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Cannabidiols & Epilepsy

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

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Cannabidiols & Epilepsy

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

  2. 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

  3. CannibasSpecies • 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

  4. 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

  5. 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

  6. Endocannabinoids DiMarzo, 2004

  7. CB1-Recepetor Gene Expression Mouse Brain : Activity-dependent activation of VGCC (increase [Ca2+]i) or mGluR1 Allen Brain Atlases

  8. Exogenous Cannabinoids Cannabidiol (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

  9. 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

  10. 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

  11. Cannabinoids: Anti-Seizure Efficacy Whalley, 2014 American Herbal Pharmacopoeia

  12. CBD : No Motor or Coordination Toxicity • Static Beam Test: % Fail • Static Beam Test: Distance Travelled Jones et al., 2012. Seizure 21: 344-352

  13. 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.

  14. Cannibas

  15. 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.

  16. 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)

  17. 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

  18. Marijuana Use Among Epilepsy Patients (Gross et al, 2004) • Tertiary care center: 136 patients • 48% lifetime use • 21% active users, 15% in last month

  19. 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

  20. Four Controlled CBD Trials in Epilepsy

  21. 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

  22. 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)

  23. 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)

  24. 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

  25. CBD: Potential Clinical Uses • Epilepsy • Neuropsychiatric disorders • Anxiety • Psychosis/Schizophrenia • Addiction • Neonatal hypoxic-ischemic encephalopathy

  26. 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

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