.

1. Cannabis for the Treatment
of Pediatric Epilepsy
Dr. Richard J. Huntsman
Pediatric Neurologist-University of Saskatchewan
and
Dr. Blair Seifert, Pharm.D.
Saskatchewan Health Authority
Cannabinoid Research Initiative of Saskatchewan

2. Conflict of Interest Declaration
Both Dr. Huntsman and Seifert report no conflicts of interest related to
the information presented. The specification of product used in the
CARE-E trial is for clarification and does not promote the use of the
specific brand. All monies from grants are administered by the
University of Saskatchewan and do not accrue directly to the
researchers.

3. Presentation Objectives-Dr. Huntsman
• Review of the Epileptic Encephalopathies
• Discuss the historical Use of Cannabis based therapies for epilepsy
• Review Contemporary Research about Cannabis based therapies for
pediatric epilepsy
• Cannabidiol in Children with Refractory Epileptic Encephalopathy
(CARE-E) study
• Advantages and challenges of studying Cannabis based therapies for
children in Canada

4. Presentation Objectives-Dr. Seifert (2)
1. Describe the considerations in choice of cannabis product for the
management of seizures disorders in children.
2. List the key pharmacokinetic characteristics of THC and CBD in
children.
3. Utilize the preliminary information on potential drug-drug interactions
with cannabis, THC and CBD when providing information to families
about the use of cannabis products in children.

5. Epileptic Encephalopathy
• The epileptic encephalopathies are age dependent refractory
epilepsies of childhood.
• Response of the immature brain to an insult (ie cerebral
malformation, HIE or metabolic disease).
• Characterized by frequent brief seizures resistant to medication and
progressive brain dysfunction (encephalopathy).
• Continuously very abnormal EEG.
• Associated with loss of developmental skills.
• Occur during period of cerebral development therefore associated
with residual permanent mental handicap.

6. Epileptic Encephalopathy
• Catastrophic Epilepsies of Early Infancy
• Ohtahara Syndrome
• Early Myoclonic Encephalopathy
• Infantile Spasms / West Syndrome
• Early Childhood and Older
• Lennox- Gastaut Syndrome
• Doose Syndrome
• Landau- Kleffner Syndrome
• Syndrome of Continuous Spike Wave Discharges During Sleep
• Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)
• Malignant Migrating Partial Seizures of Infancy

7. Infantile Spasms (West Syndrome)
• Onset usually between 3-6 months of age.
• Recurrent brief seizures (spasms) typically coming in clusters.
• High voltage and chaotic pattern (Hypsarrhythmia) on EEG.
• Poor prognosis with developmental regression.
• Only 60-70% respond to treatment.
• Earlier successful treatment can improve developmental outcome.
Shabarou R, Mikati MA. The expanding clinical spectrum of genetic pediatric epileptic encephalopathies. Sem Ped. Neurol.
2016;23:134-42

8. Infantile Spasms

9. Lennox Gastaut Syndrome
• Onset usually between 2 years of age.
• Multiple seizure types.
• Atypical absence
• Tonic
• Atonic*
• Many treatments used with variable efficacy.
• Despite successful treatment most children left with varying degrees
of developmental disability.

10. Lennox Gastaut Syndrome (Atonic Seizure)

11. Dravet Syndrome (Severe Myoclonic Epilepsy
of Infancy)
• Onset usually in the first year of life.
• Typically presents with febrile status epilepticus.
• As child gets older other seizure types emerge including afebrile
seizures.
• Developmental stagnation or regression seen by 1-4 years of age.
• Usually very resistant to treatment.
• 70% secondary to mutation in SCN1A gene.
Shabarou R, Mikati MA. The expanding clinical spectrum of genetic pediatric epileptic encephalopathies. Sem Ped.
Neurol. 2016;23:134-42

12. Historical Use of Cannabis Based Therapies in
Epilepsy
• First description of medical use of
Cannabis by Chen Nung (2600BC).
• Female Cannabis plants felt to
possess large amounts of yin energy.
• Prescribed for menstrual fatigue,
rheumatism and absentmindedness.
• Warned excessive consumption
would cause one to see demons.

13. Medicinal Cannabis in Western Medicine
• Cannabis used in Eastern cultures for a
variety of ailments.
• Described by Sir William O’Shaughnessy
while working in India.
• Reports successful treatment of 40 day
old infant with seizures. “in hemp the
profession has gained an anticonvulsive
remedy of greatest value”.
• Following this Cannabis tinctures used
widely in Europe and North America.
O’Shaughnessy W B. On the preparations of the Indian Hemp or Gunjah. Tr M and Phys Soc Bengal 1838-40;8:421-61.
Gowers W R, Epilepsy and other chronic convulsive diseases. London: Churchill;1881. P.283.

14. Limited Interest in Cannabis to treat Epilepsy
• Interest in Cannabis ended with development of new medications and
passing of the Marihuana Tax Act in 1937.
• From 1970-1980 several case reports of patients having reduction in
seizure frequency when smoking Cannabis.
• Smoking Cannabis also seemed to have a protective effect against first
unprovoked seizure.
• Cannabis during this time period had much lower concentrations of Δ9-THC
and higher concentrations of CBD.
• Interest in Cannabis resumed only in last 2 decades.
• Initially focused on Δ9-THC and other CB1R agonists.
Brust J C, Ng S K, Hauser A W, Susser M. Marijuana use and the risk of new onset seizures. Trans Am Clin Climatol
Assoc.1992;103:176-81.

15. Animal Studies of Cannabinoids and Epilepsy

16. Cannabinoids
• Over 140 Cannabinoids
produced by C. sativa.
• Referred to as
phytocannabinoids.
• Have a C21 structure with
aromatic core and with terpenyl
and pentyl side chains.
• Divided into 6 main categories

17. Δ9-THC in Animal Models of Epilepsy
• Most abundant cannabinoid in Cannabis.
• Anticonvulsant properties felt to be through
activation of neuronal CB1 receptors.
• CB1R activation affects neuronal activity via
several pathways*
• Has anticonvulsant properties in several in vitro
and in vivo models of epilepsy.**
• Potentiates the effect of several anticonvulsants.
• Toxicity and psychotropic side effects limit use as
an anticonvulsant agent.
1) Reddy DS, Golub VM. The pharmacological basis of cannabis therapy for epilepsy. J Pharmacol Exp Ther. 2016;357:45-55.
2) Turkanis SA, Karler R. Central excitatory properties of Δ9-tetrahydrocannabinol and its metabolites in iron induced epileptic
rats. Neuropharmacology. 1982;21:7-13.

18. CBD in Animal Models of Epilepsy
• Showed anticonvulsant effects in several animal
models.
• Blocked the pro-convulsant effects of Δ9-THC.
• Negative allosteric modulator of CB1R
• Anticonvulsant effects independent of CB1R.
• Increases neuronal adenosine and 5HT1-2A
activity and binds to TVPR1 receptors.
• Rats given high doses of CBD (200 mg/kg)
showed no motor impairment.
• Suggests would be an ideal potential
anticonvulsant for children.
Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, et al. Cannabidiol displays antiepileptiform and
antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332:569-77.

19. Human Studies of Cannabinoids in Epilepsy
• Human trials to assess efficacy of CBD enriched Cannabis products.
• First human epilepsy trials by Mechoulam and Carlini (1978) and
Cunha (1980). Both had significant design and reporting flaws.
• No human studies for over 2 decades.
• Largely in part because of legal restrictions on Cannabis possession
and research.
• Surge of interest following reports of Charlotte Figi who became
seizure free taking a cannabis preparation called “Charlotte’s Web”.

20. The Epidiolex Studies-Devinsky et al. (2016)
• Open label study including children and adolescents with refractory
epilepsy.
• Overal 36.5% reduction in seizures.
• Significant variability in daily dosage (up to 25 mg/kg day)
• Adverse events included somnolence, diarrhea and fatigue.
• Rosenberg (2016) performed a post study analysis of QOLCE surveys
in 20 patients enrolled.
• Significant improvements in global scores and several subscores.
1) Devinsky OE, Marsh D, Friedman D, Thiele E, Laux L, Sullivan J et al. Cannabidiol in patients with treatment resistant epilepsy: An
open label interventional trial. Lancet Neurol. 2016;15:270-8.
2) Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D. Quality of life in childhood epilepsy in pediatric patients enrolled in a
prospective, open label clinical study with cannabidiol. Epilepsia. 2017;58:e96-e100.

21. The Epidiolex Studies-Devinsky et al. (2017)
• 120 patients with Dravet syndrome randomized to receive placebo or
CBD 20 mg/kg/day or placebo.
• Median seizure frequency decreased from 12.4 to 5.9 in Epidiolex
group vs 14.9 to 14.1 in the control group.
• While difference in convulsive seizures between the CBD and control
groups reached clinical significance there was no significant change in
the number who became seizure free or had > 50% seizure reduction.
• Most common side effects in CBD group were diarrhea, vomiting,
somnolence and increased liver enzymes.
Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of Cannabidiol for drug-resistant seizures in the Dravet
syndrome. N Engl J Med. 2017;376:2011-20.

22. The Epidiolex Studies-Thiele et al. (2018)
• 171 patients with LGS randomized to receive CBD or placebo.*
• 2 week dose escalation to 20 mg/kg/day CBD then 12 weeks maintenance.
• Monthly atonic seizures decreased 43.9% in CBD vs. 21.8% in placebo group.
• Difference between groups -19.45 during 12 week maintenance phase
(p=0.0096).
• 44% of patients in CBD group had a ≥50% reduction in atonic seizures.**
• Monthly total seizures decreased 41.2% in CBD vs. 13.7% in placebo group.
• Difference between groups -23.3% during 12 week maintenance phase
(p=0.0004).
• Common adverse events in CBD group included diarrhea, somnolence and
decreased appetite.***
Thiele EA, Marsh ED, French JA et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut Syndrome.(GWPCARE4);
a randomized, double blind, placebo controlled phase 3 trial. Lancet. January 24/18

23. Cannabis Oil Preparations containing △9-THC-
Tzadok et al.(2016)
• Open label study in 74 children with refractory epilepsy given
escalating doses of CBD enriched Cannabis herbal extract.
• Dose of CBD variable. Divided into two groups: <10 mg/kg/day and
>10 mg/kg/day.
• 52% of participants had > 50% reduction in seizures.
• Those with Lennox Gastaut Syndrome responded better that those
with Dravet Syndrome.
• 7% withdrew due to side effects.
Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al. CBD enriched medical cannabis for intractable pediatric
epilepsy: The current Israeli experience. Seizure. 2016;35:41-4.

24. Questions That Remain
• Based on available data CBD appears to have a favorable efficacy and side
effect profile compared to other anticonvulsants.
• Difficult to interpret results as different doses of CBD and preparations
used.
• Many questions still remain:
• Why do some children seem to respond better than others?
• What is appropriate dose of CBD?
• Pediatric pharmacokinetics?
• Is there benefit in adding a small amount of △9-THC and how much?
• What about other cannabinoids?*
• Does response correlate better to dose or therapeutic level?
• Acceptance into mainstream medicine will not occur until these questions
are answered.

25. Cannabidiol in Children with Refractory
Epileptic Encephalopathy (CARE-E) Study
• A pilot study run by Department of Pediatrics, University of Saskatchewan.
• Open label dosage escalation design.
• 4 sites across Canada.
• Attempts to answer questions about most appropriate dose of CBD and △9-
THC.
• Looks at pediatric pharmacokinetics through measurement of Cannabinoid
levels with each dosage escalation.

26. Cannabidiol in Children with Refractory
Epileptic Encephalopathy (CARE-E) Study
• 28 children with epileptic encephalopathy enrolled across 4 sites.
• 7 visits spaced one month apart.
• On visit 1 (recruitment) participants will undergo:
• Enrollment and consent
• Medical history and data collection regarding neurodevelopmental status,
comorbidities
• Brief survey regarding parental perception of cannabis use in children.
• Seizure log to measure baseline seizure status.
• Parents instructed not to change medications or anticonvulsant
therapies.

27. Cannabidiol in Children with Refractory
Epileptic Encephalopathy (CARE-E) Study
• In subsequent visits (2-6)
• Collection of data from seizure log
• General pediatric and neurological assessment
• QOL questionnaire*
• 2 hour EEG
• Labs including levels of AED’s, CBD, Δ9-THC and metabolites.
• Adverse event reporting and side effect rating scales.
• Study drug dispensed in escalating doses.
• Data to be entered and stored on U of S Datastore using RedCap.

28. Cannabidiol in Children with Refractory
Epileptic Encephalopathy (CARE-E) Study
• Patient population
• Children 1-10 with diagnosis of epileptic encephalopathy refractory to
medical treatment.
• Inclusion and exclusion criteria include:
• At least one major seizure per week or 4 major seizures per month
• No recent change in anticonvulsant medications, ketogenic diet or
VNS settings.
• No use of cannabis based products in last 2 months.

29. CARE-E Funding
• Given nature of study external funding was felt to be vital.
• SHRF CID grant to develop assay and pursue further funding.
• Funding from CHFS, Durwood Seafoot Estate and Savoy Grant

30. CARE-E Product Considerations
• CARE-E is a dose-ranging study
• 1:20 ratio of THC & CBD
• a reliable source of product
• high quality, purified, pharmaceutical grade
• liquid dosage form (olive oil base)
• documented stability
• single batch/lot number
• no preparation/alteration required by family
• qualified for Section 56 exemption under the Controlled Drugs
and Substances Act
• available to families under the Medical Marijuana regulations if
continued post-study

32. CARE-E Pharmacokinetics
• Little is known about the pharmacokinetics of THC, CBD and their
metabolites across the pediatric age spectrum
• CBD metabolized by and inhibits CYP2C19 & 3A4
• In a 3 week trial of 34 children with CBD “solution” [Devinsky, et al.
Neurology 2018:e1204]
• linear kinetics for 5, 10 & 20 mg/kg/day
• major metabolite 7-carboxy-CBD (7-COOH-CBD)
• 7-COOH-CBD accumulated to 13-17x CBD

33. CARE-E Pharmacokinetics
• Concern about drug-drug interactions
• Devinsky, et al. Neurology 2018:e1204
• No change in plasma clobazam but N-desmethylclobazam ranged from -
10% – 526%
• No effect on valproate, carbamazepine or phenytoin
• Toronto study [Expert Opin Drug Safety 2017]
• Inhibition of CYP2C19 +/- 3A4  ↑↑ CBD
• Need pharmacogenomic studies

34. CARE-E Pharmacokinetic Findings
CARE-E study included pre-dose plasma concentrations of THC, CBD &
anticonvulsants
Observations:
1. Dose reduction of a benzodiazepine in several children during
the dose escalation phase.
2. Linear dose-concentration relationship except in one child
[which might suggest nonlinear dose-concentration with the last dose
escalation].
continued

35. CARE-E Pharmacokinetic Findings
• Observations (continued):
3. 2/6 participants became seizure free.
4. 2/6 participants had >50% reduction in seizures.
5. Both children who became seizure free of First Nations ethnicity,
suggesting a possible pharmacogenomics relationship.
6. No participants withdrawn due to side effects.
7. CanniMed product contains 4% cannabigerol.
8. Differences in effect at different doses – one dose size does not fit all.

36. Future Pharmacokinetic Studies
1. Detailed pharmacokinetic analysis following a single dose of THC:CBD
1:20 oil in 6 age-stratified, pediatric groups over 96 hours
2. Further investigation of nature of drug-drug interactions with
concurrent anticonvulsants
3. Pharmacokinetic analysis of sub-groups including patients on
antineoplastic chemotherapy, ADHD and (potentially) neonates

37. Review of CARE-E Study Participant

38. Baseline EEG (Asleep)

39. Repeat EEG (Asleep)

40. Subscale Results
0
20
40
60
80
100
120
2nd App't 3rd App't 4th App't 5th App't 6th App't 7th App't
Cog. Funct.
Emot. Funct.
Soc. Funct.
Phys. Indep.
Add. Items

41. Cannabinoid Research Initiative of
Saskatchewan
• University of Saskatchewan supported research cluster designed to
study medical applications Cannabis.
• Brings together clinical medicine, biochemistry, basic science,
pharmacology, public health, health policy and agricultural sciences.
• Active support from JPCHF, SHRF and partnerships with several
producers.
• Strengths include clinical trial development, pharmacokinetics and
assay development.

42. Saskatchewan
Knowledge Mobilization
Biomedical
Pillar
Agriculture
Pillar
Policy/Socio-
economic
Pillar
Cannabinoid Research Initiative of
Saskatchewan
• Biomedical Pillar
• Scientific evidence about application of
cannabinoids for health and disease in
humans and animals.
• Agricultural Pillar
• Analysis of genomic and trait variation in
Cannabis sp. To improve understanding of
potential medicinal agricultural uses
• Policy/Socioeconomics Pilar
• Develop policy frameworks around
economic development, health and
safety and public policy.
• Knowledge Mobilization
• To HQP, Industry and Gov’t stakeholders

43. Advantages and Challenges to Doing Pediatric
Cannabis Research in Canada
• Canada offers several advantages that could place us at forefront of
Cannabis Research.
• Federal government that has an interest in research through agencies
such as CIHR and provincial counterparts.
• Health Canada acts as a single regulatory body to approve clinical
studies.
• A collaborative environment exists between research centers.
• For pediatric neurology collaborations exist through CPEN and CLAE.

44. Advantages and Challenges to Doing Pediatric
Cannabis Research in Canada
• Some challenges exist.
• Reluctance to study Cannabinoids in Children at some institutions.
• In large part due to a lack of knowledge about Cannabinoids.
• Research funds limited at most institutions. Need for partnerships
between industry and academic research groups.