Professor Ingrid Scheffer:
I’m a Professor of Paediatric Neurology at the University of Melbourne, and I also work at the Austin, where I’m Director of Paediatrics and at the Royal Children’s Hospital.
My work as a paediatric neurologist the last 25 years has focused on the epilepsies, particularly finding genes for epilepsy. I have a particular interest in the severe epilepsies, that often begin in infancy and childhood and these are very debilitating conditions, where the child has many seizures maybe many a day and then they also have developmental problems – so they may start off normal and then lose skills, or they may never be normal but still lose skills, so they have this epileptic process that affects development.
These children also have a range of associated features, such as behavioural problems, sleep problems, maybe gut problems, the whole host of comorbidities, as we call them, that can go hand in hand with these severe disorders.
What is medicinal cannabis?
The cannabis plant is made up of hundreds of compounds and many different forms of cannabinoids. There are two main players though – cannabidiol and tetra hydrocannabinol which is actually THC. Now the CBD or cannabidiol is not psychoactive so it doesn't make you high, but the THC component can make you high. So my interest in epilepsy and children and in adults really focuses on CBD, the cannabidiol, because we know that that doesn't have psychoactive effects and it's been proven to be effective in humans with epilepsy and it's very much like our other antiepileptic drugs.
What is your interest in pursuing medicinal cannabis?
One has to be very clear about which part of the cannabis plant we wish to use to treat epilepsy in children and adults.
The only part of the cannabis plant that we know is effective for children and adults with epilepsy is called cannabidiol. So I do not want to give my patients the THC component. Because whilst that’s psychoactive it's also been proven to be associated with earlier onset of psychosis, which is very frightening. And when you see psychosis occur in a young adult with severe epilepsy and often intellectual disability. It's terrible for families so I do not think it is safe to give the patients THC. I've seen the psychosis in adults who have not had THC but you can imagine if you increase the likelihood of psychosis that could be very dangerous to the patient and devastating for their family. So I would like to use cannabidiol or CBD for patients with epilepsy.
The Government has changed the the ease with which we can prescribe it and is now the same as a regular prescription. The difficulty is access and cost and the problem is CBD, whilst it's been shown to be useful in 2 of the very severe epilepsy syndromes and they're called Dravet syndrome and Lennox-Gastaut syndrome, it is really no better than the other drugs we use in those syndromes.
It doesn't mean we shouldn't use it. I think we should use it, but I don't think it's a magic bullet. And there's so much hype around this in the media and with families that it's very hard to sort of dissect out to families so that their expectation is at the right place. Yes we should try it, but it may not be any better than the other antiepileptic drugs we use.
Is it a question of what options are available to provide the most effective treatment?
At the moment when we see a patient with severe epilepsy be it a child or an adult, we look at the right anti-epileptic drugs for their type of epilepsy and that depends on the types of seizures.
There are many types of seizures, it also is guided by their EEG findings, which is their brainwave findings, and if you know their cause, it may make a big difference to knowing that CBD might help them. But otherwise other drugs might be much better for them. So takes quite a bit of expertise to know which patient will be suitable for CBD. And at the moment, we only have proof in those two syndromes.
We published the first evidence last year in the New England Journal of Medicine, in about May 2017, and we found there was a 43% responder rate in Dravet syndrome and a responder is defined as a 50% seizure reduction. So you have to put some context around that. And you can imagine if you have 10 seizures a day and you respond it means you go down to 5 seizures a day. It’s still not a magic bullet, what we want is seizure freedom and if you can get seizure freedom, the child or the adult will improve in their learning and their alertness. So that's the holy grail – seizure freedom. And it's not just a 43% of patients improved by 50%.
Has any specific research been done?
So there are three definite research findings. Before that there are a number of papers, but they’re what we call open label so they're not reliable scientific evidence. They give you a hint that maybe CBD will help some patients. But if you want to approach this scientifically, as a good doctor, should you actually wanting to have proper evidence – that proper evidence requires a Class 1 trial – and that is a double blind, placebo-controlled randomized trial.
And how that works is that the patients entering the trial they have a baseline phase where we document the frequency of seizures, they then typically go into three month phase where they might be going onto placebo, which is effectively sugar tablets – they may not be sugar but they have no drug in them. Or 3 months of drug – they don’t know if they’re on it and I don't know and my nurses don’t know either. So nobody knows if you’re on the drug or not.
But the reason these patients go in the trial is that at the three month mark, they get open label drugs So that's why they go in the trial. I'm very keen to do these trials because I want scientific evidence that what I'm giving my patient works and that it's not going to harm them.
And there's another level to this, which is not my primary remit. But it's about cost. And you know, one of the companies was quoting that CBD for one year for an adult would be between $75,000 and $150,000 a year. And that's a huge amount of money for a drug that may be doing nothing.
The other issue around the CBD space is the placebo effect. And the placebo effect means if I as a doctor give you a drug, there’s is a 30% chance at least that you will think it works just because the doctor gave you a drug. And that really speaks to the human psyche, how we think. And somewhat surprisingly, the placebo effect is stronger for children than for adults. It seems counterintuitive. So I think one of the big issues around CBD with all the hype and all the social community interest and social media is that people have huge belief systems around it that actually affect whether they respond and there's a little bit of evidence for that.
There was a gel trial in normal adults, normal intellect adults with focal epilepsy and it was shown not to be effective but that was because the adults (the placebo group) over responded, so if you like maybe there was more placebo effect around CBD then around most drugs.
Do your patients face many difficulties in obtaining medicinal cannabis?
Many of my families are very keen for CBD and one of the issues to date has been limited access, partly around this issue of cost but also around accessing formulations that are 98% CBD which is where we're allowed to prescribe it.
Now, the reason it's so expensive is that it needs a lot of purification of the cannabis plant. It's not an easy process and it may take you know many months to get this right. One of the other issues is that there are many players in this space and many of the companies are only producing nutraceutical or dietary supplements CBD but they're not producing real CBD or I guess they’re producing medicinal cannabis but not CBD.
So to get the pure CBD is expensive. But that's the part that we know is effective. So the access has been a real issue and continues to be an issue. At the moment in Victoria you can’t get it for adults with severe epilepsy. I'm hoping that will change.
For the children, there are only a certain number of children who are eligible to get it through the Government system. But in addition to that, I'm running a trial of a gel preparation, that same gel preparation I mentioned a moment ago, in children to find the dose and if this trial works, which is an open label trial so not the gold standard trial. But if this preparation works, then the plan next year might be to go to a gold standard trial. I’m hoping the pharmaceutical company will do that, but I have no control over what they do. So I think that the space is going to open up but it hasn't at the moment and there’s a lot of frustration out there.
On the other hand, there are quite a few patients who have tried CBD – either through the Government or through a previous trial I've been involved in for Dravet syndrome and many of them find it's not helpful and they stop taking it and a few of them find it's very good. So I'm a believer, but I don't think it's a magic bullet. And I think it's a minority of patients that make a big dramatic improvement , but obviously for those I’m delighted it's really you know, anything that will change their lives that's what I’m here for.
How do you monitor the dosage of medicinal cannabis?
In terms of monitoring, the trials show that you can go to a dose of 20 mg per kg per day. But I don’t know that we are sure that that’s the maximum dose. And now some of the trials are looking at taking it a bit higher. So at the moment we only have evidence for 20 milligrams per kilogram per day.
Now it does have side effects, so CBD can be associated, particularly with sedation and diarrhoea. So sedation is very common – all the anti-epileptic drugs can cause that, but sedation with CBD can be pretty bad and we've learnt it's particularly if they're on another drug at the same time called Clobazam, which many of these patients are on. And we have to reduce the Clobazam and bring it back quite harshly. The problem is when you bring it back their seizures can escalate, so you've got this sort of balancing act that you have to do. This is very normal for us but it's a challenge.
The issue around diarrhoea is very interesting because we've never had another drug cause diarrhea, so you can imagine you've got a disabled child or adult, diarrhoea is not a not a good thing. I have been amazed at how well some of the families I work with have handled that. It hasn’t been that many, but a few have had it. They are the main side effects that one worries about.
The other thing about CBD, which I think we have yet to flesh out, is that it can help learning behaviour, maybe sleep as well. It's not surprising it helps sleep. But if these children are able to learn a bit more or their behaviour is better. That can be life changing for a family.
So we shouldn't dismiss that it's just for seizures, it's about the whole child or adult and looking after them. So you know, I think it'd be great if everyone could access it. But I think we have to do it in a very thoughtful way so that we ensure we're not just dealing with placebo effect.
So medicinal cannabis could assist with learning?
So CBD might make the child more alert. And also make them sleep better, which can be a huge problem for families. And therefore if they are more alert and sleeping better, then their behaviour often settles down. And their behavioural problems can be very challenging. Now some of the children are so severe, they don't have behavioral problems. Not all of them do. But those like with Dravet syndrome, they might have quite severe behavioural problems. Certainly not all some, just some.
Have you had some success with the use of medicinal cannabis?
I have had some treatment success. In terms of describing it to you, I think the most important thing is to look at the trial data, because that is robust scientific data.
So the data from the double blind placebo controlled randomised trials shows this 43% responder rate. Responder defined as a 50% reduction in countable seizures. And that was found in our first Dravet paper last year and this year there have been two papers on Lennox Gastaut syndrome and the results are almost the same, so around 40% of patients will reduce by 50%. For my own patients, in terms of anecdotal responses, a few have had dramatic success, many have tried it and are coming off it.
How do patients currently access medicinal cannabis?
So at the moment, it is quite difficult to access it because of the control around it in terms of the Government allowing us to access it, and then the prescribing of it.
So there are certain number of children that the Government is providing it for, but it's a relatively small number for the severity of the disease and the numbers of children with the disease. And my practice has many, many children with the disease.
In terms of otherwise accessing it through the trial that we’ve got, but in order to be able to access it through our trial, you need to have a certain number of countable seizures per month. And you have to be under 18. So we've got a few places left. But you have to be really in a specific group.
And if we look at Dravet syndrome only about 20% have a lot of seizures per month, most of them have one a month, but they often have long seizures which are life threatening, so we know that children can die. So it's a very severe disease, even though they don't fit the entry criteria, the inclusion criteria for the trial. Quite a lot of families are buying it from overseas, but I think they buy a whole range of potions. Many of them will have THC, and one of my concerns is whether the THC will have long term psychiatric effects.
How are we going to know? I don’t think we’re ever going to know. Because, say they're six years old now. And they become psychotic when they're 20, which is when that happens. No one's ever going to be able to tease apart that it was due to the THC that their parents gave them when they're 6 years old.
So this is a real concern and one that we've lost control of monitoring because so many people are using it and people grow it down the backyard and they import it. But at the moment in terms of true pharmaceutical grade products the only ones are Epidiolex and this one I’m doing a trial on from Zynerba. I don’t know the trade name of the drug.
But the other drugs like Toray, are not actually pharmaceutical drug products. So we have a problem here in that the industry is not producing drug at the right level for all the other drugs we give our patients to ensure that each time the patient gets the same drug, the same dose, the same extra things in the tablet or in the liquid. And at the moment, the industry's going wild, but not in a good way.
There are likely to be more hurdles on the way, how do you plan on overcoming them?
A lot more research needs to be done for the use of CBD in epilepsy. At the moment we only have evidence for 2 syndromes. There are many more patients that don't fit into Dravet or Lennox-Gastaut that have very severe epilepsies beginning in infancy or childhood, but usually continuing into adult life. So I think we're only at the tip of the iceberg in terms of having real data and research – high level scientific findings. So a lot more needs to be done.
There's a community issue around the nature of the CBD. And whether it's natural grown plant or synthetic. And some of the people who believe strongly in medicinal cannabis feel this sort of magical mystical entourage effect, which means that if you take a compound and it’s within a plant. And there are another 400 compounds which we know there are, that they're somehow making it better. This is not scientific thinking.
And there are companies now that are making synthetic CBD. And that is exactly the same molecule as the drug, the molecule of interest, in Epidiolex the one that is pharmaceutical grade.
So I think we have to be careful because then the sort of community opinion, might be that it's not natural, therefore, it's no good. But this doesn't make sense. It's essentially the same molecule. It's just purified when it's synthetic. So I think that we have to be careful about the field being driven by science rather than pseudoscience. And the fact that people smoke marijuana and you know, they have lots of positive effects. Well that's wonderful. But that's not what we’re talking about.
How certain are we that CBD is the compound?
There’s some lovely animal data that looks at CBD versus THC in animal models. And CBD is shown to be anti-convulsant and THC is shown to be pro-convulsant.
And then there are other compounds, other cannabinoids that have been looked at so we have got good scientific evidence. Remember, scientific is the keyword.
Do you have a preference on the way medicinal cannabis is administered to patients?
At the moment the trials are all with Epidiolex, which is a tincture or an oily syrup. The other study we're looking at is with this gel and the idea is you rub it onto your arms and it gets absorbed via skin. Now I was very keen to do that in my population of children and adults with severe epilepsy, because often feeding them is hard – they don’t like having tablets, they don’t like eating particularly. And I just thought it would be much easier for the families if they could rub it into their arms.
So the company that I'm working with is very kindly doing this study with us and a group in New Zealand, to look at whether we can get doses into children that are adequate. So that's where we're at with this open label dose-finding study, but as I mentioned, they have to have many seizures a month to be able to be included. And then my hope is that that will translate to a formal double blind, placebo controlled trial. I think the idea of the gel was very appealing, but clearly the liquid it's proven to work. So that's great and in terms of capsules and tablets I don’t quite know what’s being developed yet on that front.
Are there any hurdles in terms of monitoring treatment?
Yes. So the children can have raised liver enzymes. We have to watch that very carefully. If they become quite raised, then they may need to come off the drug because of the effects of the drug on the liver, so yes, we do need to monitor them very carefully.
How do you respond to colleagues who say ‘there should be more conclusive evidence before prescribing’?
With my colleagues. I think it's been a very rapidly moving space and you’ve got to appreciate that we've never been in a space where anybody is remotely interested in the treatments we’re using for our patients with severe epilepsy.
So this is a whole new world for us where everyone has a view and everyone's actually interested. I think in lots of ways it's been exciting to be engaged with the community, but I always feel that I need to bring balance to the discussion you know. Will it work? I hope so. Will it not work? Well that's quite possible.
And I really want to protect my wonderful families because they are on a roller coaster. This new drug – will it work? Will it reduce the seizures? And then it wears off and the seizures go up. And then will it work?
So they are on this terrible rollercoaster of hope. You need to give them reality around that hope. And say well, ‘I hope it works’. But just so you know, it's 40% of patients have a 50% seizure reduction and then you put that into English. Like you had 10 seizures today, then you go to five seizures a day, that's not really curing, but I mean, I'm not dismissing it's important, but one has to have balance.
I think with my colleagues they know that these papers are now published. Many of my colleagues have been reticent to prescribe CBD without evidence. But thankfully, we have moved in the last 18 months from no evidence to definite evidence so the landscape’s changed. And I think that we all have to take it on board and start thinking about which patients can access it, but it also needs engagement with Government around the funding, but I also think we need to be careful about making sure it’s really doing something.
I think it’s important to realise that we are only discussing CBD for epilepsy, whereas medicinal cannabis can be used for other disorders as well, such as chemotherapy-induced vomiting and pain disorders and we need to have more evidence for specific forms of epilepsy.
Epilepsy is a group of disorders: many types, many causes. And CBD might work very well for this gene and this mutation, but may not work for this type of epilepsy. And we really need to scrutinize this carefully with scientific studies.
One of the problems is that the companies may not want to know that because they just want to make money. And you've got to appreciate that there’s this huge burgeoning industry, both in Australia and around the world, where people just seeing it going to be a lot of money making. And they're talking about it in Australia with medicinal cannabis being half a billion dollar market.
But you and I want to know that we're spending our money on the right drugs and helping patients.
My concerns around the prescription of medicinal cannabis is that there is this belief that it will work for everyone and that everyone should be able to access it. I think we need a lot more evidence to show which epilepsies it works on and which ones it doesn't. It may depend on cause; may depend on seizure types. There are many variables and that needs proper trials. So my concern is this belief, you know, that it's the magic bullet and just try to give families and patients balance around that.