Cannabis for Drug Resistant Epilepsy MILA SORIN, MD PEDIATRIC NEUROLOGY APRIL 20, 2018
Introduction -Although more than 20 prescription anti-epileptic drugs (AEDs) are available, they prove to be ineffective in approximately 25 30% of people with epilepsy -Side effects may limit available options -Other options include steroids, vagus verve stimulator, responsive electrical stimulator, ketogenic diet, surgery -Other effects of uncontrolled seizures include cognitive dysfunction, psychiatric comorbidities, behavioral problems -Proportion of patients with uncontrolled seizures has not decreased -Since 2013, Cannabidiol (CBD) has been studied in 10 epilepsy centers using Epidolex
History -Cannabis has been used for thousands of years for medical, religions, and recreational purposes -Most consumed illegal recreational drug worldwide -Originated in Central Asia and cultivated in China for fiber and seed production -Has been used medicinally in China dating back to 2700 BC, in India 1000BC -The first studies on medicinal use of marijuana date back to the Chinese Emperor Shen Nung -Records exist in Arabic and Islamic literature -Cannabis was used as treatment for epilepsy in Victorian times and even earlier
History -The first publication of cannabis for treatment of seizures was in 1843 by W.B. O Shaughnessy He tested Cannabis extract in patients with various disorders -Used in the US through the early 20 th century but halted after its criminalization in the 30s -Cultivation of the plant was made illegal in many countries -In the last few decades studies have showed CBD to have a few therapeutic benefits
History -In 1970 Mechoulam randomized 9 patients with refractory temporal lobe epilepsy to receive CBD or placebo for 5 weeks in addition to their seizure medication. At 3 month follow up, 2 of 4 patients receiving CBD were seizure free compared to 0 patients in the placebo group who showed no improvement -In 1975, a study by Consroe et al described a 24 year old patient with uncontrolled seizures taking phenobarbital and phenytoin who became seizure free after smoking cannabis socially -Use in the US remains restricted because of its status as a Schedule 1 controlled substance -In late 2013, the US Food and Drug Administration granted orphan drug status to an imported, pharmaceutically standardized CBD extract (Epidiolex, GW Pharmaceuticals) as an experimental treatment for pediatric epilepsy. -Clinical trials of its safety and efficacy in children with severe forms of refractory epilepsy, such as Dravet syndrome and Lennox Gastaut syndrome, began in 2014
Number of articles from PubMed using search items cannabis and epilepsy
Cannabis -Genus Cannabis is a flowering plant with 3 main species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. -The plants have >100 biologically active chemicals called cannabinoids with the most neuro-active being CBD and THC (left). -Half life between 18-32 hours
Cannabis sativa/indica -As more states legalize cannabis, dispensaries sell extracts of the plant in oil -Typically strains are high in cannabidiol (CBD) and low in tetrahydrocannabinol (THC) -Marijuana is typically high in THC which is unsuitable for the treatment of epilepsy because of the many undesired effects -compared to THC, CBD shows anticonvulsant effects in animal models
Mechanism of Action -The endogenous cannabinoid system (ECS) is a neuromodulatory system that consists of lipid-like signaling molecules, endocannabinoids, (ECs) that interact with cannabinoid CB1 and CB2 receptors and two endogenous ligands, 2- arachidonoylglycerol (2-AG) and anandamide CB1 receptors are primarily located in neurons while CB2 receptors are primarily located in microglia and some in the immune system CB1 receptors are pre-synaptic in both glutamatergic and GABAergic interneurons, and activation of which results in inhibition of synaptic transmission including glutamate release CB1 receptors mediate neuronal inhibition by decreasing calcium influx and increasing potassium efflux in presynaptic terminals
Mechanism of Action -ECS plays a major role in regulating neuronal excitability, neuroinflammation, and excitotoxicity within the brain -Pharmacological and genetic modulation of the ECS in rodents causes major effects on seizure susceptibility -CBD changes the metabolism of other epilepsy medications such as clobazam, causing their levels to rise.
Mechanism of Action -THC acts as a partial agonist of CB1 and CB2 receptors -CBD has little affinity for CB1 and CB2 receptors but antagonizes CB1/CB2 receptor agonists -CBD also activates 5-HT serotonergic receptors, antagonizes alpha-1 adrenergic receptors and mu-opioid receptors, inhibits uptake of adenosine, dopamine noradrenaline -CBD reduces oxidative damage, T cell responses, TNF release, production of prostaglandin E2, reduces production of nitric oxide and cyclooxygenase
CBD -highly bound to proteins (>99%) -extensively metabolized by cytochrome P450 -enzyme inducing AEDs such as carbamazepine and phenytoin can accelerate CBD metabolism and reduce CBD levels -reinforces sedating effects of other psychotropic substances such as benzodiazepines and alcohol -In one study of 13 patients taking Clobazam, addition of CBD of initial dose of 5mg/kg/day titrated to 25mg/kg/day resulted in increase of clobazam levels by 60% at 4 weeks This interaction is thought to be mediated by inhibition of CYP2c19 -highly lipophilic so distributes extensively into tissues resulting in late-phase half-life of about 24 hours
Lennox-Gastaut Syndrome -may be caused by brain malformations, head injury, CNS infections, metabolic disorders, inherited degenerative disorders -onset typically before age 4 -patients have uncontrolled seizures of various types -nearly all patients are refractory to medications -most children have intellectual disability, developmental delay, and behavioral problems
Dravet Syndrome -severe myoclonic epilepsy of infancy -onset in infancy, often starts with prolonged febrile seizures, then progresses to other seizure types with myoclonic, alternating hemi-convulsions, heat sensitive. ~80-90% associated with SCN1A mutation -nearly all patients are refractory to medications -nearly all children have developmental delay
Clinical Trials -CBD was added to baseline AEDs at an initial dose of 2-5mg/kg/day divided bid -CBD was titrated by 2-5mg/kg/week until 25mg/kg/day or until intolerance -No objective testing in most studies -Most are open label, uncontrolled or surveys -Many relied on parental response bias
C.A. Press, K.G. Knupp, K.E. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav, 45 (2015), pp. 49-52 Study in Colorado reported 22% responder rate for patients originally from Colorado compared to 47% for patients that moved to Colorado, suggesting reporter bias
Drawbacks -CBD is appealing but untested and unregulated -concentration can vary based on plant, weather, soil, and other factors -Studies are mainly retrospective and based on patient or parental reportestimates of efficacy -Some marketed products when tested have been found to have different content of CBD than stated in their label, and some may have harmful contaminants -Preferential use in CBD containing oil or liquid extracts
Strain to strain consistency? State CBD concentration mg/ml Price range (US$/mg CBD) Arizona 8 33 0.20 0.28 8 33 California 3 150 0.07 0.30 1 78 Colorado 7 54 0.07 0.19 7 54 New Jersey 50 250 0.08 0.14 7 250 Tennessee 47 60 0.07 0.11 1.5 30 Washington 1.6 10 0.13 0.31 1.6 10 Manufacturer recommended dose (mg
Retrospective study at Vanderbilt University Medical Center from January 2006-December 2016-108 pediatric patients took CBD oil for epilepsy -33% had >50% reduction in seizure frequency -10% of patients achieved seizure freedom -4% had increase in seizure frequency -Duration of treatment was 1.1 years compared to 2.5 years of Clobazam -most common reason for stopping CBD was lack of benefit, 1% with dizziness, 1% with nausea -positive side effects include 9% with improved alertness, 5% more verbal, 3% with better social interaction, 2% with better mood, 2% with decreased aggression -exact dose was not documented and CBD was obtained from 10 different vendors
Cunha, J. et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology, 1980. 21-15 patients ages 14-49 with intractable temporal lobe epilepsy -Patients were enrolled in a double blind placebo controlled study with 8 patients receiving CBD for 8-18 weeks and 7 patients receiving placebo -4/8 patients receiving CBC had significant improvement in seizures with almost full control of their seizures throughout the study -3/8 patients receiving CBD had partial improvement in seizures, the other 1 patient showed no improvement -3/8 patients receiving CBD showed improvement in their EEG -1/7 patients receiving placebo showed improvement in their seizures
Devinsky O. et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial -214 patients aged 1-30 with intractable childhood-onset epilepsy -20% patients had Dravet syndrome and 19% of patients had Lennox- Gastaut syndrome -patients received oral cannabidiol 2-5mg/kg/day up to 50mg/kg -162 patients achieved 12 weeks of follow up -adverse events reported in 79% patients: somnolence in 25%, decreased appetite in 19%, diarrhea in 19%, fatigue in 13%, convulsions in 11%, status epilepticus in 6%
Devinsky study continued.. -Assessment of efficacy was performed in a subgroup of 137 patients, excluding patients with less than 12 week follow up median reduction in seizures was 36.5% (43% for Dravet patients and 36% for Lennox-Gastaut syndrome patients) 7% of patients became seizure free 50% of patients had 50% or more reduction in motor seizures if also taking clobazam compared to 27% not taking clobazam Patients taking clobazam experienced more side effects, mostly somnolence
Treat L. et al. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia. -retrospective chart review of 119 pediatric patients in Colorado that used oral cannabis extracts (OCE) for treatment of epilepsy -24% had >50% reduction in seizures -71% terminated use of OCE product -19% reported adverse events with most common being somnolence (6%) and worsening seizures (8%) this is much lower than Devinsky study (79%) which may be due to high dosing parameters in the Devinsky trial -39% reported improved behavior/alertness, 8% reported improved motor skills, 7% reported improved sleep -relocation to Colorado was associated with perceived benefit (65% vs 35%)
Tzadok M, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb; 35():41-4. -Study done in Israel in 74 pediatric patients with refractory epilepsy who mostly had epileptic encephalopathies, 90% with cognitive impairment -Patients were treated with CBD oil (CBD:THC ratio 20:1) of 1-20mg/kg/day -unlike other studies, CBD oil was prescribed by a physician -50% of patients reported at least 50% reduction in seizures-many patients reported improvement in alertness, behavior, language, communication, motor skills, and sleep -45% of patients reported side effects including somnolence (22%), seizure aggravation (18%), GI symptoms and irritability (7%)
Devinsky et al. Cannabidiol in Dravet Syndrome Study Group.N Engl J Med. 2017 -double blind study of 23 centers in US and Europe of 120 patients with Dravet syndrome ages 2-18 randomized to receive placebo or CBD 20 mg/kg/day divided bid -duration of treatment was 14 days which included a 2 week titration time -median reduction in monthly seizure frequency was 39% in the CBD group compared to 13% in the placebo group -5% of patients became seizure free in the CBD group compared to none in the placebo group -limitation of the study was 65% of patients were also taking clobazam -Side effects were reported in 75% of patients in the CBD group compared to 36% in the placebo group. Somnolence (36%), diarrhea (31%), decreased appetite (28%), fatigue (20%), worsening seizures (11%) 18/22 who developed somnolence were co-treated with clobazam 8 patients discontinued the trial prematurely in the CBD group due to side effects compared to 1 patient in the placebo group
Mazurkiewicz-Beldzinska M, et al. Treatment with cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-centre, randomised, double-blind, placebo-controlled trial (GWPCARE4). 32nd International Epilepsy Congress; 2017 Sep 2 Sep 6; Barcelona, Spain Epilepsia. In press -double blind controlled study of 171 patients with Lennox-Gastaut syndrome, with uncontrolled drop seizures randomized to receive CBD 20 mg/kg/day vs placebo for 14 weeks -14 patients in the CBD group and 1 patient in the placebo group withdrew from the study due to adverse events -median reduction of seizures was 44% in the CBD group compared to 24% in the placebo group -side effects were reported in 86% of patients in the CBD group compared to 69% in the placebo group, most common being somnolence, diarrhea, decreased appetite, and vomiting
Zuberi S et al. Cannabidiol (CBD) significantly decreases drop and total seizure frequency in Lennox-Gastaut syndrome (LGS): Rresults of a doseranging, multi-centre, randomised, double-blind, placebo-controlled trial (GWPCARE3). 32nd International Epilepsy Congress; 2017 Sep 2 Sep 6; Barcelona, Spain Epilepsia. In press -double blind controlled study of 225 patients with Lennox-Gastaut syndrome, mean age of 16, with uncontrolled seizures were randomized to three groups: CBD dose 10 mg/kg/day; CBD dose 20 mg/kg/day; Placebo -patients were taking a median of 3 anti-seizure drugs and study duration was 14 weeks -median reduction of drop seizures was 42% in the CBD 20mg/kg group, 37% in the 10mg/kg group, compared to 17% in the placebo group -94% of patients reported side effects in the CBD 20 mg/kg group, 84% in the 10 mg/kg group, and 72 % in the placebo group: somnolence and decreased appetite
Charlotte -little girl with Dravet syndrome (confirmed with SCN1A mutation) -experienced remarkable improvement in her seizures after switching to CBD oil
Porter,B. E., et al. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatmentresistant epilepsy. Epilepsy and Behavior, 2013 -Survey of Facebook group dedicated to use of CBD for treatment resistant seizures -13 children had Dravet syndrome, 1 had Lennox Gastaut Syndrome, and 1 had idiopathic epilepsy -Average number of antiepileptic drugs tried was 12 -Seizure frequency ranged from 2/week to 250/day -16/19 patients had reduction in seizure frequency -2 of these reporting complete seizure freedom -8 of these reporting reduction greater than 80% in seizure frequency -6 of these reporting 25-60% reduction in seizure frequency -Other benefits included increased alertness, better mood, improved sleep -Side effects were mild including drowsiness and fatigue
Hess ej, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57:1617 24-18 patient with tuberous sclerosis complex (TSC) took CBD fo 6-12 months -median total weekly seizure frequency reduced by 32% after 2 months, 55% after 6 months, and 63 after 12 months. -epileptic spasms and atonic seizures showed the greatest response -study limited by small sample size, uncontrolled design, and unblinded.
Conclusions -Evidence of CBD has become more prevalent in the last year with emergence of the first placebo controlled study of CBD in patients with Dravet syndrome and Lennox-Gastaut syndrome -Shows class 1 evidence that CBD improves seizure control -Limitation is that it is difficult to conclude that CBD has direct anti-seizure properties -The 2 studies of Lennox-Gastaut syndromes, proportion of patients taking clobazam was not reported
Conclusions -Part of the appeal of cannabis to parents is that by being a natural substance, it will cause less side effects Tetrodotoxin is a natural substance produced by fish -So far, side effects of CBD have been mostly benign -Elevated liver enzymes have been reported in a small percentage of patients co-medicated with valproate, and was reversible -Meta analysis of studies investigating long term effects of cannabis on neurocognitive performance in adults showed decreased ability to learn and remember new information
Future Direction -Future research should be blinded, randomized controlled trials to confirm efficacy and adverse effects -Other epilepsy syndromes should be studied -Long-term effects of CBD on the maturing brain are not available
References -Suraev A. et al. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use. Epilepsy and Behavior. May 2017. Volume 70, Part B, Pages 334 340 -Porcari G. et al. Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. Epilepsy and Behavior. Volume 80, March 2018, Pages 240-246 -Solis M. Cannabis for epilepsy: is there enough evidence of efficacy? The Pharmaceutical Journal. January 10. -Treat L. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia. Volume 58, November 2016. Issue 1. -Perucca E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? Journal of Epilepsy Research. 2017 Dec; 7(2): 61 76. -Hausman-Kedem M. et al. Efficacy of Medical Cannabis for Treating Refractory Epilepsy in Children and Adolescents, with Emphasis on the Israel Experience. IMAJ. Volume 19. February 2017. 76-78 -Capasso A. Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol Journal. 2017; 11: 61 73. -Koo C. et al. Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy? Journal of Epilepsy Research. 2017 Jun; 7(1): 16 20.