Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians

Abstract

The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

INTRODUCTION

The prevalence of epilepsy in Canadian children under the age of 14 is 6.9/1000 (1). Up to 30% of patients with epilepsy are resistant to anticonvulsant therapy (2) and this invariably leads to poor long-term cognitive outcomes, especially for those with an epileptic encephalopathy such as Lennox Gastaut Syndrome or Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome). The reported benefit of Cannabis products in children with drug-resistant epilepsy has generated intense media interest, resulting in parents requesting Cannabis products to treat their children. Physicians remain reluctant to authorize access to Cannabis products to children in part due to limited scientific data to guide them and concerns about the legality of prescribing these products (3). Parents desperate to help their children often resort to using products of questionable quality or attempt to make Cannabis products at home, potentially causing harm to the child.

Cannabis has been used since antiquity to treat patients with epilepsy, but was supplanted by modern anticonvulsants (4). The case of Charlotte Figi, a girl with Dravet Syndrome who became seizure-free while taking a high cannabidiol (CBD):low Δ⁹-tetrahydrocannabinol (Δ⁹-THC) Cannabis extract renewed the medical community’s interest in Cannabis to treat children with epilepsy.

PHYTOCANNABINOIDS OF CANNABIS SATIVA (CANNABIS) AND THEIR BIOLOGICAL ACTIVITY

Cannabis produces over 140 cannabinoid-related molecules. The most comprehensively studied cannabinoids are Δ⁹-THC and CBD (5,6).

The anticonvulsant mechanisms of the cannabinoids are not well understood. Endogenous cannabinoid receptors (CB₁ and CB₂) regulate GABAergic and glutamatergic neurotransmission by inhibiting adenylate cyclase and modulating calcium and potassium channels (3). Δ⁹-THC is a potent agonist of neuronal CB₁ receptors, which underpins its psychotropic, analgesic and anticonvulsant effects (Figure 1) (6).

Figure 1.

The distribution and function of cannabinoid receptors CB1R and CB2R at the interneuronal contact site (synapse).

CBD is a CB₁-negative allosteric modulator accounting for its lack of psychotropic activity. Its anticonvulsant effect is independent of CB₁ activation. The pharmacology of cannabinoids in the treatment of epilepsy was recently reviewed by Friedman and Devinsky (2015) and Reddy and Golub (2016) (7,8).

CANNABINOIDS IN ANIMAL MODELS OF EPILEPSY

While animal studies demonstrate the anticonvulsant properties of Δ⁹-THC and other CB₁ agonists such as anandamide, and how these compounds potentiate the effects of several anticonvulsants in preventing seizures (8), some studies demonstrate Δ⁹-THC can exacerbate seizures, which suggest ∆⁹-THC has both anticonvulsant and proconvulsant properties (9). This coupled with the toxicity and psychotropic side-effect profile of Δ⁹-THC could mitigate its potential benefit in patients with epilepsy (8).

Other studies demonstrate the antiepileptic effects of CBD administered alone or in combination with anticonvulsants (8) and show CBD could block the proconvulsive effects of Δ⁹-THC (10). Rats given CBD (200 mg/kg) intraperitoneally display limited cognitive or motor side-effects, thus making CBD a potentially attractive anticonvulsant in the paediatric population (11).

HUMAN STUDIES OF CANNABIDIOL IN EPILEPSY

Over two decades have passed since the initial studies on the tolerability and efficacy of Cannabis products such as CBD in children with drug-resistant epilepsy were published by Cunha et al. (1980) and Mechoulam and Carlini (1978) (12,13).

Devinsky et al. reported an open-label study using Epidiolex, a purified CBD formulation, in children and adolescents with drug-resistant epilepsy. They reported a 36.5% overall reduction in seizures, but there was significant variability in the daily dosage of CBD with some participants receiving up to 25 mg/kg/day. Adverse events included somnolence, diarrhea and fatigue (14). Subsequent analysis of Quality of Life in Childhood Epilepsy Scores in a subset of children enrolled in this study found a significant improvement in global scores and in several subscores including energy/fatigue, behaviour and social interactions (15). Tzadok and colleagues also reported on 74 children with drug-resistant epilepsy who were given escalating doses of a high CBD:low Δ⁹-THC oil. While 52% of participants had a greater than 50% reduction in seizure frequency, 7% had to stop the treatment due to side effects. Patients with epileptic encephalopathy had the most favourable response rate (16).

Porter and Jacobson posted a 24-point survey to a Facebook group of parents who used CBD-enriched Cannabis for their children with refractory epilepsy. Of 20 parents who responded, 84% observed a decrease in seizure frequency and over half reported their children became seizure-free or had a greater than 80% reduction in seizures. Most parents reported an improvement in quality of life indices including mood, sleep and alertness (17).

A recent randomized clinical trial of Epidiolex in children and adolescents with Dravet syndrome in which 120 patients were randomized to receive either CBD at 20 mg/kg/day or placebo added to their anticonvulsant regimen revealed that the frequency of convulsive seizures per month decreased from an average of 12.4 to 5.9 in the CBD group compared to 14.9 to 14.1 in the control group. While the difference between the CBD and placebo groups in the number of convulsive seizures was reported to reach statistical significance (P=0.01), there was no difference in the number of patients who had a greater than 50% reduction in seizures or patients who became seizure free. As well, the study noted no statistical difference in the number of nonconvulsive seizures and quality of life indices. The most common side effects seen in the CBD group (>10% frequency) included diarrhea, vomiting, somnolence and increased liver enzymes (18).

Based on the current literature, CBD appears to have a favourable efficacy and side-effect profile in comparison to other anticonvulsant medications used to treat children with refractory epilepsy (19). The two Epidiolex studies enrolled children with Dravet Syndrome only, making extrapolation of these results to children with other forms of epileptic encephalopathy difficult.

Caution must be taken in interpreting the results of these studies as some, but not all, used compounds containing both CBD and Δ⁹-THC, and considerable variability existed in the CBD dosing regimens. Consequently, recommendations about CBD dosing regimens and optimal concentrations of CBD:Δ⁹-THC remain challenging. The available literature shows that physicians following children who are taking Cannabis preparations for epilepsy should take special care to monitor for potential adverse effects such as somnolence and seizure exacerbation and for potential drug–drug interactions (e.g., CBD and clobazam) (18,20).

CONCERNS REGARDING CANNABIS AND THE DEVELOPING BRAIN

Endocannabinoid receptors are first expressed in the human brain between 16 and 22 days gestation (21). In the fetal brain, CB₁ is found predominantly in the forebrain, amygdala and hippocampi (22) and are thought to play a major role in regulating neuronal differentiation and migration as well as the development of neural pathways through synaptogenesis and/or pruning (21).

A distinction must be made between recreational Cannabis products (which are not regulated and tend to have high concentrations of Δ⁹-THC) and medical Cannabis products used to treat epilepsy (which are highly regulated and have low concentrations of Δ⁹-THC relative to CBD). It is clear that prenatal exposure to CB₁ agonists such as Δ⁹-THC can lead to abnormal brain development and poor neurodevelopmental outcomes in animals and humans (22–24). Although there are no data regarding long-term neurodevelopmental effects of CBD-enriched medical Cannabis products, one has to balance this uncertainty against the poor neurodevelopmental outcome associated with uncontrolled seizures in children with drug-resistant epilepsy and the potential therapeutic benefit of CBD.

CANADIAN REGULATIONS REGARDING THE USE OF CANNABIS FOR THE TREATMENT OF EPILEPSY

The possession of Cannabis for medical use is regulated through the Controlled Drugs and Substances Act (CDSA) with Section 56 exemptions provided for patients to obtain Cannabis for medical purposes. The Marihuana Medical Access Regulations (MMAR) introduced in 2001 allowed patients to obtain Cannabis through licensed producers or grow their own. The subsequent Marihuana for Medical Purposes Regulations (MMPR) were designed to ensure a commercial supply of quality medical cannabis in the form of dried plant. Because many patients, including children with epilepsy, could not consume (i.e., via smoking) dried cannabis, a Supreme Court of Canada ruling in 2015 required Health Canada to allow for the lawful production and possession of medical Cannabis products including oils and other consumables. These products still require authorization by a licensed health care provider and production by a Health Canada licensed producer in order for their possession to be legal. In 2016, the Access to Cannabis for Medical Purposes Regulations (ACMPR-2016) was introduced allowing patients to grow a limited supply of Cannabis or designate someone else to grow it for them. Of note, these Health Canada regulations do not list age restrictions (25).

Most physician organizations refer to physicians ‘authorizing access’ as opposed to ‘prescribing’ Cannabis. Due to limited evidence regarding safety and efficacy, both Health Canada and the Canadian Paediatric Society (CPS) have issued recommendations about physicians authorizing the access of Cannabis products to children. Health Canada recommends Cannabis be considered only for those patients not responding to conventional pharmacotherapy. The CPS recommends Cannabis should be authorized to children only after careful consideration of potential risks and therapeutic benefits, adding that physicians who treat children with Cannabis should have expertise in the use of psychotropic drugs (26,27).

Physicians must be aware of their respective provincial and territorial regulatory authority’s recommendations regarding authorizing access to Cannabis for patients including children with epilepsy. These bodies have released their own guidelines with variability between jurisdictions (Table 1).

Table 1.

Summary of provincial and territorial guidelines for physicians authorizing medical cannabis

Provincial or territorial governing body	Cannabis approved for medical use	Age restriction specified	Approved for the treatment of epilepsy (or no diagnostic restriction)
College of Physicians and Surgeons of Newfoundland and Labrador	Yes	No	Yes
College of Physicians and Surgeons of Nova Scotia	Yes	No	Yes
College of Physicians and Surgeons of New Brunswick	Yes	No	Yes
College of Physicians and Surgeons of Prince Edward Island	Yes	No	Yes
Collège des Médecins du Quèbec	No Approved for use in setting of research framework only.	N/A	N/A
College of Physicians and Surgeons of Ontario	Yes	No but for patients under 25 years of age must be able to document that all other treatment options have been exhausted.	Yes
College of Physicians and Surgeons of Manitoba	Yes	No	Yes
College of Physicians and Surgeons of Saskatchewan	Yes	No	Yes
College of Physicians and Surgeons of Alberta	Yes Prescribing physician must register with CPSA	No	Yes
College of Physicians and Surgeons of British Columbia	Yes	No	Yes
Yukon Medical Council	Yes	No	Yes
Government of North West Territories Professional Licensing	No guidelines are currently in place for physicians authorizing medical Cannabis
Registrar of Health Professionals	No guidelines are currently in place for physicians authorizing medical Cannabis.
Department of Health, Government of Nunavut

CPSA College of Physicians and Surgeons of Alberta; N/A not applicable.

FUTURE DIRECTIONS AND CONCLUDING REMARKS

While the authors feel important therapeutic potential exists for Cannabis in children with drug-resistant epilepsy, we support Health Canada and CPS recommendations. Further research on dose, efficacy, side effects and pharmacokinetics of cannabinoids is needed to inform on their routine use in children with epilepsy. The potential synergistic effects of Δ⁹-THC with CBD, and the anticonvulsant potential of the Δ⁹-tetrahydrocannabivarin and cannabidivarin derivatives also require further exploration (28,29). The well-designed phase 1 dosage escalation studies using high CBD:low ∆⁹-THC Cannabis products currently underway at the University of Saskatchewan and the University of Toronto are important antecedents to eventual randomized controlled clinical trials which should enrol paediatric patients with different seizure diagnoses and age stratifications.

Studying cannabinoids in children and the expected scrutiny this research will receive requires that special care be taken to ensure an absence of potential for experimental bias. This will require increased non-industry funding. We recommend that such research be performed in collaboration with organizations such as the CPS, the Canadian Pediatric Epilepsy Network and the Canadian League Against Epilepsy.

Conflicts of Interest

AWL reports personal fees from Roche Diagnostics Canada and personal fees from Radiometer Canada outside the submitted work. RJH reports grants from Genzyme Canada outside the submitted work.