Charlotte Figi had her first seizure when she was three months old. It began after a warm bath, a common precursor to the first seizures in Dravet Syndrome. Within a couple of years, she was experiencing over 300 spontaneous grand mal seizures a week.

You may have heard of Charlotte’s story. She’s been featured on 60 Minutes, in a CNN documentary and is the namesake of a popular medicinal compound. The beginning of her story is common for children with Dravet Syndrome, a severe childhood disorder caused by a genetic mutation that impairs the brain’s neuronal “brake.”

Parents and doctors grasp for reprieve using FDA-approved medications, piling upwards of seven of them on young children with developing brains. They may find temporary relief, only for the seizures to return with a vengeance. The side effects are damaging, the severity of seizures frightening, the risk of death ever-present.

But Charlotte’s story deviated when her parents broke from the traditional medical community and tried medicinal cannabis. It must have felt like throwing a Hail Mary, but in desperation, it felt justified. The decision was one of the greatest the Figis ever made. Charlotte experienced substantial seizure relief from a cannabidiol-rich strain, now known as “Charlotte’s Web,” which illuminated cannabidiol as a potentially efficacious new treatment strategy for combating seizures.

Charlotte’s story has had a considerable impact on the acceptance of medicinal marijuana (particularly medications with high CBD:THC ratios) as a potential treatment strategy for combating seizures in treatment-resistant epilepsies, including Dravet Syndrome (20 percent of pediatric epilepsies don’t respond to traditional medications). It spawned the migration of families to states where medicinal and recreational marijuana are legal, it supported the production and marketing of high CBD-containing products and it provided strong justification to conduct large-scale human clinical trials into cannabidiol’s efficacy.

So why has the medical community been hesitant to adopt cannabidiol as a viable treatment strategy? Despite the legal implications of recommending use of a Schedule I drug, as marijuana and its derivatives (including cannabidiol) are listed under the Controlled Substance Act, many are hesitant to accept the evidence.

For one, anecdotal reports are promising, but they’re often rife with bias (parents obviously want the drug to work and occasionally see success when none exists), and self-reported data is often unreliable. One of the most promising pieces of evidence was from a recently published early-stage human clinical trial that found seizure frequency was cut nearly in half in patients with Dravet Syndrome after taking a 99 percent pure oil-based cannabidiol compound (Epidolex, GW Pharmaceuticals). But again, the data was based on parent self-report, a potentially unreliable source, and had no placebo-control group for comparison. Furthermore, patients remained on their prescribed anti-epileptic drugs during the trial; so it’s difficult to say whether any seizure reduction was due to cannabidiol directly, or if cannabdiol interacted with the other drugs, or their metabolism, to reduce seizures. This is not to say that cannabdiol didn’t effectively reduce seizure frequency in these patients, but most docs don’t consider it a closed case. More work is to be done.

Charlotte Figi helped bring needed attention to Dravet Syndome, but it remains a largely unknown syndrome. Yet, much of the support for cannabidiol’s efficacy in treating seizures, which has received considerable media attention, stems from patients with Dravet Syndome. This, in part, is because its cause is well-known, allowing researchers to study underlying mechanisms and potential therapies for seizures which are caused by a single genetic mutation.

Individuals with Dravet Syndrome have a mutation to their SCN1A gene which likely occurred spontaneously in the egg or sperm before fertilization. Because of this mutation, beginning around two years of age, children are unable to produce a sufficient number of a particular type of protein that gets inserted into the membranes of neurons. These proteins are necessary for the excitability of a class of neurons involved in dampening large-scale brain activity. Without a sufficient number of these proteins, the number of action potentials they fire is substantially reduced. So, once the child is around two years old, this important class of neurons is less active, leading to frequent seizures and increased mortality.

To conceptualize what’s going wrong in the brain of a child with Dravet Syndrome, consider that the brain is constantly engaged in a battle of tug-of-war. Neurons are pitted against neurons. Some of these neurons traverse long distances, stretching from one brain region to another. They convey critical pieces of information that provide the basis for complex thoughts and behaviors. Unrestrained, these “projection” neurons fire action potentials, the electrical impulse that travels through a neuron and concludes with release of neurotransmitters, more frequently.

A small or brief increase in action potentials provides meaningful information. In one brain region, it may indicate that something is pleasurable, in another, it may indicate a threat. In the visual system, it may represent light and dark contrast. When only a portion of projection neurons fire at once, the information they convey can be interpreted. This restraint is maintained by the constant effort of “inhibitory” neurons. Inhibitory neurons usually only travel short distances, limiting their direct effect to within a particular brain region. They control the rate and timing at which projection neurons fire. To do so, they must maintain much higher firing rates than projection neurons (they can fire hundreds of times each second).

The tug-of-war is a close match in a healthy brain. Projection neurons may briefly gain, sending a quick signal, but then inhibitory neurons pull back, dampening further signaling. This is known in neuroscience circles as the brain’s excitatory:inhibitory balance. A seizure is initiated when the balance shifts too heavily towards excitation. Epilepsy is more of a chronic imbalance, indicative of a more permanent shift towards excitation.

You can imagine that there can be two main causes underlying epilepsy. In the tug-of-war game, either the excitatory “team” is too strong, or the inhibitory “team” is too weak. Many anti-epileptic medications work to reduce the strength of the excitatory team. However, some epileptic syndromes, including Dravet Syndrome, are caused by a weak inhibitory team. These syndromes are much more difficult to treat with traditional medications. Pharmaceutical companies have struggled to develop drugs that only work to bolster the strength of the inhibitory team, but the specificity isn’t there.

That’s why, with Dravet Syndrome and other treatment-resistant epilepsies, a new strategy is needed. Cannabidiol may be just what these patients are seeking. And the best part is cannabidiol’s impact may not be limited to stopping seizures.

Individuals with Dravet Syndrome also have cognitive impairment, sensory integration disorders and many have autism. In fact, parents of children with Dravet Syndrome often report that the cognitive impairment and social deficits substantially reduce the quality of life for the child and increase the burden on caretakers as they struggle to provide effective care. These other elements of the disorder can be especially stressful. Parents report that one of their greatest fears is that their child will get into an accident, severely injuring themselves because they’re unable to engage in normal social learning about harm and risk. So it would be ideal if cannabdiol could not only treat seizures in Dravet Syndrome, but other aspects of the disorder as well. But is that possible?

Many believe that seizures early in life rewire the brain in such a way, that normal brain functioning can never be possible. In many epileptic disorders, this is the case. Different areas of the brain are connected both anatomically by groups of neurons and functionally. That is, there is a correlated relationship in the activity of neurons between multiple brain areas. This is crucial for normal cognitive function and behavior.

Breakdown of this functional connectivity, depending on which brain regions are involved, leads to disorders from schizophrenia to autism. Childhood and adolescence are critical periods for the development of normal connectivity patterns. Repeated seizures, especially hundreds each week as in the case of Dravet Syndrome, could cause severe and irreversible damage to the brain’s functional connectivity. So is there hope for children with Dravet Syndrome?

I’m a post-doctoral scientist at the University of Washington studying the effect of cannabidiol in a mouse model of Dravet Syndrome. Our lab developed a mouse model of Dravet Syndrome by genetically mutating the same gene (SCN1A) that causes the human disease. Like in the human condition, our Dravet Syndrome mouse has spontaneous seizures, a high rate of Sudden Unexpected Death in Epilepsy (SUDEP), cognitive impairment and social deficits consistent with autism-like behavior. These similar behaviors make our mouse model an optimal precision medicine tool for testing the efficacy of therapeutic strategies—such as cannabidiol—in treating not only seizures in Dravet Syndrome, but other aspects of the disorder as well.

Using these mice, we’ve been able to identify how mutation to the SCN1A gene, which causes Dravet Syndrome, perturbs brain functioning. Our studies have determined that this genetic mutation selectively reduces inhibitory signaling in the brain. This is like having a faulty brake pedal as the car speeds downhill; the brain’s excitatory:inhibitory balance shifts towards excitation, and with a faulty brake, seizures occur. Because the brain’s excitatory drive is enhanced, the “signal to noise” decreases; it can no longer distinguish between important signals and faulty ones that only occur because of the amped up excitatory:inhibitory ratio. As a result, cognitive impairment, and sensory integration problems result, contributing to a host of problems from anxiety to autism.

For cannabidol to be an effective treatment for the complex behavioral deficits in Dravet Syndrome, including autism, we must make a critical assumption: behavioral deficits are caused primarily by the imbalance between excitation and inhibition. This assumption implies that cognitive and social deficits in Dravet Syndrome are not largely the cause of seizures, which in many cases distorts brain wiring. This is an important and controversial assumption, but it’s critical for the efficacy of cannabidiol, or any other pharmacological strategy, to be able to rescue all aspects of the disorder.

Previous work in our lab discovered that amping up the brain’s inhibitory gain with the benzodiazepine Clonazepam rescued the cognitive deficit and autism-like social deficits in Dravet Syndrome mice. These important results indicate that irreversible seizure-induced brain damage is not responsible for these deficits, and thus, could be curbed pharmacologically. Unfortunately, Clonazepam and other benzodiazepines offer only incomplete therapy for Dravet Syndrome, since high doses that cause sedation are required to treat epileptic seizures, but only low doses are effective at rescuing social and cognitive deficits in Dravet Syndrome.

Cannabidiol is an exciting pharmacological treatment strategy because it has the potential to not only reduce seizure activity in well-tolerated doses, but evidence also supports its anxiolytic and pro-social effects at low doses in a variety of laboratory animal models. Therefore, unlike with benzodiazepines, cannabidiol could work to reduce seizures and rescue behavioral deficits in Dravet Syndrome at non-impairing and well-tolerated doses.

Work is underway testing the effect of cannabidiol on seizures and social deficits in Dravet Syndrome mice, yielding promising preliminary results. Additionally, we’re searching for the mechanism through which cannabidiol provides seizure relief, such as in the case of Charlotte Figi. Reports point to a particular neuronal receptor, called GPR55, as a potential target for block by cannabidiol, which may increase the impact of inhibitory neurons (i.e., strengthening the inhibitory team). However, it remains unclear if this cannabidiol action is sufficient to rescue inhibitory neuron dysfunction in Dravet Syndrome, or if it’s also acting through an alternative mechanism.

With the cost of genetic sequencing rapidly declining (it is 10,000 times cheaper to sequence the human genome today than it was 10 years ago), Dravet Syndrome diagnosis is now largely aided by a genetic test. However, there are other epilepsy syndromes with unclear underlying causes.

One, for example, is known as Febrile Infection-Related Epilepsy Syndrome, or FIRES. FIRES can occur in normally developing school-aged children (average age of onset is 6.5 years) following a fever, and is characterized by explosive and life-threatening epilepsy. A small, open-label clinical trial found that cannabidiol, at doses of up to 25mg/kg/day (this is half of what the Dravet Syndrome clinical trials used; in both cases side-effects were minimal), reduced seizure frequency in children with FIRES.

Cannabidiol has also similarly been shown to reduce seizures in Lennox-Gastaut Syndrome, another childhood epilepsy syndrome largely resistant to traditional anti-epileptic medications, although it’s efficacy was slightly less than in Dravet Syndrome and FIRES. This may reflect wide variation in genetic contributions to Lennox-Gastaut Syndrome. Does this mean that cannabidiol is only effective in treating seizure disorders with similar genetic etiologies? This certainly warrants more investigation into the mechanism of cannabidiol action in the brain and the mechanistic link between genetic mutation and seizure generation. Either way, the burgeoning evidence from these early-stage clinical trials suggests that there’s more to cannabidiol than media hype.

Beyond seizures, it remains largely unknown whether cannabidol can also rescue some of the other behavioral impairments, such as cognitive deficits and autism, associated with these disorders. Given the different genetic influences on brain dysfunction, each one of these syndromes will have to be investigated on a case-by-case basis. But in the end, these studies may reveal that the brains of these children aren’t as permanently damaged as previously assumed and could throw open the doors of hope for patients and their loved ones.

Related Stories:
The Simple Answer: What Are THC & CBD?
Why Are So Many States Passing CBD-Only Legislation?
Doctors Using Cannabis to Treat Autism in First-Of-Its-Kind Study
How To: Finding and Procuring CBD Strains

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