Potential of Cannabidiol in Epileptic Encephalopathies

Rodney A. Radtke, MD: The most exciting new approval of an agent to treat epilepsy has been the approval of cannabidiol [CBD]. Epidiolex is the brand name. It is an oral solution that is administered twice a day for the treatment of epilepsy. The specific indication is for the treatment of seizures in the setting of Dravet syndrome and Lennox-Gastaut syndrome. However, many of us are going to use it in other seizure syndromes, including focal or partial epilepsy, and to see how it may or may not be effective. It’s a very exciting product. I mean, it has the excitement of the lay public in that there’s been a lot of talk about CBD and what it does or whatever, and there’s some really impressive stories, anecdotal stories, that have been portrayed on TV about how effective this product may be.

However, if you look at the studies, it is an effective agent. It does help with seizures in these 2 syndromes. It is not much more impressive than other products that have been evaluated in these same syndromes, and it does have adverse effects; it does have drug-drug interactions. For some reason the public perceives it as a safe drug, and not really a drug because it’s derived from a marijuana plant, but the reality is that it’s a new drug, we’re going to use it, we’ll see how effective it is, and we’ll see how well tolerated it is. But it’s certainly an exciting addition to what we have available to treat epilepsy patients.

Cannabidiol is an extract of the marijuana plant, and—as many people know—THC is the more psychoactive or mind-altering component of the marijuana plant. CBD, or cannabidiol, is the second-most prominent cannabinoid in marijuana. The thing that we know about the mechanism of CBD is that it doesn’t act at the cannabidiol 1 and 2 receptors that THC binds at. Clearly it has a different mechanism of action and has many effects on different neurotransmitter systems, etc, so right now we really don’t know the mechanism of action of this new product.

When starting cannabidiol, there are guidelines in the package insert about how to initiate the drug, and a couple of concerns about its safety. The guidelines are to begin with a dosage of 5 mg/kg—and this is even for adult patients, 5 mg/kg per day, and then after a 1- to 2-week interval, go to 10 mg/kg. You split that dosage in half, so you’re taking half that twice a day. Many of us are going to go slower, just as we do with many of our other products. Rather than getting there in a week or 2, we may take 3 or 4 weeks, hoping to enhance tolerability.

In any case, the therapeutic range is 10 to 20 mg/kg, so in my own experience I’m going to titrate up to 10 mg/kg. I’m going to stop there. I’m going to see how the patient does in terms of efficacy and tolerability. And then if we’re still having active seizures after a month or 2, we’re going to continue to titrate up to the goal of 20 mg/kg.

Before I start somebody on the cannabidiol, I do liver function tests, because there are a small number of patients who will have an elevation of their liver function test, particularly if the patient is coadministered valproate. The other thing I’m going to do is also check AED [antiepileptic drug] levels of the concomitant AEDs that I have on board, because there are significant drug interactions. The biggest drug interaction is with clobazam. Clobazam levels go up by at least double and sometimes much more than that. So my own practice is, as I start the cannabidiol, I’m going to, 1, have a baseline clobazam level to begin. And I’m also going to cut the clobazam in half as I initiate the drug, trying to avoid kind of the immediate sedative adverse effects that you’re going to get when your clobazam doubles. Long term, we’ll see how this plays out, but that’s kind of my initial approach, and so far things have gone well in terms of tolerability. But it’s really too early to make a judgment on efficacy.

While CBD has been available for several years through dispensaries or health care product lines or whatever, it’s really been difficult to know what you’re really getting. There really was nobody controlling the product, testing the product, or forcing the manufacturing to guarantee the product in any way. So when anyone looked at how much CBD was in the various products, it was really quite variable and at times alarming. So it’s reassuring, now that we have a pharmaceutical-grade product, that we know what’s in it. We know it’s got to be consistently made and be able to test a drug much more effectively. The other advantage to having the pharmaceutical-grade product is that it’s now going to be covered by third-party insurance. CBD, kind of through mail order or through the dispensary or whatever, was not inexpensive, and now for the individual patient and their family, this CBD product is going to be more affordable because of health care coverage.

The availability of cannabidiol gives us another effective agent in the difficult-to-treat patients with Dravet and Lennox-Gastaut. It will be interesting as we go forward as to where it plays out in terms of how we use it and how early we use it. At the present time, while there’s a great deal of excitement from patients and their families, we’re still going to be using the traditional agents like valproate and clobazam or whatever to treat these syndromes before moving on to cannabidiol. At this time, I don’t think it’s appropriate to use it as a first-line agent because we have more tried-and-true agents. With time and experience that may change, but I don’t think we’re there yet.