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

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Cannabidiols & EpilepsyOrrin Devinsky, M.D.Department of NeurologyNYU Langone School of MedicineCannibas in HistoryCannibas sativa ? ~8,000 bce in China - ropeCultivated, used for garments, bowstrings, paper and medicine in China2700 bce cannibas (ma) for menstruation, gout, rheumatism, malaria, constipation, and absentmindedness (Abel, 1980)1st Century AD in China > 100 ailmentsMedicinal use in ancient Egypt, India, Africa, Greece, Rome and Arab world Cannibas SpeciesCannabis sativa oldest known species used by humans (China)>420 compounds: e.g. Eugenol: acts at GABAA receptors80 terpeno-phenol compounds, cannabinoidsCannabis indica reference in Ancient Vedas text in India, ~ 1700 bceSativa usually THC:CBD ratio v. indica. Sativa more psychic and stimulatoryIndica strains have more sedative properties Endodogenous Cannabinoids (Endocannabinoids (eCBs))Wilson and Nicoll 2002, ScienceNeuromodulatory lipids released by the postsynaptic membranes in response to neuronal activity Arachidonic acid derivatives produced by neurons and gliaPrincipal eCBs2-Arachidonoylglycerol (2-AG)Anandamide Hydrolyzed by fatty acid amide hydrolase (FAAH)CB Receptors G-protein-coupledCB1 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 firingActivation of some Gq-coupled neurotransmitter receptors and glucocorticoid receptorseCBs 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.EndocannabinoidsDiMarzo, 2004CB1-Recepetor Gene ExpressionMouse Brain: Activity-dependent activation of VGCC (increase [Ca2+]i) or mGluR1Allen Brain AtlasesExogenous CannabinoidsCannabidiol (CBD) Non-psychoactive Very slight CB1/CB2 indirect antagonist; opposes some CNS effects of THC Antagonist at GPR55 receptor, ? CBD receptor9 Tetrahydrocannabinol (THC) Psychoactive CB1 agonistCBD: Mechanisms of ActionG-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 permissionCBD: Anti-seizure & Anti-epileptic effectsFrom Whalley with permissionCBD 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 EfficacyWhalley, 2014 American Herbal PharmacopoeiaCBD : No Motor or Coordination ToxicityStatic Beam Test: % FailStatic Beam Test: Distance TravelledJones et al., 2012. Seizure 21: 344-352Cannibas Efficacy Claims:US Dispensary (1854): neuralgia, depression, hemorrhage, pain and muscle spasmOhio 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.CannibasGowers: C. indica for Epilepsy40yo 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 effectExt. 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 DataDavis & Ramsay (1949) THC for 5 institutionalized children who failed PB & PHT - 1 seizure free, 1 almost seizure free; 3 no changeConsroe et al (1975) - young man with epilepsy on PB & PHT. Marijuana led to seizure free with AEDs but not aloneCase 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 effectsMost 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 PharmMarijuana Use Among Epilepsy Patients (Gross et al, 2004)Tertiary care center: 136 patients48% lifetime use21% active users, 15% in last monthSmall Controlled TrialsCunha et al (1980) 16 refractory TCSz pts: 8 received CBD 200 or 300 mg/dy, 8 placebo; all onAEDsCBD: 3 seizure free, 4 improved, 1 unchangedPlacebo: 1 improved, 7 unchangedAmes (1986): 12 pts given CBD 200 to 300 mg/dy with AEDs: no benefitTrembly & 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 toleratedFour Controlled CBD Trials in EpilepsySTUDYINCLUSION CRITERIANotesPT #DOSETIMEEFFICACYSAFETYMechoulam (1978)TLE/TREGroups not matched; ? AEDs, no stats94 CBD5 PLA200/d x 3 mos5 Rxd: 2 Sz free, 1 better, 1 unchanged4 Placebo: unchangedNo adverse eventsCunha (1980)TLE/TRE >= 1 TCSz/wkDB?157 CBD8 PLA200-300 mg/d3-18 wks4 CBD seizure free; 1 control seizure freeSeizure-free:1 placebo4 CBDAmes (1985)Residential/MR/TRE-baseline data12? CBD v PLA200 mg/d x 4wksNo group differencesMild drowsinessTrembly (1990)TRE adultsConflict of 90 paper and 92 chapter12 ?CBD v PLAPLAC x 6 mos, CBD 300/dy x 6 mos No group differences on seizures or cogn-behavior tasksNo dataEvidence 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 controlsHeroin use was a risk factor (unprovoked OR 2.8; provoked 3.6)CannabisUnprovoked 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 daysIOM (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>THC19 children (2-16 years) used a CBD-enriched medical marijuana 16 (84%) reduction in seizure frequency2 were seizure free8 (42%) >80% reduction in seizures6 had a 25-60% reduction in seizures. (Porter & Jacobson, Epilepsy & Behavior, 2013) Survey of 19 Pediatric Epilepsy Patients on CBD-enriched CannabisBenefits 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) StudiesNYU enrolled 25 children and young adults with TRE Dravet, LGS, Focal epilepsy, CDKL4, etc5 other site are enrolling or will soon enroll 25 children/site (UCSF, Lurie Childrens, MGH, CHOP, Great Ormond St)Orphan drug indication approved by FDA for Dravet and LGS plans for RCTCBD: Potential Clinical UsesEpilepsyNeuropsychiatric disordersAnxietyPsychosis/SchizophreniaAddictionNeonatal hypoxic-ischemic encephalopathyConclusionsData 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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