Medical cannabis for paediatric developmental–behavioural and psychiatric disorders

Developmental and behavioural disorders including autism spectrum disorders (ASD), attention‐deficit hyperactivity disorder, anxiety and intellectual disability (ID) represent the largest group of diagnoses managed by Australian paediatricians today.1 Children with ASD and ID have a high risk of developing severe and impairing mental health problems,2, 3 which cause enormous distress for the children and their families,4 and place an additional burden on education and health‐care systems, which often struggle to meet the demands imposed by them. Mental health symptoms in this patient population are a major contributor to functional impairments and reduced quality of life, and are difficult to treat. Troublesome symptoms, including aggression, self‐injury, agitation, mood changes, crying, screaming, stamping feet and banging objects, are sometimes collectively described in drug trials as ‘irritability’.5 Common drivers of these behaviours include anxiety and frustration in relation to communication impairments, and difficulties regulating emotional states. These patients may not be amenable to psychological interventions, such that environmental modification and medication are the main strategies available.
Psychotropic medications, including stimulants, antidepressants and antipsychotics, are the medications most frequently prescribed by Australian paediatricians.6 These medications carry a risk of serious adverse effects in children and adolescents in general,7 and patients with developmental disabilities may be at particularly high risk.8, 9 Antipsychotic‐induced weight gain has negative health effects and poses an additional practical problem in this population, as they are often dependent on carers for everyday activities, such as dressing, bathing and toileting. Furthermore, the difficulty in managing challenging behaviours such as pushing or hitting is compounded by larger patient size.
Current pharmacotherapy in this patient group is characterised by several concerning practices, including polypharmacy, with potential for drug interactions; frequent changes to medication regimens, referred to by Einfeld as ‘knee‐jerk psychiatry’9; adding drugs to treat side effects, such as use of metformin to control weight gain caused by antipsychotic medication10; and long‐term use of drugs off‐label and untested in this patient group. This latter category includes atypical antipsychotics such as quetiapine and olanzapine, mood stabilisers such as lithium and valproate, and novel agents including naltrexone, oxytocin and N‐acetylcysteine. There has been little drug discovery work in the field of child and adolescent mental health for many years, and there is an urgent need to develop safe and effective therapeutics for this vulnerable patient group. Medical cannabis (MC) may be one such treatment.
Humans have used marijuana for millennia, variously as a spiritual sacrament, herbal medicine, dietary supplement or psychoactive inebriant.11 The main acute effects of plant cannabis include relaxation, euphoria, increased sociability, heightened perception and increased appetite, although some individuals experience anxiety and paranoia. Common physiological effects include tachycardia, conjunctival injection and dry mouth. Δ⁹‐tetrahydrocannabinol (THC) is the primary psychoactive compound in the cannabis plant, acting via cannabinoid receptors in both the central and peripheral nervous systems. In contrast, cannabidiol (CBD) does not appear to have psychoactive properties,12and so has the potential to provide health benefits without adverse psychological effects.
Use of MC is advocated for an increasing range of medical indications. To date, the symptoms with best evidence for MC use are chronic non‐cancer pain and spasticity in adults (e.g. in multiple sclerosis and spinal cord injury), although it is also used to treat chemotherapy‐induced nausea and vomiting.13 In adult mental health and neuropsychiatry, MC has been used in patients with epilepsy, anxiety, depression, sleep disorders, Tourette syndrome and psychosis, despite a lack of supportive evidence.14 In children, the main indication for MC is drug‐resistant epilepsy, with some supportive evidence emerging for treatment of specific seizure types and epileptic syndromes with CBD, given in addition to conventional antiepileptic medications.15, 16
CBD has been delivered orally in an oil‐based capsule or sub‐lingual spray in human trials, in variable ratios with ∆⁹‐THC. Oral bioavailability is low because of extensive hepatic first pass metabolism. Transdermal approaches to CBD delivery have also been investigated. CBD is highly lipophilic and so accumulates in fat, resulting in a very long elimination half‐life. It is metabolised predominantly by cytochrome P450 (CYP) enzymes 3A and 2C in the liver.14
The potential therapeutic effects of CBD on human behaviour are biologically plausible. There are two endocannabinoid receptors in humans, CB1 found mostly in the brain, and CB2 located in the peripheral nervous system as well as in lymphoid tissue. These receptors modulate neurotransmitter release and regulate the release of cytokines from immune cells, with potential anti‐inflammatory and analgesic effects.17 CBD is thought to act indirectly by inhibiting the breakdown of the endogenous ligand anandamide, resulting in increased binding to CB1 receptors.18 Alterations in endocannabinoid signalling have been found in mice carrying a mutation related to autism,19 and also in a mouse model of Fragile‐X syndrome,20 raising the possibility of this system playing a role in neurodevelopment and behaviour.
Anecdotally, use of naturally occurring cannabis (phytocannabinoids) is said to have a calming effect in some children. At present, however, there is little evidence to support or refute the use of MC to treat behavioural and psychiatric disorders in children. One case report described improvements in hyperactivity, irritability and speech in a 6‐year‐old autistic boy given dronabinol (THC),21 and improvements in self‐injurious behaviour were observed in 7 of 10 adolescents with ID‐treated open‐label with dronabinol.22 A 10‐year‐old girl with post‐traumatic stress disorder was reported to derive substantial benefit from CBD oil, with reduced anxiety and improved sleep; no side effects were observed over 5 months of treatment.23 Improvements in mood, behaviour and alertness were reported in both a chart review24 and a Facebook survey25 of parents of children given oral cannabis extracts for epilepsy. There is currently only one registered controlled trial of MC use for behavioural problems in children. This is an Israeli double‐blind, placebo‐controlled crossover trial using cannabis oil with a 20:1 ratio of CBD to THC, in patients with ASD aged 5–21 years, with a primary outcome of ‘non‐compliant behaviour’.26
Regarding safety of CBD in humans, studies in healthy adults have shown it to be well tolerated across a wide dose range, with no significant adverse effects on vital signs, cognition or mood seen with oral doses of up to 1500 mg/day.14 In children with epilepsy taking antiepileptic medications up to 50 mg/kg/day has been prescribed.27 Adverse events reported in more than 10% of those patients were somnolence, decreased appetite, diarrhoea, fatigue and convulsions. CBD inhibits certain cytochrome P450 isoenzymes and drug interactions with antiepileptic medications have been noted.28 Similar interactions with potential for adverse effects might be expected to occur in children taking concomitant psychotropic medications. Long‐term safety data of CBD in clinical populations is not available, but there are concerns about potential psychiatric and physical adverse effects from chronic non‐MC use in childhood and adolescence.29, 30
The use of MC to treat children and adolescents with psychiatric problems has been discussed by mainstream media,31 and a number of social media groups are advocating the use of MC for children with conditions such as autism (Mothers Advocating Medical Marijuana for Autism; https://www.facebook.com/TexasMammas). Some parents report that they give cannabis products to their children to help with their behaviour and increasingly, Australian parents of children with developmental disabilities and/or mental health disorders are asking their paediatricians if MC treatment is advisable and whether they can assist them in obtaining it for their child. The American Academy of Pediatrics has highlighted the need for further research into the therapeutic uses of cannabinoids in children and adolescents,32 a position supported by a recent systematic review.33
In Australia, laws have been enacted and regulations changed to facilitate the cultivation, manufacture, importation and prescription of high quality (and high cost) MC products. Unlike countries where only medical certification of illness is required, in Australia a doctor prescribing MC under the Special Access or Authorised Prescriber schemes assumes responsibility for monitoring patient safety, and must report all adverse effects to the therapeutic goods administration. The consequence of this model is that parents who are determined to administer MC products to their children have two options – either persuade the doctor to prescribe in the absence of strong evidence for efficacy, or obtain a cannabis product illegally and risk the use of low grade products.
In summary, MC has potential as a therapeutic option in the management of paediatric mental health symptoms; however, the evidence to support its use for these patients is not yet in. There is an urgent need to conduct well‐designed trials of pharmaceutical‐grade MC products in children with behavioural and psychiatric disorders. In the meantime, paediatricians should counsel caution in relation to MC treatment for these indications.
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