Use of cannabidiol in the treatment of drug-refractory epilepsy in children and young adults: A systematic review

INTRODUCTION

Epilepsy is among the neurological pathologies that most frequently affect pediatric and adolescent patients, accompanied by various psychological, behavioral, and cognitive comorbidities that profoundly impact the quality of life of the patients;^[1] Among these, intellectual disability, attention deficit hyperactivity disorder, autism, anxiety, depression, and sleep disorders stand out.^[2] The condition of epilepsy is characterized by the presence of irregular neuronal discharges or abnormal overexcitation of neurons with synchronization; it is classified into three subtypes: Acquired, idiopathic, and epilepsy of genetic origin with approximately 1000 linked genes. The essence of the pathology lies in the influence of inhibition through g-aminobutyric acid (GABA) as well as glutamate-mediated stimulation.^[3] Moreover, mortality rates in pediatric and young patients with epilepsy are 5–10 times higher than in the general population. This substantial increase in risk is attributed to neurometabolic conditions, systemic complications, and neuro disability.^[4]

The international league against epilepsy defines treatment-resistant epilepsy as the lack of a successful response to the administration of two antiepileptic drug regimens.^[5] It is estimated that 30% of pediatric patients are resistant to conventional drug treatments.^[6] Considering that treatment-resistant epilepsy may impact pediatric populations at a rate ranging from 7% to 20%.^[7] Conversely, the likelihood of refractoriness increases in the presence of epileptic syndromes such as Lennox–Gastaut, Dravet syndrome, and tuberous sclerosis, as well as other underlying etiologies. These conditions might exhibit an unfavorable clinical outcome for patients due to their severity, early onset, and slow progression.^[8,9]

The need for novel therapies and the lack of response to antiepileptic drugs have positioned scientific research in a critical role in the development of new approaches that enhance the quality of life for patients, such as the therapeutic use of Cannabis sativa L. and its metabolites. To date, 566 chemical compounds have been isolated from cannabis, including 125 cannabinoids and 198 non-cannabinoids. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the cannabinoids with the highest concentration.^[10,11] THC is a cannabinoid with psychoactive activity, whereas CBD lacks such activity. Nevertheless, it exhibits various therapeutic properties; experimental studies have identified anticonvulsant, analgesic, anxiolytic, antiemetic, immunomodulatory, anti-inflammatory, neuroprotective, and antitumorigenic effects.^[12]

Knowledge of the use of cannabis products for the treatment of epilepsy dates back to ancient times; however, it was not until the 1990s that CBD began to be employed as a treatment option for this condition. This was deemed advantageous due to its anticonvulsant activity without inducing psychoactive effects. The versatile applications and safety profile of CBD led to its approval in the United States in 2018 under the trade name Epidiolex.^[13] Furthermore, it is worth noting that this type of product has expanded its coverage and usage due to its efficacy in reducing the frequency of epileptic seizures for different types of epilepsy, such as tonic, tonic-clonic, epileptic encephalopathy, focal seizures, and generalized seizures. However, it is important to mention that, while it has benefits, it can also generate adverse effects, such as drowsiness, decreased appetite, elevated liver transaminases, fatigue, diarrhea, changes in behavior, and sleep disorders.^[14]

This systematic review provides updated information on the efficacy and safety of the therapeutic use of CBD for treatment-resistant epilepsy in the pediatric and juvenile populations.

MATERIALS AND METHODS

RESULTS

A total of 6351 articles were identified from the databases of EBSCO, PubMed, ScienceDirect, Scopus, Taylor and Francis, Web of Sciences, and Wiley Online. Of these, 1686 were duplicates and were therefore eliminated. A total of 4665 articles were evaluated according to title and abstract and discarded. Of the 21 articles obtained, exclusion criteria were applied to obtain eight articles at the end [Table 1 and Figure 1].^[16-23]

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Figure 1:

Preferred reporting items for systematic reviews and meta-analyses flowchart on the strategy for selecting eligible studies about refractory epilepsy (RE) in pediatric and young people treated with cannabidiol.

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Quality of the studies included

Using CASP, the quality of the included articles was assessed by 11 questions in the case of cohort studies, nine questions for quasi-experimental studies, and eight questions in the case of analytical cross-sectional studies. Assigning one point (1) if the question was corresponding, 0.5 if it was unclear, and zero (0) if it was not corresponding. The quality of the studies indicated that the average score was 8.17 ± 1.61 for cohort studies, 7.33 ± 0.29 for quasi-experimental studies, and 7.0 ± 0.0 for analytical cross-sectional studies [Figure 2].

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Figure 2:

Evaluation of quality of included studies by Joana Briggs Institute checklist. Green: 1 point, Yellow: 0.5 points, Red: No point. In order to evaluate the quality of the included studies, these were evaluated with items that allow to know their quality. Each item has a question. Each question answered correctly is equivalent to 1 point and is colored green, answered partially is equivalent to 0.5 point and is colored yellow, and not answered is equivalent to no point and is colored red.

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DISCUSSION

Despite the existence of records proving the use of cannabis since ancient times, it is only in recent years that studies have been conducted demonstrating the efficacy and safety of the use of cannabis compounds in epilepsy in pediatric patients and young patients. In this review, multiple researchers mostly observed that CBD could positively impact seizures in patients. These models provide significant results to validate the efficacy of cannabinoids in the regulation of neurological processes involved in the regulation of GABA and glutamate neurotransmitters.

In the review of eight articles with pediatric and young populations, CBD was administered with purity between 24% and 98%, which showed improvements in tonic-clonic seizures of more than 50% and a complete reduction of seizures in patients, in agreement with the findings of Lazarini–Lopes et al., who indicated that CBD reduced the generalized tonic-clonic seizures dose-dependent of GEPR-3, as well as decreasing the severity and duration of limbic seizures of the brainstem in animal models at doses of 10 mg/kg.^[24] It could be explained by some mechanisms in which the endocannabinoid system is directly associated with the brainstem and limbic neural networks, which could modulate the activity of GABA as well as the functioning of sodium and calcium channels induced by CBD, which can reduce neuronal excitability, prevent the propagation of convulsions, and finally generate a reduction in the frequency.^[25]

Similarly, in epileptic encephalopathy, 51% of patients showed improvements in seizure reduction, 3% were seizure-free, and 3% showed improvements of <50% regardless of their convulsions, which is notably supported by Caraballo et al., where it has been shown that the use of CBD resulted in an 80% decrease in epileptic encephalopathy.^[19] In the same way, in the approach to infantile syndromes of complex management such as Dravet syndrome and Lennox–Gastaut syndrome, some studies, such as GWPCARE1 Part B and GWPCARE2, addressed patients mostly under age, identifying an average decrease of 45–74% in the monthly frequency of seizures in a period of 12 weeks up to week 156. As for total seizures, the average reduction was 49–84%.^[26]

In individuals affected by epileptic encephalopathy with SYNGAP1 gene expression, it has been observed that CBD induces an increase in the expression of the cation channel subfamily V member 1 protein. This channel plays a crucial role in the mechanisms underlying the excitatory/inhibitory imbalance associated with drug-resistant epilepsy. CBD has been shown to cause rapid activation and desensitization of the aforementioned member 1, leading to channel regulation.^[27] This phenomenon has also been explored in the context of the SCN1A genes linked to Dravet syndrome, which encode the NaV1.1 and NaV1.2 sodium channels. These channels are highly expressed in the brains of patients with this epileptic pathology and are mainly affected by the loss of function due to stop codons, deletions, or single residue inactivating mutations in the SCN1A gene.^[28] In this context, it has been identified that CBD has the ability to prevent the opening of NaV1.2 and NaV1.6 channels, inhibiting their electrical activity and thereby reducing the seizures associated with these syndromes.^[29]

At the pediatric level, even though there are benefits in the consumption of CBD, doses higher than 50 mg/kg/day should be evaluated as they may act as triggers for side effects in children following the administration of cannabis. Most of the pediatric epilepsy studies reported high rates of these side effects, which tended to be mild, such as gastrointestinal symptoms reported in patients taking more than 15 mg/kg/day, increasing drug intolerance, and the likelihood of reports of diarrhea or related side effects (weight loss, nausea, and decreased appetite). Likewise, potential associations have been reported between the administration of CBD oils and the development of microscopic colitis.^[30,31]

In addition, drowsiness and fatigue have been observed as a result of the interaction between clobazam and CBD. It is important to mention that clobazam was used simultaneously with CBD in some cases and that the patients were on this drug before the CBD treatment began; furthermore, in the majority of cases, clobazam was used in the majority of monitored patients because it is a drug with a common usage among the different types of refractory epilepsy and shows the reaction between the two drugs. The side effects are derived from the increase in the concentrations of the clobazam metabolite, N-desmethyl clobazam, through the inhibition of CYP2C19 by CBD, thus intensifying its effects.^[29,32] Elevations in liver enzymes are noted, especially in children taking valproic acid, which is associated with worsening seizures and blood dyscrasias, with possible effects on cognitive development.^[14] The interaction between valproic acid and CBD generates transient metabolic stress in the liver in patients who suspend treatment. On the other hand, evidence related to short-term memory impairment has been found as an established effect of acute cannabis intoxication, attributed to THC on hippocampal CB1 receptors.^[30] THC and CB1 agonists reduce presynaptic neurotransmitter release, thereby altering long-term synaptic plasticity in the hippocampus. On the other hand, extensive research has indicated that CBD consumption could influence cognitive performance, which can be supported by randomized studies in which individuals exposed to CBD in a single dose (12.5 mg CBD) established better performance in verbal episodic memory but not in working memory.^[33] However, other research has indicated that administration of 800 mg of CBD daily may improve working memory manipulation.^[34]

CONCLUSION

The use of cannabis is a tool for refractory epilepsy when first-line therapies do not have the expected efficacy. The benefits of the crisis are clear, in the reduction and even elimination or blocking of seizures, impacting positively their quality of life such as sleep, behavior, and cognitive functions. There is great efficacy against different types of epileptic seizures, such as tonic, tonic-clonic, epileptic encephalopathy, focal seizures, and generalized seizures, making its use advisable for patients, without forgetting that more information is still required regarding its long-term use. As for the adverse effects, it can be noted that, despite being almost constant, these mainly appear due to the interaction of CBD with the medications used by these patients, although it is clear that none of these adverse effects turned out to be a reason not to stop the treatment that was presented during the different studies.