Real-World Approaches to Cannabinoids in Pediatric-Onset Epilepsy: What Do the Data Tell Us? CME, Anup Patel,, 2019

Real-World Approaches to Cannabinoids in Pediatric-Onset Epilepsy: What Do the Data Tell Us? CME

Anup Patel, MD

Posted: 12/19/2019


Educational Impact Challenge

The goal of this activity is to improve knowledge and competence related to the selection of cannabinoid-based therapies for pediatric-onset seizure disorders.

Before you begin this activity, please assess your clinical knowledge by completing this brief survey. Answering these questions again after the activity will allow you to see what you learned and to compare your answers with those of your peers.

What did you learn from this activity? Please click on the “Next” button to proceed to a brief survey to see how your knowledge improved after the education. You can also see how your answers compare with those of your peers.

Question 1 of 4

Pharmaceutical-grade cannabidiol oral solution (CBD-OS) has been studied in 2 randomized controlled trials (RCTs) in Lennox-Gastaut syndrome (LGS) and 2 RCTs in Dravet syndrome.

What is the highest dose of pharmaceutical-grade CBD-OS reported to be tested in these phase 3 RCTs for seizures associated with LGS or Dravet syndrome?

5 mg/kg/d

10 mg/kg/d

15 mg/kg/d

20 mg/kg/d

25 mg/kg/d

Question 2 of 4

After engaging in shared decision making with the parents of Sarah, your 12-year-old patient with Dravet syndrome, you have together decided to add pharmaceutical-grade CBD-OS at 5 mg/kg/d to Sarah’s antiseizure drug (ASD) regimen.

If Sarah is taking which of the following drugs would you caution her parents to be particularly vigilant about increased sedation?





Question 3 of 4

Ian is a 9-year-old boy with LGS. He has intellectual disability, uses a wheelchair, requires assistance with all activities of daily living, and has daily tonic-clonic seizures that are not controlled with his current 3-drug antiseizure regimen. Four previously tried ASDs also failed to control his seizures. His parents would like to try a “natural” treatment and have informed you that they have purchased a bottle of CBD oil online (artisanal CBD) and would like to add it to Ian’s ASD regimen.

Which of the following treatments are you most likely to recommend to the parents?

Artisanal CBD oil because it does not cause adverse effects, nor is there any concern about drug-drug interaction with Ian’s other medications

Artisanal CBD oil because each batch of a brand of artisanal CBD oil is manufactured in the same manner and therefore a specific dosing can be recommended

Pharmaceutical-grade CBD-OS because it has FDA approval for the treatment of seizures associated with LGS

Off-label pharmaceutical-grade CBD-OS even though it has FDA approval only for seizures associated with Dravet syndrome and tuberous sclerosis complex

Question 4 of 4

How confident are you right now in prescribing pharmaceutical-grade CBD-OS for your patients with seizures? (Select ranking from 1 [Not confident] to 5 [Very confident])

1 – Not confident

2 – Slightly confident

3 – Moderately confident

4 – Mostly confident

5 – Very confident

AE = adverse event
AED = antiepilepsy drug
ANA = antinuclear antibodies
ASD = antiseizure drug
CBD-OS = cannabidiol oral solution
CI = confidence interval
CLB = clobazam
COX = cyclooxygenase
DEA = Drug Enforcement Administration
DS = Dravet syndrome
EAP = expanded access program
FIRES = febrile infection-related epilepsy syndrome
5-HT = 5-hydroxytryptamine
GABA = gamma-aminobutyric acid
ILAE = International League Against Epilepsy
LGS = Lennox-Gastaut syndrome
LTD = leading to discontinuation
MR = mental retardation
N-CLB = N-desmethylclobazam
NDA = New Drug Application
NO = nitric oxide
NSAID = nonsteroidal anti-inflammatory drug
PBO = placebo
PK = pharmacokinetics
RCT = randomized controlled trial
THC = tetrahydrocannabinol
THCA = tetrahydrocannabinolic acid
TNF = tumor necrosis factor
TRE = treatment-resistant epilepsy
TSC = tuberous sclerosis complex
ULN = upper limit of normal


  1. Atsmon J, Heffetz D, Deutsch L, et al. Single-dose pharmacokinetics of oral cannabidiol following administration of PTL101: a new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev. 2018;7:751-758.
  2. Barnes G, Sullivan J, Sears L, et al.Safety and tolerability of GWP42006 (CBDV) in subjects with drug resistant epilepsy and autism. Presented at: American Epilepsy Society Annual Meeting. New Orleans, LA. November 30-December 4, 2018. Poster 3.288.
  3. Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the fourteenth Eilat conference on new antiepileptic drugs and devices (EILAT XIV). II. Drugs in more advanced clinical development. Epilepsia. 2018;59:1842-1866.
  4. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the thirteenth Eilat conference on new antiepileptic drugs and devices (EILAT XIII). Epilepsia. 2017;58:181-221.
  5. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318:1708.
  6. Centers for Disease Control and Prevention. Epilepsy data and statistics. Available at: Accessed November 10, 2019.
  7. Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75:279-286.
  8. Cannabidivarin (CBDV) vs. placebo in children with autism spectrum disorder (ASD). NCT03202303. Accessed November 15, 2019.
  9. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011-2020.
  10. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270-278.
  11. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888-1897.
  12. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204-e1211.
  13. Devinsky O, Verducci C, Thiele EA, et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018;86:131-137.
  14. EPIDIOLEX® (cannabidiol oral solution) [prescribing information]. Approved 2018. Carlsbad, CA: Greenwich Biosciences, Inc.; Updated December 2018.
  15. Ferrie CD, Patel A. Treatment of Lennox-Gastaut Syndrome (LGS). Eur J Paediatr Neurol. 2009;13:493-504.
  16. Gaston TE, Bebin EM, Cutter GR, et al. Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label expanded access program. Epilepsy Behav. 2019;98:201-206.
  17. Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58:1586-1592.
  18. Gaston TE, Szaflarski JP. Cannabis for the treatment of epilepsy: an update. Curr Neurol Neurosci Reps. 2018;18.
  19. Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246-1251.
  20. Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32:35-40.
  21. Gowers WR. Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms & Treatment. New York: NY: William Wood & Company; 1885:223-224.
  22. Hazekamp A. The trouble with CBD oil. Medical Cannabis Cannabinoids. 2018;1:65-72.
  23. Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57:1617-1624.
  24. Institute of Medicine. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press; 2012.
  25. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51:1069-1077.
  26. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314-319.
  27. Laux LC, Bebin EM, Checketts D, et al. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results. Epilepsy Res. 2019;154:13-20.
  28. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55:783-786.
  29. Mathern GW, Beninsig L, Nehlig A. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia’s survey. Epilepsia. 2015;56:1-6.
  30. McCoy B, Wang L, Zak M, et al. A prospective open‐label trial of a CBD / THC cannabis oil in Dravet syndrome. Ann Clin Transl Neurol. 2018;5:1077-1088.
  31. Mitelpunkt A, Kramer U, Hausman Kedem M, et al. The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: a phase II, open-label, single-center study. Epilepsy Behav. 2019;98:233-237.
  32. O’Shaughnessy WB. On the preparations of the Indian hemp, or gunjah: Cannabis indica their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov Med J Retrosp Med Sci. 1843;5:363-369.
  33. Miller I, Perry MS, Saneto RP, et al. Cannabidiol (CBD; 10 and 20 mg/kg/day) significantly reduces convulsive seizure frequency in children and adolescents with Dravet syndrome (DS): Results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE2). Presented at: 71st American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA. Emerging science abstract.
  34. O’Brien T, Berkovic SF, French J, et al. Synthetic transdermal cannabidiol for the treatment of focal epilepsy in adults. Presented at: American Epilepsy Society Annual Meeting. Washington, DC. December 1-5, 2017. Poster 2.428.
  35. O’Brien T, Berkovic SF, French J, et al. Synthetic transdermal cannabidiol for the treatment of focal epilepsy in adults. Presented at: American Epilepsy Society Annual Meeting. New Orleans, LA. November 30-December 4, 2018. Poster
  36. Ostendorf AP, Ng YT. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions. Neuropsychiatr Dis Treat. 2017;13:1131-1140.
  37. Pietrafusa N, Ferretti A, Trivisano M, et al. Purified cannabidiol for treatment of refractory epilepsies in pediatric patients with developmental and epileptic encephalopathy. Paediatr Drugs. 2019;21:283-290.
  38. Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. 2015;45:49-52.
  39. Reynolds JR. On the therapeutical uses and toxic effects of Cannabis indica. Lancet. 1890;135:637-638.
  40. Rho JM, White HS. Brief history of anti‐seizure drug development. Epilepsia Open. 2018;3:114-119.
  41. Rijckevorsel K. Treatment of Lennox-Gastaut syndrome: overview and recent findings. Neuropsychiatr Dis Treat. 2008:1001.
  42. Shaw J. On the use of the Cannabis indica (or Indian hemp)-1st-in tetanus-2nd-in hydrophobia-3rd-in cholera-with remarks on its effects. Madras Q Med J. 1843;5:74-80.
  43. Sommerville K, VanLandingham K, Hill T, Jones N, Patel A, Gray R. Cannabidivarin. Presented at: EILAT XIII. Madrid, Spain. June 26-29, 2016.
  44. Suraev A, Lintzeris N, Stuart J, et al. Composition and use of cannabis extracts for childhood epilepsy in the Australian community. Sci Rep. 2018;8.
  45. Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59:1540-1548.
  46. Szaflarski JP, Bebin EM, Cutter G, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018;87:131-136.
  47. Szaflarski, J. Drug-drug interaction (DDI) studies with coadministration of cannabidiol (CBD) and clobazam (CLB), valproate (VPA), stiripentol (STP) or midazolam (MDZ) in healthy volunteers (HVTs) and adults with epilepsy. Presented at: 71st American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA. S3.003.
  48. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085-1096.
  49. Thiele E, Wong M. Cannabidiol (CBD) treatment in patients with seizures associated with tuberous sclerosis complex: a randomized, double-blind, placebo-controlled phase 3 trial (GWPCARE6). Presented at: American Epilepsy Society meeting 2019; December 6-10, 2019; Baltimore, Maryland. Abstract 1.293.
  50. Treat L, Chapman KE, Colborn KL, et al. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia. 2017;58:123-127.
  51. US Food and Drug Administration. FDA and cannabis: research and drug approval process. December 6, 2019. Available at: Accessed on December 6, 2019.
  52. US Food and Drug Administration. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds, includingCBD. November 25, 2019. Available at: Accessed on November 25, 2019.
  53. Vandrey R, Raber JC, Raber ME. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313:2491-2493.
  54. VanLandingham K, Jones N, Gray R, et al. Cannabidivarin: preclinical and initial clinical data on seizures and future development. Presented at: EILAT XIV. Madrid Spain. May 13-16, 2018.
  55. VanStraten AF, Ng YT. Update on the management of Lennox-Gastaut syndrome. Pediatr Neurol. 2012;47:153-161
  56. Vashi N, Justice MJ. Treating Rett syndrome: from mouse models to human therapies. Mamm Genome. 2019;30:90-110.
  57. Vigli D, Cosentino L, Raggi C, et al. Chronic treatment with the phytocannabinoid cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome. Neuropharmacology. 2018;140:121-129.
  58. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American Consensus panel. Pediatr Neurol. 2017;68:18-34.e13.

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