Medicinal cannabis has been of interest to the epilepsy community with greater interest fueled in 2018 by the FDA approval of a cannabidiol (CBD) extract called Epidiolex®.  In fact, the marijuana or cannabis plant contains over 100 different substances, two of which specifically, CBD and tetrahydrocannabinol (THC), have been widely studied to understand their effects on the brain.

THC is the major chemical compound found in marijuana that creates a psychoactive effect when it binds to receptors in the brain. CBD binds to a different set of receptors and is not psychoactive. Epidiolex® is a purified, plant-based CBD extract used to treat seizures associated with rare genetic epilepsies. Because of its effectiveness, there is great interest in further understanding how CBD acts in the brain and also if other cannabinoids might be useful in the treatment of seizures.

In contrast, marijuana products sold in dispensaries and online are not approved or regulated by the FDA. They can vary significantly in quality, dosage, safety, and effectiveness. In some cases, commercial, nonprescription cannabis products are thought to increase seizures.

This webinar will review the basics of cannabis biology and the differences between cannabis strains. It will also explain the medical uses of medical marijuana and the recent approval of CBD to treat specific types of epilepsy.

This webinar is generously supported with funding from Jazz Pharmaceuticals.

 

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About the Speaker:
Dr. Eric Marsh is an Associate Professor of Neurology at the University of Pennsylvania Perelman School of Medicine and the Children’s Hospital of Philadelphia (CHOP). He is the Clinical Director of the Penn Orphan Disease Center, and Director of the CHOP Rett and Related disorders clinic.

Dr. Marsh’s clinical interests include developmental and epileptic encephalopathies (DEE), neurodevelopmental disabilities, and cortical malformations. His research interests have focused on the role of intraneuronal development and altered excitability on epilepsy, analyzing intracranial EEG recordings to better localize the epileptic zone and network, and performing natural history and biomarker studies. In addition, he has studied the role of mutations in specific genes related to epilepsy such as ARX and CDKL5. Dr. Marsh has been involved in a number of clinical trials for children with the DEEs, including Dravet, Lennox Gastaut and Rett syndromes.

 

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Q&A with Dr. Eric Marsh

Has CBD been found to affect the metabolism of benzos other than
Onfi?

So yes it does. Onfi is a unique benzodiazepine, in that its structure is different. So most benzodiazepines, the side chains off the benzo ring, which is why it’s called a benzodiazepine, are on the first and sixth carbon. Onfi, it’s the first and fifth carbon, so it’s a unique benzodiazepine. That’s the name Onfi, one five. It’s off of the first and fifth carbon, so it’s a unique benzodiazepine. But all benzodiazepine are affected, though Onfi more so than the rest.

Would CBD or Epidiolex be considered a treatment for epilepsy or autism in megalencephalic leukoencephalopathy (MLC)?

So there’s kind of two ways to answer that. So our expanded access program included a lot of different rare genetic disorders, and the effect was the same across the board. I think everyone now believes that Epidiolex, or purified CBD, is a good broad-spectrum anti-seizure medication, and that, for any different cause of epilepsy, it should potentially have some effect. As the data showed, it’s not a cure for most, it just reduces seizures. And you would expect the same for whether MLC is the cause of the person’s epilepsy or anything else.

The second way to answer is that too, for the FDA-approved Epidiolex, there are indications that are required, including Lennox-Gastaut syndrome, Dravet, and TSC. So for MLC, the question would be, does the child have the electrical clinical pattern consistent with LGS, in which case, they could have LGS due to their MLC, in which case they’d actually be allowed to be prescribed the FDA approved Epidiolex. If they don’t, then your doctor would have to prescribe it off label, and that’s a discussion to have with your doctor.

And then same thing with the behavior, as I said, there might be positive responses in behavior. I think you just have to be very critical if you try to treat an individual with this. If you don’t see anything, then like any drug, stop it. Don’t continue it just because you want it to work, but really be critical of whether you think it’s working or not

Can oils from dispensaries be tested, to understand what they correct amounts are from using a third-party tester?

Yeah, so absolutely. There are labs around the country that will test. I don’t know what the cost is, so I don’t know if it’s prohibitive to have something tested. Which also brings up the other issue with dispensaries, which I didn’t mention, because that study didn’t go over it, is batch to batch variability. So if you test it at one time, you might say, oh look, it actually is exactly what it says, but the next time they produce that batch, will they have the same accuracy of what they say is in the product is now in the product?

So you could get to a third party tester to test, but that will just give you reassurance for that batch of the product you have. For the next batch, you’d have to do it again. So I think, to some degree, when you go to a dispensary, you have to have a conversation with them, get as much reassurance from them that they’re doing it in a rigorous way, the way they grow, and the way they extract, and the way they produce. And then, just know that if you see a difference from time to time that it could happen. And if seizures are in good control, and seizures stop being under good control, it could be because the product has changed.

Is there a shelf life for these products in oil? How long can you keep them?

Yeah, so there is. Cannabinoids are actually light-sensitive compounds. So that’s why the bottle that it comes in, like Epidiolex comes in, is a brown bottle, in order to filter out light getting into it. And you should store any dispensary or FDA-approved cannabidiol in a cabinet out of the light, because light will make the product degrade rapidly. In the dark, in a cool environment, its shelf life is fairly stable. I don’t want to give you numbers, because I don’t actually, don’t quote me on a number, but it is fairly stable if it’s kept in the dark and cool. But I’m not going to give a number, because I don’t remember offhand what the stability is

What is the dosage of CBD in Epidiolex?

Epidiolex is 100 milligrams of CBD per ml. And the FDA recommended starting dose is five milligrams per kilogram per day, divided in two doses. And there actually is no max dose. So it’s based by weight. There’s no max dose in reality. The FDA label might have one, so I don’t remember if the FDA label has a max dose of like 1000 milligrams a day. Most of my patients are little kids, so we don’t get to that, they’re all small, so that’s not an issue. It’s all weight-based dose for me.

So is cannabidiol only used as a treatment for tonic, clonic, and atonic seizures? Are there other seizure types that might be, it might be useful for?

So for the studies, motor seizures, whether tonic, clonic, or atonic, were the primary endpoint, and that’s where we saw the greatest effect. In my own personal practice, I’ve had families who have LGS with multiple different seizure types, see response to a variety of the different seizure types, including myoclonic seizures, absence seizures, and focal seizures. Though it seems to be greatest for the kind of generalized tonic, clinic, bigger seizures.

Would using THC recreationally affect the effectiveness of clobazam or lamotrigine in generalized epilepsy?

So yeah, THC also alters the metabolism of some of the CYP enzymes, and I don’t remember the direction to which it does, but it does. So medical marijuana, taking a whole product recreationally, is going to potentially alter the metabolism of some of your medications, particularly in that case, clobazam. Less so lamotrigine, but I’d have to look up what the metabolism of lamotrigine is, to say for sure.

Have the individual terpenes been studied for their potential therapeutic effects on epilepsy?

Not that I’m aware of. So I know that GW/Jazz is really interested in exploring other aspects of the cannabinoids and terpenes for their role. But I’m not aware of any information that they’ve published to this end. And there are mouse basic science studies looking at some terpenes and other cannabinoids, but nothing human that I’m aware of.

Are there substantial side effects, such as liver or kidney damage, with use of CBD?

So far, the answer is no. That it is, in all the studies, there was no effect on kidney function. The liver questions a good question. So what was found in the studies, was that there was a increase in liver enzymes in a group of the patients. None of the patients got to the point where there was any issue of liver damage, but there was suggestion that the liver was being irritated. Because an elevation of the ALT and AST, the enzymes we used to measure kind of liver function, and they all went back to normal when you stopped the cannabidiol. So we don’t think there’s any long-term effect, but again, the medication’s only been approved now for six, seven years. So I think, long-term we’ll learn more about that, as people follow patients who are on cannabidiol for longer and longer periods of time.

This person says that their son is on Epidiolex, and it causes high anxiety. Is there anything else that might explain this, or might not cause the high anxiety? Is there anything that could be done?

Yeah. That’s a good question, and I would need a lot more information to really answer that question. As the Epidiolex could be interacting with other drugs, it’s possible by the alteration of the metabolism of another drug is bringing out his anxiety. So it could be related, but indirectly related. And in my experience, I’ve had families report that when they started Epidiolex, that it improved anxiety. But I also have some families who’ve reported that they think their kid’s more anxious, or their behavior has gotten worse on Epidiolex. So I think there’s a lot of variability there.

And one of the things I didn’t mention is that, these cannabinoids are actually, they don’t get absorbed very well via the gut, and so, they’re the metabolism and the individual’s ability to absorb and process these are going to be very variable. So some of the differences we might be seeing in this might be due not to how the drug works in their brain, but also, how the drug even gets into the body. So differences you see, something like that, could potentially be what we call pharmacokinetic, or pharmacodynamic properties, and not actual brainderived properties. But that said, we do, there’s a lot more we need to learn about these things

In the graph that you showed, there where a majority of people showed a reduction in seizure activity, but some actually saw an increase in seizure activity. I’m wondering if you can comment on that, and the variability there?

Yeah. So there’s two aspects of that. So one is that, we know that individuals who have epilepsy, and particularly epilepsy that has not responded to many medications, their seizures often fluctuate, and that they go up and down. And there’s some really nice data from people who’ve had RNSs implanted in them, where they’ve been able to follow count, people’s seizure counts for months on end, that we see these oscillations in people’s seizures. So one possibility for that increase, is that they started the trial at the low point, and they, as the trial went on, they just were in their normal up oscillation, and the medication had no effect, neither good nor bad, but it just looks like it went up, because they happened to be on an up oscillation.

The other potential possibility is that, yeah, for whether it’s a metabolism issue or a brain issue, that it actually altered the brain dynamics in such a way that it made someone’s seizures worse. So again, there’s still a lot we need to learn about that group who did really well. Who are they? Why are they? And can we figure those people out? So we know, hey, you’re their best people to put on Epidiolex. That would be something that would be great to be able to do. And unfortunately, we don’t have that type of data.

Can you take Epidiolex at the same time as Depakote or other seizure drugs, or should you be separating them in time?

Yeah. So you can take them at the same time. What’s important for Epidiolex is, because of the absorption issues that I just mentioned, is that you try to do it always at the same time, or approximately the same time, particularly around meals. So you don’t want to give it one time with food, and the next time without it, because it’s going to be absorbed differently. So always give it with food, or always give it without food, so that you’re just consistent. So that’s the best advice for when you give it, is trying to give it as consistently as possible, so that you know its effect, and that you’re not getting variable amounts based upon how it’s being absorbed.