Epilepsy and Cannabis: An Overview
By Diana Hahn and Stacey Marie Kerr MD
Historical documentation for the use of cannabis to treat epilepsy ranges from 2900 B.C. in ancient Sumeria, through case studies from 19th century England, into the early days of the United States. 
But by the middle of the 20th century, cannabis was effectively made illegal in the United States and could no longer be used legally as a treatment for any condition.  Today, several high profile success stories from states with legalized medical cannabis have brought epilepsy to the forefront of many conversations regarding cannabis as medicine.
What is epilepsy?
Epilepsy refers to a broad range of conditions that cause seizures. Patients are often diagnosed with a “syndrome,” which is defined by the characteristics of symptoms and a variety of other markers.
Even patients diagnosed with the same syndrome, however, may have key differences in their conditions that could determine whether a medication works or not. Considering the diversity of causes, pathways, and symptoms of epilepsy and seizures in general, it is still a challenge to predict which medicines, including cannabis/cannabinoids, will work for a particular patient.
Cannabinoids and Seizures
We have learned much from animal model experiments. It is known that cannabinoids reduce inflammation, and inflammation is often associated with seizures. We also know from these experiments that endocannabinoids lessen the severity of seizures while preventing seizure-caused damage to the nervous system.
The direct activation of CB1 receptors in the brain reduces seizure severity, thus limiting activity and protecting nerve tissue. THC has been shown to regulate the neurons’ excitability during seizures. And CBD, recently the most popular cannabinoid looked at for seizure control, is effective at controlling seizures (when used in the exact right amounts), perhaps in part by reducing the toxic effects of inflammation.
THC vs. CBD in Treating Seizures: Data from 34 Studies Across 6 Animal Species
Percentages show response rate.
|THC||CBD and CBDV|
|Mixed (Anti- and Pro- Convulsant)||2.9%||0%|
|No Significant Effect||32.4%||19.5%|
Case Studies and Surveys
Most of the information we have regarding cannabinoids and epilepsy comes from case studies and surveys. While much of this information is interesting, promising, and serves as proof that further research is warranted, both methods of data collection have drawbacks including reliability and applicability of the information to other patients.
Nevertheless, the majority of information we have is positive, pointing to cannabinoids, particularly CBD, being an effective anti-seizure treatment. Many patients have been willing to experiment with CBD. Up to 20% of epilepsy patients in the United States today use cannabis, many moving their families to states with medical cannabis laws specifically to pursue this therapy. 
Examining case study and survey data may be helpful for patients and doctors to get an overview of probability of success and what may be possible. It is important to remember, however, that statistics and case studies do not guarantee success with cannabinoid therapy for any particular patient, and it is best to keep expectations tempered as we still do not fully understand the mechanisms of cannabinoid anti-seizure activity. Case studies like Charlotte Figi’s (‘Charlotte’s Web’) are useful in that they may open patients’ and doctors’ minds to an alternative treatment that is worth trying in certain cases based on risk, possibility, and the seriousness of a patient’s condition.
The following clinical research is representative of what currently exists regarding cannabinoids and epilepsy.
Cannabinoids and Preclinical Seizure Models
Much of the work done regarding cannabinoids, the ECS and seizures has been preclinical. The data below represents a compilation of 34 studies done with animal models. Note that THC is a CB1 receptor (CB1R) agonist, and that CBD is as well, although to a lesser extent.
Open Label Study Using 99% CBD
Length of Study: 12 weeks
Number of Patients: 137
Patient Age Range: 2-26 years, with a mean age of 10.8 years
Identified Diagnoses: Primarily Dravet Syndrome and Lennox-Gestaut Syndrome. Also included Aicardi Syndrome, Doose Syndrome, tuberous sclerosis complex, CDKL5, Dup15q syndrome, and others.
Results: Efficacy and Side Effects
|Patient Subgroups||Changes in Seizure Occurrence|
|Convulsive and Nonconvulsive Seizures||54% Reduction|
|Convulsive Seizures||51% Reduction|
|Dravet Syndrome||53%, with 16% having no seizures by week 12|
|Lennox-Gestaut Syndrome Atonic Seizures||52% Reduction|
|Adverse Effects||Rates of Occurrence|
|Most adverse effects were tolerable, however 9 of the 137 participants (4%) did not complete the study because of side effects.|
Canadian Adults Using Smoked Cannabis - Anonymous Questionnaire
Length of Study: 14 months
Number of Patients: 292
Patient Age Range: 27-49 years, with a median age of 35 years
Identified Diagnoses: Epilepsy, Psychogenic Non-Epileptic Seizures (PNES), Both Epilepsy and PNES
Results: Benefits and Side Effects
|Effect||Epilepsy Reporting||PNES Reporting|
|Improvement in Seizures||84%||72.7%|
|Antiepileptic Drug Side Effect Reduction||53.2%||N/A|
|Adverse Effects||30.7%, with 5 patients reporting possible seizure precipitation||30.7%|
Charlotte Figi Case Study
Charlotte Figi is a well-known case study in cannabinoids and epilepsy. By the time Charlotte was 5 years old:
Diagnosed with Dravet Syndrome with a SCN1A gene mutation;
Experienced up to 50 generalized tonic-clonic seizures per day;
Had tried many treatment options with no success including levetiracetam, xcarbazepine, topiramate, zonisamide, valproate, clobazam, clonazepam, valium and the ketogenic diet;
Had significant cognitive and motor delays, required a feeding tube for nutrition and water, struggled to walk and talk, and needed assistance with basic every day activities.
At 5 years old, Charlotte started cannabinoid treatment:
Utilized a high CBD-low THC (< .3% THC) strain of cannabis now known as “Charlotte’s Web”;
Delivery method was sublingual whole plant extract;
Started at low dose and slowly increased to 8.8 mg CBD/kg per day.
By month 3 of CBD treatment, Charlotte’s generalized tonic-clonic seizures were reduced by >90%;
Discontinued all other antiepileptic drugs;
At 20 months Charlotte was still on 8.8 mg CBD/kg per day and was having 2-3 nocturnal seizures per month, could eat and drink independently, walk, sleep through the night, and autistic behaviors had improved.
After the 20-month mark, Charlotte’s parents tried to reduce CBD dosage, however seizure occurrence rose once the dosage was lowered to 4.4 mg CBD/kg per day. With no CBD, seizures returned to original level pre-CBD treatment. Once CBD treatment was restarted and titrated up to 8.8 mg CBD/kg per day, seizures returned to the rate of 2-3 nocturnal seizures per month. Charlotte’s parents tried to wean her off CBD several times, and each time the result was the same. 
According to the American Academy of Neurology, there is no definitive proof that cannabinoids are effective at preventing or reducing the severity of seizures in humans.  There is evidence, however, that CBD (dosing up to 200-300 mg/day) is a safe treatment for epilepsy in humans, and it has a low occurrence of side effects. 
There is the potential for drug-drug interactions. One example of this is with clobazam (Frisium, a drug commonly prescribed for Lennox-Gastaut Syndrome) and CBD. These are both degraded by the same enzyme in the liver, and they compete for that enzyme. This competition can lead to elevated blood levels of clobazam, leading to increased side effects, all of which are reduced when the clobazam doses are lowered.  It is interesting to note that although the purpose of that study was to show drug-drug interaction safety, 9 of 13 patients experienced >50% reduction in seizures.
Due to the current lack of clinical evidence for CBD’s anti-epileptic properties, patients should not stop taking other medicines if they decide to pursue cannabinoid therapy. We do recommend patients fully communicate with their doctors, and particularly with their neurologists and/or epileptologists (seizure specialists) about their cannabis use as there are some potential drug-drug interactions. Of note, increased sedation can occur with the combination of CBD and many of the commonly prescribed anti-epileptic pharmaceuticals. Side effects and serum levels of pharmaceuticals should be carefully monitored.
Currently, there are over 20 antiepileptic drugs on the market, however these drugs do not work for 30% of epilepsy patients who continue to experience refractory (uncontrolled) seizures on a regular basis.  Of those patients who are able to control seizures with antiepileptic drugs, many experience undesirable side effects that compromise quality life.
While 95% of patients and 80% of primary care physicians believe that cannabinoids help with epilepsy, only a minority of neurologists and epileptologists believe there is sufficient evidence of the efficacy and safety. Only half of these specialists would recommend cannabis even in severe cases.  It is important to remain cautious and not become overly optimistic in regards to cannabinoids and epilepsy. At the same time, it may be worth the risk of experimenting with an unproven treatment (cannabis) whose safety profile has been proven (though efficacy has not) for patients who have reached the “end of the line” with conventional epilepsy treatment.
Rosenberg E et al. Cannabinoids and Epilepsy. Neurotherapeutics DOI 10.1007/s13311-015-0375-5 (2015)
Detyniecki K and Hirsch L. Marijuana Use in Epilepsy: The Myth and the Reality. Curr Neurol Neurosci Rep (2015) 15:65
Massot-Tarrus A, McLachlan RS. Marijuana Use in Adults Admitted to a Canadian Epilepsy Monitoring Unit. Epilepsy Behav. 2016 Oct;63:73-78. doi: 10.1016/j.yebeh.2016.08.002. Epub 2016 Aug 30.
Maa E and Figi P. The Case for Medical Marijuana in Epilepsy. Epilepsia, **(*):1–4, 2014 doi: 10.1111/epi.12610
Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 6. Art. No.: CD009270. DOI: 10.1002/14651858.CD009270.pub2.
Geffrey A et al. Drug-Drug Interaction Between Clobazam and Cannabidiol in Children with Refractory Epilepsy. Epilepsia, 56(8):1246–1251, 2015 doi: 10.1111/epi.13060