CBD Oil and Medical Marijuana for Pediatric Seizures

Intractable pediatric seizures are one of the most disheartening and frustrating diagnoses that a parent must manage for their child, especially when the child has Lennox-Gastaut Syndrome, Dravet Syndrome, West Syndrome, Tuberous sclerosis syndrome, or other disorders marked by refractory seizures.  Many of these children have multiple seizures per day. A parent only wants for their child to have a good quality of life, which means reducing seizures while minimizing side effects of therapies. We have talked previously about Keppra as an anticonvulsant When traditional anticonvulsants aren’t enough for intractable seizures, parents will turn toward any option to help. It is important for us to be aware of these options. We have previously discussed patients using a ketogenic diet or having a vagal nerve stimulator placed to reduce the seizures. Now let us review another option that you may encounter – CBD oil and medical marijuana for pediatric seizures:

CBD Oil and Medical Marijuana for Pediatric SeizuresBasics 

  • Have been used for a long time:
    • Have been used for medicinal purposes since 2700 BCE by Chinese. [Porcari 2018]
    • Have been studied for medical uses since the 1800’s. [O’Shaughnessy 1843]
  • Recreational and medical marijuana were regulated in the US since the Marihuana Tax Act of 1937.
    • They were made illegal in the United States in 1970 (Controlled Substances Act) and in the United Kingdom in 1971 (Misuse of Drugs Act 1971).
    • Laws made it difficult to study for many years. [Peat 1977, Siff 2019, Zafar 2021]
  • Nothing is perfect:
    • Anti-epileptic drugs (AEDs) can have side effects which adversely affect quality of life, which is one of the main causes of discontinuation and seeking alternatives [Zafar 2021]
    • Ketogenic diet and vagal nerve stimulators may not resolve all seizures. [Zafar 2021]

CBD Oil and Medical Marijuana for Pediatric SeizuresMechanism

  • Exact mechanism is unknown.
  • Human nervous system has many cannabinoid receptors (types CB1 And CB2). [Samanta 2019]
    • THC has well-documented mechanism of action with these
    • CBD has low affinity for CB1 and CB2, but may inhibit THC binding at CB1
    • CBD is structurally different than THC, and binds to non-cannabinoid receptors too
    • CBD may have GABA-mediated inhibition, modulation of intracellular calcium, orphan G-protein-coupled receptor action, or may work on voltage-dependent anion channel 1
    • May have anti-inflammatory effect due to TNF-alpha release, or adenosine reuptake inhibition
  • CBD oil is lipophilic, poor oral bioavailability
    • Has extensive but variable first pass metabolism through two CYP450 isoenzymes
    • Long half-life, between 2-5 days
    • Rapidly goes to highly perfused organs, such as brain
    • Highly protein-bound
    • May accumulate in adipose tissue

CBD Oil and Medical Marijuana for Pediatric SeizuresProducts

  • Cannabis Based Medical Products (CBMP) are available in many forms and formulations [Zafar 2021]
    • Plant-based or synthetic
    • Purified single compound (THC or CBD) to complex mixtures
    • Oils, solutions, sprays, capsules
    • Oral, nasal, rectal, inhalation
  • Cannabidiol (CBD) oil may have better antiepileptic potential than tetrahydrocannabinol (THC) [Samanta 2019]
  • However, there are some case reports of pure CBD failure with subsequent combination CBD/THC having success [Zafar 2021]
  • Dosing reports have ranged from 2.4 mg/kg/day up to 50 mg/kg/day, depending on the formulation (with or without THC) [Reithmeier 2018, Porter 2013, Davinsky 2017, Thiele 2018, Tzadok 2016, Marchese 2022]

CBD Oil and Medical Marijuana for Pediatric SeizuresPure CBD Oil

  • Epidyolex/Epidiolex is purified CBD oil, pharmaceutical grade, FDA-approved for epilepsy treatment in children greater 2yo with Dravet Syndrome or Lennox-Gastaut Syndrome. [Samanta 2021, Samanta 2019, Marchese 2022]
    • FDA has now re-classified pharmaceutical grade CBD oil (<0.1% THC) as Schedule V.
  • Long term safety has been studied; reports indicate an acceptable safety profile. [Samanta 2021]
  • CBD can reduce seizure frequency by 37% or more and some become seizure-free. [Uliel-Sibony 2020, Tzadok 2016, Samanta 2021, Samanta 2019, Porter 2013, Porcari 2018, Marchese 2022]
  • Studies overall have been small, have variable dosing, and it’s difficult to find conclusive evidence with large trials of statistically significant efficacy. [Samanta 2019]
  • Three small RCTs have shown promise with statistically significant reduction of seizures. [Davinsky 2017, Davinsky 2018, Thiele 2018]
  • Larger clinical trials are needed to evaluate clear efficacy, safe and effective dosing, evaluate steady state plasma levels, report adverse effects, and further classify drug-drug interactions. [Reithmeier 2018]
  • Artisanal versus Pharmaceutical
    • Due to expense of Epidyolex, some are turning to artisanal formulations. [Porcari 2018]
    • There is some variability in how much CBD concentration patients receive with artisanal vs pharmaceutical grade CBD oil, the efficacy of the product, and the rate of side effects. [Cohen 2022]
  • Some may still stop pure CBD oil treatment due to lack of efficacy or adverse side effects. [Uliel-Sibony 2020, Tzadok 2016]
  • One study reported 25% of patients developed a tolerance after about 7 months [Uliel-Sibony 2020]

CBD Oil and Medical Marijuana for Pediatric SeizuresWhole Plant Based Medical Marijuana  

  • Some evidence suggestions that a combination of THC and CBD works better than CBD alone [Zafar 2020, Zafar 2021]
  • Zafar et al reported a case series of 10 patients [Zafar 2021]
    • Average of 7 AEDs before starting CBMPs and an average of 1 AED after starting CBMP
    • 7 patients completely weaned off AEDs
    • 2 patients failed Epidyolex
    • Average reduction of seizures of 86%
    • Parents reported improved sleep, eating, behavior, cognition, possibly due to reduced seizures and reduced AED use/side effects.

CBD Oil and Medical Marijuana for Pediatric SeizuresSide Effects and Adverse Events

  • CBD oil may cause elevation of liver enzymes when combined with topiramate. [Samanta 2019, Samanta 2021]
  • Epidyolex [Samanta 2021, Marchese 2022, Lattanzi 2021]
    • Increases active metabolite of clobazam, caution with dosing
    • May cause diarrhea, sedation, appetite suppression, elevated liver enzymes and bilirubin level
  • CBD oil may increase serum levels of AEDs. [Samanta 2019]
    • Clobazam, N-desmethylclobazam, topiramate, eslicarbazepine, zonisimide, rufinamide
  • CBD oil, pharmaceutical grade, is expensive, and insurance may limit use [Zafar 2021, Samanta 2019]

Moral of the Morsel 

  • By Any Means Necessary! AEDs, Ketogenic diets, and Vagal nerve stimulators are sometimes not enough to control refractory seizures. CBD oil and medical marijuana show promise as an alternative for seizure control in these patients.
  • There is an option. The FDA has approved Epidyolex pure CBD oil for patients with Dravet Syndrome and Lennox-Gastaut Syndrome!
  • Nothing is perfect! Be vigilant of the potential drug-drug interactions and lab impacts of combination treatment of CBD oil and AEDs when children come to your ED.
  • The Law May Not Agree! Be aware of your state laws before prescribing these products!
References
  • Porcari GS, Fu C, Doll ED, Carter EG, Carson RP. Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. Epilepsy Behav. 2018 Mar;80:240-246. doi: 10.1016/j.yebeh.2018.01.026. Epub 2018 Feb 9. PMID: 29429908.
  • O’Shaughnessy, W.B., 1843. 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. BMJ s1-5, 363–369.. https://doi.org/10.1136/bmj.s1-5.123.363
  • Peat, Marwick, Mitchell and Co. Marijuana: A Study of State Policies and Penalties. Washington: National Institute of Law Enforcement and Criminal Justice, Law Enforcement Assistance Administration, U.S. Dept. of Justice; 1977. 
  • Siff S. The illegalization of marijuana: A brief history. Origins: Current Events in Historical Perspective. https://origins.osu.edu/article/illegalization-marijuana-brief-history?language_content_entity=en. Published 2019. Accessed March 1, 2023. 
  • Zafar, R., Schlag, A., Phillips, L., Nutt, D.J., 2021. Medical cannabis for severe treatment resistant epilepsy in children: a case-series of 10 patients. BMJ Paediatrics Open 5, e001234.. https://doi.org/10.1136/bmjpo-2021-001234
  • Samanta D. Cannabidiol: A Review of Clinical Efficacy and Safety in Epilepsy. Pediatr Neurol. 2019 Jul;96:24-29. doi: 10.1016/j.pediatrneurol.2019.03.014. Epub 2019 Mar 22. PMID: 31053391.
  • Reithmeier D, Tang-Wai R, Seifert B, Lyon AW, Alcorn J, Acton B, Corley S, Prosser-Loose E, Mousseau DD, Lim HJ, Tellez-Zenteno J, Huh L, Leung E, Carmant L, Huntsman RJ. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study. BMC Pediatr. 2018 Jul 7;18(1):221. doi: 10.1186/s12887-018-1191-y. PMID: 29981580; PMCID: PMC6035794.
  • Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013; 29:574–7. 
  • Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant sei- zures in the Dravet syndrome. N Engl J Med. 2017;376:2011e2020. 
  • Thiele EA, Marsh ED, French JA, et al, GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018:1085e1096. 
  • Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. PMID: 26800377.
  • Marchese F, Vari MS, Balagura G, Riva A, Salpietro V, Verrotti A, Citraro R, Lattanzi S, Minetti C, Russo E, Striano P. An Open Retrospective Study of a Standardized Cannabidiol Based-Oil in Treatment-Resistant Epilepsy. Cannabis Cannabinoid Res. 2022 Apr;7(2):199-206. doi: 10.1089/can.2019.0082. Epub 2020 Jul 21. PMID: 33998856; PMCID: PMC9070734.
  • Samanta D. Management of Lennox-Gastaut syndrome beyond childhood: A comprehensive review. Epilepsy Behav. 2021 Jan;114(Pt A):107612. doi: 10.1016/j.yebeh.2020.107612. Epub 2020 Nov 24. PMID: 33243685.
  • Uliel-Sibony, S., Hausman-Kedem, M., Fattal-Valevski, A., Kramer, U., 2021. Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?. Brain and Development 43, 89–96.. https://doi.org/10.1016/j.braindev.2020.06.018
  • Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378:1888e1897. 
  • Cohen NT, Bahar B, Conry JA, Schreiber JM. Variability in Serum Concentrations and Clinical Response in Artisanal Versus Pharmaceutical Cannabidiol Treatment of Pediatric Pharmacoresistant Epilepsy. J Pediatr Pharmacol Ther. 2022;27(6):558-563. doi: 10.5863/1551-6776-27.6.558. Epub 2022 Aug 19. PMID: 36042959; PMCID: PMC9400177.
  • Zafar RR, Schlag AK, Nutt DJ. Ending the pain of children with severe epilepsy? an audit of the impact of medical cannabis in 10 patients. Drug Sci Policy Law 2020;6:205032452097448.
  • Lattanzi S, Trinka E, Striano P, Rocchi C, Salvemini S, Silvestrini M, Brigo F. Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox-Gastaut Syndrome. CNS Drugs. 2021 Mar;35(3):265-281. doi: 10.1007/s40263-021-00807-y. Epub 2021 Mar 22. PMID: 33754312; PMCID: PMC8005394.

Author

Christyn Magill
Christyn Magill
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