title: Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
abstract: BACKGROUND
  Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.
  
  
  METHODS
  In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.
  
  
  RESULTS
  Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7).
  
  
  CONCLUSIONS
  Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.
  
  
  BACKGROUND
  GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
authors.affiliation: Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA. Electronic address: od4@nyu.edu.
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
authors.affiliation: Departments of Neurology and Pediatrics, Division of Child Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Marsh
authors.affiliation: Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Massachusettes General Hospital for Children, Boston, MA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thiele
authors.affiliation: Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Laux
authors.affiliation: Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sullivan
authors.affiliation: Miami Children's Hospital, Miami, FL, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Miller
authors.affiliation: Pediatric and Adolescent Neurodevelopmental Associates, Atlanta, GA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Flamini
authors.affiliation: Texas Children's Hospital, Houston, TX, USA.
authors.forename: Angus
authors.initials: A
authors.lastname: Wilfong
authors.affiliation: University of Utah Medical Center and Primary Children's Hospital, Salt Lake City, UT, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Filloux
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wong
authors.affiliation: Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Tilton
authors.affiliation: Massachusettes General Hospital for Children, Boston, MA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bruno
authors.affiliation: Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Bluvstein
authors.affiliation: Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Hedlund
authors.affiliation: Departments of Neurology and Pediatrics, Division of Child Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kamens
authors.affiliation: Departments of Neurology and Pediatrics, Division of Child Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Maclean
authors.affiliation: Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Srishti
authors.initials: S
authors.lastname: Nangia
authors.affiliation: Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Nilika Shah
authors.initials: NS
authors.lastname: Singhal
authors.affiliation: University of Utah Medical Center and Primary Children's Hospital, Salt Lake City, UT, USA.
authors.forename: Carey A
authors.initials: CA
authors.lastname: Wilson
authors.affiliation: Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Patel
authors.affiliation: Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002185:Cannabidiol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D004831:Epilepsies, Myoclonic / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D065768:Lennox Gastaut Syndrome / Q000188:drug therapy*; D008297:Male; D017063:Outcome Assessment, Health Care; D012640:Seizures / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002185:Cannabidiol