Cannabidiol: A step in the right direction for treating epilepsy

Epilepsy is a common chronic neurological disorder that is characterized by sudden, uncontrolled electrical activity between neurons in the brain. These electrical disturbances typically manifest in the form of seizures which, in their mild forms, can go unnoticed, but in more severe cases can cause uncontrollable muscle twitches, loss of consciousness and, ultimately, memory loss. There are two classes of seizures: general, whole brain seizures and focal seizures, in which only a part of the brain is affected. Based on these two classes, additional seizure types are characterized by their severity and symptoms. 

The underlying cause of a seizure has many origins, some of which include high fever, infectious disease, lack of oxygen to the brain, genetics, or even a tumor. Individuals who are diagnosed with epilepsy, especially with refractory, drug-resistant forms, unfortunately experience a high level of risk and uncertainty in their daily activities and are unaware of when their next seizure will occur. In some cases, individuals diagnosed with the disorder may not be allowed to legally drive or even obtain their driver’s license for fear that the seizures are uncontrollable. Although there is no cure for epilepsy, medications known as antiepileptic drugs (AEDs) have been beneficial in reducing the frequency with which seizures occur; however, in some cases, these AEDs are inadequate. 

Lennox-Gastaut and Dravet syndromes are two rare forms of childhood epilepsy for which many basic AED treatments fail to mitigate their severity. Enter a little molecule called cannabidiol, also known as CBD, and what at first appears to be a bleak and hopeless situation suddenly offers reason for optimism.

In recent years, scientists and medical doctors have explored the therapeutic profile of CBD, a non-psychoactive derivative of the Cannabis plant, and have determined that the phytocannabinoid improves seizure control, even in patients with Lennox-Gastaut and Dravet syndromes. The seizure-reducing characteristics of CBD, which took the research and medical fields by storm, also led to its subsequent approval by the Food and Drug Administration for use as an anti-epileptic drug. CBD has changed the way epilepsy can be treated; yet, how CBD induces its remedial effect remains to be fully understood. 

Further studies of CBD have shown that it interacts with a liver enzyme system that is integral for drug metabolism, which partially explains why the compound is successful in reducing seizures. This system, called the cytochrome P450 pathway, consists of more than 50 different enzymes that are essential for the production of things like cholesterol and steroids, as well as the breakdown of foreign chemicals and drugs. Certain medications and foods can act as either “inducers” or “inhibitors” of the enzymatic activity in this pathway, which can result in drug-drug interactions that could cause adverse reactions, if not monitored properly. 

If a drug is considered an enzyme “inducer,” it will enhance or increase the rate at which another drug is metabolized in the body, subsequently stunting that drug’s therapeutic profile. As a hypothetical example, let’s say a patient is prescribed the AEDs carbamazepine and clobazam. Carbamazepine is a common AED that is known to augment the activity of enzyme(s) in the P450 pathway, especially those that metabolize clobazam. Since carbamazepine is considered an inducer, if it taken in conjunction with clobazam, it could lead to the rapid metabolism and elimination of clobazam from the body. Because clobazam is prescribed to reduce the frequency of seizures, its absence could lead to a worsening of seizure activity. 

On the flip side, if a drug is considered an enzyme “inhibitor,” it will reduce or slow down the rate in which another drug is broken down and eliminated from the body. As another hypothetical example, let’s say a patient is prescribed the AEDs stiripentol and clobazam. Stiripentol is a common AED that is known to curtail the activity of enzyme(s) within the P450 pathway, even those that metabolize clobazam. In this scenario, we would see a decrease in metabolic activity associated with the enzyme(s) that break down clobazam. This would result in increased blood plasma levels of the latter AED, which could extend the efficacy of the clobazam treatment. With enzyme inhibition, the therapeutic influence of an AED can be prolonged; however, this is still something that needs to be monitored, since levels of the impacted AED could reach toxic levels and have a negative effect.

So back to our original question: how exactly does CBD reduce seizures, and how does it interact with the cytochrome P450 pathway? Well, studies suggest that CBD acts as an enzyme “inhibitor” which, when taken concomitantly with certain AEDs, will lengthen the active state and therapeutic profile of the AED being used. 

CBD’s inhibitory properties were discovered in a study by the Pediatric Epilepsy Program at Massachusetts General Hospital. By measuring blood plasma levels in children with refractory epilepsy who had been taking clobazam to manage their condition, researchers found that the addition of CBD led to a significant increase in clobazam metabolites in all but one of the patients in only a matter of one week. Over time, this treatment allowed the children’s doctors to reduce the dose of clobazam being used without there being any negative side effects (i.e., an increase in seizures). In addition, all the participants experienced more than a 50% reduction in seizures.

Although CBD treatment appears to be safe and effective and these results have been replicated in subsequent studies, many medical professionals advise against patients solely using CBD to treat their epilepsy. Abrupt termination of the original AED treatment, they say, could lead to negative side effects.

Beyond influencing the metabolism and elimination of certain AEDs via the cytochrome P450 pathway, additional mechanisms by which CBD exerts its therapeutic and anti-epileptic effects are currently being explored. One of the leading institutions for this specific field of research just so happens to be Indiana University Bloomington! For years, the Program in Neuroscience and Department of Psychological & Brain Sciences have been hubs for cannabinoid research which, collectively, have been an important player in the study of cannabinoid pharmacology. With CBD and other Cannabis derivatives showing up on the market, it is important that we continue to study what they do and how they work.

While there is still much to be uncovered about how CBD elicits its therapeutic effect, it has been repeatedly proven to help those struggling to maintain control of their seizures and, thus, has revolutionized the way epilepsy can be treated and has positively changed the lives of so many in a short period of time. 

Acknowledgements:

I would like to thank my sister Gensyn Bosquez, whose strength in living with epilepsy and willingness to try CBD as a treatment inspired this post.

References:

Geffrey, A. L., Pollack, S. F., Bruno, P. L., & Thiele, E. A. (2015). Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia, 56(8), 1246–1251. https://doi.org/10.1111/epi.13060

Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W. G., Martinez-Orgado, J., Robson, P. J., Rohrback, B. G., Thiele, E., Whalley, B., & Friedman, D. (2014). Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6), 791–802. https://doi.org/10.1111/epi.12631

Landmark, C. J., & Brandl, U. (2020). Pharmacology and drug interactions of cannabinoids. Epileptic disorders : international epilepsy journal with videotape, 22(S1), 16–22. https://doi.org/10.1684/epd.2019.1123

Lynch, T., & Price, A. (2007). The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American family physician, 76 3, 391-6.

Edited by Liz Rosdeitcher and JiHae Koo