Clinical Neurology and Neurosurgery 227 (2023) 107638

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Second-line cannabis therapy in patients with epilepsy

Erica Braun e, Francesca M. Gualano b, *, Prabha Siddarth c, Eric Segal a, b, d
a
Hackensack University Medical Center, Hackensack, NJ 07601, USA
b
Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
c
Semel Institute for Neuroscience and Human Behavior, School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA
d
Northeast Regional Epilepsy Group, Hackensack, NJ 07601, USA
e
Joseph M. Sanzari Children’s Hospital, Hackensack, NJ 07601, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe
Seizure and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (EpidiolexⓇ) was approved by the FDA in 2018 for
Drug-Resistant Epilepsy the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for
Medication-Refractory Epilepsy
tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a
Marijuana-Based Therapy
Marijuana
previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation
Cannabidiol of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also
investigated the clinical impact that a second MBT has on side effect profile.
Methods: We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2
different formulations of MBT, including a pharmacologic formulation of CBD (EpidiolexⓇ), artisanal marijuana,
and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however,
subjects’ historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data
on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects.
Seizure frequency, side effect profiles, and predictors of responder status were evaluated.
Results: Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure
frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4).
However, we did find that patients with greater baseline seizure frequency were significantly more likely to
respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that
patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to
those who did not (p = .04).
Conclusion: We found no significant seizure frequency reduction from baseline to after a second MBT in patients
who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction
with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings
need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative
MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative
class of therapy.

1. Introduction
Inadequate seizure control is still common in patients with drug-
resistant epilepsy (DRE). Traditional anti-seizure medications (ASMs)
can often cause severe adverse effects, and therefore there continues to
be a growing interest in marijuana-based therapy (MBT) products to
help treat epilepsy [1,2]. Following several major placebo-controlled
randomized trials, pharmaceutical-grade cannabidiol (CBD) was
approved by the FDA in June 2018 for seizure control in patients greater
than 2 years of age with Dravet Syndrome (DS) or Lennox-Gastaut
Syndrome (LGS). In patients with these drug-resistant epilepsies
(DREs), MBT has been shown to offer significant reduction in seizure
frequency [3].
Several randomized clinical trials have explored the risk and benefits
associated with MBT; however, there is limited research exploring the
clinical benefit of trying a different MBT formulation(s) after a first is

* Correspondence to: Hackensack Meridian School of Medicine, 123 Metro Blvd., Nutley, NJ 07110, USA.
E-mail address: francesca.gualano@hmhn.org (F.M. Gualano).

https://doi.org/10.1016/j.clineuro.2023.107638
Received 6 January 2023; Received in revised form 6 February 2023; Accepted 19 February 2023
Available online 21 February 2023
0303-8467/© 2023 Elsevier B.V. All rights reserved.
E. Braun et al. Clinical Neurology and Neurosurgery 227 (2023) 107638

tried. Artisanal MBT encompasses all other non-pharmaceutical-grade Table 1

MBT, including medical marijuana, hemp oils, and other Patient Demographics.
commercially-available MBT products. Hemp is defined under the 2018 Total Number of Patients 30
Farm Bill to include any cannabis plant, or derivative thereof, that
Sex
contains not more than 0.3% delta-9 tetrahydrocannabinol ("THC”) on a Male 16
dry-weight basis [4]. Female 14
In this retrospective study, we reviewed the response to a second Seizure Type
MBT after a first was already tried. Specifically, we studied efficacy rates Generalized Only 21
Focal Only 5
in patients taking artisanal products, pharmaceutical-grade MBT, and Generalized and Focal 4
hemp. The goal of this study was to determine if utilization of different Seizure Syndrome
MBT formulations would be effective after a first is tried. Lennox-Gastaut Syndrome 16
Dravet Syndrome 1
Aicardi Syndrome 1
2. Materials and methods
No Syndrome, Focal Epilepsy 2
No Syndrome, Mixed Epilepsy 1
The Local Institutional Review Board at White Plains Hospital No Syndrome, Generalized Tonic-Clonic Seizures 7
waived the need for informed consent for the collection, analysis, and Static Encephalopathy 1
publication of the retrospectively obtained and anonymized data for this Infantile Spasm 1
Age at Seizure Onset, Median (IQR), Range (Years) 0.75 (3.75), 0–24
non-interventional study (Protocol no. MMP-001; approved on 20 Age at First MBT, Median (IQR), Range (Years) 10.0 (10.0), 0.25–35
August 2020). Time-to-Treat, Median (IQR), Range (Years) 7.5 (13.4), 0–29.25
Average Number of AEDs Used Prior to First MBT, 2.8 (1.4), (0–6)
2.1. Study participants Mean (SD), Range
Most Common Prior AEDs Levetiracetam (N = 13)
Divalproex Sodium (N
We queried the electronic medical records (EMR) at our center for = 9)
patients with epilepsy as a primary diagnosis and who used at least 2 Clobazam (N = 8)
marijuana-based preparations (pharmaceutical-grade MBT, artisanal Rufinamide (N = 7)
marijuana, or hemp). Demographic information (age, sex), type of epi­ Clonazepam (N = 7)
Lamotrigine (N = 6)
lepsy, history of epilepsy, medication history, seizure count, and drug Abbreviations
side effects were collected for each patient included in the study. In­ SD Standard Deviation
clusion criteria were: (1) patients with a diagnosis of DRE; (2) age of at MBT Marijuana-Based
least 2 years; and (3) patients prescribed pharmaceutical-grade CBD Therapy
AEDs Antiepileptic Drugs
(EpidiolexⓇ) or who were using artisanal MBT. The exclusion criterion
IQR Interquartile Range
was systemic illness, specifically patients with any other clinically un­
related systemic illness(s) that, in the investigators’ opinions, could have
influenced the measured outcome. used logistic regression models to examine predictors of this categorical
response. All analyses were conducted using SAS 9.4 (SAS Institute,
2.2. Statistical analysis Cary, NC) and significance was set at p < .05 for all inferences, so as to
avoid loss of findings due to over-correction, since this was an explor­
Demographic measures (age, sex, seizure type, seizure syndrome, atory pilot study.
age of seizure onset, time to treatment) of all participants were described
using medians and interquartile ranges (IQR) or frequencies (Table 1). 3. Results
Average weekly seizure frequency over the 3 months immediately pre­
ceding the first MBT was taken to be the baseline seizure frequency. After the initial chart review, 30 patients were identified and met
Average weekly seizure frequencies after the first MBT and the second criteria to be included. Sixteen of these patients were males. The median
MBT were calculated using the number of seizures during the 3 months age at the time of first MBT was 10.0 (IQR=10.0) years (range: 0.25–35
after starting MBT (if the patient was on a specific MBT for less than 3 years). Table 1 further details patient demographics. Within this patient
months, then the weekly frequency was calculated for however long the population, 21 patients had generalized seizures, 5 had focal seizures,
patient was on the MBT within the timeframe of 3 months). To note, and 4 had mixed seizure semiologies. A genetic etiology was known for 1
during these three months, there were no changes to or additions of patient with Dravet Syndrome, with genetic and/or structural etiologies
other antiseizure medications. Also, since the raw seizure frequencies for the 1 patient with Aicardi syndrome and the 16 patients with Lennox-
did not have a normal distribution, seizure frequencies were log- Gastaut syndrome. Twenty-two patients (73.3%) experienced no side
transformed prior to all analyses, to ensure that the assumptions for effects after the first MBT, and 26 (86.7%) experienced no side effects
parametric tests were satisfied. We first examined whether the seizure after the second MBT. For the first MBT, 10 patients started with
frequencies were associated with any of the demographic measures pharmaceutical-grade CBD (EpidiolexⓇ), 8 patients started with arti­
using correlations (for age, age of seizure onset, time to treatment), t- sanal marijuana (through their state’s medical marijuana program), and
tests (sex), and ANOVAs (seizure type, seizure syndrome). We then used 12 patients started with a hemp product. For the second MBT, 17 pa­
mixed linear models to examine whether there was significant change in tients took pharmaceutical-grade CBD (EpidiolexⓇ), 7 took artisanal
seizure frequencies from baseline to the first and then to the second marijuana, and 6 took a hemp product. Furthermore, patients took on
MBT, controlling for covariates identified as above. average 2.8 (mean 2.8 (SD 1.4)) antiseizure medications prior to the first
Further, we examined predictors of seizure frequencies at baseline, cannabidiol treatment. Seizure frequencies per week (median (IQR),
first MBT, and second MBT, with general linear models, using the var­ range) prior to patients starting any MBT, following the first MBT, and
iables identified from the univariate models. In addition, for modeling after the second MBT are presented in Table 2.
seizure frequencies after the first and the second MBT, seizure fre­ At baseline, the seizure frequency (log-transformed) was signifi­
quencies at the previous time points were used as additional predictors. cantly greater for generalized seizures than for focal seizures (mean 2.5
We also classified participants as responders (based on the standard (SD 1.7) vs. 1.4 (0.9), t(28) = 2.35, p = .03) and correlated negatively
definitions of participants with ≥50% reduction in seizure frequency) or with age (r = − .36, p =.05). Seizure frequency after the first MBT was
non-responders (those with <50% reduction in seizure frequency), and

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E. Braun et al. Clinical Neurology and Neurosurgery 227 (2023) 107638

Table 2 4. Discussion
Seizure Frequency Per Week: Prior to Patient Starting MBT; Following First
MBT; and Following Second MBT. Whilst the efficacy of CBD for drug-resistant epilepsy (DRE) was once
Timepoint N Median IQR Minimum Maximum predominantly anecdotal, a number of studies have emerged that
Prior to MBT 30 5.6 27 0.25 212.5
demonstrate the empirical benefit of prescribing it. This is particularly
1st MBT 30 4.4 24 0 563.8 true in cases of Dravet Syndrome and Lennox-Gastaut Syndrome, where
2nd MBT 30 3.4 20 0 401.6 studies suggest the clinical advantage of adding CBD to a therapeutic
MBT = Marijuana-based therapy
regimen in patients suffering from DRE [3]. Treatment of DRE with
cannabidiol products is becoming a more pervasive alternative, given
both the anecdotal and empirical support for its use. For example,
very strongly associated with baseline seizure frequency (slope =.85, t
Massot-Tarrús and McLachlan found that patients with the disease
= 4.85, p <.0001). Seizure frequency following the second MBT was
burden of refractory epilepsy who used marijuana eventually perceived
significantly associated with both baseline seizure frequency (slope
improvements in the control over their seizures [5]. However, to our
=.39, t = 2.68, p =.01) and seizure frequency following the first MBT
knowledge, there have been no studies investigating the efficacy of
(slope =.41, t = 3.10, p =.005). Mixed models indicated that seizure
trying more than one formulation of marijuana-based therapy (MBT). In
frequencies did not change significantly with time: that is, from baseline
instances where one formulation fails, presents financial barriers to a
to after the first MBT to after the second MBT (F(2,29) = 1.1, p = .4).
patient or family, or is discontinued for any given reason (including side
After controlling for baseline seizure frequency, age, and seizure type,
effects), will trying more than one formulation of MBT be clinically
seizure frequencies did not change significantly from ‘after the first
effective, or even prudent, in the course of care? To this question, we
MBT’ to ‘after the second MBT’ (F(1,26) = 0.1, p = .7).
assessed the utility in prescribing patients with DRE a second MBT
Although we did not find significant changes in seizure frequency
formulation after a first had already been tried.
after the first and/or second MBT compared to baseline, we did find that
The two primary endpoints included: (1) seizure frequency reduction
seizure frequency after the second MBT was significantly associated with
and (2) side effect profiles in patients. Seizure frequencies did not
the presence of side effects. Patients who experienced side effects had
change significantly with time (i.e. from baseline to after the first and to
greater seizure frequency (2.5 (0.31)) after the second MBT compared to
after the second MBT). Regarding our second endpoint, patients who
those who did not experience side effects (1.7 (0.19), t(26) = 2.22, p =
experienced side effects were significantly more likely to have also
.04). The patient’s sex and the type of MBT treatment had no significant
experienced greater seizure frequencies after the second MBT. This
effect upon seizure frequency. Moreover, we found no effect of the type
correlation may suggest that patients with greater seizure frequencies,
of MBT on seizure frequency after the second MBT.
and thus a higher disease burden overall, were perhaps more susceptible
Table 3 denotes responders and non-responders after the first and
to developing side effects. It is unclear if the side effects themselves
second MBT. Overall, we found that of the 18 patients who were non-
somehow became a trigger that exacerbated seizure frequency.
responders after the first MBT, 15 remained non-responders following
We also found that of the 30 subjects in the study, 12 were classified
the second MBT. Of the 12 patients who were responders after the first
as responders after the first MBT; nevertheless, they went on to try a
MBT, 7 were non-responders after the second MBT. We found that first
second MBT therapy. This may have been for a number of reasons,
and second responder statuses were not associated with each other
including change of preference, financial barriers to a specific product, a
(Fisher’s exact test, p = .2). Also, while no variables were associated
new product becoming available, or a decreased response after three
with responder status after the first MBT, baseline seizure frequency was
months of using a product. Moreover, one cannabis product may have
a significant predictor associated with responder status after the second
been chosen at one time point over another for reasons including: in­
MBT: patients with greater baseline seizure frequency were significantly
surance; authorization challenges, as in the case of pharmaceutical-
more likely to respond to treatment after the second MBT (OR = 2.6,
grade cannabidiol, especially for off-label use (i.e. in patients with an
95% CI 1.1–6.2, p = .03).
epilepsy etiology that did not include Dravet Syndrome, Lennox-Gastaut
Furthermore, it is important to clarify why some individuals who
Syndrome, or Tuberous Sclerosus Complex); higher THC concentrations
responded to the first MBT discontinued it and began a different MBT.
in certain artisanal formulations being preferable to some practitioners
This was not necessarily due to side effects, but included reasons such as
and families; and shorter wait times to start treatment with hemp
financial constraints and accumulating costs to families that could not be
products versus pharmaceutical-grade marijuana.
overcome. Therefore, despite one formulation being effective and
Also, it is important to note that we captured seizure frequency
satisfactory for a patient, that product may have been discontinued due
within the first three months of starting a product. For example, a pa­
to financial limitations to costs that accumulated over time. Also, in
tient may have stopped responding at some time after the first 3 months
some patients, side effects to a formulation did serve as a reason for
of use (i.e. at 5 months of use), and an alternative, second MBT product
changing to a different MBT, even if that MBT proved effective for a
was started. Of note, no variables predicted responder status after the
patient. These side effects included: lethargy; gastrointestinal distress;
first MBT; however, a higher baseline seizure frequency significantly
hyperactivity; weight loss; weight gain; transaminitis; dehydration; and
predicted a greater response to treatment after the second MBT. While
increased seizure frequency. Twelve patients experienced side effects
the reason for this is unclear, we hypothesize that with a higher number
that necessitated an alteration to their treatment or a discontinuation of
of baseline seizures to start, the chance of finding a statistically signif­
their treatment with these products.
icant change in seizure frequency in 3 months of treatment is more likely
than it would be in a population of patients with lower baseline seizure
frequency. Patients with a higher baseline seizure frequency may also
Table 3
have a clinical diagnosis that corresponds with an epileptic encepha­
The Number of Responders After First and Second MBT.
lopathy, such as patients with Dravet Syndrome or Lennox-Gastaut
2nd CBD Syndrome. Overall, the disease burden is higher, and so the likelihood
Response
of observing a statistically significant change in outcomes following an
Non-Responder Responder TOTAL intervention is generally greater. As we have seen, the efficacy of highly
1st CBD Response Non-Responder 15 3 18 purified cannabidiol (EpidiolexⓇ) in seizure frequency reduction has
Responder 7 5 12 been demonstrated in pivotal trials, specifically for the high-burden
TOTAL 22 8 30 etiologies of Dravet Syndrome and Lennox-Gastaut Syndrome [6,7].
MBT = Marijuana-based therapy Limitations of this study include the small sample size of 30 patients,

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E. Braun et al.
as well as the retrospective nature of the study. Given the exploratory
nature of the study, we set significance at p < .05 for all inferences, so as
to avoid loss of findings due to over-correction. Our findings should be
replicated in a future study with a larger sample size. Also, data was only
collected through one center’s EMR, which could have potentially
introduced bias to the results. A larger patient sample size would also
enable investigators to assess any differences that pharmaceutical-grade
versus artisanal versus hemp cannabidiol products may have upon
seizure frequency reduction in patients with DRE.
5. Conclusion
Patients with a higher baseline seizure frequency are significantly
more likely to respond to treatment after the second formulation of
marijuana-based therapy (MBT) tried; however, patients with drug-
resistant epilepsy who do not respond to a first MBT will likely not
respond to a second formulation in the same therapeutic class, and there
is not a significant seizure frequency reduction after the first or the
second MBT tried. Furthermore, our data suggests that patients with a
higher seizure frequency are significantly more likely to experience side
effects from MBT, particularly after the second MBT. Both of these re­
lationships require further study, but are points of intrigue as to which
patients are more likely to respond to therapy and/or experience side
effects from MBT, based upon seizure frequency.
CRediT authorship contribution statement
EB and FMG contributed to the conceptualization, data curation,
investigation, methodology, visualization, original draft writing, and
review and editing for this study. PS contributed to the formal analysis,
validation, and review and editing for this study. ES contributed to the
Clinical Neurology and Neurosurgery 227 (2023) 107638
conceptualization, data curation, investigation, methodology, project
administration, resources, supervision, validation, and review and
editing for this study.
Declaration of Competing Interest
Eric Segal, MD is a consultant for Neurelis, GW Pharmaceuticals,
Encoded Pharmaceuticals, Aquestive, and UCB. He is a speaker for
Neurelis, GW Pharmaceuticals, Lundbeck, Eisai, Aquestive, UCB, and
Novartis.
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