Children with rare epilepsy disorders now have access to a purified cannabidiol (CBD)-based drug that can drastically reduce the number and severity of their seizures. But that doesn’t mean researchers know exactly how the drug works, or what sort of effect individual genetics plays on cannabis treatment for epilepsy in general.

The mechanism by which CBD — now prescribed as the FDA-approved Epidiolex — impacts the brain’s generation of seizures has been largely a mystery, though we know CBD can drastically reduce their occurrence in some cases.

The latest thinking is that CBD reduces seizures by adjusting neural oscillations that go out-of-whack because of either genetic mutations, epigenetic problems, physical head trauma or other hidden factors. Neural oscillations are just a measurement of the electricity humming through your brain and making it function; just like a light bulb or a smartphone, your brain circuits generate an electrical field measured in Hertz. CBD seems to modulate those electromagnetic oscillations, returning them to the roughly 40 Hz frequency seen in brains of healthy control populations. 

patient receiving an EEG to measure their epilepsy, which can be impacted by genetics and helped with cannabis
An electroencephalogram (EEG) is used to measure fluctuations in regionally specific brain-activity. Epileptic patients experience large, synchronous bursts in activity during a seizure.

That individual human genetic variation has a lot to do with how your body responds to cannabis seems clear. The question is, how do genetic variations in people with epilepsy affect how they handle cannabis-based medications and whether those medications are therapeutic. Genetic predisposition also may affect how quickly seizure patients develop a tolerance to therapeutic CBD, as about a third do.

In 2017, the European Journal of Drug Metabolism and Pharmacokinetics published a meta analysis of many of the known genetic mutations/instructions that govern cannabis response.

“Knowledge based on proteins and molecules involved in the transport, action, and metabolism of cannabinoids in the human organism leads us to predict candidate genes which variations are responsible for the presence of the therapeutic and side effects of medical marijuana and cannabinoid-based drugs,” the study states.

This schematic shows the known components of the human endocannabinoid system, their synthesis and breakdown. These processes are all governed by genes, and understanding how those genes build the ECS can lead to new drugs and other treatments. For a full description, visit the European Journal of Drug Metabolism and Pharmacokinetics, which provided this image.

What are the genetic factors influencing epilepsy?

Epilepsy — a general term for a constellation of different seizure disorders — is somewhat influenced by genetics, but not entirely. For instance, epilepsy diagnoses are more frequent among people who have a parent or sibling with epilepsy, but only by a few percentage points compared with the general population’s risk for epilepsy.

There are about 500 genes involved with a predisposition to epilepsy, and specific mutations are implicated in some forms of the disorder. But the picture is more complicated, even in conditions where a specific gene mutation is identified.

“The most common type of childhood epilepsy, juvenile myoclonic epilepsy (JME), tends to be inherited from family members but at least 50% of individuals with JME do not have mutations in genes associated with epilepsy,” writes Isabel Derara, a neuroscientist at Tufts University. “Epilepsy can also be caused by traumatic brain injury, infection, fevers and autoimmune disease, known as acquired epilepsy. In about 30% of all people, a cause for epilepsy cannot be identified.”

Fun fact: when the cause of a disease is unknown, it is dubbed “idiopathic”

Some of the risk for epilepsy may be epigenetic — that is, inherited, but not specifically linked to the contents of DNA. An epigenetic effect can usually be seen as “turning on” or “turning off” a gene that was inherited. These epigenetic problems in brain formation may be at least part of the explanation for the debilitating disorder. 

What do genetic factors for epilepsy have to do with cannabis?

Most exciting for epilepsy patients and cannabis researchers is that epilepsy may be linked directly to malfunctions in the endocannabinoid system that marijuana-based drugs could fix.

To figure this out, researchers secured a bunch of brains from dead people (i.e. post-mortem investigations) with and without epilepsy for a 2008 study published in the Journal of Neuroscience. Once they completed the unenviable task of chopping up the gray matter and sticking it under microscopes, they realized the epileptic brains had a severe dearth of CB1 receptors (one of the most important components of the endocannabinoid system) in the hippocampus.

brain staining shows that cannabis affects genetics for epilepsy because CB1 receptors are reduced
Immunostaining for CB1 cannabinoid receptor is reduced in the hippocampus of epileptic patients, particularly in the inner molecular layer of the dentate gyrus (DG).

The researchers linked this not to a specific gene, but to malfunctions in the mRNA, the molecular component that translates DNA’s building instructions into action.

Think of it this way: Your DNA is the architect, while your different types of RNA act as the building contractors. Even when the blueprint is perfect, you’re gonna get a crooked building if the contractor shows up drunk every day.

CB1 receptors are the openings on brain and neuron cell membranes that are built to receive endocannabinoid neurotransmitters produced naturally by your body. The endocannabinoid system uses these to help regulate your nervous system’s response to all sorts of stimuli, including, it seems, governing neural oscillations.

genetics could explain both why cannabis helps epilepsy by impacting the expression of CB1 receptors, which are reduced in epileptic patients
CB1 receptors are significantly reduced in individuals with epilepsy compared to normal, healthy controls. This could help explain why increasing CB1 activity (with cannabis)

The hippocampus is a little noodle-shaped chunk of brain meat that’s part of the limbic system, or your primitive “lizard brain”, and is most classically associated with our ability to process space, make, and retrieve memories. The limbic system as a whole, though, is where all your baseline functions originate, from hunger to fear to sexual desire– functions that rely, predominantly on subconscious and conscious memories. Interestingly enough, most seizures originate in the Medial Temporal Lobe (MTL), which is exactly where the hippocampus is located.

Such reasoning permits one to suggest that using CBD or other cannabinoids to flood the hippocampus just might help the epileptic brain keep functioning nominally, despite its missing CB1 receptors. The rationale would be that putting the depreciated system into overdrive may help it resemble a normal system.

Research has shown that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice according to a 2006 study published in Neuron— which also found that when you genetically reduce the number of CB1 receptors, mice show stronger seizures.

Did you know that a genetic blockade of CB1 receptors cam lead to epileptic discharges (Bernard et al., 2005)? It should come as no surprise that cannabis, genetics, and epilepsy are interrealted.

What are neural oscillations?

Your brain is a dense and complex electro-chemical circuit, and like all electrical circuits, it operates on a frequency. The chemical electricity coursing through your brain creates electromagnetic waves that repeat at a host of different frequencies– for example 40 hertz. That is, the circuit completes about 40 times per second, creating 40 uniform waves and troughs when measured on a chart. 

Neuroscientists call frequencies falling with the 30–80 Hz range Gamma waves, and many believe that mapping and altering brainwave frequencies may be the key to unlocking treatments for all sorts of neurological disorders and explanations for diverse brain phenomenon, including the Holy Grail: the mechanism of consciousness.

neural oscillations can rely on genetics and underlie the phenomenon of epilepsy

The functioning of the brain and how it might integrate consciousness and will with physiologic response and function is a murky area of science. Discussions about consciousness and the role these neural oscillations play often start with pure speculation and devolve into pop psychology, pseudoscience and philosophy.

Here we’re only concerned with neural oscillations as they affect people with epilepsy and if there is a basis in genetics. Wild swings from the standard 40hz neural oscillations in the human brain to much higher frequencies often happen before a seizure. Cannabis, specifically CBD, seems to reduce the number and severity of these frequency swings.

a brain about to seize has changes in neural oscillations, which can be altered with cannabis
Normal vs. Seizure EEG shows a dramatic change in the typical neural oscillations throughout the brain.

“The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis,” according to a 2019 article published on Intechopen.com, an open-source science reference site. “The endocannabinoid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in Cannabis a potential therapeutic option for patients with treatment-resistant epilepsy.”

One of the next steps in genetics research regarding epilepsy and CBD as a treatment will involve tracing how different humans process cannabinoids differently. Geneticists have already isolated a bundle of genes that may predispose someone to cannabis addiction.

Yes, you can get addicted to weed, though the social and health consequences of a cannabis habit tend to be far milder than from addiction to other drugs. You can find out if you have a genetic predisposition to marijuana use disorder (i.e. cannabis dependence) or cannabis-induced psychosis with Strain Genie’s Cannabis DNA Test.

It may be that people who are genetically predisposed to cannabis addiction have this tendency because their DNA makes them more receptive to lower doses of cannabis. Maybe a combination of these genes and genes causing epilepsy would make someone a prime candidate for CBD-based epilepsy therapy. But this remains speculative in the absence of further study.