Abstract
Background:
Medicinal cannabinoids have generated significant interest from clinicians and families as a potential therapy for a range of paediatric conditions in recent years. There are increasing numbers of clinical studies in this area and also an increased awareness of medicinal cannabinoids in the community.
Objective:
The aim of this review was to identify the available evidence for medicinal cannabinoids in paediatrics, identify significant gaps in the evidence base, summarise the findings from included studies, and inform the need for further research and systematic reviews.
Design:
A scoping review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. A literature search was performed, including the reference lists of included studies. Inclusion criteria consisted of peer-reviewed articles that measured the effect of cannabinoids in children, from any time period, written in English, included human paediatric subjects, and involved the administration of any formulation of cannabinoid.
Results:
A total of 1825 articles were screened in the review process, of which 111 were included in the final analysis. Good evidence was found for the use of medicinal cannabinoids in severe seizure disorders and for the control of chemotherapy-induced nausea and vomiting. There was limited but promising evidence for a range of other conditions, including Fragile X syndrome, fetal alcohol syndrome, post-traumatic stress disorder, autism, and some gastrointestinal disorders.
Conclusions:
Medicinal cannabinoids have been shown to be effective for some paediatric conditions; however, further research is required, particularly in the area of chronic pain and palliative care.
Introduction
There has been significant interest in recent times around the use of cannabis-derived products for a range of paediatric conditions,1,2 including intractable seizures, autism spectrum disorder (ASD), cancer symptoms, cancer treatment-related side effects, and chronic pain. There are an increasing number of clinical studies being conducted to try and address this issue,3–5 and there has also been an increase in the awareness of cannabis-derived products from parents, leading to more frequent enquiries about their use.6,7
There are over 110 biologically active compounds called phytocannabinoids that have been found in the cannabis plant. 8 The most common phytocannabinoids to have been studied include cannabidiol (CBD) and tetrahydrocannabinol (THC). 8 The endogenous equivalent to phytocannabinoids are endocannabinoids. 8 The similar chemical structure of phytocannabinoids to endocannabinoids allows for the former’s action in the endocannabinoid system. 8 The exact mechanism of action of cannabinoids remains unclear.8,9 However, it is proposed that THC binds to and activates the G protein-coupled type 1 and type 2 cannabinoid receptors (CB1 and CB2), whereas CBD blocks these receptors through both allosteric and indirect mechanisms that are tissue specific.8,9 Phytocannabinoids are also thought to interact with other cell targets where the mechanism of action is also unclear. 9 CB1 receptors are predominantly located in the central nervous system (CNS) and influence mood, appetite, stress response, immune and inflammatory responses, metabolism, and pain pathways and inhibit excessive neuronal excitation. CB2 receptors are predominantly located in the peripheral immune system providing an anti-inflammatory effect. 9 Cannabinoids, both synthetic and endocannabinoids, are proposed to also work at other noncannabinoid receptors. For example, CBD is an agonist at vanilloid receptors, a receptor where capsaicin acts. 9 How this translates to children remains unclear.
There have also been recent reviews,10–13 including a systematic review and meta-analysis, 10 on this topic. However, these have either had a narrow focus for review, for example, focusing only on randomised controlled trials (RCTs) at the expense of excluding lower quality studies for a topic with limited existing research 10 and focusing only on the North American experience. 13 These studies have also included up until 2020 in their literature searches.10–13 Clinicians require good quality evidence regarding the tolerability, safety, and efficacy of these products to prescribe them correctly. To this end, we conducted a scoping review of the evidence that exists regarding medicinal cannabinoids for paediatric use that seeks to add to the existing literature.
Objectives
To identify the available evidence for medicinal cannabinoids in paediatrics, including the extent, range, and nature of the evidence.
To identify and analyse gaps in the knowledge base.
To summarise the findings from the available evidence.
To inform the need for research.
Methods
We conducted a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (see Fig. 1). 14
Selection of sources of evidence (see PRISMA flow diagram). PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Articles were eligible for inclusion if they measured the effect of medicinal cannabinoids in children. Peer-reviewed articles were included from any time period if they were written in English, included human paediatric subjects, and involved the administration of any formulation of medicinal cannabinoids. RCTs, cohort studies, open-label prospective studies, retrospective chart reviews, qualitative studies, case series, and case reports were included. Data extracted included first author, year of publication, country of publication, the aims of the study, the study population, sample size, type of study, intervention, outcomes, and key findings.
Outcome measures of efficacy, tolerability, safety, and pharmacokinetics were included, and studies that included both adults and children were also included for the paediatric-specific data. Studies were excluded if they were reviews, letters, or studies of cannabinoid receptors rather than clinical studies and if they focused on genetic or biomarker testing. Articles dealing with recreational use of cannabis were also excluded.
“Children” was defined by the terms child, infant, neonate, pediatrics, and paediatrics in the various search strategies. Ages included 0–18 years, and studies were excluded if they did not differentiate between paediatric and adult data.
To identify potentially relevant studies, MEDLINE, Embase, CINAHL, Scopus, and Google scholar were searched from 1946 up until October 25, 2022. A search of the gray literature was also performed via the Australian and New Zealand College of Anaesthetists (ANZCA) Library Discovery Platform to identify any additional relevant published articles. The search strategies were drafted by an experienced librarian from ANZCA with input from the authors. The final search strategy for MEDLINE can be found in Supplementary Appendix S1. The final search results were exported into EndNote, and duplicates were removed. Further studies were found by manually searching the reference lists of included studies and by consulting experts in the field. Furthermore, major paediatric conferences from 2018 to 2022, including European, American, and Australian and New Zealand conferences, were also searched to identify potentially relevant studies.
Two reviewers evaluated the titles and abstracts and relevant full-text articles for suitable studies to include in the final analysis. Any conflicts or disagreements regarding study selection or data extraction were resolved by consensus, and there was no need to involve a third reviewer.
A data extraction form was developed by the authors with the variables to be included agreed upon before commencing the review process. The reviewers extracted the data independently and then discussed the results. No additions or changes were made to the data charting form after commencing the study.
Studies were grouped into categories based on the indication for medicinal cannabinoids, epilepsy/seizures, autism spectrum, cancer symptoms, and other. Any excluded studies were also recorded with the reason for exclusion. For the included studies, data was extracted on author, year of publication, country of origin, aims and purpose, study population, sample size, methodology, interventions, outcomes, and key findings.
Within each category of medicinal cannabinoid use, we grouped studies based on the level of evidence starting with RCTs, then prospective observational cohort studies, and finally retrospective chart reviews and case series. Relevant data was then prepared in a narrative review.
Results
Epilepsy and seizures
Four RCTs, with a cumulative total of 715 patients, were conducted between 2017 and 2020 (see Table 1).5,15–17 These trials all measured the effectiveness of CBD on seizure frequency in paediatric patients with seizure disorders such as Dravet syndrome and Lennox–Gastaut syndrome. Two of the trials included both paediatric and adult patients.15,16 In all of the trials, participants received 10 mg/kg/day of oral CBD solution, 20 mg/kg/day of oral CBD solution, or placebo. Children given 20 mg/kg/day had a reduction in seizure frequency between 41.9% and 52.4%, those given 10 mg/kg/day had a reduction in seizure frequency of between 37.2% and 48.7%, and those receiving placebo had a reduction in seizure frequency of between 5.4% and 26.9%.5,16 Adverse events (AEs) were relatively common and included decreased appetite, diarrhea, somnolence, pyrexia, fatigue, and increased liver enzymes.5,15–17 The proportion of AEs for children taking 20 mg/kg/day of CBD was reported as being between 86% and 94%. For children taking 10 mg/kg/day, AEs were between 84% and 87.5%, and in those taking placebo between 69% and 89%. Serious AEs occurred in 15.4%–23% in the 20 mg/kg/day patients, 17.8%–20% in the 10 mg/kg/day patients, and 5%–25.4% in the placebo patients.5,15–17 The serious AEs reported included raised liver enzymes, status epilepticus, lethargy, somnolence, constipation, and worsening chronic cholecystitis.5,15–17 An increase in liver enzymes (alanine aminotransferase or aspartate aminotransferase) greater than three times the upper limit of normal occurred in between 10% and 23% of patients receiving CBD compared with between 1.1% and 1.7% in patients receiving placebo. Elevated liver enzymes were more likely in those receiving 20 mg/kg/day compared with 10 mg/kg/day. Withdrawals from studies due to AEs occurred between 7.5% and 14% in those taking 20 mg/kg/day, between 0% and 1.4% in those taking 10 mg/kg/day, and between 0 and 1.7% in those taking a placebo.5,15–17
CBD, cannabidiol; QOL, quality of life; THC, tetrahydrocannabinol; CI, confidence interval.
Another RCT was published in 2021 18 with additional results from an open-label extension published in 2022 (see Table1). 19 The original RCT randomised 224 children and adults (median age 11.4 years) with tuberous sclerosis to receive oral CBD (25 mg/kg/day or 50 mg/kg/day) or placebo for 16 weeks. 18 There was a reduction in seizure frequency compared with baseline of 48.6% and 47.5%, respectively, in the 25 mg and 50 mg groups. The placebo group had a reduction of 26.5%. More side effects were reported in the CBD groups, with diarrhea and somnolence more common in those taking the active drug, especially at the 50 mg/kg/day dose. A total of 20 patients discontinued the trial, 8 in the 25 mg group, 10 in the 50 mg group, and 2 in the placebo group. An increase in liver transaminases was seen in 18.9% of patients taking CBD. The authors concluded that CBD was effective at reducing seizures in tuberous sclerosis patients and that the lower dose had a better safety profile. The same cohort of patients was followed up in an open-label extension trial that included 199 patients (see Table 1). The one-year retention rate was 79% with patients taking a mean dose of 27 mg/kg/day. Side effects included diarrhea, seizures, and decreased appetite, which led to permanent discontinuation of the treatment in 6% of participants. The median reduction in seizures over the subsequent 12 months ranged between 54% and 68%. A post hoc analysis of the data from this cohort of patients was conducted to determine the onset time of treatment effect. The authors found the emergence of seizure reduction evident by day 6 and statistically significant effect by day 10. Patients had discontinued a median of four antiseizure medications (see Table 1). 20
Thirty-eight open-label prospective studies were identified that examined the effect of medicinal cannabinoids on seizures between 2016 and 2022 (see Table 1).21–58 Over 3600 patients were included in these studies, the vast majority were children and young adults, and their conditions included treatment-resistant epilepsy,21–32,34,36–38,41–48,50,55–57 Lennox–Gastaut syndrome,39,40,52 Dravet syndrome,27,40,54,58 and epileptic encephalopathies.33,35,49,51,53 The interventions included CBD in doses starting from 2 mg/kg and titrated up to a maximum of 50 mg/kg/day and cannabis extract in CBD:THC ratios varying from 20:1 to 5:3. Most of these studies used seizure frequency as the primary outcome; however, some also examined AEs, pharmacokinetic data, and cognitive assessments.21–58 These studies generally found treatments to be effective at reducing the frequency of seizures and improving quality of life (QOL). The incidence of AEs showed wide variability, but often with low discontinuation rates reported. Some studies demonstrated increases in liver transaminases.23,29,40,58
Ten retrospective chart reviews,59–68 four qualitative studies,12,13,69,70 seven case reports,71–77 and six case series78–83 were reported on the effect of cannabinoids on seizures between 2017 and 2022 (see Table 1). The retrospective chart reviews found a greater than 50% reduction in seizure frequency in between 31.4% and 73% of patients. Adverse effects were uncommon and usually mild. The case series included patients with treatment-resistant epilepsy,78,80,82,83 Rett syndrome, 81 and West syndrome. 79 All demonstrated a significant reduction in seizure frequency. One series reported improvement in seizure control with THC rather than CBD, whereas another series reported less side effects and less signs of intoxication with purified CBD with no THC component. Most of the case reports describe successful use of medicinal cannabinoids for the treatment of seizures in children ranging from 6 months to 12 years of age; however, one report details severe liver dysfunction in a toddler taking nonprescribed hemp extract. 73 The qualitative studies looked at attitudes and opinions regarding cannabinoid use for seizures and found that it was often used as a last resort, it was usually given for more severe forms of epilepsy, families often found out about it through nontraditional channels such as word of mouth or social media, and there was a high variability in the cannabinoid content and dosing used.12,13,69,70
Autism spectrum
One RCT, 4 four observational studies,84–87 and two case reports88,89 were published on children with ASD between 2019 and 2022 (see Table 2). The RCT included 150 patients between the ages of 5 and 21 years. 4 Participants were randomised to receive cannabinoids (CBD:THC ratio 20:1) or placebo for 12 weeks followed by a 4-week washout period and then a further 12-week crossover period. Improvement in behavioral problems overall did not differ between groups; however, disruptive behavior improved in 49% of those on cannabinoids compared with 21% on placebo. Scores on the Social Responsiveness Scale also improved more in the cannabinoids group than placebo (14.9 vs. 3.6 points). There were no serious AEs; however, common side effects included somnolence (23%–28%) and decreased appetite (21%–25%). 4 The authors published a secondary analysis of sleep parameters from the same study cohort in 2022 (see Table 2). 90 There were no differences in any of the sleep outcomes as measured by the Children’s Sleep-Habit Questionnaire between the treatment and placebo groups. Outcomes included bedtime resistance, sleep-onset delay, and sleep duration.
Characteristics of Studies Investigating Autism
ASD, autism spectrum disorder.
An open-label study from Israel examined the effect of CBD-rich cannabinoids on children and adolescents with autism using standardised clinical assessments. 84 Participants ranged from 5 to 25 years old (mean 9.2 years) and had 6 months of treatment. Of the 110 patients enrolled, 82 completed the treatment and assessments. Reasons reported for dropouts were side effects (12), no improvement (8), and lack of cooperation (8). Of those that completed the study, there was a significant improvement on the Vineland Adaptive Behaviors Scale in the domains of communication (mean difference 4.37, standard deviation [SD] 1.61, p = 0.008), daily living (mean difference 4, SD 1.47, p = 0.007), and socialisation (mean difference 5.66, SD 1.5, p < 0.001). There was also a significant improvement in scores on the Autism Diagnostic Observation Schedule (mean difference −0.56, SD 0.17, p = 0.003) with the authors noting that CBD appeared to be more effective if patients had more severe symptoms initially. There was no significant change detected in cognitive abilities.
An observational study of 188 children and adolescents (mean age 12.9 years) conducted between 2015 and 2017 found that 6 months treatment with CBD-rich cannabinoid (cannabis oil 30% CBD, 1.5% THC) was safe and generally effective (average dose 79.5 mg ± 61.5 mg CBD, 4 mg ± 3 mg THC thrice a day). Of the initial 188 patients, 155 were assessed at 6 months, and of these, there was significant improvement in 30.1%, moderate improvement in 53.7%, slight improvement in 6.4%, and no change in 8.6%. Improvement in symptoms was noted in the domains of QOL, daily living, positive mood, and concentration. 85
Two other observational studies examined a total of 113 patients aged between 4 and 22 years of age receiving CBD-rich cannabinoid or CBD oil. Behavioral outbreaks improved between 61% and 68% and worsened in 9%, hyperactivity improved in 68% and worsened in 3%, sleep problems improved in 71% and worsened in 5%, and anxiety improved in 47% and worsened in 24%. One transient psychotic event was reported.86,87
A case study of a 15-year-old reported not only reduced anxiety, irritability, and aggressiveness but also reduced communication and motivation. 88 Another case report found that a 9-year-old male patient with nonverbal ASD showed significant improvement in symptoms after taking CBD-rich cannabis oil. He had less violent outbursts and self-injurious behavior and improved sleep, emotional stability, concentration, and social interactions. 89
Cancer symptoms
Three RCTs examining the effect of cannabinoid on chemotherapy-induced nausea and vomiting (CINV) were published between 1979 and 1987 (see Table 3). These trials showed that nabilone reduced the number of vomits and incidence of retching in those taking nabilone compared with both prochlorperazine and domperidone. However, there was also more dizziness, drowsiness, and mood alteration in those taking nabilone (see Table 3).91–93
Characteristics of Studies Investigating Cancer Symptoms
Two observational studies in paediatric oncology patients have been published since 1995 (see Table 3). The first looked at eight patients between the ages of 3 and 13 years with a diagnosis of a haematological malignancy. Subjects were given delta9-THC 2 hours before chemotherapy and continued every 6 hours for 24 hours. All patients had complete prevention of vomiting. 94 The second observational study included 50 children and young adults from a single center in Israel. The patients in this report all had poorly controlled symptoms related to their cancer diagnosis, despite conventional treatment. The indications for commencing medical marijuana included the following: nausea and vomiting, depressed mood, sleep disturbances, poor appetite, weight loss, and pain. Positive effect was seen in 80% of patients. 5
Five retrospective chart reviews have been conducted on cancer-related symptoms and cannabinoids. Two studies by Polito et al.95,96 demonstrated that complete control of chemotherapy-induced vomiting was achieved in between 34% and 54% of patients who were taking nabilone (see Table 3). AEs occurred in approximately one-third of patients with the most common side effects being sedation, dizziness, euphoria, and headache. In one of the studies, 9% of patients discontinued nabilone due to AEs. 96 A chart review by Rower et al (see Table 3). 97 in 2020 examined dronabinol prescriptions in the United States and found that it was prescribed almost exclusively for cancer patients. Ten patients had blood samples taken within 72 h of dronabinol administration; however, quantifiable concentrations of THC and metabolites were consistently low and seemingly unrelated to dose. Doherty and colleagues reported on 21 patients prescribed oral cannabinoid for terminal conditions and found that the most common indications were seizures (52%) and pain (19%) (see Table 3). All children taking it for pain or vomiting had improvement, and in those taking it for seizures, 64% had improvement, 27% had no change, and 9% were worse. AEs occurred in 33% of patients and included somnolence, insomnia, and vomiting. 98 Elder and colleagues published a retrospective review of 66 children and adolescents who received dronabinol between 2000 and 2010 in a single center in the United States (see Table 3). Sixty percent of patients had a positive response in relation to reduction of CINV; however, the authors noted that 95% of patients received doses lower than reference guidelines. 99
Another retrospective study on cancer patients receiving cannabinoids was performed by Skrypek and colleagues in 2019 (see Table 3). 100 The authors looked at 103 patients and found that the most common indication for prescription was CINV in patients with leukemia, lymphoma, and high-grade brain tumors and pain in patients with solid tumors. Other indications included seizures, autism, and cachexia.
Two cases of hypotension following CBD administration were reported by Li and colleagues in children aged 2 and 4 years. Both of these cases involved parental administration of the drug outside of medical advice (see Table 3). 101
Spasticity
Between 2016 and 2022, one randomised trial, 102 one prospective cohort study, 103 and two observational studies104,105 were conducted on children with spasticity (see Table 4). The RCT included 72 patients with cerebral palsy or traumatic brain injury who were randomised to receive nabiximols for 12 weeks (n = 47) or placebo (n = 25). Patients received up to 12 sublingual or oral sprays per day titrated over 9 weeks. Each spray of nabiximol contained 2.7 mg THC and 2.5 mg CBD. There was no significant difference in spasticity between groups nor was there any difference in secondary outcomes, including sleep quality, pain, health-related QOL, comfort, depression, or safety. AEs were generally mild; however, three cases of hallucinations were recorded. 102
Characteristics of Studies Investigating Spasticity
An open-label prospective cohort trial examining the effect of cannabinoids on children with complex motor disorders with associated impaired QOL was performed in 2018. 103 Twenty children were included in the study, and differing ratios of CBD:THC (6:1 vs. 20:1) were compared in relation to their effect on symptoms. Spasticity, pain severity, and QOL improved in both groups. Adverse effects were mild and included worsening of seizures in two patients, behavioral changes in two patients, and somnolence in one patient.
An observational study of 16 patients with refractory spasticity was conducted in Germany in 2016 by Kuhlen and colleagues. The patients included in the study received dronabinol in a dose ranging from 0.08 to 1 mg/kg/day. Twelve patients had some benefit, there was no effect in two, and the effect could not be determined in a further two. 104 Another observational study examining the effect of dronabinol was published in 2017 and included 15 patients. This study recorded parental perceptions of the benefit of the drug in patients with a range of neurological conditions (cerebral palsy, developmental delay, brain injury, Angelman syndrome). Overall, 73% of parents felt that dronabinol was effective. Improvement in spasticity was reported in 20%, improvement in physical violence in 20%, and improvement in sleep in 13%. The vast majority of the cohort (87%) continued on medicinal cannabinoids after the trial was completed. 105
Fragile X syndrome
Fragile X syndrome causes significant impairment through its developmental and behavioral symptoms. One open-label observational cohort study was performed by Heussler and colleagues in 2019 to investigate whether medicinal cannabinoids would improve symptoms (see Table 5). 106 Twenty patients (aged 6 to 17 years) with Fragile X were included, and they received transdermal CBD gel twice daily for 12 weeks, with the dose titrated from 50 mg daily to a maximum of 250 mg daily. There was a significant reduction in the score on the Anxiety, Depression, and Mood Scale and also in secondary end points such as social avoidance, irritability, and QOL. AEs were common (85%), but mostly mild with no serious AEs reported. The CONNECT-FX trial assessed the efficacy and safety of transdermal CBD gel in children and adolescents with Fragile X syndrome. A total of 212 patients were included in the study (mean age 9.7 years), they were randomised to 12 weeks of the transdermal gel or placebo, and the primary end point was change in social avoidance. The trial found that in patients with greater than 90% or 100% methylation of the promoter region of the FMR1 gene, there was significant improvement in social avoidance, irritability, disruptive behaviors, and social interactions. Statistically significant benefit could not be demonstrated for the entire cohort, but the product was generally well tolerated, and the authors concluded that there was favorable benefit versus risk for patients with severe impacts from Fragile X (see Table 5). 107 Tartaglia and colleagues presented a case series of one child and two adults with Fragile X treated with CBD. The child was a 3-year-old male who was given a CBD-rich paste by his parents. They reported improvements in behavior, motor coordination, vocalisation, and social interactions. These improvements were also noted by the child’s occupational and speech therapists (see Table 5). 108
Fetal alcohol syndrome
A retrospective case series was reported by Koren et al. in 2021 on five patients diagnosed with fetal alcohol syndrome who were taking various ratios of CBD:THC in differing formulations and doses (see Table 5). Two of the five patients were children, and three were young adults. All five had severe disruptive behavior. The use of cannabinoids resulted in significant improvement in behavior in all five subjects as measured by the Nisonger Child Behavior Rating Form. 109
Gastrointestinal disorders
A descriptive study of cannabinoid use in patients with inflammatory bowel disease was published in 2019 by Hoffenberg and colleagues (see Table 5). 110 Fifteen patients using a variety of strengths and CBD:THC ratios were included. The main perceived benefits were improved sleep quality, less nausea, and increased appetite. A report of a 17-year-old patient with chronic intestinal pseudo-obstruction was published in 2020 (see Table 5). This patient was total parenteral nutrition (TPN) dependent and started taking 2.5 mg dronabinol twice a day. They reported improved appetite and less feelings of fullness or blockage. There was also an increase in tiredness while on the dronabinol. 111
Other indications
There has been a pilot RCT in children and adolescents with intellectual disability and severe behavioral disturbance (see Table 5). Eight patients were randomised to receive either CBD or placebo for 8 weeks. The pilot found the study to be feasible and acceptable to families, and the product was well tolerated by patients. Although this trial was not powered for efficacy outcomes, there was a signal of improvement in behaviour in those taking the active product. A fully powered RCT is planned for the future. 112
A variety of case series and reports have been published on the use of medicinal cannabinoids for a range of indications. One case showed improvement in anxiety and sleep quality in a child with post-traumatic stress disorder (PTSD) (see Table 5). 113 A case series by Lorenz and colleagues showed reduced spasticity, increased initiative, and increased interest in surroundings with dronabinol in doses ranging from 0.04 to 0.12 mg/kg/day in children with various neurological conditions (neurodegenerative disease, mitochondrial disorder, posthypoxic state, PTSD, epilepsy). At higher doses, there were incidences of disinhibition and increased restlessness (see Table 5). 114 Another case series by Divisic and colleagues reported on six children receiving palliative care for a range of indications who all had severe seizures and chronic pain. All patients were given a titrated plant extract of cannabis sativa for a year. Side effects were mild, and no patient discontinued treatment. There was a reduction in seizures and a benefit in pain based on caregiver’s evaluation. 4
Chelliah and colleagues published a case series of children taking CBD for epidermolysis bullosa. This blistering skin disorder is difficult to manage and causes itch, pain, reduced mobility, and recurrent skin infections. The cases reported were a 6-month-old boy, a 3-year-old girl, and 10-year-old boy. All patients had improvements in wound healing and less blistering in addition to reduced pain. One patient was able to completely wean off opioid analgesia (see Table 5). 115
A case of a patient taking everolimus concurrently with CBD showed that plasma levels of everolimus increased beyond therapeutic levels, presumably due to both drugs sharing the same CYP450 3A4 pathway (see Table 5). 116 Another adverse drug reaction was published in 2020 by Madden involving a patient with chronic pain taking methadone who was also given CBD by the parents outside of medical advice. The patient experienced increased fatigue and sleepiness (see Table 5). 117 Pralong published a case of a 12-year-old patient taking Sativex for chronic pain who had surgery to correct her scoliosis. The Sativex is thought to have attenuated the neuromuscular monitoring during the case with absent motor-evoked potentials in the thigh and right hand (see Table 5). 118 There has been a case report of precocious puberty in a 2-year-old boy who had been taking CBD oil for 6 months. While it is known that delta9-THC can affect the hypothalamic–pituitary–gonadal axis, it was not clear in this case if the medicinal cannabinoid was the cause of the precocious puberty. 71
Discussion
This scoping review identified 111 publications that focused on the use of cannabinoids in paediatric patients. The types of studies included in the review were RCTs, open-label studies, prospective cohort studies, retrospective cohort studies, qualitative studies, case series, and case reports. Good evidence was found for the use of cannabinoids in seizure disorders and the control of CINV. There is a signal for effectiveness in a range of other neurological and behavioral disorders. There was a lack of evidence in the alleviation of cancer symptom burden and palliative care, which has been identified as an area for the focus of future research.
Medicinal cannabinoids have the potential to improve a variety of paediatric conditions due to its positive effects on a range of neurological, behavioural, and emotional symptoms. It has been trialed in a range of conditions with mixed success.
There are a range of regulatory and ethical issues associated with the prescription of medicinal cannabinoids. There are also social and cultural factors that influence the opinion of the drug, further adding to the complexity for prescribers. One study in Canada found that clinicians identified four main themes relating to the authorisation of medicinal cannabinoids as follows: access, autonomy within relationships, medically appropriate use, and research priorities. 119 All of these themes relate to harm reduction, and it was felt that for children with neurodevelopmental and life-threatening conditions, the benefits of treatment outweighed the risks. The authors highlight the desire from clinicians for more research to ensure the alignment of medicinal use of cannabinoids with regulatory and community standards.
There is good evidence for benefit in seizure disorders, with several RCTs and many observational trials showing benefit. The exact dose and optimal formulation of CBD is yet to be fully elucidated; however, 10 mg/kg appears to offer similar efficacy in seizure control with fewer side effects. A post hoc analysis conducted to determine onset time of treatment effect found statistically significant seizure reduction by day 10 of treatment. 20 Most side effects reported in these trials were mild, and there was no clear causal relationship between dosage of cannabinoid and incidence of side effects, including severe side effects. It should also be noted that similar incidences of side effects were often reported in those receiving a placebo. However, it appears that some children do not tolerate the treatment particularly well as indicated by the number of patients that withdraw from the studies reported. Some studies reported a worsening of liver function with medicinal cannabinoids; however, there was often a lack of detail regarding concomitant antiepileptic medications, and there is a possibility that the elevated liver function tests (FTs) observed were due to drug interactions rather than a primary effect of cannabinoids. In any case, the prescription of cannabinoids should be under the supervision of a qualified paediatric neurologist or equivalent who can identify those patients at risk for serious side effects. In Australia, CBD is an “Authority Required” prescription requiring strict clinical criteria to be met and prescription to be made by a suitably qualified specialist.
There is inconsistent evidence for improvement of behavioral problems in patients with autism. Only one RCT was found, which showed no improvement overall in behavioral problems or sleep outcomes. 4 However, there were improvements in disruptive behavior with no serious AEs reported. 4 An open-label study of children and adolescents with autism found a statistically significant improvement in communication, daily living, and socialisation but not cognition. 84 The improvement in symptoms was greater in those with more severe symptoms to begin with. These results were also supported by the observational studies.
There is also good evidence for efficacy in control of CINV with trials dating back to the late 1970s showing a positive effect on CINV with nabilone compared with other commonly used antiemetics. However, there were more adverse effects notably mood alteration in those taking nabilone. More recent observational studies have confirmed the results from these early studies; however, a significant number of children reported some mild side effects.
The evidence regarding the effect of cannabinoids on spasticity is less clear. A RCT which included children with cerebral palsy and traumatic brain injury showed no significant difference in spasticity between the treatment groups and placebo. In contrast, some observational work and subjective qualitative studies suggest some benefits in using cannabinoids on symptoms like spasticity, pain, QOL, and parental perceptions of benefit in spasticity, physical violence, and sleep. One observation study of 16 patients with refractory spasticity receiving dronabinol in varying doses reported 14 out of 16 patients having improvement in symptoms. However, the effect of treatment was unable to be determined in two patients. 104 This reflects the challenging nature of assessing spasticity in children with neurological impairment. In this study, none of the patients was verbally communicative; therefore, other important variables like psychological side effects could also not be assessed.
There is limited but encouraging evidence for benefit in a range of conditions with neurological and behavioral symptoms, including Fragile X syndrome, fetal alcohol syndrome, and PTSD. Similarly, there is a suggestion that some gastrointestinal conditions may see an improvement in symptoms with medicinal cannabinoids; however, further research is required to confirm this. There is also limited knowledge of the impact of cannabinoids in younger children given their developing nervous systems and the proposed mechanism of action in the CNS.
Limitations
This review is limited by its nature as a scoping review, and it was not designed to answer a specific clinical question regarding medicinal cannabinoids in children. There may be further studies that were not identified through our search strategy, and we are cognisant that new research is being published in this area all the time.
Future directions
This review found that a significant gap in the literature exists in the area of chronic pain control in paediatric patients. A number of studies include pain as a secondary outcome; however, the evidence base is quite limited to be able to make any conclusions around analgesic efficacy. Prospective trials, either randomised or open label, are required in this area to better inform clinicians and families around the role of medicinal cannabinoids for persistent pain using appropriate patient- and family-reported outcome measures. Similarly, there have not been any recent randomised trials examining the effect of medicinal cannabinoids on cancer symptoms. Regulatory and funding bodies in Australia and around the world recognise the lack of evidence in this area and are encouraging well-designed trials to be performed. One such trial is the medicinal cannabis for symptom burden in children with advanced cancer (MINI) trial (Australian and New Zealand Clinical Registry number ACTRN12622000037707). Results from this trial will help fill the evidence gap in this area. In addition, future studies can also focus on the relative efficacy of CBD versus THC for a variety of paediatric conditions.
Conclusions
There is significant interest in the potential applications of medicinal cannabinoids for a range of paediatric conditions. There is an ever-increasing body of literature in this area, and legislation, prescribing practices, and guidelines will need regular updates to keep current with the available evidence. In addition, there are new products regularly introduced into the market requiring the Therapeutic Goods Administration oversight of cannabinoids to ensure safety and quality.
Currently, there is good evidence to support the use of medicinal cannabinoids for severe seizure disorders and for the control of CINV. There is promising evidence for a range of other neurological and behavioural disorders, but more research is needed. One area with a relative lack of evidence is chronic pain and palliative care, and it would be useful for clinicians, patients, and their families for large clinical trials to examine the efficacy of medicinal cannabinoids in these settings.
Footnotes
Authors’ Contributions
S.S. and P.L.A.: Conceptualization, methodology, formal analysis, writing—original draft, and writing—review and editing. A.B. and A.H.: Writing—review and editing.
Author Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Information
No funding was provided for this work.
Abbreviations Used
References
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