Post on 20-Jan-2016
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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))
Wilson and Nicoll 2002, Science
• 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)
Endocannabinoids (eCBs)
Wilson and Nicoll 2002, Science
• -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.
Endocannabinoids
DiMarzo, 2004
CB1-Recepetor Gene Expression
Mouse Brain
: Activity-dependent activation of VGCC (increase [Ca2+]i) or mGluR1
Allen Brain Atlases
Exogenous CannabinoidsCannabidiol (CBD) Non-psychoactive Very slight CB1/CB2 indirect antagonist; opposes some CNS effects of THC Antagonist at GPR55 receptor, ? CBD receptor
Δ9
Tetrahydrocannabinol (THC)
Psychoactive CB1 agonist
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
From Whalley with permission
• 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)
Cannabinoids: Anti-Seizure Efficacy
Whalley, 2014 American Herbal Pharmacopoeia
CBD : No Motor or Coordination Toxicity
• Static Beam Test: % Fail
• Static Beam Test: Distance Travelled
Jones et al., 2012. Seizure 21: 344-352
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 anti-seizure 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 CRITERIANotes
PT # DOSETIME
EFFICACY SAFETY
Mechoulam (1978)
TLE/TREGroups not matched; ? AEDs, no stats
94 CBD5 PLA
200/d x 3 mos
5 Rx’d: 2 Sz free, 1 better, 1 unchanged4 Placebo: unchanged
No adverse events
Cunha (1980)
TLE/TRE >= 1 TCSz/wkDB?
157 CBD8 PLA
200-300 mg/d3-18 wks
4 CBD seizure free; 1 control seizure free
Seizure-free:1 placebo4 CBD
Ames (1985)
Residential/MR/TRE-baseline data
12? CBD v PLA
200 mg/d x 4wks
No group differences
Mild drowsiness
Trembly (1990)
TRE adultsConflict 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 cogn-behavior 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