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Treatment of Epilepsy with Cannabadiol (CBD)
Jonathan J. Halford, MD Professor of Neurology, Psychiatry, and Behavioral Science The Medical University of South Carolina Charleston, SC
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Disclosures Consultant: Brain Sentinel, Takeda, NCGH
Investigator for clinical trials funded by Biogen, Greenwich Biosciences, SK Life Sciences, Brain Sentinel, Takeda, Biogen and the Epilepsy Study Consortium.
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Modulation of the Endocanabanoid System by Phytocannabinoids
VanDolah HJ et al. Clinicians’ Guide to Cannabidiol and Hemp Oils. Mayo Clinic Proceedings. Mayo Clin Proc. 2019;94(9): DiMarzo, 2004
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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: ; 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
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CBD Mechanism of Action Epilepsy
Cannabidiol does not exert its anti-convulsant effects through CB1 receptors, nor through voltage-gated sodium channels. CBD does not directly bind to, nor activate, CB1 and CB2 receptors at concentrations pharmacologically relevant to its anticonvulsant effect. CBD may exert a cumulative anti-convulsant effect, modulating a number of endogenous systems including, but not limited to: modulation of intracellular calcium (desensitizes TRPV1, antagonizes GPR55) possible anti-inflammatory effects (inhibiting ENT1 leads to reducing adenosine uptake) Nichol, Kathryn et al. The proposed multimodal mechanism of action of cannabidiol (CBD) in epilepsy: modulation of intracellular calcium and adenosine-mediated signaling (P ). Presented at American Academy of Neurology Annual Conference. April 2019
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CBD Pharmacology Oral bioavailability: low ~13-19%
Not very water soluble (lipophilic; dissolved in oil) Oral Cmax: within 1-4 hours (~2 hours) Protein binding: high (~90%) Volume distribution: very high (lipophilic) Linear pharmacokinetics Taylor L et al. A Phase I, Randomized, Double‑Blind, Placebo‑Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs (2018) 32:1053–1067
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CBD Pharmacology Half life: ~1-2 hours for single-dose oral CBD, possibly 2-5 days after chronic oral CBD – and we don’t know about minor metabolite 7-OH-CBD which is active Extensive first-pass hepatic metabolism and major metabolite 7-COOH-CBD (inactive) is excreted via kidney Drug-drug interactions: many Inhibits CYP2C family of isoenzymes -- can elevate blood levels of clobazam and 7-OH-CBD metabolite Can cause liver toxicity, especially when used with valproate Taylor L et al. A Phase I, Randomized, Double‑Blind, Placebo‑Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs (2018) 32:1053–1067
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CBD Pharmacology – Dravet Patients
Devinsky O et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018; e1-e8.
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CBD/clobazam Interaction – Dravet Patients
Devinsky O et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018; e1-e8.
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CBD : No Motor or Coordination Toxicity
Static Beam Test: % Fail Static Beam Test: Distance Travelled Jones et al., Seizure 21:
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Controlled Substances Act (CSA) 1970 Controlled Substances Act (CSA) 1970: DEA Scheduling
Class I: highest risk for abuse/dependence: heroin, LSD, marijuana, CBD (natural and synthetic) Class II: high risk for abuse/dependence: include cocaine, morphine, opium, oxycodone, Dexedrine, Adderall, and Ritalin Class III: Lower potency opiates, others: products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone, perampanel (Fycopa) Class IV: Benzos, sleep aids, others: Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol, phenobarbital Class V: antidiarrheal, antitussive, and analgesic purposes: cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Parepectolin, pregabalin (Lyrica), lacosamide (Vimpat)
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CBD : Probably No Abuse Potential
Static Beam Test: % Fail Static Beam Test: Distance Travelled Jones et al., Seizure 21:
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CBD : Probably No Abuse Potential
Static Beam Test: % Fail Static Beam Test: Distance Travelled Jones et al., Seizure 21:
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Recent Controlled Treatment Studies in Epilepsy with CBD
Dravet Syndrome (pediatric studies; Greenwich Biosciences; Epidiolex) Two positive double-blind placebo controlled studies Open label long term data looks good (so far) after ~3 years Lennox-Gastaut Syndrome (adult and pediatric; Greenwich Biosciences; Epidiolex) One positive pediatric double-blind placebo controlled study One positive adult double-blind placebo controlled study (adult) Tuberous Sclerosis Complex (adult and pediatric; Greenwich Biosciences; Epidiolex) One positive double-blind placebo controlled study: 224 subjects (age 1-65) who had medication refractory TSC-related focal and generalized seizures Focal Epilepsy (adult; Zynerba; ZYN002 gel) One Phase 2 double-blind placebo controlled study (STAR trial) failed on primary outcome measure
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Lennox-Gastaut Syndrome
Severe epilepsy that begins in childhood, usually between ages 3 and 5. Multiple seizure types (most are brief seizures), often AED refractory Tonic seizures (more than 75% of pts), most often during sleep. atypical absence seizures, atonic seizures (“drop attacks”), which can result in falls that cause serious or life-threatening injuries. generalized tonic clonic seizures Non-convulsive status epilepticus Cognitive disability (usually moderate to severe) EEG with interictal slow spike-wave complexes No uniform cause –epileptic encephalopathy secondary to multiple brain conditions: West syndrome, development brain disorder, tuberous sclerosis, hereditary metabolic diseases, encephalitis, meningitis, and toxoplasmosis, hypoxia-ischemia, injury and other birth injuries; and lesions of the frontal lobe
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Dravet Syndrome Genetic epileptic encephalopathy (SCN1A)
Prolonged febrile and non-febrile seizures (often long ~30 min) within the first year of a child’s life. Progression to other seizure types: myoclonic seizures Focal seizures Generalized tonic clonic seizures Psychomotor delay and ataxia Cognitive impairment, behavioral disorders (ADHD), and motor deficits.[3] Becomes worse as the patient ages, as the disease is not very observable when symptoms first appear.[3] Large range of severity Poor response to many AEDs and sodium channel AEDs can worsen the condition
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Inclusion Criteria (LGS)
Diagnosis of Lennox-Gastaut Syndrome Slow spike-wave (less than 3 per second) on EEG More than one type of generalized seizure, including drop seizures for at least 6 months Medication refractory (having failed at least 2 previous drugs) and on 1-4 concomitant AEDs Having at least 2 drop seizures per week during 4 week baseline period
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Thiele, Elizabeth A. , et al
Thiele, Elizabeth A., et al. "Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial." The Lancet (2018):
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LGS Results
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LGS Results
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Hy’s Law The drug causes hepatocellular injury, generally ALT or AST > 3X ULN with aminotransferases much greater (5-10x ULN) Among subjects showing such aminotransferase elevations, they also have elevation of their serum total bilirubin of greater than 2× the upper limit of normal, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2× the upper limit of normal). No other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injury.
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Dravet Syndrome Results
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Dravet Syndrome Results
Convulsive seizures = tonic, clonic, tonic-clonic or atonic seizures
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Dravet Syndrome Results
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MUSC Comprehensive Epilepsy Center
Changing What’s Possible
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