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].