“Not a miracle drug” experts give cautious nod to CBD as third-line treatment for epilepsy in kids


By Tessa Hoffman

16 Aug 2018

Cannabidiol can be “cautiously construed” as a moderately effective and appropriate treatment for children with severe epilepsy, according to two of Australia’s leading experts in the field.

However, cannabidiol (CBD) – which due to its comparative lack of  psychotropic effects has become the most researched compound found in the Cannabis sativa plant – should be considered a third-line agent due to lack of long-term data, the existence of 25 established antiepileptic medications and the high cost of production.

“Cannabidiol is a medicine, not a miracle and should be managed as such … It is hoped that further investigation in class 1 trials and high level research is encouraged and continues, otherwise we may return to the days of snake oil,” conclude Dr John Lawson, paediatric neurologist at Sydney Children’s Hospital and Professor Ingrid Scheffer, paediatric neurologist and professor at the University of Melbourne, in a review article published in the British Journal of Pharmacology.

They find the best evidence for short-term efficacy and adverse events is contained in three recently published double-blind randomised controlled trials of the cannabidiol (CBD) extract formulation Epidiolex: a trial of 120 children (aged 2-18) with Dravet syndrome, and two trials involving 171 and 225 patients (age range 2-55) with Lennox-Gastaut syndrome, which showed significant median seizure frequency reductions of 17% to 23% respectively compared to placebo.

However they acknowledge that critics say the efficacy seen in the trials may be partly related to drug interactions such as with clobazam and that this secondary endpoint data had not been published.

“The implication here is that the CBD is merely increasing the available clobazam and its metabolites to achieve its anti-epileptic effect; an issue that still remains to be resolved,” they write.

The authors also note the long-term safety has not been established for cannabidiol, which they says was a mainstay in epilepsy treatment until the development of phenobarbital (1912) and phenytoin (1937).

The relevance of the well-known adverse health effects associated with recreational use of marijuana, such as psychosis, to pure CBD products “is very uncertain”, they add.

“A particular worry is the effect on children as little is known about the potential adverse side effects of CBD on brain development and behaviour,” they write, noting while there is little scientific evidence in this area, an animal study has shown CBD produces behavioural abnormalities in offspring, and other research found prenatal exposure in humans leads to higher rates of anxiety and depression in teens.

“These risks cannot be ignored but need to be balanced against the known impact of severe epilepsy.”

The use of cannabinoids as medicine is a complex task, due to the marked instability of compounds, variability in absorption and metabolism, and the plethora of products with different pharmokinetic profiles.

“One could cautiously construe that cannabidiol has modest efficacy and is appropriate for children with severe epilepsy with due attention to important adverse effects and potential drug interactions,” the authors conclude.

“There is no evidence to guide its ranking in AED prescribing choices. Currently CBD must be considered a third-line agent because of the comparatively low patient years of use in terms of exposure and adverse events, and the presence of well-established first and second line agents, not to mention the costs involved in making purified (>95%) formulations.”

Dr Lawson is a co-author of a separate article in the MJA that describes clinicians’ experience using cannabidiol in 40 paediatric patients enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures.

When used as an adjunct treatment cannabidiol “had some subjective benefit for overall health, with a manageable adverse event profile,” they conclude.

The most common side effects were somnolence, which resolved in 10 of 15 patients, and gastrointestinal effects. Four children were withdrawn from treatment, and two had elevated transaminase levels – showing the need to monitor liver function. The caregivers of 12 children felt the overall health of their children had much improved.

The authors conclude that cannabidiol is safe in the short term treatment of children with severe, drug-resistant epilepsy, but controlled studies of its therapeutic efficacy are required.

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