Cannabis for Kids: Can Marijuana Treat Childhood Seizures?
“The gap between patient beliefs and available scientific evidence highlights a set of factors that confound cannabinoid research and therapy, including the naturalistic fallacy (the belief that nature’s products are safe), the conversion of anecdotes and strong beliefs into facts, failure to appreciate the difference between research and treatment, and a desire to control one’s care, including access to therapies of perceived benefit.” 1
— Cannabinoids in the Treatment of Epilepsy, Daniel Friedman and Orrin Devinsky
Cannabis for Kids?
If you believe the “pro-marijuana” lobby, cannabis is nothing short of nature’s wonder drug, virtually side-effect free and with astounding health benefits ranging from preventing Alzheimer’s disease to curing cancer. In 2013, such views gained a foothold in the mainstream when celebrity media doctor Sanjay Gupta famously declared that he had “changed [his previously skeptical] mind about weed” after witnessing the seemingly miraculous effects of marijuana on Charlotte Figi, a 3-year-old girl with intractable seizures despite taking 7 different medications. “Medical marijuana,” Gupta wrote, “calmed her brain,” bringing her seizure count down from 300 per week to just two to three per month.
As a result of a handful of anecdotal accounts like Charlotte’s, the possibility that marijuana might have therapeutic potential has been a hot topic in the media as well as in medical research. While that research is in its infancy, existing enthusiasm and hope has led several states to legalize the use of cannabinoids in children with refractory epilepsy. In turn, parents of children with epilepsy have flocked to Colorado in order to obtain easy access to cannabinoids reputed to be effective for childhood seizures. The most well-known product, called Charlotte’s Web, is manufactured in Colorado, but is now widely available, can be purchased online, and is delivered across state borders based on it being classified as a hemp product and marketed as a dietary supplement (a claim that the Food and Drug Administration disputes). This and other similar cannabis products are typically sold in liquid form (described as “cannabis oil”) or as tablets. Children using them for seizures are therefore not typically smoking marijuana, but ingesting an extracted product in the form of a liquid or pill.
With cannabinoids available that have bypassed the traditional process of Federal Drug Administration (FDA) approval for a medical treatment and the companies that manufacture them profiting from worried patients desperate for a cure, where’s the evidence to support treating childhood seizures with cannabis?
In order to answer that, it’s important to first understand that the anecdotal cases of childhood epilepsy responding to cannabinoids have mostly been reported in kids with extremely rare and difficult to treat seizure disorders such as Dravet syndrome or Lennox-Gastaut syndrome. These conditions are often associated with uncontrollable seizures that begin in infancy and continue recurrently throughout the day unchecked by existing FDA-approved anticonvulsants, with seizures that sometimes result in death. No wonder then that the parents of children suffering from such conditions are beside themselves, feeling let down by what doctors have to offer them and eager for the promise of something new.
Cannabis and Cannabinoids
Next, we have to understand the difference between cannabis and cannabinoids. Cannabis, also known as marijuana, is a plant that contains hundreds of cannabis-specific chemicals called “phytocannabinoids.” The two best-characterized cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Different breeds or strains of the cannabis plant contain variable amounts of THC and CBD, but the overall trend over the past few decades has been to breed cannabis with increasing amounts of THC and negligible amounts of CBD. This trend has been a consumer driven-change, with high THC and low CBD generally contributing to a more potent “high.”
However, it’s generally thought that the therapeutic potential of cannabis for seizures lies with CBD, not THC. Accordingly, Charlotte’s Web, the cannabis strain developed by the company CW Hemp and marketed for “daily health and wellness,” contains less than 0.3 percent THC. This is a tiny amount compared to the typical cannabis product found in medical marijuana dispensaries that often contain as much as 20-30 percent THC. As such, it is not associated with any euphoric “high” effects and can be legally classified as “hemp.” In contrast, the CBD content of Charlotte’s Web is described as “high” although the exact amount does not appear on the product labeling.
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Because the FDA does not recognize CBD products as dietary supplements, such products are not subject to federal purity standards or monitoring (and even if they were, adherence to purity standards for dietary supplements often falls far short of FDA requirements). The actual composition or cannabinoid content of cannabis products is therefore unreliable at best. A 2015 study of edible cannabis products sold in medical marijuana dispensaries found that less than 20 percent of products were accurately labeled with respect to THC and CBD composition. 2 Likewise, the FDA has found that product labeling of high-CBD products is often inaccurate, with some products not containing CBD at all.
What’s the Evidence?
Now that we understand those specifics, what’s the evidence that Charlotte’s Web or other high-CBD products sold in medical marijuana dispensaries are effective for childhood seizures? Beyond scattered anecdotal case reports like Charlotte Figi’s, there is no such evidence. Rigorous testing – for example, through randomized controlled trials like those required for FDA approval of a medication – is not necessary for Charlotte’s Web or other high-CBD products available in medical marijuana dispensaries to be sold (although a study involving Charlotte’s Web is reportedly in the works).
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In addition to retrospective case reports, a few surveys of parents with children with refractory seizure disorders have been published that describe a reduction in seizure frequency with CBD treatment. 3 But caregiver reports of seizures are poor measures of outcome, with a previous study finding that family reports of seizure have not been well-correlated with electroencephalogram (EEG) recordings of seizures. 4 Therefore, subjective reports by parents may carry a significant potential for bias, with perceived effects of CBD representing more of a placebo response than an actual response (see my most recent blogpost on the placebo effect). While a few small placebo-controlled trials involving CBD for seizure disorders were conducted in the 1970s and 80s, these studies involved adults rather than children, enrolled too few subjects to draw firm conclusions (a total of only 30 subjects received CBD across 4 studies), and two of them found no clear benefit for CBD. 3
Without controlled clinical trials to support the efficacy of high-CBD products in children, what hope is there for parents looking for more solid evidence to inform their decision of whether CBD might be worth trying? Enter Epidiolex, a pure CBD drug (containing 99 percent CBD and less than 0.1 percent THC) manufactured by GW Pharmaceuticals that was granted orphan drug status (a special status that allows a drug to be used to treat a rare disease even though it has not yet been fully tested and approved for the condition) by the FDA in 2013. Since then, this new medication has been made available to qualifying patients within “expanded access programs” located in within epilepsy treatment centers across the country.
In 2016, the first clinical trial of Epidiolex for treatment-resistant epilepsy was published in Lancet Neurology – an “open-label” study (meaning that it wasn’t controlled or blinded – see my earlier blogpost about the importance of blinding in controlled trials) involving 214 patients with intractable childhood epilepsy. 5 Enrolled subjects were 1 to 30 years old (average 10.5 years) and had to have 4 or more countable seizures per day despite being on stable doses of antiepileptic medications in order to participate. Nearly half of the subjects had either Lennox-Gastaut syndrome or Dravet syndrome. Subjects treated with Epidiolex were followed over a 12-week period with the major outcome being seizures reported by families and caregivers. The main study finding was that the number of reported seizures decreased from an average of 30/month to 16/month over the 3-month study, representing a reduction in seizure frequency of about 35 percent.
These results were encouraging to say the least, but still represented caregiver reports without a placebo comparator such that it’s impossible to say with confidence that the reported improvements were reliable or actually occurred as a result of treatment with Epidiolex. Also, while five subjects (4 percent) had no seizures at all during treatment with Epidiolex, just as many had to stop treatment due to an adverse event including some subjects who experienced an increase in seizures. In fact, 9 subjects (6 percent) developed a condition called status epilepticus (a sustained form of unremitting seizure activity) that was rated by investigators as “possibly due to CBD use.”
Just this past month however, a second study was published in the New England Journal of Medicine that significantly adds to the case for Epidiolex in refractory childhood epilepsy. 6 Performed by some of the same investigators, this clinical trial involved 120 children and young adults (up to age 18 years) with Dravet syndrome and included a placebo control. Subjects were followed for 14 weeks, with the main outcome again limited to caregiver reports of seizures. Epidiolex-treated subjects experienced a reduction in seizure frequency from 12 to 6 per month on average (a median improvement of about 40 percent), while placebo-treated subjects had only modest negligible improvement, a statistically-significant difference. Overall improvement was rated in 62 percent of Epidiolex-treated subjects and 34 percent of placebo-treated subjects. Although no patients developed status epilepticus in this study, more Epidiolex-treated than placebo-treated subjects dropped out of the study due to adverse events (eight vs. one), with somnolence, diarrhea, loss of appetite, and seizures (“convulsions”) reported more frequently as adverse events in the Epidiolex group.
Overall then, by addressing the potential reporting bias and limited ability to infer causality in the first open label study, this second placebo-controlled trial of Epidiolex does provide promising evidence to support a therapeutic role of cannabidiol in children with refractory seizures associated with Dravet syndrome.
What does this mean for parents hoping for an upgrade in available treatments for their children with refractory epilepsy? Here are some take-home points based on the existing research to date:
► The best data on Epidiolex comes from children with Dravet syndrome, which is a distinct seizure disorder. The evidence from controlled trials that CBD is effective for other types of seizures or for seizures in adults in minimal at this time. Without question, the limited available data argues for additional controlled trials of CBD in other seizure disorders.
► While CBD may be effective for refractory childhood seizure disorders like Dravet syndrome, evidence to support the use of marijuana for seizures in lacking. Although some surveys report benefits from users, evidence from animal studies suggests that THC has may have pro-convulsant properties. 7 Seizures have been reported adverse event within published cases of synthetic cannabinoid toxicity (see my previous blogpost on synthetic cannabinoids). 8 Accordingly, there is not yet any convincing evidence that cannabis or marijuana is an effective treatment for seizures and some limited evidence suggests that using marijuana could worsen seizures.
► Like any medication, CBD is not free of side effects — some patients don’t tolerate treatment with CBD.
► As a highly purified CBD medication manufactured by a drug company, Epidiolex’s clinicial trial benefits cannot be assumed to hold true for other high-CBD products like Charlotte’s Web. Although the currently limited availability of Epidiolex might incentivize parents to seek out other CBD products from other sources, the uncertain composition of CBD products found in medical marijuana dispensaries (including those containing no CBD at all) is good cause for concern. As marijuana is increasingly legalized and as medical research with cannabinoid pharmaceuticals expands, expect the battle over profits between marijuana growers and pharmaceutical companies to heat up.
► In the only two clinical trials of Epidiolex published to date, the percentage of subjects who had no seizures during active treatment was four percent in the open-label study and less than one percent in the placebo controlled study. Epidiolex’s potential to reduce seizure frequency is an important advance in the treatment of children with life-threatening refractory epilepsy, but it’s not a miracle cure.
To read more of this 3-part series on A Parent’s Guide to Modern Marijuana:
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Disclosure: The author reports no conflicts of interest with regard to this blogpost, including no financial affiliation with GW Pharmaceuticals, CW Hemp, or any other purveyor of “medical marijuana” products.
1. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. New England Journal of Medicine 2015; 373:1048-1058.
2. Vandrey R, Raber JC, Raber ME, et al. Cannabinoid dose and label accuracy in edible medical cannabis products. Journal of the American Medical Association 2015;313:2491-2493.
3. Leo A, Russo E, Elia M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacologic Research 2016; 107:85-92.
4. Press CA, Krupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior 2015; 45:49-52.
5. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurology 2016; 15:270-278.
6. Devinsky O, Cross H, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine 2017; 376:2011-2020.
7. Karler R, Calder LD, Turkanis SA. Prolonged CNS hyperexcitability in mice after a single exposure to delta-9-tetrahydrocannbinol. Neuropharmacology 1986; 25:441-446.
8. Courts J, Maskill V, Gray A, et al. Signs and symptoms associated with synthetic cannabinoid toxicity: systematic review. Australasian Psychiatry 2016; 24:598-601.
Marijuana-Based Drug Found to Reduce Epileptic Seizures
An experimental drug derived from marijuana has succeeded in reducing epileptic seizures in its first major clinical trial, the product’s developer announced on Monday, a finding that could lend credence to the medical marijuana movement.
The developer, GW Pharmaceuticals, said the drug, Epidiolex, achieved the main goal of the trial, reducing convulsive seizures when compared with a placebo in patients with Dravet syndrome, a rare form of epilepsy. GW shares more than doubled on Monday.
If Epidiolex wins regulatory approval, it would be the first prescription drug in the United States that is extracted from marijuana. The drug is a liquid containing cannabidiol, a component of marijuana that does not make people high.
As many as 30 percent of the nearly 500,000 American children with epilepsy are not sufficiently helped by existing drugs, according to GW. Parents of some of these children have been flocking to try marijuana extracts, prepared by medical marijuana dispensaries.
A number of states, in response to pressure from these parents, have passed or considered legislation to make it easier to obtain marijuana-based products. And some families have become “marijuana refugees,” moving to Colorado where it has been easier to obtain a particular extract, known as Charlotte’s Web, after the girl who first used it to control seizures.
Hundreds of other children and young adults have been using Epidiolex outside of clinical trials, under programs that allow desperate patients to use experimental drugs.
While many parents have reported significant reductions in seizures, experts have been cautious about anecdotal reports, saying that such treatments needed to be compared with a placebo to make sure they work. As such, the results from the GW trial have been closely watched.
“I’m very proud and happy about this study because it is science — we did things the way they should be done,” the study’s lead investigator, Dr. Orrin Devinsky of the Comprehensive Epilepsy Center at New York University Langone Medical Center, said in an interview. “I would strongly advocate that in the United States we need to do systematic assessments of medical marijuana.”
The study involved 120 patients with an average age of 10 and an average frequency of 13 convulsive seizures a month at the start of the study, despite taking an average of three other drugs. Half of the children were randomly assigned to take the drug and the other half the placebo, in addition to the epilepsy medicines they were already taking.
The company said that for the patients who received Epidiolex, the frequency of convulsive seizures fell by 39 percent during the 14-week treatment period, compared with a four-week period just before the treatment started. For those getting the placebo, the reduction was 13 percent. The difference between the two groups was statistically significant.
Eight patients getting Epidiolex and one getting the placebo withdrew from the trial because of side effects. Major side effects included drowsiness, diarrhea, decreased appetite, fatigue, fever, vomiting and upper respiratory infection. But GW said that over all, the drug was well tolerated.
One caution is that the full details of the study were not released; the company said they would be presented at a medical conference.
GW, which is based in London, said Monday that it would meet with the Food and Drug Administration to see if Epidiolex could be approved based on this single study. It is expecting the results of another trial for Dravet syndrome later this year, and the results of two trials in another form of epilepsy, Lennox-Gastaut.
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There are no drugs approved specifically for Dravet syndrome, which typically starts in infancy and affects about 5,000 children in the United States, according to the company. It is not yet known if Epidiolex can help with the walking problems and intellectual disability that can come with Dravet, Dr. Devinsky said.
American depositary receipts of GW closed up about 120 percent on Monday. The company, which specializes in cannabis-based pharmaceuticals, already sells Sativex to treat spasticity associated with multiple sclerosis. It is approved in many countries, though not the United States.
While Epidiolex could be the first prescription drug in the United States extracted from marijuana, two drugs already on the market, dronabinol and nabilone, are synthetic chemicals either similar to or identical to delta-9 THC, the component of marijuana that produces the highs.
Those drugs are approved to treat nausea and vomiting caused by cancer chemotherapy. Dronabinol is also approved to treat weight and appetite loss in patients with AIDS.
GW executives say that an approved pharmaceutical should be favored by doctors and patients because the other medical marijuana products have not gone through the same rigorous vetting.
A study last year by researchers at Johns Hopkins University and elsewhere found that medical marijuana products rarely contained the amount of ingredients stated in their labels.
The F.D.A. has been sending warning letters to some companies, many of them selling hemp oil, saying that they are illegally marketing their products as drugs and that cannabidiol cannot be sold as a dietary supplement because it is being studied for use as a drug.
But even if Epidiolex wins approval, some parents might stick with other products, either because they do not want to disrupt their child’s treatment or they prefer a fuller plant extract to the single ingredient in Epidiolex.
“My kid’s stable. I’m not touching it,” said Allison Ray Benavides, whose 6-year-old son, Robby, is using Charlotte’s Web, to which a little of the psychoactive component THC is added.
Robby used to have 15 to 25 seizures a day, even while taking the approved drug Depakote, and had to wear a helmet all day to protect his head from falls, said Ms. Ray Benavides, a medical social worker in San Diego.
Since starting on Charlotte’s Web more two years ago, while continuing with Depakote, he has had a total of only five seizures.
“I don’t need a double-blind placebo-controlled study to know something,” she said, while nonetheless welcoming the Epidiolex trial results.
Analysts expect Epidiolex to cost $2,500 to $5,000 a month, which would be more expensive than some of the medical marijuana products, which cost from about $100 to more than $1,000 per month. However, Epidiolex might be covered by insurance, unlike the other products.