1.5.1 Epilepsy
For cases of intractable seizures such as Dravet syndrome,
Lennox-Gastaut syndrome and tuberous sclerosis complex, the use of CBD
(branded as Epidiolex) was approved in 2018 and 2019 by FDA and the
European Medicines Agency, respectively.
Epilepsy is a neurological disorder that affects people of all ages; it
is a chronic disorder of the brain characterized by convulsive crises
with events of hyperactivation and synchronization of groups of neurons
that lead to motor, sensory, autonomic, and behavioral alterations
[97]. Roughly 50 million people worldwide have epilepsy, making it
one of the most common neurological disorders in the world, and
approximately 30% of patients are affected by treatment-resistant
epilepsy due to the failure of common antiepileptic therapies [98,
99].
With the advance in the
understanding of neurotransmitter systems in recent years, it has been
accepted that the break in the balance between excitatory and inhibitory
neurotransmitter systems may underlie the triggering of epileptic
disorders. However, a precise relationship between such neural systems
and the characteristics of epileptiform syndromes has not yet been
established [30].
Many epilepsy induction models have been used to study the antiepileptic
properties of CBD [100-104]. Broadly, both antiepileptogenic effects
with CB1 and CB2 receptor agonists and pro-epileptogenic effects using
blockers of these receptors in temporal lobe models of epilepsy have
been observed [62, 105-107].
In fact, there is evidence that the ES participates in seizure control
mechanisms in developing animals through the CB1 receptor [108]. In
preclinical seizure models, the anticonvulsant effect has been related
to a pharmacological increase in endocannabinoid levels, and AEA and
2-AG are released after neuronal hyperexcitability to combat glutamate
excitotoxicity during seizures [36, 107, 109, 110]. Nonetheless,
according to Schlicker and Kathmann [111] and Alger [112], many
axon terminals of the CNS express CB1 receptors with the function of
inhibiting the release of excitatory and inhibitory neurotransmitters.
A recent review by Bilbao and Spanagel [113] showed that CBD has a
significant therapeutic effect (high grade) for epilepsy. Regarding the
effects of CBD in epilepsy, it is not yet clear how it exerts its action
(a summary of this mechanism was shown in figure 2). However, it has
been proposed that the anticonvulsant action of CBD is exerted through
several mechanisms independently of CB1 receptors [114], instead
including the effects on 5-HT1A receptors, vanilloid
TRPV1 receptors, N-metil D-Aspartat receptors (NMDA), GPR55 receptors,
Ca++ flux regulation, increased adenosine signaling,
and interaction with GABAergic receptors [36, 101, 103, 115-122]. In
addition to the anticonvulsant potential of CBD [103, 123], a
neuroprotective effect has been proposed, restoring hippocampal
interneuron functions in a temporal lobe epilepsy model [124-126].
Fig. 2 . Diagram of interactions and therapeutic effects of CBD
in epilepsy
It is noteworthy that other compounds derived from Cannabis are being
studied, with emphasis on CBDV, which has shown anticonvulsant results,
and future analyses may better identify its potential for epilepsy
treatment [116, 127, 128]. In summary, several well-designed trials
have shown the effectiveness of cannabinoids in controlling epileptic
seizures (Table 1). This review presents some studies using CBD,
preferably randomized, double-blind, placebo-controlled clinical trials.
Serious adverse effects are relatively rare, with somnolence, decreased
appetite, and diarrhea being common. However, the use of concomitant
medications such as clobazam and sodium valproate has been associated
with somnolence and elevated liver enzymes [99, 129, 130].
Currently, CBD can be considered a reasonable treatment for several
types of refractory epilepsy, with a favorable profile of adverse events
and prolonged and sustained efficacy. However, it is necessary to be
careful that these results, which have been demonstrating safety and
efficacy, do not extrapolate to other formulations that lack rigorous
standards of production and purity; nevertheless, there is more to learn
and less to fear with CBD as a treatment for epilepsy [129].
Table 1. Preclinical and
clinical evidence using Cannabis derivatives in epilepsy models and
patients.
It is important to consider that in addition to pediatric epilepsies,
people over 65 years of age can be diagnosed with epilepsy
(cryptogenic), underlying seizures resulting mainly from
neurodegenerative diseases and also from traumatic brain injury,
cerebrovascular diseases and brain tumors. Therefore, in the context of
neurodegenerative diseases, epilepsy has been highlighted, including in
the search for evaluative procedures for early diagnosis and
intervention in elderly people with initial seizures.[19].