Results from a study published in the British Journal of Clinical Pharmacology may help explain why – a chemical component of marijuana with no psychoactive properties–reduces the frequency of seizures in patients with a severe form of epilepsy.
The effect may be explained by a drug-drug interaction between cannabidiol and the anti-seizure medication clobazam.
The form of epilepsy examined in the study is called Lennox-Gastaut syndrome.
Investigators conducted clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on seizure frequency in patients with this syndrome.
“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, antiepileptic effects,” said senior author Geert Jan Groeneveld, MD, PhD, of the Centre for Human Drug Research, in The Netherlands.
The form of epilepsy examined in the study is called Lennox-Gastaut syndrome.
Dr. Groeneveld also co-authored an accompanying editorial that highlights some of the shortcomings of past clinical trial analyses on cannabidiol’s effectiveness for reducing seizures.
Cannabis sativa L. is an ancient medicinal plant wherefrom over 100 cannabinoids are extracted [1].
Among them, the most studied are Δ9–tetrahydrocannabinol (Δ9–THC), a psychoactive compound, and the CBD, a non-psychotropic phytocannabinoid [2].
CBD is a cyclohexene which is substituted in position 1 by a methyl group, by a 2,6-dihydroxy-4-pentylphenyl group at position 3, and with a prop-1-en-2-yl group at position 4 (Figure 1).
Most cannabinoids exert their action by interacting with cannabinoid receptors, but CBD shows a low affinity for these receptors. Nevertheless, it affects the activity of other receptors such as serotonin receptors [5-HT], opioid receptors [ORs], and non-endocannabinoid G protein-coupled receptors (GPCRs) [3] and other targets (ion channels and enzymes).
In recent years, the scientific community has shown interest in this compound due to its good safety profile and neuroprotective properties [4] in several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis [5], Parkinson’s [6,7], Huntington’s [8] and Alzheimer’s diseases [9,10,11].
This neuroprotective action is due to its anti-inflammatory [12,13] and antioxidant [14,15] properties. CBD shows anti-inflammatory properties in several experimental studies, modulating some pro-inflammatory cytokines such as interleukin-1β (IL-1β ) [16], interleukin-6 (IL-6) [17,18] and tumor necrosis factor α (TNF-α) [16,18], as well as regulation of cell cycle and immune cells’ functions [19].
Furthermore, another mechanism by which CBD performs its anti-inflammatory action is mediated by interaction with the Transient Potential Vanilloid Receptor Type 1 (TRPV1). TRPV1 receptor is a nonselective cation channel that, when activated, allows the influx of Ca2+.
The sensitivity but also the density of TRPV1 is increased during neuro-inflammatory conditions. The binding of CBD to TRPV1 leads to a desensitization of these receptors, with a consequent reduction in inflammation [20].
The CBD also carry out a potent antioxidant activity, modulating the expression of inducible nitric oxide synthase and nitrotyrosine as well as reducing production of reactive oxygen species [21].
CBD is also generating interest due to its therapeutic properties such as antidepressant [22], antipsychotic [23], analgesic [24], and antitumor [25]. In addition, it has been shown that CBD can significantly reduce two important forms of anxiety, namely obsessive-compulsive disorder [26] and post-traumatic stress disorder [27,28].
Moreover, for a long time, the CBD has been investigated for its anticonvulsant effects [29,30,31].
Several studies confirmed its efficacy in the treatment of epileptic seizures, especially in pediatric age [32,33]. In 2016, the first results of phase III clinical trials showed beneficial effects of CBD (Epidiolex®; GW Pharmaceutical, Cambridge, UK) in treatment-resistant seizure disorders, including Lennox-Gastaut Syndrome (LGS) and Dravet syndromes (DS).
Epilepsy is a chronic neurological disorder. About 30% of epilepsy patients are affected by Treatment-Resistant Epilepsy (TRE) due to the failure of common anti-epileptic therapies [34]. This form of epilepsy is characterized by recurrent seizures that negatively affect the quality of life.
The purpose of this review is to provide an overview of recent clinical trials registered on ClinicalTrial.gov. These trials study the use of different CBD formulation in patients affected by severe forms of drug-resistant epilepsy. Moreover, we have described studies approved by local ethics committees published in PubMed.
Epilepsy
According to the World Health Organization, epilepsy affects more than 50 million people worldwide. Epilepsy is the most common neurological disorders characterized by recurrent seizures [35]. A “seizure” is a paroxysmal transient phenomenon determined by an abnormal excessive or synchronous neuronal activity in the brain [36].
Epilepsy can also cause deficit sensorimotor, cognitive, compromising quality of life and an increased risk of premature death [37]. The International League Against Epilepsy, according to the point of onset, classifies epileptic seizures into focal, generalized and unknown seizures [38].
Focal convulsions caused by an anomalous electrical activity in a circumscribed part of the brain and are classified into simple and complex.
Simple focal convulsions are characterized by motor, sensory and sensory manifestations without loss of consciousness.
On the contrary, complex focal convulsions involve a loss of consciousness [39]. Generalized seizures begin in one or more areas of the brain and can then spread to the entire brain.
Generalized seizures are divided into crises absences, characterized by a rapid and transient loss of consciousness; tonic crises that cause muscle stiffening; atonic crisis, characterized by loss of muscular control; clonic seizures that cause rhythmic muscle movements; myoclonic seizures, characterized by muscle contraction and localized tremors.
Finally, tonic-clonic seizures represent the most serious type of epileptic seizures, last about 5–10 min and are characterized by intense generalized contractions to the whole body [39,40].
The unknown seizures are called so when the beginning of a seizure is not known. These seizures can also be defined as “epileptic spasms” characterized by sudden extension or flexion of the limbs.
Is defined Secondary Epilepsy when the onset is caused by several factors such as head trauma, infectious diseases (meningitis, AIDS, viral encephalitis), developmental disorders, alcohol or drug abuse, and other pathological conditions (brain tumors, stroke).
The most well-known epilepsies are DS, Sturge-Weber Syndrome (SWS), Tuberous Sclerosis Complex (TSC) and West Syndrome (WS) and LGS. DS is a rare encephalopathy, which has its onset in the first year of life [41].
DS is associated with the mutation in the gene encoding the α1 subunit of the voltage gated sodium channel (SCN1A) [42]. SWS is caused by a somatic mutation of the GNAQ gene (9q21) that encodes the Gq protein, involved in the intracellular signal of several G protein-coupled receptors that control the function of various growth factors and vasoactive peptides [43].
Patients manifest neurological abnormalities of variousdegrees, focal epileptic seizures [44]. TSC is an autosomal dominant disease, caused by a mutation of two genes: TSC1 (localized on chromosome 9p34.3) that encodes for hamartin and TSC2 (localized on chromosome 16p13.3) that encodes for tubulin. Often TSC patients present generalized epilepsy.
WS or Infantile Spasm (IS) is the epileptic encephalopathy. This syndrome is characterized by genetic heterogeneity and the mutated gene most frequently observed in patients with this syndrome is CDKL5 (cyclin-dependent kinase-like 5) [45].
WS is characterized by the association between axial spasm discharges and psychomotor retardation [46]. LGS is a severe epileptic encephalopathy of childhood.
This syndrome is a rare condition likely associated with a genes mutation. Nevertheless, to date, it is quite unclear how the involved genes may cause this syndrome mainly characterized by recurrent seizures from early in life. An epileptic form that does not respond to therapy with at least two or three appropriately selected anti-epileptic drugs (AEDs) is defined as TRE and this is estimated to affect 30% of patients [47,48].
Common Antiepileptic Drugs
AEDs are the mainstay for the treatment of epilepsy and are intended to mitigate seizures. Epileptogenic discharges occur as a result of neuronal hyperexcitability caused by voltage-dependent ion channels and neurotransmitter concentrations alteration.
AEDs primarily act reducing neuronal excitability blocking excitatory neurotransmitter action such as glutamic acid and enhancing inhibitory neurotransmitters such as γ-aminobutyric acid (GABA).
Furthermore, the antiepileptic actions of most AEDs are due to the modulation of voltage-gated ion channels such as sodium (Na+) and calcium (Ca2+).
The neuronal Na+ and Ca2+ channels are responsible for the rise of the action potential and for the intrinsic excitability control of the neuronal system [49].
Some AEDs act inactivating a single voltage-dependent channel while others instead simultaneously inactivate bothchannels. Both of these mechanisms result in a reduction for neuronal hyperexcitability.
Examples of drugs that perform interacting with a single channel are phenytoin that selectively blocks the Na+ channel [50] and ethosuximide that blocks the T-type Ca2+ channel [51]. Instead, carbamazepine, lamotrigine, oxcarbazepine and zonisamide control seizures blocking both these voltage-dependent ion channels [52].
There are also anti-epileptics that act enhancing the GABAergic system. GABA is the main inhibitory neurotransmitter of the nervous system that acts on GABA receptors, ligand-dependent ionic receptors that increase chlorine conductance.
AEDs are responsible for increasing GABA transmission reducing neuronal excitability. Drugs that exert their action through these mechanisms are benzodiazepines, phenobarbital, stiripentol, tiagabine and vigabatrin.
Benzodiazepines (such as clobazam diazepam, lorazepam, clonazepam) phenobarbital and stiripentol enhance the inhibitory transmission of GABA by allosteric activation of the GABAA receptor thus increasing the frequency of chloride (Cl−) channel openings [53,54]. Vigabatrin, instead, is an inhibitor of GABA transaminase, the enzyme responsible for the catabolism of GABA [55].
In addition to enhancing the inhibitory transmission of GABA, other drugs exert their antiepileptic action, also exploiting the blockage of the Ca2+ and Na+ channels. Among the AEDs that perform their action through these effects are included, felbamate, lamotrigine and topiramate [56]. Other drugs are valproic acid and levetiracetam that perform their mechanism of action enhancing the transmission of GABA and blocking Ca2+ channels [57,58].
The anticonvulsant and neuroprotective efficacy of some drugs is also given by the inhibitory action of neurotransmitters, such as glutamate. Glutamate (or glutamic acid) is the most common excitatory neurotransmitter and is responsible for excitatory transmission on neurons. Felbamate and topiramate also perform their mechanism of action inhibiting glutamate thus decreasing l’ hyperexcitability neuronal [59,60].
The choice of drugs is mainly linked to the identification of the type of seizure and epileptic syndrome. For patients with epilepsy, effective seizure control is the determining factor for a good quality of life. AED dosages must be individualized to maximize therapeutic effects and avoid side effects.
The early childhood epilepsy syndrome such as DS, LGS and WS present no easy medical management due to the fact that subjects often show convulsion resistant to the available treatment. Therefore, of safe and effective therapies arenecessary to reduce the risk of neurological sequelae. The drugs preferentially used in particular forms of pediatric epilepsy are phenobarbital, phenytoin, benzodiazepine, topiramate, levetiracetam and valproic acid [61].
Cannabidiol and Molecular Targets in Epilepsy
CBD shows a low affinity for endocannabinoid receptors and it carries out its mechanisms of action by interacting with other molecular targets.
One of the most important ion channel targets towards which the CBD shows a high affinity is the Transient Receptor Potential Vanilloid (TRPV).
Specifically, TRPV1 is a non-selective channel that shows a high Ca2+ permeability and is involved in the modulation of seizures and in epilepsy.
In fact, when active, it promotes the release of glutamate and the increase in Ca2+, with consequent neuronal excitability [62].
The antiepileptic action of CBD does not seem to be due to direct interaction with these molecular targets.
However, it has been observed that the CBD agonist action towards TPRV1 determines one a desensitization of these channels with consequent normalization of intracellular Ca2+ [63].
T-Type Ca2+, are another class of ion channels with which CBD interacts.
These channels control Ca2+ peaks in neurons and they are involved in the regulation of cell excitability.
The activation of these channels due to a hyperpolarization of the membranes of neurons determines an increase in the concentration of intracellular Ca2+, in this way the T-Type Ca2+ channels increase the excitability of neurons.
This mechanism is often observed in pathophysiological conditions such as epilepsy [49].
The interaction of the CBD with the T-type Ca2+ channels causes a blockage of these channels, this mechanism could be responsible for the antiepileptic action, even if there are no studies available that confirm this.
Receptors represent other molecular targets that have been evaluated to describe their potential role in epilepsy through interaction with CBD. Serotonin receptor (5-hydroxytryptamine [5-HT]) belonging to the superfamily of the G protein-coupled receptors are divided into seven distinct classes (5-HT1 to 5-HT7).
These receptors may depolarize or hyperpolarize neurons, modifying the conductance and/or concentration ionic within the cells.
This suggests that 5-HT receptors are involved in epilepsy even though their role is still not entirely clear [64].
CBD shows a high affinity towards two subtypes of serotonin receptors: 5-HT1A e 5-HT2A.
These receptors can have different functions and regulatory characteristics, in fact, for example, the activation of 5HT1 receptors in the hippocampus causes an increase of neurotransmission; in contrast, in raphe nuclei, activation of 5-HT1A receptors produces the inhibition of serotonergic neurons [65].
The dysregulation of brain neurotransmission mediated by 5-HT2 might results responsible for the pathophysiology of depression and epilepsy [66].
However, although the role of serotonin receptors in epilepsy is unclear, 5-HT1A e 5-HT2A subtypes may represent a valid therapeutic target through which CBD can perform its anti-epileptic action [61,67].
Opioid receptors (OR) are G-protein-coupled receptors involved in a variety of brain disorders, including epilepsy [68,69].
The CBD at high micromolar concentrations determines the blocking of µ and δ OR, and this block would seem to generate anticonvulsant actions, even if there are still no studies to support this theory.
The CBD also shows a good affinity towards the orphan G-protein-coupled receptor (GPR55), a class of receptors involved in the modulation of the synaptic transmission. The agonist action of CBD towards these receptors would seem to attenuate synaptic transmission with consequent antiepileptic effects [70].
An important enzyme target of CBD involved in epilepsy is cytochrome P450 (CYP450). CBD inhibits CYP450 [71], but this mechanism does not seem to be directly involved in the antiepileptic mechanism. It seems to be responsible for the hepatic metabolism of a variety of AEDs, as shown by the combined administration of CBD and clobazam (CLB) [72].
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Original Research: Closed access
“Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop‐seizure frequency”. Kirsten Riber Bergmann, Karen Broekhuizen, Geert Jan Groeneveld.
British Journal of Clinical Pharmacology doi:10.1111/bcp.14158.
