Pediatrics

Considering pediatric patients, the best-supported evidences involving medical cannabis are those in the field of epilepsy. It is known that about 30% of the pediatric population with epileptic conditions does not find adequate control of their seizures with the currently available antiepileptic drugs, according to the International League Against Epilepsy (ILAE). For these clinically refractory epilepsy cases, cannabinoid derivatives are therefore valid therapeutic alternatives.¹

In this context, the most relevant compound is CBD, for its anticonvulsant action and also for the greater safety it offers to the pediatric population. In 2018, the use of CBD in Dravet and Lennox-Gastaut Syndromes was approved by the american regulatory agency, FDA.

It is known that the convulsive process comes with a series of harmful events, such as neuronal prejudice, damage to the blood-brain barrier, exacerbated inflammation, changes in neurogenesis processes and in cellular plasticity.² CBD is a compound with a potent neuroprotective action, which is related to its ability to prevent the production and accumulation of reactive oxygen and nitrogen species, preventing oxidative damage and its consequences on cell survival.³

Inflammatory processes, especially those in epileptogenic foci, are also negative factors for the condition considered. Here, CBD assumes a protective role, by attenuating the production of pro-inflammatory molecules (such as IL-6, TNF alpha, COX-2 and iNOS).4 Regarding neurogenesis, CBD has shown to prevent the loss of efficiency of the process, that can be induced by physiological stress.5 It is important to note that the reduction of neurogenic capacity, especially in the hippocampal region, is associated with psychiatric disorders (such as anxiety and depression),6 which epileptic patients are more likely to develop .

One of the most famous cases of cannabis use in children is the case of Charlotte Figi, a girl born in 2006 in the United States, diagnosed by the age of 3 months old with Dravet Syndrome. Charlotte suffered multiple daily seizures and already had a significant cognitive delay at the age of 5, despite having tried several pharmacological options. It was then that her parents sought medical cannabis as a therapeutic alternative, and in only 3 months with this new treatment, Charlotte got over 90% reduction in her seizure frequency. After 20 months of therapy the child was able, for the first time, to carry out her daily activities independently. The frequency of seizures came to be of 2 to 3 nocturnal tonic-clonic seizures per month, much lower than the 300 seizures per week that she would previously experienced.7

An electronic survey was carried out in 2013, seeking to highlight the role of cannabis in the therapy of epileptic syndromes, involving the parents of 19 children who had Dravet Syndrome (13), Doose Syndrome (4), Lennox-Gastaut Syndrome (1) and idiopathic epilepsy (1). All of them were momentarily using CBD-rich cannabis extracts (doses ranging from <0.5 mg/kg/day to 29 mg/kg/day of CBD), with the average number of antiepileptic drugs previously tried by these patients being 12 drugs per patient. The results showed that 84% of the participants observed a reduction in the frequency of epileptic episodes with the cannabis extract, of which 11% reported a complete absence of epileptic seizures with the therapy, 42% reported a greater than 80% reduction in seizures and 32% reported a reduction of 25-60% in seizures. The research also showed other gains from the cannabinoid therapy, such as increased alertness in children (74%), improved mood (79%) and improved sleep (68%). Reported side effects were mild, such as dry mouth (37%) and fatigue (16%). It is important to note that, before the intervention with the cannabis extract, the epileptic frequency held by these patients ranged from 2 to 250 seizures per day. The time on cannabis therapy among participants ranged from 2 weeks to 1 year.8

A recent phase 1 clinical study with girls with Rett Syndrome demonstrated the efficacy and safety of cannabidivarin (CBDV), a compound analogous to CBD. It is known that 50 to 90% of patients with Rett Syndrome suffer from epileptic seizures, commonly refractory to medication, a situation in which the 5 participants of the study in question fit. The average age of the participants was 12.6 years. Prior to the study, the average amount of anticonvulsant drugs used by patients was 3 drugs, and the average seizure frequency was 32 seizure episodes per month. During the study, all participants achieved CBDV dosing of 10 mg/kg/day and all experienced a reduction in seizure frequency, with an average of 79% reduction. No serious adverse effects were observed and there were no cases of withdrawal from the trial by the participants. The median time for maximum CBDV concentration to be observed in plasma was 1-2h, being consistent with the Cmax time of other cannabinoid compounds. Finally, the trial concluded that CBDV at the dose studied is safe and effective for pediatric patients with Rett Syndrome, being effective in controlling epileptic seizures in these patients.9

Considering Autism Spectrum Disorder (ASD), in vivo studies show that this condition seems to be related to a dysregulation of the endocannabinoid system (ES). It is known that the ES is involved in the modulation of excitatory and inhibitory neurotransmitters, as well as in the hormones oxytocin and vasopressin, involved in social behaviors. Both modulatory mechanisms are compromised in ASD.¹ A study was carried out with 53 pediatric patients, involving the administration of a cannabinoid extract with a CBD:THC ratio equal to 1:20. Here, the results obtained showed improvements related to sleep disorders (71.4%), hyperactivity (68.4%), aggressiveness (67.7%) and anxiety (47.1%) among patients. Considering the general symptoms considered as ASD comorbidities, the improvement observed was of 74.5% in these same patients. Regarding the adverse effects seen in the study, the most frequent were drowsiness (n=12) and decreased appetite (n=6).10

Fragile X Syndrome is characterized by neuropsychiatric, behavioral and developmental disorders. A study was carried out with 20 children and adolescents with Fragile X Syndrome, evaluating the action of transdermal CBD in the context of this health complication. A significant improvement was observed in the behavioral symptoms of anxiety, compulsion, manic/hyperactive and social aversion.11

The action of cannabis was evaluated in 20 children with complex motor disorders, aged between 1 and 18 years.12 For this study, of 5 months length, two different cannabis extracts were used, one with a CBD:THC ratio equal to 20:1 and the other with a 6:1 ratio. The maximum dose administered was 90 mg/day and 210 mg/day, respectively, for the aforementioned extracts. The study concluded that both extracts proved to be effective in the therapy of the evaluated condition, by reducing the severity of dystonia and spasticity and by bringing improvements in motor functions and in the patients’ quality of life. It is noteworthy that the average dose of THC observed to be effective for the improvement of spasticities was 0.44 mg/kg/day. There was also an overall improvement in the patients’ mood and appetite, improvement in constipation disorders (more significant in patients using the 20:1 extract) and improvement in sleep disturbances (more significant in patients using the 6:1 extract).

It is known that medical cannabis can be valuable as an adjunctive cancer therapy. However, as in other therapeutic areas, most of the evidence is supported by observations in the adult population. A survey was carried out through the application of a questionnaire, distributed to pediatric patients and/or their caregivers, in an oncology clinic. Evaluating the results, 14 of the 64 participants reported using medical cannabis for the management of oncological symptoms or for the treatment of the cancer itself. Among such cannabis users, the most prevalent diagnosis was leukemia (64%) and all of them reported experiencing improvement in their symptoms with the use of medical cannabis.13

Overall, the evidence regarding medical cannabis in pediatric therapy is still limited. Although its therapeutic potential in several pediatric conditions is quite promising, one of the biggest concerns surrounding this therapy is the impairment of child neurodevelopment, a risk mainly linked to THC.¹ Thus, the risk benefit must be extensively evaluated and weighed, and there should still be a constant therapeutic follow-up of the pediatric patient using medical cannabis.

References:

  1. CIENTÍFICO, D. et al. Indicações para uso da Cannabis em pacientes pediátricos: uma revisão baseada em evidências. [s.l: s.n.]. Disponível em: <https://www.sbp.com.br/fileadmin/user_upload/_22241c-DocCient_-_IndicUso_Cannabis_pacientes_pediat.pdf>.
  2. REDDY, D. S.; KURUBA, R. Experimental Models of Status Epilepticus and Neuronal Injury for Evaluation of Therapeutic Interventions. International Journal of Molecular Sciences, v. 14, n. 9, p. 18284–18318, 5 set. 2013.
  3. CAMPOS, A. C. et al. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. Frontiers in Pharmacology, v. 8, 23 maio 2017.
  4. CASTILLO, A. et al. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiology of disease, v. 37, n. 2, p. 434–40, 2010.
  5. CRIPPA, J. A. et al. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Frontiers in Immunology, v. 9, 21 set. 2018.
  6. LUCASSEN, P. J. et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action☆. European Neuropsychopharmacology, v. 20, n. 1, p. 1–17, jan. 2010.
  7. CAMPBELL, C. T.; PHILLIPS, M. S.; MANASCO, K. Cannabinoids in Pediatrics. The Journal of Pediatric Pharmacology and Therapeutics, v. 22, n. 3, p. 176–185, maio 2017.
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157067/
  9. HURLEY, E. N. et al. Efficacy and safety of cannabidivarin treatment of epilepsy in girls with Rett syndrome: A phase 1 clinical trial. Epilepsia, v. 63, n. 7, p. 1736–1747, 20 abr. 2022.
  10. BARCHEL, D. et al. Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Frontiers in Pharmacology, v. 9, 9 jan. 2019.
  11. HEUSSLER, H. et al. A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome. Journal of Neurodevelopmental Disorders, v. 11, n. 1, 2 ago. 2019.
  12. LIBZON, S. et al. Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders. Journal of Child Neurology, v. 33, n. 9, p. 565–571, 16 maio 2018.
  13. CHAPMAN, S. et al. Medical cannabis in pediatric oncology: a survey of patients and caregivers. Supportive Care in Cancer, 1 maio 2021.