Ghostbusting with cannabis? An ancient remedy for epilepsy!

What is Epilepsy?

Epilepsy is a common neurological disorder. It is a chronic disease  where the brain manifests a predisposition for recurrent and unprovoked seizures. The "International League Against Epilepsy" (ILAE) defines the diagnosis of the disease as follows:

• At least two unprovoked (or reflex) seizures occurring more than 24h apart

• One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next ten years

• Diagnosis of an epilepsy syndrome

Epileptic seizures result from abnormal synchronization of neurons in the brain which disrupt the typical sequence of neuronal activity and lead to various symptoms ranging from mild to severely debilitating. Clinical diagnosis of epilepsy consists primarily of monitoring the brain's electromagnetic activity using electroencephalography (EEG), or neuroimaging (like magnetic resonance imaging (MRI), supported by general laboratory and genetic testing methods. Traditionally, epilepsy is diagnosed after at least two unprovoked seizures more than 24h apart.

Epileptic seizures result from abnormal synchronization of neurons in the brain

Epileptic seizures are the central feature of the disorder, and come in different flavors.  Seizures are classified based on where they originate in the brain (generalized vs. focal), on the involvement of involuntary muscle movement (motor vs. non-motor), and on the patient’s state of consciousness at the time (aware vs. absent) of the seizure. Generalized onset seizures originate within bilaterally distributed networks on both hemispheres of the brain, and thus they affect both sides of the body. On the other hand, focal onset seizures are limited to only one hemisphere of the brain. That classification is a lot more granular than that of epilepsy. For example, there are differences in the involvement of muscles: seizure affected muscles can either suddenly contract and stiffen, or relax entirely (and in different sequences). For more detail, you can find an excellent educational resource (including seizure videos) at this website curated by the International League Against Epilepsy:

http://www.epilepsydiagnosis.org

Much effort has gone into finding ways to mitigate epileptic seizures, since they can be so debilitating that it can become difficult for some afflicted to participate in society. Additionally, some epileptic seizures can be extremely disturbing to witness. The etiology of epilepsy, the underlying cause for the condition, has proven very complex and requires careful analysis. To date, the international research community has identified the following causes for epilepsy:

• structural brain abnormalities

• genetic defects

• infection

• metabolic causes

• immune system disorders

• unknown (anything that doesn't fit the other categories)

Epilepsy is a general term encompassing a variety of "epilepsy diseases", but we have a better understanding of the underlying cause in some cases.

Epilepsy is a general term encompassing a variety of "epilepsy diseases"

In those instances, we can aggregate a collection of known symptoms into a more defined "epilepsy syndrome." To date, there are at least 30 different epilepsy syndromes.

A history lesson

Epilepsy has an enormous impact on a patient's quality of life. It has social, physical, psychological, and vocational impacts on a patient. In terms of "disability weight," it ranks in the top 10, among the hundreds of health conditions listed in the "Global Burden of Disease" study. Witnessing someone suffer a severe epileptic seizure is often very disturbing, especially for family members of affected patients. It is no wonder that ancient healers documented encounters with epilepsy, even in the distant past. Historians have unearthed Sumerian and Akkadian cuneiform tablets dating to 1800 B.C. recording an affliction called "Hand of Ghost," that matches a collection of symptoms documented in cases of nocturnal epilepsy. The tablet recommends a medicinal plant called "azallû" to banish the ghosts of the possessed individual(s). Oxford scholar R. Campbell Thompson has translated that word as "gan.zi.tar.nu"/"ganja" / "cannabis." The historical record is full of instances where medics have successfully administered cannabis to treat epilepsy.  Famously (and most recently) is the story of 5-year old Charlotte Figi. She suffered from a rare and severe form of epilepsy called Dravet Syndrome (SCN1A+). She experienced 50 seizures (generalized tonic-clonic) daily. In 2012 Charlotte's mother began administering marijuana oil (high CBD, low THC) to her daughter. Soon, Charlotte's seizure frequency and severity dropped dramatically: Instead of her typical 50 seizures a day, cannabis reduced her episodes to 2–3 nocturnal seizures each month. The improvement in her quality of life was so dramatic that the case of Charlotte Figi has been widely publicized, and is likely partially responsible for the uptick in biomedical research of cannabis in the context of epilepsy over the last decade. The plant used to treat Charlotte has been renamed from "Hippie's Disappointment" to "Charlotte's Web." Sadly, Charlotte passed away last year (April 7th, 2020) at the age of 13.  She was hospitalized with pneumonia which exacerbated her seizures and resulted in respiratory failure, and eventually cardiac arrest. To honor her memory, Colorado's Governor has since declared April 7th "Charlotte Figi Day."  Historically, other notable individuals believed to be sufferers of epilepsy include Vincent Van Gogh, George Gershwin,  Socrates, Neil Abercrombie, Fyodor Dostoyevsky, and Ian Curtis (to name a few).

Treatment options

Anti-epileptic drugs (AEDs) are the first-line treatment against epilepsy. AEDs are anti-seizure medications that help limit the intensity and frequency of seizures. This treatment strategy aims to increase the patient's quality of life by mitigating a "symptom" of epilepsy, but it does not address the underlying causes of the disease. It is effective, as about 2/3 of all patients become seizure-free with AEDs. Numerous AEDs are in clinical use for several forms of epilepsy, such as Carbamazepine, Ethosuximide, Phenytoin, Valproic acid, Lamotrigine Levetiracetam, Oxcarbazepine, Topiramate. If a patient does not respond well, or has too many adverse side effects, with one treatment, several other options are available.

Anti-epileptic drugs (AEDs) are the first-line treatment against epilepsy.

Luckily, about 50% of patients react beneficially to the first AED. Unfortunately, it does happen that AED therapies are unsuccessful. About 20–40% of patients become drug-resistant over time. Those cases of epilepsy are considerably more challenging to treat. The go-to defense against drug-resistant epilepsy is epilepsy surgery. In some cases, it is possible to remove the brain tissue that causes the seizures, surgically. When feasible, epilepsy surgery is usually very successful. Even so, open brain surgery comes with its own set of risks that need to be evaluated carefully for each case.

Cannabis: a third-line treatment option

Cannabis represents a third-line option as a potential treatment for epilepsy! Ancient cuneiform tablets document anecdotal evidence that cannabis has already been effective as an anti-convulsive treatment in the age of the ancient Sumerians.  The most recent successes in the treatment of severe infantile-onset epilepsy (Dravet syndrome) in 5-year old Charlotte Figi has led to an explosion of interest in the investigation of cannabis and cannabinoids in controlled scientific studies, formally. Since 2012, many studies in animal models of epilepsy have shown significant promise. In particular, cannabidiol (CBD), cannabidivarin (CBDV), and tetrahydrocannabinolic acid (THCA) have shown promise in animal models. Still one should note that accidental carboxylation of THCA would turn it into the psychoactive THC. The consensus appears to indicate that high THC products utilized primarily for recreational purposes have too many undesired side effects and are unsuitable for epilepsy treatment. There have also been cases where THC exacerbated the seizures. Consequently, most studies investigating cannabis in the context of epilepsy either use extracts from low-THC strains or defined CBD, CBDV, or THCA. 

Studies in animal models have shown promise of treating epilepsy with CBD, CBDV and THCA, but the psychoactive THC can worsen the condition !

The most exciting clinical data on cannabis and epilepsy comes from three proper randomized controlled clinical trials from 2017. The trials investigated CBD for Dravet Syndrome and Lennox-Gastaut Syndrome in hundreds of patients. All trials found a significant reduction of seizure intensity and frequency in the CBD group than in placebo controls. While this is fascinating data, many questions remain unanswered. The exact mechanism by which CBD reduces seizures is still unclear. Classical cannabinoid receptor signaling does not appear to mediate the effect, and is presumed to result from some unknown secondary mechanism.

While the CBD data from the clinical trials are promising, they are still tricky to conclusively interpret. A weakness of the trial design was that patients were co-administered with other medications such as clobazam, which can interact with CBD. Lastly, the question remains to what extent it is possible to minimize undesired adverse side-effects of CBD in childhood epilepsy. More than 75% of trial participants experienced various negative effects, such as drowsiness, diarrhea, fatigue, vomiting, and fever. Side-effects like these can be quite impactful, especially for small children. Due to the widespread distribution of the endocannabinoid system in the human body, it will be unlikely to avoid side effects entirely. In any case, the success in treating refractory( i.e., otherwise drug-resistant epilepsy) is exciting. 

There is mounting scientific evidence that implicates the endocannabinoid system itself in the pathogenesis of epilepsy. Clinical observations include demonstrations of changes in CB1-receptor expression levels in surgical samples of human epileptic brain tissues (hippocampus) as well as reduced concentrations of the natural endocannabinoid (meaning from “inside the body”) anandamide in the cerebrospinal fluid of patients with new-onset temporal lobe epilepsy. Defects in the endocannabinoid system may play a role in some forms of epilepsy. Research into cannabis and the endocannabinoid system will remain a priority for biomedical research in the foreseeable future. As the case of Charlotte Figi has so dramatically demonstrated, it would be worth discussing possible cannabis-based therapy options with your physician if you are a parent of a child suffering from epilepsy.