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 Medicine

  • Cannibas 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 glia

    Principal 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 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.

  • EndocannabinoidsDiMarzo, 2004

  • CB1-Recepetor Gene ExpressionMouse Brain: Activity-dependent activation of VGCC (increase [Ca2+]i) or mGluR1Allen Brain Atlases

  • Exogenous Cannabinoids

    Cannabidiol (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 agonist

  • CBD: 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 permission

  • CBD: 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 Pharmacopoeia

  • CBD : No Motor or Coordination ToxicityStatic 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 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.

  • Cannibas

  • Gowers: 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 Pharm

  • Marijuana Use Among Epilepsy Patients (Gross et al, 2004)Tertiary care center: 136 patients48% lifetime use21% active users, 15% in last month

  • Small 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 tolerated

  • Four Controlled CBD Trials in Epilepsy

    STUDYINCLUSION 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 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 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 RCT

  • CBD: Potential Clinical UsesEpilepsyNeuropsychiatric disordersAnxietyPsychosis/SchizophreniaAddictionNeonatal hypoxic-ischemic encephalopathy

  • ConclusionsData 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