http://practicalneurology.com/2018/10/cannabis-cannabidiol-and-epilepsy
The endocannabinoid system, which may play a role in
epileptogenesis, includes 2 G-protein coupled receptors (cannabinoid type 1
[CB1] and cannabinoid type 2 [CB2]) and 2 endogenously synthesized,
lipid-signaling endocannabinoids (anandamide [N-arachidonyl ethanolamide] and
2-arachidonoyl glycerol [2-AG]) that bind to CB1 and CB2. A presynaptic
receptor, CB1 is highly expressed in the hippocampus, amygdala, cingulate,
cerebral cortex, basal ganglia, midbrain, and medulla. Therapeutic effects of
CB1 binding are via modulation of neurotransmitter release, including dopamine,
GABA, glutamine, serotonin, norepinephrine, and acetylcholine. Concentrated in
peripheral immune tissues (i.e. spleen, bone marrow, B-cells, macrophages), CB2
receptors have limited expression in the brainstem and hippocampus. In the
context of seizures and epilepsy, although it seems CB1 would be a likely
target, that does not appear to be the case.
Cannabis contains more than 100 unique compounds called
phytocannabinoids, which are quite similar to lipophilic
endocannabinoids—differentiated only by the origin of synthesis (ie, plants).
The 2 primary phytocannabinoids are THC and CBD. A direct agonist of the CB1 and CB2 receptors,
the psychoactive effect of THC is secondary CB1 activation. There are mixed
reports of seizure treatment success and seizure exacerbation. Unlike THC, CBD does not directly agonize CB1
receptors and subsequently is not psychoactive. Some believe this is a benefit
as it may have less potential for abuse. CBD’s mechanism of action is not fully
elucidated yet and appears to be related to its effects on serotonergic and
GABAergic activity, intracellular calcium modulation, and potential
anti-inflammatory effects. CBD is highly lipophilic and becomes distributed in
the brain rapidly.
Much remains to be ascertained regarding cannabis and its
precise mechanism(s) of action in epilepsy. Evidence suggests that in addition
to THC and CBD other components of cannabis may have anticonvulsant properties
(eg, δ-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV],
δ-8-tetrahydrocannabinol [δ-8-THC], and cannabinol [CBN].4 Only time and
additional scientific effort will help discern their potential as medications…
A large analysis of expanded access to pharmaceutical-grade
CBD included 607 patients and 25 institutions. Of these patients, 76% continued treatment at
a mean of 48 weeks. Of those who discontinued therapy, 15% withdrew because of
lack of efficacy and 5% withdrew due to adverse effects. With adjunctive CBD
therapy, the number of median monthly convulsive seizures was reduced by 51% at
12 weeks and this was largely sustained through 96 weeks. Likewise, the total
number of seizures per month was reduced by 48% at 12 weeks and similarly
sustained through 96 weeks.11
Many other studies examining both artisanal and
pharmaceutical-grade CBD show efficacy in patients with LGS, DS, and convulsive
and atonic type seizures . Current data
strongly support that pharmaceutical-grade CBD is efficacious for seizures
classified as convulsive or drop type. Data are lacking for nonconvulsive
seizures, which are more difficult to quantify; the studies discussed in this
article were not designed to assess this endpoint….
In the study that included 607 patients at 25 centers, 88%
experienced some sort of side effect.11 Severe side effects were reported in
33% of patients, the most common being convulsion (9%), status epilepticus
(7%), pneumonia (5%), and vomiting (3%). Milder side effects included
somnolence, fatigue, diarrhea, and reduced appetite. Other reports validate these findings and
report statistically significant instances of somnolence, decreased appetite,
fatigue, and diarrhea in patients receiving pharmaceutical-grade CBD. More
specifically, somnolence occurred in 22% to 36% of patients, diarrhea in 29% to
31%, decreased appetite in 20% to 28%, and fatigue in 20% to 22%. Other notable side effects include convulsion,
respiratory tract infections, weight loss, status epilepticus, irritability,
and pyrexia, which appear to be dose-related and can be therapy-limiting.
Hepatotoxicity has emerged as an adverse effect of CBD
treatment of particular concern. Many antiepileptic drugs (AEDs) carry some
risk of hepatotoxicity, but with a clear monitoring plan, this concern could be
reduced. The manufacturer of pharmaceutical-grade CBD recommends
discontinuation if liver function test (LFT) levels rise to 3 times the upper
limit of normal (ULN) and bilirubin levels are twice or more the ULN. If patients experience sustained LFT
elevation more than 5 times the ULN, CBD treatment should be discontinued.
Elevation of LFTs appears to be most common in the first 2 months of treatment
but has also been observed in later stages of treatment. Liver monitoring is
recommended at months 1, 3, and 6 after initiating treatment with
pharmaceutical-grade CBD or monthly after dose changes or addition of another
AED that interacts with CBD.
The hepatotoxicity risk of pharmaceutical-grade CBD appears
to be more common if there is polypharmacy with valproic acid products or
clobazam, although LFT elevation has also been shown to occur without these concomitant
drugs. Some have postulated that
interaction with liver enzymes may contribute to the positive therapeutic
effects seen in clinical trials of pharmaceutical-grade CBD. There are several other pertinent interactions
to consider when implementing CBD treatment for patients with epilepsy. Varying
reports of alterations in serum concentration of rufinamide, topiramate,
zonisamide, and eslicarbazepine have also been noted. Topiramate and rufinamide
both appear to have dose-related increases in serum concentrations in the
presence of CBD whereas the serum increases of zonisamide and eslicarbazepine
were present to a lesser extent…
Cannabis and CBD have a long history of use for medical
purposes throughout human history. Until recently, standardized studies with
large datasets have been lacking. Now, with the change in social climate and
attitude towards the potential of cannabis and CBD, data are amassing to
provide much-needed insight into the practical application of CBD in patients
with seizures and epilepsy.
In patients with refractory epilepsy syndromes—especially in
those characterized by convulsive and “drop attack” seizures—CBD is a promising
adjunctive alternative treatment. More studies are needed to determine the
exact mechanism of therapeutic efficacy (ie direct antiepileptic target vs.
optimization of concomitant medications), but in the meantime appears to be
reasonably safe and efficacious.
Practitioners still must be cognizant of individual patient
factors because CBD is not a benign entity. Vigilance for concomitant
hepatotoxic antiepileptics, potential interactions, and side-effects must be
maintained and cost and variability between different formulations considered.
New options are on the horizon and expanding potential medical treatment with
CBD. Governmental acceptance of a CBD-based product is helping to open doors
for many families and patients with previously limited options. The CBD safety
and efficacy profiles combined with the great need for better treatment options
in refractory epilepsy make this a promising therapy for patients and
practitioners alike. We are likely experiencing the first among many therapies
to be derived from the cannabis plant in the coming years.
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