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) 1 st Century AD in China > 100 ailments Medicinal use in ancient Egypt, India, Africa, Greece, Rome and Arab world
Cannibas Species Cannabis sativa oldest known species used by humans (China) >420 compounds: e.g. Eugenol: acts at GABA A 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
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
Endocannabinoids (ecbs) -ecb production stimulated by: Ca ++ influx 2 o 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
DiMarzo, 2004 Endocannabinoids
CB1-Recepetor Gene Expression Mouse Brain : Activity-dependent activation of VGCC (increase [Ca2+]i) or mglur1 Allen Brain Atlases
Exogenous Cannabinoids Δ 9 Tetrahydrocannabinol (THC) Psychoactive CB1 agonist Cannabidiol (CBD) Non-psychoactive Very slight CB1/CB2 indirect antagonist; opposes some CNS effects of THC Antagonist at GPR55 receptor,? CBD receptor
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-HT 1a 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 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
Cannabinoids: Anti-Seizure Efficacy Whalley, 2014 American Herbal Pharmacopoeia
CBD : No Motor or Coordination Toxicity Static Beam Test: % Fail Static Beam Test: Distance Travelled
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.
Cannibas
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.
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)
Cannabidiol (CBD) has antiseizure 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
Marijuana Use Among Epilepsy Patients (Gross et al, 2004) Tertiary care center: 136 patients 48% lifetime use 21% active users, 15% in last month
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
Four Controlled CBD Trials in Epilepsy STUDY INCLUSION CRITERIA Notes PT # DOSE TIME EFFICACY SAFETY Mechoul am (1978) TLE/TRE Groups not matched;? AEDs, no stats 9 4 CBD 5 PLA 200/d x 3 mos 5 Rx d: 2 Sz free, 1 better, 1 unchanged 4 Placebo: unchanged No adverse events Cunha (1980) TLE/TRE >= 1 TCSz/wk DB? 15 7 CBD 8 PLA 200-300 mg/d 3-18 wks 4 CBD seizure free; 1 control seizure free Seizure-free: 1 placebo 4 CBD Ames (1985) Residential/M R/TRE -baseline data 12? CBD v PLA 200 mg/d x 4wks No group differences Mild drowsiness Trembly (1990) TRE adults Conflict 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 cognbehavior tasks No 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 1 st 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
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)
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)
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
CBD: Potential Clinical Uses Epilepsy Neuropsychiatric disorders Anxiety Psychosis/Schizophrenia Addiction Neonatal hypoxic-ischemic encephalopathy
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