Medical Cannabis Treatment for Pediatric, Drug-Resistant Epilepsy: An Overview & Summary for those New to the Conversation
In order to help readers gain a perspective on the available literature, we have summarised the key studies and evidence to-date regarding the use of medical cannabis for epilepsy
Brenden S. Rabinovitch; BSC Candidate; | Neurology Centre of Toronto
Magda Nowicki MD; | The Hospital for Sick Children
Evan C. Lewis, MD, FRCPC; | Neurology Centre of Toronto
There are a number of studies and reviews regarding the use of medical cannabis for epilepsy in both children and adults. Navigating the literature requires an advanced understanding of the various cannabinoids (e.g. THC and CBD) and non-cannabinoids (e.g terpens) found in cannabis and the different formulation and composition of products that are produced through industry.
In order to help readers gain a perspective on the available literature, we have summarized the key studies and evidence to-date regarding the use of medical cannabis for epilepsy. The majority of modern clinical work has been completed in the pediatric population suffering from severe forms of epilepsy called epileptic encephalopathies. The aim here is to present the highest-quality peer-reviewed evidence available for purified CBD and CBD-rich extracts. A summary of the major purified CBD and CBD-rich extract studies is shown in Table 1.
Purified CBD
There is particular supportive evidence for seizure reduction in patients diagnosed with Lennox-Gastaut Syndrome (LGS), Dravet Syndrome (DS), and Tuberous Sclerosis. Other epileptic encephalopathies identified in the following trials, such as CDKL-5 have also shown responsiveness. These studies were the basis for the FDA’s (Federal Drug Administration – USA) and EMA’s (European Medicines Agency’s) approvals of the current indications for Epidiolex®, a purified CBD oral extract containing 99% CBD, <1% THC, minor cannabinoids, and terpenes. (1,2) The trials described were double-blind, randomized placebo-controlled trials. The results of these studies all showed a median decrease in seizure frequency from baseline compared to placebo contorls.(1–4) The accompanying Table 2 summarizes the dosing and results from these studies.
Thiele et al., 2018 & Devinsky et al., 2018 | The first of these studies enrolled 225 patients (aged 2-55 years old) diagnosed with LGS who experienced at least one drop seizure per week. Patients were given either 10 (n=73) or 20mg/kg/day (n=76) of purified CBD (Epidiolex®); the control group (n=76) received an indistinguishable placebo oil.2 The next study examined 171 patients (aged 2-55 years) diagnosed with drug-resistant LGS and minimum two drop seizures per week. All patients were treated for fourteen weeks. Patients assigned to the CBD group (n=86) had a starting dose of 2.5mg/kg/day, followed by twelve weeks of stable dosing up to 20mg/kg/day, then a ten-day tapering period, and a four-week safety follow-up period. The placebo group comprised 85 similar individuals.(1)
Devinsky et al., 2017 | One-hundred twenty children and young adults (aged 2-18 years) diagnosed with Dravet Syndrome participated in this trial. Patients were given 20mg/kg/day of a purified CBD oral solution (Epidiolex®) in addition to their typical antiepileptic medications for a 14-week period vs placebo.(3)
Thiele et al., 2020 | Two-hundred twenty four patients (aged 1-65 years) diagnosed with tuberous sclerosis and drug-resistant epilepsy, who experienced a minimum of 8 seizures in 1 month were examined. This double-blind placebo-controlled study used a 100mg/mL solution of Epidiolex® starting at 5mg/kg/day. One group was titrated up to 25mg/kg/day (CBD25), one to 50mg/kg/day (CBD50), and one was the control group (no CBD).
CBD-Rich Extracts
There is supportive evidence for seizure reduction in patients diagnosed with Dravet Syndrome (DS) and other epileptic encephalopathies. Compared to the purified CBD trials, these were open label studies and; therefore, the evidence is not as strong. However, pooled comparison of dosing and adverse events indicate that CBD-rich extracts may provide a similar degree of seizure reduction with less short-term adverse events. Table 3 compares purified CBD evidence to CBD-rich extract from a 2018 meta-analysis.12 CBD-rich extracts containing THC have not been approved in North America nor Europe.
Hausman-Kedem et al., 2018 | One study looked at 57 patients (aged 1-20 years) with drug resistant epilepsy – 46 patients included in the efficacy analysis. They were treated with a 1:20 THC:CBD ratio with an average CBD dose of 11.4mg/kg/day and followed prospectively for 3 months. This study found that 56% of patients (26/46) had a ≦50% reduction in mean monthly motor seizure frequency.(5)
Huntsman et al., 2019 | Next, 7 pediatric participants (aged 1-10 years) with drug-resistant Dravet Syndrome (4/7) and LGS (3/7) due to various etiologies and a minimum of 1 seizure per week were given CBD-rich extract (1:20 THC:CBD) dosed up to 10-12mg/kg/day of CBD. Six of the 7 patients experienced a >50% reduction in seizure frequency.(6)
McCoy et al., 2018 | Finally, an open label trial examining 20 patients with Dravet syndrome dosed patients with a CBD range of 2-16mg/kg/day, and with a THC dose range of 0.04-0.32mg/kg/day. The average CBD and THC doses were 13.3mg/kg/day and 0.27mg/kg/day. This study found a median reduction in motor seizure frequency of 70.6% and 12 of 19 patients had a reduction in seizure frequency from baseline during the final 4 weeks of treatment (weeks 17 – 20) with two patients seizure-free.(7)
Quality of Life
All of the studies explored showed a median reduction in seizure frequency, which alone has a positive impact on quality of life among those suffering from epilepsy.(1–9) Specific studies measured quality of life separately from seizure reduction. In the study by Devinsky et al (2017), 62% of patients were reported to have overall improvement (measured by the Caregiver Global Impression of Change scale) with the reduction of all seizure types in the CBD group. The study by Rosenberg et al (2017) measured QOL by the Quality of Life of Childhood Epilepsy (QOLCE) scale. Patients taking CBD had significant improvement in energy/fatigue, memory, other cognitive functions, control/helplessness, social interactions, and behaviour.8 Similar findings on the QOLCE were seen in the CBD-Rich extract study by McCoy et al and Huntsman et al.
Safety, Tolerance, and Pharmacokinetics
Most of the studies had common adverse effects (AEs) in the groups that received cannabis and these included: diarrhea, somnolence, and decreased appetite.(1–4) Some studies found non-life threatening liver abnormailities3,7,10; such as liver transaminase and platelet abnormalities in patients on cannabis and valproate. (7) Further, CBD was shown to have no significant effect on concomitant AED levels, with the exception of N-desmethylclobazam (N-CLB) where levels were increased.(9,10) The studies support CBD as a generally well-tolerated and safe seizure intervention in children. (1–3) (6) (10) (11)
Safety profile of THC and other minor cannabinoids present in CBD-rich extracts has not been well studied to date. It has been described that recreational THC can have long term developmental, cognitive and psychiatric effects in the pediatric population. Of note, THC of up to 0.32 MKD as described in the study by McCoy et al (2018) was well-tolerated by participants. More studies need to be completed to understand the anti-convulsant and adverse effects of THC and other cannabinoids present in whole plant cannabis extracts.
Final Thoughts
Medical cannabis studies to-date report positive findings with respect to seizures, safety and quality of life outcomes in children with epileptic encephalopathies. Tolerability of CBD is dose dependent and significant adverse effects are rare. .1–9,11 Further studies are required to describe the safety profile of THC and other minor cannabinoids present in whole plant cannabis extracts in this population; however based on these studies, THC doses of up to 0.4mg/kg/d appear to be well-tolerated in the context of CBD. The next critical step is to compare purified CBD oral solutions to CBD-rich extracts containing THC in head-to-head randomized placebo-control trials. This information is vital to the epilepsy community and will help elucidate some of the key questions in medical cannabis treatment for epilepsy.
References
1. 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(10125):1085-1096. doi:10.1016/S0140-6736(18)30136-3
2. 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(20):1888-1897. doi:10.1056/nejmoa1714631
3. 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(21):2011-2020. doi:10.1056/nejmoa1611618
4. Thiele EA, Bebin EM, Bhathal H, et al. Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. JAMA Neurol. 2020;02114(3):285-292. doi:10.1001/jamaneurol.2020.4607
5. Hausman-Kedem M, Menascu S, Kramer U. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study. Brain Dev. 2018;40(7):544-551. doi:10.1016/j.braindev.2018.03.013
6. Huntsman RJ, Tang-Wai R, Alcorn J, et al. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: Preliminary results of the CARE-E study. Front Neurol. 2019;10(JUL):1-9. doi:10.3389/fneur.2019.00716
7. 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(9):1077-1088. doi:10.1002/acn3.621
8. 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(8):e96-e100. doi:10.1111/epi.13815
9. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278. doi:10.1016/S1474-4422(15)00379-8
10. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-1592. doi:10.1111/epi.13852
11. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204-e1211. doi:10.1212/WNL.0000000000005254
12. Palpmlona F, Silva LR, Coan AC. et al. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front/ Neurol. 2018;9(759)