Does cannabidiol reduce severe behavioural problems in children with intellectual disability? Study protocol for a pilot single-site phase I/II randomised placebo controlled trial

Daryl Efron, Kaitlyn Taylor, Jonathan M Payne, Jeremy L Freeman, Noel Cranswick, Melissa Mulraney, Chidambaram Prakash, Katherine J Lee, Katrina Williams

BMJ Open, 2020, 10, e034362.

doi : 10.1136/bmjopen-2019-034362

 

Abstract

Introduction : Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP.

However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID.

Methods and analysis : This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8–16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group.

Ethics and dissemination : This protocol has received ethics approval from the Royal Children’s Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media.

Trial registration number : ACTRN12618001852246

 

Strengths and limitations of this study

►► This is the first study to investigate cannabidiol (CBD) for severe behavioural problem in children
with intellectual disability and will contribute to the literature more broadly on the use of cannabinoids in children.

►► Randomised, placebo-controlled study using online completion of outcome measures.

►► This pilot study will inform the design of a full-scale randomised controlled trial of CBD for this indication, and will inform other CBD trials in children.

►► The study is not powered to provide meaningful efficacy outcomes.

 

Introduction

Intellectual disability with severe behaviour problems and associated burden

Two per cent of children and adolescents have an intellectual disability (ID),1 and approximately half of these individuals have mental health problems,2 including many with challenging behaviours. These commonly include aggression, self-injury, agitation, mood changes, screaming and banging objects. We use the term severe behavioural problems (SBP) to describe this clinical phenotype.

SBPs in children with ID are a major contributor to morbidity, functional impairments, missed opportunities for learning and reduced quality of life. SBP also places an enormous burden on families and carers,3 as well as health, education and disability sectors. Parents and siblings of youth with SBP often live in fear of them and are at increased risk of mental health problems.4 Expensive long-term
residential placement is often the only option.5 ID is estimated to cost $A15 billion annually in Australia.6 Much of this cost, including personal expenses, service use, government expenditure and
opportunity cost for families, relates to SBP impacting on the health and care needs of these patients.7 Patients with ID and SBP cause challenging demands for hospitals to manage, with implications for staff training, ward design and safety of both staff and patients.

Problems with current treatment of SBP in youth with ID Challenging behaviours are extremely difficult to treat in children with ID and SBP. Psychological interventions are often ineffective in patients with ID,8 leaving environmental modification and medication as the main strategies available. Psychotropic medications are prescribed by Australian paediatricians for almost 50% of youth with ID.9 The medications—antipsychotics, psychostimulants and antidepressants—carry a high risk of side effects for
children and adolescents in general; however, patients with developmental disabilities are at particularly high risk,10 and less able to report side effects. For example, adults with ID exposed to antipsychotic drugs have a higher incidence of treatment-emergent movement disorders compared with patients without ID.11 Another common side effect of antipsychotics, weight gain, affects health in a patient group already at increased risk of chronic illness,12 and is a risk factor for avoidable death.13

Weight gain also brings practical problems in youth with ID, who are often dependent on carers for everyday activities such as dressing, bathing and toileting, as well as compounding the management of aggressive behaviour.

Current pharmacotherapy in children with ID and SBP is characterised by concerning practices, including polypharmacy and frequent changes to medication regimens10; adding drugs to treat side effects, such as use of metformin to control weight gain caused by antipsychotic medication14 and long term use of drugs ‘off-label’, for example, atypical antipsychotics. Innovative and safer interventions are urgently needed for children with ID and SBP.

Medicinal cannabis

The potential for medicinal cannabis products to treat a range of medical and psychiatric conditions is becoming increasingly understood.15 There has recently been great interest in the potential therapeutic role of cannabinoids. The primary psychoactive compound in the cannabis plant is Δ9 tetrahydro-cannabinol (Δ9-THC), which can cause serious side effects such as paranoia and hallucinations. 16 In contrast cannabidiol (CBD), another cannabis extract, does not have intoxicating properties and may provide benefits with minimal adverse psychological effects.

CBD pharmacology and safety

CBD has been delivered orally in an oil-based capsule or sublingual spray in human trials, in variable ratios with Δ9-THC. The onset and duration of activity depends on the preparation and route of administration. The plasma half-life of CBD following oral administration is approximately 60 hours after two times per day dosing for 7 days in healthy adults.17 It is highly lipophilic and accumulates in fat.18 CBD is metabolised by cytochrome P450 enzymes 3A and 2C in the liver.

Both animal and human studies have indicated that CBD does not affect physiological parameters or psychological functions.19 Studies in healthy adults have shown CBD to be well tolerated across a wide dose range, with no significant adverse effects on vital signs, cognition or mood in oral doses of up to 1500 mg per day.18 In children with epilepsy up to 50 mg/kg/day of CBD has been prescribed.20 Reported tolerance in trials has been generally good, with the most common adverse effects, somnolence, diarrhoea and decreased appetite, occurring in a minority of exposed patients.21

Indications for CBD

Medical cannabis is being advocated for an increasing range of indications. In children, the main indication for CBD is drug-resistant epilepsy, with supportive evidence emerging for its effectiveness as an adjuvant treatment to conventional antiepileptic medications for some specific epileptic syndromes.21 In 2018, Epidiolex, a pure CBD oral solution manufactured by GW Pharmaceuticals, received approval from the US Food and Drug Administration for patients with Lennox-Gastaut syndrome and Dravet syndrome.22 It is possible that reported improvements in ‘overall condition’ of children given CBD in epilepsy trials were due to more settled behaviour, although this has not specifically been reported.23

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