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

Transcription

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) 1 st Century AD in China > 100 ailments Medicinal use in ancient Egypt, India, Africa, Greece, Rome and Arab world

3 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

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 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

6 DiMarzo, 2004 Endocannabinoids

7 CB1-Recepetor Gene Expression Mouse Brain : Activity-dependent activation of VGCC (increase [Ca2+]i) or mglur1 Allen Brain Atlases

8 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

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-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

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: ; 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

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 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

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 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 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

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 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

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