Cannabinoids in paediatric neurology

A debate on the use of cannabinoids in paediatric neurology has been resonating both in the media and in the clinic for several years. Two compounds in cannabis (tetrahydrocannabinol and cannabidiol) are now the focus of promising research into their potential antiepileptic effect. Many other compounds act on cannabinoid receptors. Interestingly, the endogenous ligands were discovered after the receptors were first characterized in the late 1980s. Together, they form the endocannabinoid system, which modulates a number of physiological processes including motor learning, memory, appetite, mood, immune response, and pain perception. This system also mediates the psychoactive effects of cannabis, which mainly result from activation of the CB1 cannabinoid receptor by tetrahydrocannabinol. In contrast, cannabidiol is not psychoactive and seems to act as an indirect antagonist of cannabinoid receptors. In animal models, cannabidiol has a more consistent anticonvulsant effect than tetrahydrocannabinol, which has been found to be proconvulsant in some species. There have been clinical studies with promising results, mostly in Dravet syndrome (severe myoclonic epilepsy of infancy), but interpretation of a proportion of them has been limited by methodological issues. More fundamentally, human research has been restricted by legal regulation of the use of cannabis-derived medicine. Consequently, while research is underway, the main substance of the debate on cannabinoids as antiepileptic drugs appears to be wanting in consistency and factual accuracy. Discussion very much draws on anecdotal reports. It is often emotional and confused, oscillating between non-specific notions of harm from giving ‘drugs’ to children and accounts of dramatic recovery from intractable seizure disorder. The public representation of cannabis, and associated social and legal aspects further blurs the issue. Both parents and others involved in the care of children with epilepsy are thus over-exposed to an alarmist debate, which is unusual with other novel, potential antiepileptic drugs. Moreover, expectation of positive effects in individual experiences or open studies also alter the perception of benefit from the drug. Ironically, brain changes associated with expectation of positive outcomes involve the reward circuit including signalling by endogenous cannabinoids. Unfortunately, published evidence to support or disprove the safety and efficacy of cannabinoids in children with epilepsy is very scarce. Both these issues require specific, well-designed studies. It is difficult to infer much on safety of cannabinoids in young children from the existing literature regarding marijuana exposure in adolescence; this is due to many confounding factors and a different scope of maturational processes. Reliable information pertaining specifically to the long-term effect of cannabidiol on the concerned age groups is critical. At this stage, it is hoped that the clinical trials of this drug that are being conducted in various conditions (including infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) will be helpful in clarifying issues. It is of utmost importance to make sure that the preparations used in the studies have reliable purity, stability, and bioavailability properties. The effect of cannabinoids on levels of concommitantly administered antiepileptic drugs also remains an unsolved question. In addition, in order to approach the possible role of the endocannabinoid system in epilepsy more comprehensively, it will be important to evaluate the interaction of other drugs with it, given increasing evidence of upregulation by various antiepileptic drugs and other compounds, including anxiolytics, antipsychotics, antidepressants, paracetamol, non-steroidal anti-inflammatory drugs, opioids, and steroids. Non-pharmacological interventions, such as massage and acupuncture, and more generally lifestyle modification, such as diet or exercise, can modulate the endocannabinoid system. Some of these could have implications on therapy. Early results in adults with a variety of conditions suggest that it might be interesting to study the therapeutic effect of cannabinoids in children experiencing pain (e.g. neuropathic pain), motor disorders (e.g. spasticity), or psychiatric disorders (e.g. anxiety disorders, autism), with the same rigour as that required for studies to be carried out in epilepsy. Meanwhile, parents of children with a condition that is not managed by current therapy will understandably enquire about the possibility of giving them cannabis or cannabinoid. This raises both good-practice and ethical questions pertaining to clinicians’ responsibilities to adequately inform patients and parents, as well as the potential for liability if inappropriate management results in harming patients. When this is possible, one option is enrolment into sound clinical trials. In an era when many aspects of science move quickly, we must carry out useful preclinical and clinical research, and accept that it will take time. The complexity of appropriate indication of cannabinoids in paediatric neurology still calls out for such discipline and patience. Current discussions in the media are mostly superficial because of the remaining gaps in our knowledge. This publicity is unlikely to help directly except by attracting interest in research, which will hopefully benefit the children we treat.