The Journal of the Arkansas Medical Society Med Journal June 2019 Final | Page 16

crease five fold when CBD is added). It is notable
that 66% of patients in the CBD group were on
clobazam; it was uncertain if improvement in
seizure frequency was due to a direct action of
CBD or increased plasma level of the active me-
tabolite of clobazam. A multicenter, randomized,
double-blind, placebo-controlled trial (GWP-
CARE4) investigated the efficacy of CBD as add-
on therapy for drop seizures in patients (aged
2-55 years) with treatment-resistant Lennox-
Gastaut syndrome. 7 The median percentage re-
duction in monthly drop seizure frequency from
baseline was 43.9% (IQR −69.6 to −1.9) in the
CBD group and 21.8% (IQR −45.7 to 1.7) in the
placebo group. Adverse events were common
in patients treated with CBD occurring in 86%
(74/86), and 14% withdrew from the study due
to adverse effects with the most common being
diarrhea, somnolence, pyrexia, decreased ap-
petite, and vomiting. Twenty (16 with concurrent
use of valproate) patients experienced serum
transaminase elevation without concomitant
bilirubin elevation. Potential drug-drug interac-
tion, long-term safety, and efficacy were not ex-
amined in this study.
Smaller, uncontrolled studies and case re-
ports have suggested that CBD may be effective
in the treatment of other forms of drug-resistant
epilepsy and seizures such as tuberous sclero-
sis, febrile infection-related epilepsy syndrome
(FIRES), and Sturge-Weber syndrome.
In summary, a class 1 evidence of CBD as
an add-on therapy is now available in Dravet
syndrome and Lennox-Gastaut syndrome. How-
ever, clarification of the independent effects of
CBD and clobazam comedication effect needs
to be addressed. Controlled studies are required
to determine the effectiveness of CBD in new-
onset seizures, other epilepsy syndromes, and
refractory focal seizures. Controlled, randomized
trials have revealed that the actual reduction in
seizure frequency in response to CBD is com-
parable to that achieved in response to other
antiepileptic drugs, and have failed to achieve
the 80-85% responder rates in unblended, web-
based surveys based on parental reports. CBD is
far from a miracle cure, and it is of paramount
importance to have a reasonable expectation of
its usefulness as an antiepileptic medication. It is
also a misconception that CBD is free of adverse
effects, a claim attributed to its derivation from
a natural source. Rather than spontaneous treat-
ment without medical supervision, adequate
medical oversight is indicated to monitor and
manage adequate dose, side effects, the validity
of the product, and drug-drug interaction.
Many parents continue to purchase CBD
products from local growers or online. Many
of these products are without quality validation
and may have contents significantly different
from that stated on the label. Furthermore, many
parents do not pay attention to the CBD concen-
tration of the purchased product or comprehend
that a very dilute solution is unlikely to provide
a therapeutic effect. One report described two
children with symptoms concerning for THC in-
toxication and seizure exacerbation with a reso-
lution of symptoms after switching from a “CBD-
enriched cannabis extract” to a purified CBD for-
mulation. 8 Well-standardized formulations with
fixed high-CBD and low-THC concentrations
should be preferred for treatment of epilepsy.
It is essential that formulations have a very low
THC content, as the antiseizure activity of THC
is equivocal and can potentially aggravate sei-
zures; moreover, it can be associated with addic-
tion liability, psychiatric disorders, cognitive and
motor impairments, and cardiovascular toxicity.
The adverse effects of THC can be more prob-
lematic in the immature brain with impairment
of structural and functional connectivity. Ad-
equate safety data for young children exposed
to CBD, and safety of use during pregnancy, are
needed in the future. Evolving legislation and the
increased use of cannabinoid products with little
or no regulation and medical oversight may in-
crease the risk of accidental ingestion, increased
emergency room visits, and increased call vol-
umes at Poison Control Centers. Strict regulation
in manufacturing, packaging, and labeling should
be absolutely warranted in order to ensure safe
administration. Yet, in many cases, unregulated
products may be marketed and sold in a number
of venues, including online orders via the inter-
net. The American Academy of Pediatrics has
recommended robust health surveillance; strict
enforcement of rules and regulations that limit
access, marketing, and advertising to youth; and
use of child-proof packaging to prevent acciden-
280 • THE JOURNAL OF THE ARKANSAS MEDICAL SOCIETY
tal ingestion and discourage adults from using
marijuana in the presence of children. 9
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