Editor's Choice

Seizure 2021, Vol 85, Editor’s Choice: Interaction of cannabidiol with other antiseizure medications: A narrative review

Given that the proportion of patients with epilepsy who achieve full control of their seizures has not changed much since the introduction of bromide in the 19th century, the interest in better antiseizure medicines (ASMs) – especially drugs using different modes of action that might complement the current epileptological armamentarium, remains high. Thankfully, there has been a steady supply of new ASMs. In the UK, lacosamide became available in 2008, perampanel in 2012, brivaracetam in 2016, cannabidiol (CBD) in 2018 and there is a good chance that fenfluramine will be licenced soon. In this sort of list, the introduction of cannabidiol seems routine and not extraordinary. It looks just like the sort of new ASM introduction which the world of epileptology has been used to. However, CBD is different from other ASMs in more ways than one:

For a start, it has a much longer history than the other compounds introduced as ASMs over recent years. Almost 5,000 years ago, the Chinese Emperor Fu Hsi described cannabis as having sacred yin (weak, passive forces) and yang (strong, active forces) features, suggesting that it might help to restore a healthy balance of these forces. Cannabis is mentioned in Sumerian text from the third millennium BC. In ancient times, physicians in India, Egypt, Persia, Rome, Arabia, and Greece used it as a medicine for a wide range of different ailments. More recently, two of the UK’s most prominent 19th century neurologists, J.R. Reynolds and W. R. Gowers confirmed the potential benefits of cannabis in epilepsy. However, since the beginning of the 20th century Cannabis has increasingly been regarded as a drug of abuse and fallen out of favour as a medicine (1). The potential to use cannabinoids as medicines increased with the identification of the main chemical constituents of cannabis from the 1960s onwards. This and an increasing understanding of the endocannabinoid system from the 1990s onwards enabled researchers to differentiate between compounds more closely associated with (largely unwanted) psychoactive effects (like Δ9-THC ) and molecules more likely to produce beneficial medical effects (like cannabidiol). Unlike Δ9-THC, CBD hardly binds to CBD-1 or CBD-2 receptors. Instead its effects are mediated through a range of different mechanisms (as an agonist at Transient Receptor Potential (TRP) channels, 5-hydroxytryptamine1α receptors, and glycine receptors and as an antagonist at TRP melastatin type-8 channels, T-type voltage-gated calcium channels, and G protein-coupled-receptor GPR55 (1).

A second important way in which CBD differs from other recently introduced ASMs (likely to be related to the first) is the great interest of patients with epilepsy and there families as well as society at large in this particular medicine. Not many clinicians will have been asked by patients or their families when they might finally be able to try lacosamide, perampanel or brivaracetam. In contrast, there has been considerable pressure on clinicians as well as politicians, licencing authorities, healthcare purchasers and insurers to make CBD available to patients with epilepsy. Even more than two years after CBD could first be prescribed in the UK, patients and families seem to have much higher expectations of this drug than of any other ASM.

A third way in which CBD differs from other recently developed ASMs (related to first and second) is that CBD has a much greater potential for drug interactions than the much newer compounds. In fact, CBD may well have failed the sort of preliminary interaction analyses pharmaceutical companies undertake when they decide which compounds to invest in.

The second and third differences between CBD and other recently introduced ASMs are the most important reasons why I have chosen the narrative review by Christopher George Sean Gilmartin et al. as my Editor’s Choice from the current volume of Seizure (2). Their review demonstrates the potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. Last but not least, an animal study showed that brain concentrations of other ASMs may be changed by CBD while the serum concentration remains the same. Of course, not all pharmacological interactions between medicines are clinically relevant. However, experience with the combination of CBD with many other ASMs is still limited, so it is important to be vigilant – especially as the high expectations patients and their families have of CBD may lead them to tolerate side effects they would not accept if they were related to other drugs.

References

(1) Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics 2015;12:747-768.

(2) Gilmartin CGS, Dowd Z, Parker APJ, Harijan P. Interaction of cannabidiol with other antiseizure medications: a narrative review. Seizure 2021; 86: 189-196