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MEDICINAL cannabis for epilepsy has been a hot topic in Australia, particularly in Victoria where Premier Daniel Andrews made its legalisation a key pledge in his successful 2014 election campaign.
But until recently, actual evidence for the use of cannabinoids to reduce seizure frequency has been hard to come by. Now, a randomised, double-blind trial of cannabidiol, a cannabis derivative that does not contain the psychoactive ingredient tetrahydrocannabinol, has for the first time provided hard data that the treatment works.
For the study, published in the New England Journal of Medicine, a group of international researchers, including Professor Ingrid Scheffer from the University of Melbourne, randomised 120 children with the Dravet syndrome – a severe form of childhood epilepsy with often drug-resistant seizures and a high mortality rate – to either an oral cannabidiol preparation or placebo, in addition to their normal antiepileptic treatment.
Tracking the change in convulsive seizure frequency from baseline across the 14 weeks of the trial, the researchers found convulsive seizures were reduced by around 40% (from a median of 12.4 to 5.9 per month) in the treatment group, compared with 13% (from 14.9 to 14.1 per month) with placebo. The difference in convulsive seizure reduction between the two groups was both statistically significant and clinically consistent.
In 43% of patients taking cannabidiol, the number of convulsive seizures more than halved over the course of the treatment. Five percent of treated children became completely seizure-free, compared with none in the placebo arm. There was no significant reduction in non-convulsive seizures.
There was a downside, however, with 93% of the treatment group suffering from side effects, compared with 74% in the placebo arm. The most common of these were vomiting, fatigue and fever. These side effects were generally not considered serious, although eight patients in the cannabidiol group did drop out of the trial.
Professor Scheffer, who is chair of Paediatric Neurology at the University of Melbourne, described the trial findings as a “major scientific breakthrough”.
“It’s the first evidence that cannabidiol works. There have been anecdotal reports in the past, and people with firm beliefs that it works in epilepsy, but this is the first time it’s been proven,” she told MJA InSight.
Professor Scheffer cautioned that cannabidiol wasn’t a cure for these children.
“Sadly, this is not a panacea … but it does give cause to be optimistic about further research for its use. It also raises lots of questions, not just in terms of the treatment of epilepsy, but where else it could be applied medicinally.”
David Penington, an Emeritus Professor at the University of Melbourne who has long campaigned for the legalisation of medicinal cannabis, said the trial findings were “without a doubt robust”.
“It’s a very valuable study, with very credible evidence as the extent of efficacy of treatment in these severely disabled children. But it needs to be seen in context. Dravet is not the only form of juvenile epilepsy, and it remains to be seen whether this treatment has broader application in epilepsy.”
Professor Penington said that a narrow focus on medicinal cannabis for epilepsy, as has been the case in Victoria, could mean that other people who may benefit are being ignored.
“Medicinal cannabis for painful inoperable cancer or neuropathic pain, such as in multiple sclerosis, hasn’t been seen as a priority at all in Victoria. There need to be trials for pain and for people undertaking chemotherapy in addition to those for [patients with] juvenile epilepsy. I also personally believe there’s a case for people with post-traumatic stress disorder being considered for a trial.”
Professor Penington said that another problem with medicinal cannabis in Australia was that at present it’s being imported from overseas at great expense.
“I believe we can produce medicinal cannabis here at a fraction of the cost if we’re allowed to do so. Hopefully, within the next few years we’ll get approval to do that, under tightly regulated conditions.”
Australia’s approach to medical cannabis has been “very cautious and slow,” Professor Penington said, compared with other jurisdictions, in particular in many states in the US where the treatment is available for a number of conditions.
“There are many people here in Australia who are suffering and who could benefit from medicinal cannabis, and I think it’s very sad that it’s not available for them. I think we’ll come around to it step by step, but we have some distance to go.”
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This 2005 New England Journal review is worth reading: Cannabinoids in the Treatment of Epilepsy (the full paper is accessible at http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2011.03007.x/full).
The authors remark that “Despite the preclinical data and anecdotal reports on the efficacy of cannabis in the treatment of epilepsy that include reports from epileptologists, a recent Cochrane review concluded that “no reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy” owing to the lack of adequate data from randomized, controlled trials of Δ9-THC, cannabidiol, or any other cannabinoid. This assessment was confirmed in a recent systematic review by the American Academy of Neurology.”
Much of the evidence is anecdotal, as relayed by Andrew Katelaris above. It is difficult to see how the addition of mixed CBD and THC could make an “impressive” improvement to a child’s intellectual performance.
Cannabis has been considered in combination therapy in the most difficult to control infant epilepsy, such as Dravet’s Syndrome. Other drugs with some evidence of efficacy here include Topiramate and Stiripentol, as well as ketogenic diets. (ref Epilepsia 2011 – The pharmacologic treatment of Dravet syndrome).
Optimal treatment for any difficult seizure disorder would involve management by a highly specialised paediatric neurology seizure clinic – rather than purchasing plant extract as described above.
Results obtained across many forms of intractable epilepsy using whole plant extract with CBD/THC of 3:1 and a component of CBDA and THCA (ie not heated) with individualised dosing regimen are greater than what is reported here. Also, the impact on the child’s social and intellectual performance is often impressive
Dr Andrew Katelaris MD
The circulating information on cannabis extracts used for therapeutic reasons (so-called “medical cannabis”) has been mudied by the argument for legalised recreational use. This has led to an exaggeration of the touted benefits of the “whole herb”, well-beyond the psychotropic, muscle relaxation and anti-convulsant effects that reflect its known pharmacology. Cannabis is being promoted in the wider community as a miracle cure for everything from cancer to diabetes (a quick search, using the term “cannabis miracle cure” will reveal the extent of this).
So, we know that cannabidiol has some anti-seizure activity, as do benzodiazepines and barbiturates – but each also has side-effects and adverse effects. We also now have a wider range of safer anti-convulsants with fewer side effects and little if any sedative or psychotropic effects.
In my view, prescribed cannabis extracts could easily be incorporated into the therapeutic toolbox for evidence-based uses – just as narcotics are. Morphine is an invaluable analgesic with enormous benefit in palliative care – but not a miracle cure for any pathology. And morphine prescription does not require legaised recreational use.
The potential legalisation of cannabis for recreational use is a different discussion altogether. We don’t have to wait for that to start using cannabis extracts for uses that are backed by good evidence, but nor should we tolerate the spread of mythology that would have cannabis as some sort of magic cure.
It is concerning that so many, including the medical news outlets, are generalising this result to “epilepsy” when the study looked at a very specific subgroup, Dravet Syndrome, with a severe seizure disorder. Given the study demonstrated adverse effects sufficient to make some participants cease therapy, it is quite likely that those with less severe seizure disorders may find the benefit to risk ratio not in their favour. At this point we don’t know, so for media outlets to hail this study as proving general utility is irresponsible.
…sorry, should be: “…increasing the tTHC:CBN ratio”.
Cannabidiol (CBN) could still raise seizure threshold while THC seizure lowers it (similarly, cannabidiol seems to be protective against THC-induced psychosis). Meanwhile total THC content has been vastly increased over the past 30 or so years, probably increasing the CBN:tTHC ratio, with likely implications for seizure and psychosis risk.
I am confused, and would like more official information. It is well known and anectodally experienced by many GPs that epileptics who smoke marijuana have more fits, it seems it lowers the seizure threshold. Yet Medicinal Cannabis is used to control epilepsy in a small number of mainly children who are not adequately controlled on three drugs. Is this because Medicinal Cannabis is a pure extract with only one of the 200 odd cannabinoids found in the plant, or because it doesn’t contain Tetrahydrocannabinol, the cannabinoid believed to be the one responsible for the high, the hallucinations and schizoid reactions, and the fits?
It may be that the THC rather than the CBD component is the anti-emetic
Yes, it may work, but to do a study against placebo?
it should be a proper randomised trial against full dose antii-epileptics as per gold standard therapy for today’s care. also, it is intersting that the side effects included vomiting, and yet, cannabis is touted as anti-emetic medication. something is not quite correct. while I applaud the actual willingness to do trials finally to prove or disprove the usefullness of this chemical, it needs to be correctly, and with the right approach.
otherwise, we are blindfolded to adopt this without correct evidence.