cannabidiols & epilepsy orrin devinsky, m.d. department of neurology nyu langone school of...

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Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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Page 1: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Cannabidiols & Epilepsy

Orrin Devinsky, M.D.Department of Neurology

NYU Langone School of Medicine

Page 2: 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

Page 3: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 4: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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)

Page 5: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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.

Page 6: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Endocannabinoids

DiMarzo, 2004

Page 7: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

CB1-Recepetor Gene Expression

Mouse Brain

: Activity-dependent activation of VGCC (increase [Ca2+]i) or mGluR1

Allen Brain Atlases

Page 8: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 9: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 10: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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)

Page 11: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Cannabinoids: Anti-Seizure Efficacy

Whalley, 2014 American Herbal Pharmacopoeia

Page 12: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

CBD : No Motor or Coordination Toxicity

• Static Beam Test: % Fail

• Static Beam Test: Distance Travelled

Jones et al., 2012. Seizure 21: 344-352

Page 13: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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.

Page 14: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Cannibas

Page 15: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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.

Page 16: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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)

Page 17: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 18: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Marijuana Use Among Epilepsy Patients (Gross et al,

2004)

• Tertiary care center: 136 patients• 48% lifetime use• 21% active users, 15% in last month

Page 19: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 20: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 21: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 22: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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)

Page 23: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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)

Page 24: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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

Page 25: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

CBD: Potential Clinical Uses

• Epilepsy•Neuropsychiatric disorders• Anxiety• Psychosis/Schizophrenia• Addiction•Neonatal hypoxic-ischemic encephalopathy

Page 26: Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

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