD in China > 100 ailments
• Medicinal use in ancient Egypt, India, Africa,
Greece, Rome and Arab world
Cannibas
Species
• Cannabis sativa – oldest known species used by
humans (China)
• >420 compounds: e.g. Eugenol: acts at GABAA
receptors
• 80 terpeno-phenol compounds, “cannabinoids”
• Cannabis indica – reference in Ancient Vedas
text in India, ~ 1700 bce
• Sativa usually THC:CBD ratio v. indica.
• Sativa more psychic and stimulatory
• Indica strains have more sedative properties
Endodogenous Cannabinoids
(Endocannabinoids (eCBs))
• Neuromodulatory lipids released by the postsynaptic
membranes in response to neuronal activity
• Arachidonic acid derivatives produced by neurons and glia
Principal eCBs
• 2-Arachidonoylglycerol (2-AG)
• Anandamide
• Hydrolyzed by fatty acid amide hydrolase (FAAH)
CB Receptors – G-protein-coupled
• CB1 receptors (mainly CNS)
• CB2 receptors (mainly immune cells)
Wilson and Nicoll 2002, Science
Endocannabinoids (eCBs)
• -eCB production stimulated by:
• Ca++ influx 2o to strong neuronal depolarization or
burst firing
• Activation of some Gq-coupled neurotransmitter
receptors and glucocorticoid receptors
• eCBs modulate retrograde synaptic signaling
• Activation of CB1-R ’s neurotransmitter release
• CB1-R on GABAergic and glutamatergic axon terminals
synapsing onto neurons whose axons project distally.
• CB1 synaptic suppression is transient or longer lasting
depending on pre- & postsynaptic activity levels.
Wilson and Nicoll 2002, Science
Endocannabinoids
DiMarzo, 2004
CB1-Recepetor Gene Expression
Mouse Brain
: Activity-dependent activation of
VGCC (increase [Ca2+]i) or mGluR1
Allen Brain Atlases
Exogenous Cannabinoids
Δ9 Tetrahydrocannabinol
(THC)
Psychoactive
CB1 agonist
Cannabidiol (CBD)
Non-psychoactive
Very slight CB1/CB2
indirect antagonist; opposes
some CNS effects of THC
Antagonist at GPR55 receptor,
? CBD receptor
CBD: Mechanisms of Action
• G-protein-coupled receptor GPR55 antagonist:
presynaptic Ca++ release (Sylantyev et al, PNAS 2013)
• Inhibit the degradation (FAAH) and reuptake
of anandamide, ECs (Bisogno. 2001, Brit J Pharm)
• Equilibrative nucleoside transporter
• 5-HT1a receptor
• Neuroprotective and anti-inflammatory effects
• Alters Ca2+ flux
(De Petrocellis et al. 2011, Brit J of Pharm;
Bisogno et al. 2001, Brit J of Pharm, Qin et al 2008, J Neurosci) Whalley
with permission
CBD: Anti-seizure &
Anti-epileptic effects
• CBD has anticonvulsant effects in > 6 seizure
models in rats and mice; independently of CNS
CB1 receptors (Jones et al, Seizure 2012; Hill et al,
Endocannabinoids 2013:164-204; Hill et al, Brit J of
Pharm 2013; Karler & Turkanis, J Clin Pharm 2013)
• CBD reduces epileptiform activity in vitro (Jones
et al. 2010, J Pharm Exp Ther)
• CBD reduces mortality in pentylenetetrazol
(PTZ) induced seizures (Jones et al. 2010, J Pharm
Exp Ther)
From Whalley with permission
Cannabinoids: Anti-Seizure Efficacy
Species
Compound
Number of
discrete
conditions/mo
dels/designs
Dose
Anticonvulsan
t
No effect
Proconvulsant
THC
6
31
0.25-200
mg/kg
61%
29%
10%*
CBD
2
21
1-400 mg/kg
81%
19%
0%
Other plant
cannabinoids
2
7
N/A
100%
0%
0%
CB1 receptor
agonists
2
55
N/A
73%
18%
2%
(7% mixed
effect)
Whalley, 2014 American Herbal Pharmacopoeia
CBD : No Motor or Coordination Toxicity
• Static
Beam
Test: %
Fail
• Static
Beam
Test:
Distance
Travelled
Cannibas Efficacy Claims:
• US Dispensary (1854): neuralgia, depression,
hemorrhage, pain and muscle spasm
• Ohio Medical Society Committee on
Cannabis Indica (1860): efficacy for neuralgic
pain, dysmenorrhea, hysteria, delirium
tremens, mania, palsy, whooping cough,
infantile convulsions, asthma, nervous
rheumatism, chronic bronchitis, spasms,
tetanus, epilepsy and appetite stimulation.
Cannibas
Gowers:
C. indica for Epilepsy
• 40yo M , sleep & waking fits x 25 years, 1/2wks.
• Attacks ceased for a time on bromide, but recurred
when he discontinued attendance.
• 2 years later, potassium bromide had no effect
• Ext. cannabis indicae 1/6 gr. three times a day: no fit
for six months, discontinued attendance  fits
• At once arrested by the same doses of Indian hemp.
• Free from fits for months, until, during my absence,
bromide substituted for hemp; fits recurred. Return in
6 mos, on hemp passed two months fit free but third
month fit recurred, and he never returned.
Anecdotal Data
• Davis & Ramsay (1949) – THC for 5
institutionalized children who failed PB & PHT
- 1 seizure free, 1 almost seizure free; 3 no
change
• Consroe et al (1975) - young man with epilepsy
on PB & PHT. Marijuana led to seizure free
with AEDs but not alone
• Case reports of marijuana reducing seizure
activity,(Mortati et al, 2007) provoking
seizures,(Tilleli, 2006), or withdrawal causing a
seizure (Hedge et al, 2012)
Cannabidiol (CBD) has antiseizure and anti-epileptic effects
Most notably, in these studies and
others, CBD acts independently of
CB1 receptors in the CNS
(unlike endocannabinoids and THC)
Hill et al 2013, Brit J of Pharm
Marijuana Use Among
Epilepsy Patients (Gross et al, 2004)
• Tertiary care center: 136 patients
• 48% lifetime use
• 21% active users, 15% in last month
Small Controlled Trials
• Cunha et al (1980) – 16 refractory TCSz pts: 8
received CBD 200 or 300 mg/dy, 8 placebo; all
onAEDs
• CBD: 3 seizure free, 4 improved, 1 unchanged
• Placebo: 1 improved, 7 unchanged
• Ames (1986): 12 pts given CBD 200 to 300 mg/dy
with AEDs: no benefit
• Trembly & Sherman (1990): 12 pts on CBD 300
mg/day: ? Slight benefit (no stats)
• Further info in Consroe (1992) – 10 patients in the trial did
not have any change in seizure frequency/intensity. Well
tolerated
Four Controlled CBD Trials in Epilepsy
STUDY
INCLUSION
CRITERIA
Notes
PT #
DOSE
TIME
EFFICACY
SAFETY
Mechoul
am
(1978)
TLE/TRE
Groups not
matched; ?
AEDs, no stats
9
4 CBD
5 PLA
200/d x 3
mos
5 Rx’d: 2 Sz free, 1
better, 1
unchanged
4 Placebo:
unchanged
No adverse
events
Cunha
(1980)
TLE/TRE >= 1
TCSz/wk
DB?
15
7 CBD
8 PLA
200-300
mg/d
3-18 wks
4 CBD seizure free; Seizure-free:
1 control seizure
1 placebo
free
4 CBD
Ames
(1985)
Residential/M
R/TRE
-baseline data
12
? CBD
v PLA
200 mg/d x
4wks
No group
differences
Mild
drowsiness
Trembly
(1990)
TRE adults
Conflict of 90
paper and 92
chapter
12
?CBD v
PLA
PLAC x 6
mos, CBD
300/dy x 6
mos
No group
differences on
seizures or cognbehavior tasks
No data
Evidence from Epidemiology?
• Ng et al (1990) – illicit drug use and risk of new onset
seizures (Am J Epidemiology)
• 308 patients in Harlem after 1st seizure v. 294 controls
• Heroin use was a risk factor (unprovoked OR 2.8; provoked 3.6)
• Cannabis
• Unprovoked OR 0.42 ever used; 0.36 for use last 90
days.
• Provoked OR 1.03 ever used; 0.18 for use in last 90
days
• IOM (1999) – Ng study weak due to lack of health status
before admission; health status may have influenced drug
use rather than vice versa
Survey of 19 Pediatric Epilepsy
Patients on CBD>THC
• 19 children (2-16 years) used a CBD-enriched
medical marijuana
• 16 (84%) reduction in seizure frequency
• 2 were seizure free
• 8 (42%) >80% reduction in seizures
• 6 had a 25-60% reduction in seizures.
(Porter & Jacobson, Epilepsy & Behavior, 2013)
Survey of 19 Pediatric Epilepsy
Patients on CBD-enriched Cannabis
• Benefits included improved alertness, mood,
and sleep.
• Side effects: drowsiness and fatigue.
• Diagnoses: Dravet syndrome (13), Doose
syndrome (4), Lennox Gastaut syndrome (1),
and idiopathic epilepsy (1).
(Porter & Jacobson, Epilepsy & Behavior, 2013)
Epidiolex (98% CBD) Studies
• NYU enrolled 25 children
and young adults with TRE –
Dravet, LGS, Focal epilepsy,
CDKL4, etc
• 5 other site are enrolling or
will soon enroll 25
children/site (UCSF, Lurie
Children’s, MGH, CHOP,
Great Ormond St)
• Orphan drug indication
approved by FDA for Dravet
and LGS – plans for RCT
CBD: Potential Clinical Uses
• Epilepsy
• Neuropsychiatric disorders
• Anxiety
• Psychosis/Schizophrenia
• Addiction
• Neonatal hypoxic-ischemic
encephalopathy
Conclusions
• Data from methodologically limited
clinical trials of CBD, parental reports of
CBD-enriched medical marijuana and
animal studies suggest that CBD may
have valuable anti-seizure properties and
the benefit:risk ratio may be favorable.
• Randomized, placebo-controlled clinical
trials are warranted