Posted on

cbd causing seizures

Cbd causing seizures

Even with treatment, people with LGS or Dravet syndrome may continue to experience persistent seizures.

Dravet syndrome is a developmental disorder that begins in early childhood and is associated with multiple seizure types as well as seizures triggered by fevers. People with Dravet syndrome often have behavioral challenges and learning difficulties.


Cannabidiol (CBD)—a component of the marijuana plant—has gotten a lot of attention for medical use, including the treatment of epilepsy. Epidiolex is the only prescription form of CBD available, and it was approved by the U.S. Food and Drug Administration (FDA) in June 2018 for the treatment of seizures in two hard-to-treat forms epilepsy—Lennox-Gastaut syndrome (LGS) and Dravet syndrome. Epidiolex is approved for adults and children over the age of 2 who have one of these rare disorders.

What About Other Seizure Types?

Sometimes, children and adults who have LGS or Dravet syndrome have some difficulties taking oral medication due to difficulty swallowing, behavioral problems, and/or cognitive issues. It may be a challenge to get your child to take any medication, and you might need to develop strategies to help with this process.

Cbd causing seizures

The phase I clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02286986","term_id":"NCT02286986">> NCT02286986 is a multi-center study that to investigate the pharmacokinetics and dose-ranging tolerability, efficacy and safety of CBD (GWP42003-P), in 25 children and young adults (2 to 25 years) with epilepsy. The study was divided into two parts: Part A and Part B. Part A was used to evaluate the safety and tolerability of more ascending doses of GWP42003-P compared to placebo. The best-tolerated dose in Part A of the study was used to treat patients in Part B for 60 consecutive days. The antiepileptic efficacy of GWP42003-P compared to placebo was evaluated by monitoring the incidence in convulsions, determining the plasma concentration of GWP42003-P and its main metabolite following the escalation of multiple doses of GWP42003-P. Furthermore, was investigated the effect of GWP42003-P on the pharmacokinetics of concomitant and cognitive function, sleep quality and daytime sleepiness were also observed. The trial is still active and the results have not been published, yet.

All doses of CBD were well-tolerated and the 20 mg/kg/day dose was chosen by the for Part B ( <"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375) study. <"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375 enrolled 120 children (2 to 10 years) with DS and drug-resistant epileptic seizures. Patients received either the CBD oral solution at a dose of 20 mg/kg/day (n = 61) or placebo (n = 59), for 14 weeks, in addition to the standard antiepileptic treatment. During CBD-treatment, SAEs (status epilepticus, convulsion and somnolence) occurred in 16.39% of patients and in 5.8% of the placebo group. Instead, non-serious AEs (diarrhoea, vomiting, pyrexia, fatigue, upper respiratory tract infection, nasopharyngitis, decreased appetite, somnolence, lethargy, headache, convulsion, cough, irritability, gamma-glutamyltransferase increased, transaminases increased, weight decreased) occurred in 75.41% of patients who had taken CBD at the dose of 20 mg/kg/day and in 47.46% of the placebo group. The results suggested that, following the administration of CBD, the median frequency of seizures decreased from 12.4 to 5.9, compared to a decrease from 14.9 to 14.1 in the placebo-treated group. In 43% of patients treated with CBD and in 27% of patients in the placebo group occurred a reduction in seizure frequency by 50% or more and 3 patients were free of seizures [74]. Although the administration of CBD has caused high rates of AEs, CBD appears to be efficacy in the treatment of patients with DS.

Six randomized, double-blind, placebo-controlled studies were funded by GW Pharmaceuticals for evaluated the activity of the new formulation of purified CBD oral solution (GWP42003-P or Epidiolex), an epileptic medication and now Food and Drug Administration (FDA) approved for the treatment of seizures associated with DS and LGS in patients two years of age or older.

5.1. Completed Clinical Trials

The study conducted by Geffrey, et al. [72], approved by Massachusetts General Hospital (MGH) Institutional Review Board (IRB) evaluated the CBD interaction with CLB. The aim of this study was to evaluate possible interactions between CBD and CLB, assessing its efficacy, safety and pharmacokinetics. For this study, 13 patients (4 to 19 years) with refractory epilepsy and treated with CLB were recruited. Patients started taking CBD at a dose of 5 mg/kg/day and treated up by 5 mg/kg/day each week to a dose of 25 mg/kg/day, for 8 weeks. CLB was administered daily at a stable dose of 0.5 mg/kg that was decreased during the study when side effects were observed. The plasma levels of CBD, CLB and [N-CLB] were measured at baseline and at weeks 4 and 8 of treatment. The results of the efficacy study showed a 50% convulsion reduction in nine out of 13 subjects, corresponding to a 70% response rate. In two patients, however, there was an increase in the frequency of seizures during the treatment period, therefore the dose of CLB was reduced. Increases in plasma levels of CBD, CLB and its metabolite were recorded. Already in the fourth week, the mean of CBL levels had been an increase of 60 ± 80%, while the mean in [N-CLB] was an increase of 500 ± 300%. The results of the safety study show that in 77% subjects AEs were reported as somnolence (n = 6), ataxia (n = 2), irritability (n = 2), restless sleep (n = 1), urinary retention (n = 1), tremor (n = 1) and loss of appetite (n = 1). After adjusting the doses of CLB all AEs were resolved. Therefore, the results reported by the authors show an interaction between CBD and CLB, and that CBD influences [N-CLB] levels much more than CLB levels.

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).

5. Cannabidiol: Clinical Trials for Epilepsy

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].

The clinical trials of phase I <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 and <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412, will evaluate prospectively and longitudinally the safety and tolerability of CBD oral solution (Epidiolex) at various doses, between 5 mg/kg/day and 25 mg/kg/day with additional titration in some cases up to 50 mg/kg/day. These two trials will enroll both 100 patients with drug-resistant epilepsy. Clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 will enroll patients aged 1 to 18 years, while the <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412 patients aged 17 to 99 years. However, Gaston, et al. [78] evaluated possible CBD interactions with antiepileptic drugs typically used in 39 adults and 42 children of these trials. An analysis was carried out to check for non-uniform changes in both the CBD dose and the dose of other AEDs. In the two combined arms (pediatric and adult) the results recorded linear increases in serum levels of topiramate, rufinamide and [N-CLB] and linear decreases in CLB levels correlate with increasing CBD does. However, there were no significant changes in the levels of other AEDs analyzed (valproate, levetiracetam, phenobarbital, clonazepam, phenytoin, carbamazepine, lamotrigine, oxcarbazepine, ethosuximide, vigabatrin, ezogabine, pregabalin, perampanel and lacosamide). During the study, six adults and eight children showed sedation. The intake of concomitant CBD and valproate resulted in high levels of AST and ALT. Liver function tests showed elevated damage greater than three times the normal limit in four children who dropped out of the study, while the damages of about twice the upper normal limit in eight adults were resolved with valproate withdrawal. A major onset of somnolence following the concomitant administration of CBD and CLB and high levels of transaminases following co-administration of CBD and valproate was also recorded in another study [73] and in clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690. In conclusion, the results obtained by the researchers show that the use of CBD with other drugs can be considered safe. On the contrary concomitant use of CBD with valproate is not recommended as a significant liver dysfunction has been observed. Probably because CBD enhances the toxic action of valproate. The interaction between CBD and CLB was also highlighted. Since both of these drugs are metabolized of the cytochrome P450 pathway, this interaction can often induce high plasma levels of n-CLB. Therefore, it is important to monitor this drug-drug interaction. However, as the adverse effects occurring, in this case, are not serious, the concomitant use of CBD with CLB can be considered safe and above all effective, especially in pediatric patients with refractory epilepsy. Part of the results of <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 and <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412 were described by Szaflarski, et al. [79]. The study showed the efficacy and safety of Epidiolex in 72 children and 60 adults. The results obtained show an average reduction of all types of seizures of 63.6% with difference significant between baseline and 12 weeks. The reduction in seizures seems to have remained stable, in fact, there were no significant differences between 12 and 24 weeks and between 24 and 48 weeks. The severity of the seizures assessed by the Chalfont Seizure Severity Scale (CSSS) also showed an improvement from a baseline score of 80.7 to enroll at 39.3 at 12 weeks with CSSS scores stable even between 12 and 24 weeks and between 24 and 48 weeks. The analysis of AE Profile indicates a significant improvement in the presence/severity of adverse events between the baseline and 12 weeks with stable AEDs thereafter without significant differences between 12 and 24 weeks and between 24 and 48 weeks. The results of this study show significant improvements in the profile of adverse events, in the severity of crises and in reducing the frequency of seizures as early as 12 weeks; improvements that have been maintained during the 48 weeks of treatment.