It’s a holiday here in the US, and I have a grant deadline later this week; so I thought I’d (sort of) take the day off. I say “sort of,” because, as editor here I’m always loathe to leave a weekday without a post, even if it is a Memorial Day here in the US and the Spring Bank Holiday in the UK, the two countries from which most of our traffic arises. (I do so love how the UK calls some of its holidays bank holidays.) Fortunately, this blog isn’t my only outlet for writing about medicine, so I almost always have material to revise, reuse, and repurpose. So, if some of you have seen my discussion of this study before, fear not. I did add a bit to it and elaborate on some aspects I had disregarded before. If you haven’t, then it’s new to you! I think it’s interesting and important enough that it should be on SBM for the record.
And it’s about cannabis, too!When I first started to take an interest in medical marijuana, I was struck by how much it reminded me of herbalism, so much so that I have a series on medical marijuana in which it is explicitly referred to as the “new herbalism” that’s up to four parts now. Although herbalism is scientifically the most plausible of modalities commonly associated with “complementary and alternative medicine” (CAM) or “integrative medicine” (or whatever you want to call combining quackery with medicine these days), the use of herbal medicines still involve a number of problems, the biggest of which is what I like to call either the delivery problem or the bioavailability problem. In brief, herbs, when they work, are, in essence, the equivalent of adulterated drugs. True, the contaminating compounds were not (unless you’re referring to heavy metals or real pharmaceutical drugs often found in Chinese herbs) from external sources. They’re inherent to the plant. Whatever you want to call the contaminating compounds, in herbal medicines, the herb’s content of active ingredient is usually relatively small, with the active ingredient combined with thousands of other constituents that make up the herb. It’s also very difficult to control lot-to-lot consistency with respect to content of active ingredient(s) given how location, weather, soil conditions, rainfall, and many other factors can affect how the plants from which the medicines are extracted grow and therefore their chemical composition. To demonstrate the concept, I frequently point out that it’s much safer and more predictable to administer digoxin to a patient who needs its activity on the heart than it would be for the patient to chew on some foxglove leaves, given how narrow the therapeutic window (the difference between the doses needed to produce therapeutic effects and the lowest dose that will cause significant toxicity) is for digoxin.
Indeed, to overcome these problems using plants as medicines is the very reason the specialty in pharmacology known as pharmacognosy, in essence natural products pharmacology, exists. Active chemicals in plants need to be identified, isolated, and purified in order to provide safe, reliable dosing.
A clinical trial of cannabidiol against severe seizures
I have nothing against recreational marijuana use and have come around to the view that it should be legalized, taxed, and regulated, just like alcohol and tobacco. Unfortunately, medical marijuana has been co-opted as a “foot in the door” to try to legalize marijuana. The problem with this approach is that it necessitated massively overblown claims for marijuana’s health benefits, up to and including claims that it is a great treatment for autism and that it can cure cancer. It isn’t and can’t. Nor does it stop exaggerated miraculous claims. Basically, the bottom line in terms of scientific evidence for medical marijuana is that it mostly doesn’t do what it’s claimed to be able to do.
None of this is to say that it might not have some value in some conditions. One condition for which cannabinoids isolated from marijuana have shown some promise is seizure disorders. That’s why I learned with interest of a study published in the New England Journal of Medicine (NEJM). This study is a randomized, placebo-controlled clinical trial of a candidate drug isolated from marijuana on severe drug-resistant seizures in children that made the national news last week. To be honest, over the last few days, the study’s gotten less press coverage than I would have predicted, particularly given that it was published in the NEJM, but it is an interesting study nonetheless. Medical marijuana proponents frequently misrepresent the skeptical position as being unalterably opposed to the idea that marijuana might have value as a medication. I can’t speak for anyone else, but what I’ve always objected to are the exaggerated, evidence-free claims so many advocates make, and the veritable cult that has sprung up around it. I actually like evidence, which is why this study caught my attention.
So let’s look at the study by Dr. Orrin Devinsky, a neurologist at New York University Langone Medical Center, and colleagues, “Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.” The first thing I can’t help but note is that this is not really medical marijuana, but rather an oral solution of cannabidiol (CBD), known for purposes of the study as Investigational Medicinal Product GWP42003-P. It’s manufactured by GW Pharmaceuticals under the trade name Epidiolex®. GWP42003-P is formulated from extracts prepared from Cannabis sativa L. plants that contain consistent levels of CBD as the principal phytocannabinoid. Extracts from these plants are processed to yield pure (>95%) CBD that contains less than 0.5% (w/w) THC. This highly purified CBD is subsequently dissolved in excipients with added sweetener and flavoring. So basically, it’s a drug isolated from a plant, as many drugs are isolated from plants (and sometimes chemically modified). It has the advantage of having low THC, which is the constituent of marijuana most responsible for its psychoactive effects.
Another thing that’s important to note is that this trial was to test whether CBD was useful against drug-resistant seizures due to a specific genetic disorder, Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI). Dravet syndrome is due to a mutation in the voltage-gated sodium channel α1 subunit gene SCN1A, which encodes the pore-forming subunit of the NaV-1.1 voltage-gated sodium channel. There are currently more than 700 known SCN1A mutations, and 90% of them occur in DS patients. Two-thirds of these mutations give rise to truncations in the protein while the remaining third are missense mutations that are predicted to severely impair channel function. In patients with Dravet syndrome, the severity of the epilepsy can vary, but myoclonic seizures are the defining feature of Dravet syndrome, and can be massive, contributing to a mortality rate as high as 20% by age 20. The syndrome is also associated with developmental delay. The most devastating aspect of Dravet syndrome is that the epilepsy associated with it is among the most drug resistant forms, and most anti-epilepsy drugs provide inadequate relief.
This trial was pretty straightforward. Basically, it was a multi-institution phase II study carried out in the US and Europe with the following protocol, summarized by this flow sheet (click to embiggen):
The baseline characteristics of the two groups were well matched, ranging in age from 2 to 18, and patients had previously tried a median of 4 antiepileptic drugs, with a range from 0 to 26(!). Subjects were randomized to receive either placebo or CBD, and the primary end point measured was frequency of convulsive seizures. The CBD solution contained 100 mg/ml, and the placebo solution was identical except for the absence of CBD. Before the intervention began, there was a four week baseline period in which investigators trained caregivers to record daily seizure information. Then CBD or placebo was added to the subjects’ regular anti-seizure regimen.
This is actually a very important point that most reporting of the trial I’ve seen misses. This trial does not show that CBD has anti-seizure activity as a single agent administered alone, only that, when added to existing anti-seizure multi-drug regimens, CBD can decrease seizure frequency. We can’t conclude from this trial that CBD alone would be a useful treatment for Dravet syndrome seizures. You might ask why this trial was designed this way, and the answer is simple. Given the severity of the seizure disorder associated with Dravet syndrome, comparing any investigational drug against placebo would be highly unethical, because it would mean leaving severe seizures untreated for half the children enrolled in the study. This is the same reason why many new anticancer drugs are not tested alone versus placebo, but in addition to existing systemic therapy regimens. One difference, though, is that anticancer drugs have to have robust preclinical evidence for efficacy as a single agent.
Back to the trial design. The dose was escalated up to 20 mg/kg per day with the use of a 14-day dosing regimen of twice daily administration. At the end of the treatment period, the cannabidiol and placebo solutions were tapered (10% each day) over a period of 10 days. After trial completion, all patients could enter a long-term open-label study. Each day, patients or caregivers recorded the number and type of seizures (tonic, clonic, tonic–clonic, or atonic) for the primary end point. Laboratory assessments were carried out at baseline and after 2, 4, 8, and 14 weeks of the trial regimen, as well as at the end of the taper period for those patients who did not enter the open-label extension study or who withdrew early and tapered the trial agent.
The results were encouraging. In the CBD group, the median frequency of seizures decreased from 12.4 to 5.9 per month, compared with a decrease from 14.9 to 14.1 in the placebo group. The percentage of patients with at least a 50% reduction on convulsive seizure frequency was 43% with CBD and 27% with placebo. The percentage of patients who became seizure-free was 5% in the CBD group, and 0% in the placebo group, but neither of these results achieved statistical significance (p=0.08 for both). I must admit that the way NBC reported Devinsky saying, “Quite remarkably, 5 percent of the children in the active treatment group with CBD were completely seizure free during the 14 weeks of the trial” but neglecting to point out that the result didn’t achieve statistical significance did irk me. I understand that there were some children who had dramatic remissions, but such observations do have to be put into context.
There were some adverse events due to the CBD, including diarrhea, vomiting, fatigue, fever, somnolence, and abnormal liver-function tests. There were more withdrawals from the trial in the cannabidiol group. Indeed, nine out of the 61 subjects in the CBD group withdrew from the study, compared to only three from the placebo group. Overall, serious adverse events were more common in the cannabidiol group than in the placebo group (16% vs. 5%).
One interesting aspect of this trial is that the mechanism of CBD against seizures in patients with Dravet syndrome is not known. The clinical manifestations of Dravet syndrome are due to a single gene, SCN1A. In an accompanying editorial, Dr. Samuel Berkovic notes:
A major aim in the field of the Dravet syndrome and other genetic encephalopathies is to develop precision therapies — treatments directed at the specific genetic defect. Because the Dravet syndrome has a single-gene basis, it is an attractive target for precision medicine. However, cannabidiol is not a precision treatment for the syndrome, because there is no established link of the cannabinoid receptors with the inhibitory interneuron pathology of the Dravet syndrome, and the response across the cohort of the current study was not uniform.
He also notes:
Devinsky et al. found a significantly greater reduction in seizure frequency among patients who received cannabidiol than among those who received placebo, and the seizure-free rate was 5% with the active drug as compared with 0% with placebo. Thus, anecdote has been confirmed by data, and one might ask whether a controlled trial was really necessary. The answer is absolutely yes. Perhaps counterintuitively, the rate of response to placebo in clinical trials is higher among children than among adults. Moreover, parents who go to enormous efforts to get cannabis for their children report a higher response rate than those who can easily obtain it. Cannabidiol is not without side effects. The dropout rate in the active-treatment group was appreciable, and common side effects included vomiting, loss of appetite, and diarrhea. With additional experience, perhaps these effects can be modified with dose adjustment and other strategies.
I would quibble again here. If you look at Table 3, you’ll see that the difference between placebo and control didn’t achieve statistical significance for reaching 100%, 75%, and 50% decreases in seizure frequency. Now, I’m not so dogmatic that I won’t accept that this difference is probably real, failure to achieve a p-value less than 0.05 notwithstanding, but if you state beforehand that you are going to use frequentist statistics and define a statistically significant difference between placebo and experimental group as a p-value under 0.05, then you should at least be consistent. That quibble aside, I do agree with Dr. Berkovic that absolutely a clinical trial was indicated. I would also add a further quibble that “anecdote has been confirmed by data” is overstating it a bit, given the tiny percentage of patients who were seizure free. However, some patients do apparently have fairly dramatic responses.
Another interesting aspect is that, counterintuitively, seizure frequency did decrease in the placebo group by 13.3%, compared to the CBD group, where seizure frequency decreased by 38.9%. This should be a lesson as to why placebo controls are necessary, even for seemingly objective measures. Of course, given that these were either self-reported or caregiver-reported measures, they are not completely objective; so it is not surprising that there was a slight decrease in seizure frequency, even in the placebo control group.
What’s good for the goose…
Finally, I can’t help but note that medical marijuana advocates, the ones who will be flogging this study as vindication that marijuana is a miracle drug (even though what this study shows is much more modest) tend also to be very much anti-pharma and pro-alternative medicine. That’s why I want to draw attention to this part of the methods section:
The funding source, GW Pharmaceuticals, was responsible for the trial design (with input from investigators and other experts), trial management, site monitoring, trial pharmacovigilance, data analysis, and statistical analysis. GW Pharmaceuticals prepared and provided the active treatment and placebo. Trial procedures were reviewed at multisite investigator meetings. Services were used for clinical laboratory testing; bioanalytical laboratory testing; design of the case-report form; data management; trial-agent distribution, returns, and destruction; the interactive voice-response system; diagnosis of the Dravet syndrome and seizure classification; and translation of documents. The authors vouch for the accuracy and completeness of the reported data and analyses and for the adherence of the trial to the protocol (available with the full text of this article at NEJM.org). The authors affirm that they approved the final draft of the manuscript.
This is, of course, a not uncommon practice for a drug company doing a clinical trial upon which it wants to base an application for FDA approval for its drug, and that’s exactly what GW Pharmaceuticals is doing. Nothing wrong with that. As is the case with most clinical trials of new experimental drugs (and, make no mistake, Epidiolex® is an experimental drug) whose manufacturer is seeking FDA approval for an indication, this study was heavily influenced by the company as well as funded by it. It’s what a drug company needs to do, and GW Pharmaceuticals is a drug company. It is, however, a good idea to be a little more skeptical about the results of this study than most medical marijuana advocates I’ve seen gloating over it as total vindication are doing. This is a positive study, but not as strongly positive as it’s being spun, and there are issues with CBD and adverse events. As Dr. Berkovic puts it:
This trial represents the beginning of solid evidence for the use of cannabinoids in epilepsy. It requires replication. Future trials may answer further questions about the applicability of cannabinoids to the many other syndromes of childhood epilepsy and to treatment in adults. After an era dominated by anecdote and obfuscated by medicolegal issues and emotionally infused debate, more scientific studies are under way. Much more research is needed to understand the basic science, benefits, and risks of cannabinoids in epilepsy.
Correct. This is a study that demonstrates that one chemical that can be isolated from marijuana has promise as a treatment for the epilepsy associated with Dravet syndrome. The mechanism by which it appears to work is not clear, as the relationship between cannabinoid receptor and SCN1A is not clear. It’s thus not clear whether this result is generalizable to other forms of seizure disorders, but it’s worth investigating. In other words, CBD is just like any other drug. It appears to have reasonable activity against the epilepsy due to Dravet syndrome, but it also has significant side effects, just like a lot of other antiepileptic drugs. It’s no miracle, but it could be a step forward, particularly if its study leads to a greater understanding of the role of cannabinoid receptors in seizure disorders.
As is the case with all first phase II clinical trials of new experimental drugs, this trial is a start, not a finish. Does it definitively demonstrate that CBD has antiseizure activity? Not quite, but it is promising. Also, one has to remember that this is a very specific and uncommon form of epilepsy for which the genetic and biochemical basis is known to result in defective function of a single sodium channel. It’s not clear whether the results of this trial are generalizable to other seizure disorders due to other causes, but it will be worth investigating whether it is. It would also be worth investigating whether chemically modifying CBD could increase its efficacy while decreasing side effects, although preclinical mechanistic studies would be necessary to figure out how CBD works in the first place so that scientists can use a science-based strategy to chemically modifying the drug. This is how you turn herbalism into science.