LAUSR

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. Children with ASD and ID have a high risk of developing severe and impairing mental health problems, which cause enormous distress for the children and their families, 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, selfinjury, agitation, mood changes, crying, screaming, stamping feet and banging objects, are sometimes collectively described in drug trials as ‘irritability’. 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. These medications carry a risk of serious adverse effects in children and adolescents in general, and patients with developmental disabilities may be at particularly high risk. 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’; adding drugs to treat side effects, such as use of metformin to control weight gain caused by antipsychotic medication; 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. 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. Δ-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, and 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. 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. 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. CBD has been delivered orally in an oil-based capsule or sublingual spray in human trials, in variable ratios with Δ-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. 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 antiCorrespondence: Dr Daryl Efron, Royal Children’s Hospital, Flemington Road, Parkville, Vic. 3052, Australia. Fax: +61 39345 4751; email: daryl. [email protected]