Doctors treating patients with epilepsy are increasingly confronted with a request
for “cannabis‐oil” instead of well‐studied and registered anti‐epileptic drugs (AEDs).
While the possible anti‐epileptic potential of cannabidoids has been known for decades,
beginning with the first reports of beneficial effects of cannabidiol (CBD) in animal
models of epilepsy 40 years ago, patients with epilepsy asking to be treated with
CBD is a development stemming from more recent years. CBD appears to be the most important
non‐intoxicating constituent of cannabis and is sold without prescription as an oil
solution in many jurisdictions at concentrations ranging typically from 1% to 5%.
There is an array of targets at which CBD has been demonstrated to interact that may
underlie its anti‐epileptic activity in seizure models, including inhibition of voltage‐gated
sodium channels, transient receptor potential (TRP) channels, calcium channels, glycine
receptors, and G‐protein‐coupled receptor‐55 (GPR55) that may also underlie its ability
to control neuroexcitability.1, 2, 3, 4, 5 Furthermore, CBD has been demonstrated
to interact with 5HT1A receptor controlled pathways in brain,6 an activity that has
been linked with certain types of epileptic activity.7
Evidence for the efficacy of CBD in humans was primarily based on case reports, or
open‐label1 and uncontrolled studies, and therefore, the scientific quality of the
data for CBD in the treatment of seizures was considered weak. However, recently,
two randomised placebo‐controlled and appropriately powered studies were performed
with CBD in patients with Lennox–Gastaut syndrome (LGS) and severe myoclonic epilepsy
of infancy, also known as Dravet syndrome (DS).8, 9 Both of these randomised placebo‐controlled
trials (RCTs), published in the New England Journal of Medicine (NEJM), met their
primary endpoint of comparative CBD efficacy, and in June 2018, this led to the FDA
approval of Epidiolex (CBD) for the treatment of seizures associated with these rare
and severely disabling epilepsy syndromes. Specifically, these studies showed that
in patients with LGS, 20 mg/kg/day CBD was able to induce a median percent reduction
in drop‐seizure frequency of 41.9% as compared to 17.2% in the placebo group, and
in paediatric patients with DS, treatment with CBD 20 mg/kg/day led to a reduction
in drop seizure frequency of 6.5% compared to 0.9% in the placebo group.8, 9
Devinsky et al, the same authors as the NEJM published studies pivotal to the CBD
listing, earlier published the results of an open‐label intervention trial in patients
with treatment‐resistant epilepsy on stable doses of antiepileptic drugs, also in
the NEJM.10, 11 This open label study showed a reduction in monthly motor seizures
of 36.5% after treatment with 2 to 5 to a maximum of 50 mg/kg/day of CBD.10 However,
this publication provoked some critical responses,12 related to the suggested interaction
between CBD and clobazam, an AED often used by paediatric patients with severe epilepsy
syndromes, and likely responsible for the observed reduction in motor seizures in
the open‐label trial. It is known that CBD has an inhibitory effect on CYP450 iso‐enzymes
CYP3A4 and CYP2C19, which are also involved in the metabolisation of clobazam. In
previous studies, CBD doses of 20 mg/kg/day had shown to increase the exposure of
the active metabolite of clobazam (N‐desmethylclobazam) with on average fivefold,
but with a range (90% CI) of twofold to sevenfold in children with refractory epilepsy
despite clobazam dose reductions13 and with threefold in adults with epilepsy (NCT02565108).14
Data from both the Devinsky open‐label and the randomised controlled trials in LGS
and DS patients show that, respectively, 52%, 49%, and 66% of the patients taking
CBD during the studies were taking clobazam as a concomitant antiepileptic drug. This
fact urged Tang et al to express their concern in a Letter to NEJM, referring to the
known drug‐drug interaction between clobazam and cannabidiol,15 supported by the aforementioned
increase of the active metabolite of clobazam in children with refractory epilepsy13
and to the acknowledged effect of clobazam on seizure frequency.16 In response, Devinsky
el al stated that “subgroup analyses” would not be appropriate in view of the small
sample size of the RCT in DS (n = 120), referring to a publication on statistics in
medicine published in NEJM and to an FDA guideline.17, 18 This is unusual considering
a PK substudy to investigate this specific fact was detailed in the http://clinicaltrials.gov
registration of this study, and an author of the Devinsky group was the senior author
of the 2015 manuscript detailing this very interaction.13
Further evidence that a drug‐drug interaction may have been responsible for the reduction
in seizure frequency was also pointed out to the NEJM based on other analyses. The
side effect profile of cannabidiol in the RCT with CBD in LGS showed that serious
adverse events (SAEs) occurred in 16% of CBD patients vs 5% of placebo patients.8
This pattern of (S)AEs was remarkably similar to the side effect profile of clobazam,
leading to the hypothesis that there must have been an important increase in clobazam
and N‐desmethylclobazam concentrations, which could have led to both the increase
in side effects due to clobazam, and the observed decrease in drop seizures among
the patients on clobazam. After being approached, NEJM replied in a response to the
submitting team of clinical pharmacologists that the point of a possible drug‐drug
interaction had already been made by others, referring to the letter by Tang et al,
and that they were not interested in publishing the manuscript. Ultimately, this observation
was made public in the form of an article published in Clinical Pharmacokinetics in
201819 as it was considered that this was a significant issue for clinicians, medicine
regulators, and payers to be aware of.
The authors of the NEJM papers did acknowledge the possibility of a drug‐drug interaction
between CBD and clobazam based on the results of the registration trials,12 but argued
that data showing a correlation between N‐desmethylclobazam metabolite and CBD concentrations
related to safety or efficacy outcomes were lacking. Surprisingly, GW Research Ltd
and Devinsky et al were also involved in the initiation of a trial about possible
drug‐drug interactions between CBD and clobazam (NCT02565108),14 that was noted in
their study protocol, completed in 2016 but which is not in the public domain.
Following the ongoing concerns raised about a drug‐drug interaction between CBD and
clobazam and Devinsky's various rebuttals, we still see an important issue that is
undervalued. Based on nonclinical studies, there is biological plausibility suggesting
that CBD could have anti‐epileptic effects.1, 2, 4, 5, 7, 20, 21, 22, 23 However,
we hypothesise that the reported effect of CBD on drop‐seizure frequency in the open‐label
trial and the RCTs of Devinsky et al8, 9, 10 could also be attributed solely to the
drug‐drug interaction with clobazam. To evaluate this hypothesis, we conducted clinical
trial simulations with emphasis on the pivotal trial in LGS. In the paper published
on page 380 in the current issue of BJCP, the results of this study are presented.
Through clinical trial simulations, for which we used the Devinsky et al NEJM 2018
paper and data available in the public domain, we demonstrate that the reduction in
seizure frequency observed in the CBD groups can be entirely explained by a drug‐drug
interaction with clobazam. We believe this has important implications for the use
of CBD as an anti‐epileptic drug, for the credibility of the NEJM papers and by extension
the FDA registration of Epidiolex. The lack of publication of the pharmacokinetic
data, which was part of the original trial, in NEJM and the apparent dismissal of
the strength of the concern by international pharmacologists writing directly to the
NEJM are also of significant concern.
We believe that one of the most important aspects of scientific research is the need
for objectivity and self‐critical investigation. And while cannabis itself and derived
cannabinoids have received a large amount of media attention,24, 25 it is of utmost
importance to be guided by appropriate rigorous data from unbiased trials instead
of the public opinion. As to the reasons why the NEJM decided to not even consider
publication of both the manuscript on the side effect profile of CBD that resembles
that of clobazam and of our clinical trial simulations we can only guess, but this
may be related to a diminished interest or understanding in pharmacology that can
also be observed globally.26 As clinical pharmacologists, we observe that this decreasing
interest leads to less familiarity with basic pharmacological phenomena such as common
CYP450 inhibition and drug‐drug interactions and thereby to important medical errors.
We should prevent that it also leads to registration of a drug that may actually not
be better than grapefruit juice and significantly more expensive.
COMPETING INTERESTS
There are no competing interests to declare.