cbd oil use for seizures

Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Marijuana and other cannabis products with high content in Δ(9) – tetrahydrocannabinol (THC), utilized primarily for recreational purposes, are generally unsuitable for this indication, primarily because THC is associated with many undesired effects. Compared with THC, cannabidiol (CBD) shows a better defined anticonvulsant profile in animal models and is largely devoid of adverse psychoactive effects and abuse liability. Over the years, this has led to an increasing use of CBD-enriched extracts in seizure disorders, particularly in children. Although improvement in seizure control and other benefits on sleep and behavior have been often reported, interpretation of the data is made difficult by the uncontrolled nature of these observations. Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. In these studies, CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. For the first time, there is now class 1 evidence that adjunctive use of CBD improves seizure control in patients with specific epilepsy syndromes. Based on currently available information, however, it is unclear whether the improved seizure control described in these trials was related to a direct action of CBD, or was mediated by drug interactions with concomitant medications, particularly a marked increased in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Clarification of the relative contribution of CBD to improved seizure outcome requires re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies controlling for the confounding effect of this interaction.

Introduction

The history of human use of the Cannabis plant goes back to the dawn of mankind. The plant, which originated in Central Asia or in the foothills of the Himalayas, was initially cultivated in China for fiber and seed production, and in India for resin production.1 For many centuries, European and East Asian societies have used mostly Cannabis strains containing low amounts (< 1% dry weight) of the psychoactive principle 9-Δ-tetrahydrocannabidiol (THC), and their main utilization was for fiber and food. Conversely, African, Middle-Eastern, South Asian, and Southeast Asian societies have used cannabis primarily for its psychoactive properties, with strains from these regions often containing 5–10% THC.1

The first studies on the medical use of cannabis date back to the Chinese Emperor Shen Nung (about 2,700 B.C.).2 As evidence of the important role of the plant in ancient Chinese culture, archeological excavations in the Xinjiang-Uighur Autonomous Region of China have recently unearthed a 2,700-year-old grave of a shaman which contained a large cache of cannabis, perfectly preserved by climatic and burial conditions, presumably employed as a medicinal or psychoactive agent, or as an aid to divination.3 Early written records of medical applications can be traced to Sumerian and Akkadian tablets, around 1,800 B.C., which mention the use of a medicinal plant, most likely cannabis, to treat a variety of ailments, including nocturnal convulsions.2,4 In less ancient times, there are records in the Arabic and Islamic literature which mention explicitly cannabis as a treatment for seizures and epilepsy.4

The first detailed modern description of the utility of cannabis-based products as an anti-seizure medication was published in 1843 by W.B. O’Shaughnessy, physician in the Bengal Army and Late Professor of Chemistry and Materia Medica at the Medical College of Calcutta. After testing the behavioral effects of various preparations of Cannabis indica in healthy fish, dogs, swines, vultures, crows, horses, deers, monkeys, goats, sheep, cows, and military assistants, he investigated the potential value of extracts of the plant in patients with different disorders, and reported remarkable anti-seizure effects in a 40-days-old baby girl with recurrent convulsive seizures.5 These observations were taken up by other physicians, including Sir William Gowers, who described the effectiveness of Cannabis indica against seizures resistant to bromides.6

In the twentieth century the use of cannabis declined somewhat because cultivation of the plant was made illegal in many countries. However, scientific advances on the properties of the plant progressed as chemists and pharmacologists started on work on the chemical characterization of its active ingredients, and on the relationship between their molecular structure and biological activity. While various reports focused on the effects of smoked cannabis on seizure control, it soon became clear that the psychoactive effects of THC limited the applicability of crude cannabis preparations in the treatment of seizures, and attention shifted to the potential utility of non-psychoactive ingredients such cannabidiol (CBD).2 Although interest in ‘medical marijuana’ and its individual constituents for the treatment of seizures persisted through the years, it is only in the last decade that preclinical and clinical research into the potential application of cannabis in the treatment of epilepsy has literally exploded ( Fig. 1 ). The purpose of the present article is to review the pharmacological basis of the anti-seizure effects of cannabis and particularly its non-psychoactive constituents, and to discuss critically the expanding range of evidence on the efficacy of these compounds in the management of different seizure types and epilepsy syndromes.

Number of articles retrieved in PubMed by using the search terms ‘cannabis and epilepsy’, grouped by year of publication.

Chemistry and mechanisms of action

The genus Cannabis refers to a flowering plant of which there are three main species, Cannabis sativa, Cannabis indica and Cannabis ruderalis. These plants contain over 100 biologically active chemicals called cannabinoids, with the most abundant and best characterized among those being THC and CBD ( Fig. 2 ).7 Crude preparations of cannabis include dried leaves, stems and flower pods (marijuana), resins (hashish), and oily extracts (hashish oil), all of which have been used through the centuries mostly for their psychoactive properties. In general, cannabis products derived from Cannabis sativa exhibit a higher CBD/THC ratio than products derived from Cannabis indica. Different Cannabis strains have been bred either to maximize THC content or, conversely, to reduce THC content and increase the concentration of CBD and other non-psychoactive ingredients.8

Chemical structure of cannabidiol and 9-Δ-tetrahydrocannabinol.

Many biological actions of cannabinoids are mediated by their interaction with two closely related receptors, cannabinoid receptor type 1 (CB1) and 2 (CB2), although a variety of other receptors and targets are also involved in the effects of these compounds.9–13 Both the CB1 and the CB2 receptors belong to the class of Gi/o-coupled metabotropic receptors and are widely distributed throughout the central nervous system (CNS), with CB1 receptors being localized primarily in neurons and CB2 receptors being expressed in microglia and, to a greater extent, in the immune system.9 The discovery of cannabinoid receptors in the CNS led to a search for endogenous substances interacting with these receptors and to the identification of so-called ‘endogenous cannabinoids’, the most important of which are the arachidonic acid derivatives anandamide (2-arachido-noylethanolamide) and 2-arachidonoyl glycerol.9 Extensive evidence has now accumulated that endocannabinoids play an important role in the control in synaptic transmission and the regulation of the rate of neuronal firing.13–17 In the CNS, CB1 receptors are expressed pre-synaptically on both glutamatergic and GABAergic interneurons, and activation of these receptors results in inhibition of synaptic transmission, including glutamate release.9,10,16 An involvement of endo-cannabinoid signaling pathways in the pathophysiology of epilepsy (and the possibility of targeting these pathways for therapeutic purposes) is suggested by a number of experimental and clinical observations. Experimentally, many studies reviewed in recent articles10,14,16,17 have demonstrated that endogenous cannabinoids systems are altered in a variety of models of seizures, epilepsy and epileptogenesis, whereas external modulation of these systems can prevent or modulate seizure activity. Clinically, observations implicating a role of endocannabinoid systems in epilepsy include the finding of reduced anandamide concentrations in the cerebrospinal fluid of individuals with new-onset temporal lobe epilepsy;18 demonstration of downregulation of CB1 receptors and related molecular components in glutamatergic neurons from surgical samples of epileptic human hippocampus;19 demonstration of sprouting of CB1-receptor expressing GABAergic axons (or increased expression of CB1-receptors on these fibers) in sclerotic human hippocampi;20 and PET evidence of differential changes in CB1 receptor availability in the seizure onset zone and in the insula of patients with temporal lobe epilepsy and hippocampal sclerosis.21

Cannabinoids have numerous and complex pharmacological properties. In experimental models, for example, THC displays complex psychoactive effects, variable anticonvulsant effects, and analgesic, cognitive, muscle relaxant, anti-inflammatory, appetite stimulant, and antiemetic activity.9,12,22 On the other hand, CBD is mostly devoid of adverse psychoactive effects and possesses anticonvulsant, analgesic, anti-anxiety, antiemetic, immune-modulating, anti-inflammatory, neuroprotectant, and anti-tumorigenic properties.9,12,22 In the case of THC, anti-seizure activity seems to be mediated to an important extent by its partial agonist action on the CB1 receptor, which is also primarily involved in the expression of psychoactive effects.9,13,23 CBD, on the other hand, has very weak affinity for the CB1 and CB2 receptors and its anti-seizure activity at clinically relevant concentrations is considered to be mediated by other mechanisms,13,24,25 possibly including functional agonism or antagonism at multiple 7-transmembrane receptors, ion channels, and neurotransmitter transporters ( Table 1 ).24–35 In particular, an effect on adenosine reuptake and antagonism of G protein-coupled receptor 55 (GPR55) have been recently suggested to play an important role in CBD anti-seizure activity.36

Table 1

A list of targets and actions reported for CBD based on results of studies in different experimental models and systems24–36

Receptor/target Action of CBD at the indicated receptor/target
CB1 Non-competitive antagonist
CB2 Inverse agonist
TRPV1–3 Agonist
TRPV4 Agonist
TRPM8 Antagonist
TRPA1 Agonist
α1, α 3 glycine Agonist
5-HT1a Agonist
GPR55 Antagonist
PPAR-γ Agonist
TNFα Modulator
Voltage-gated T-type calcium channels Antagonist
Resurgent sodium current Inhibition
VDAC1 Modulator
Adenosine reuptake Inhibitor
Adenosine A1 and A2 receptors Modulator
Anandamide reuptake Inhibitor
Fatty acid amide hydrolase Inhibitor

The list is not exhaustive and not all reported actions may be relevant to anti-seizure activity.

CBD, cannabidiol; CB1, cannabinoid type 1 receptor; CB2, cannabinoid type 2 receptor; TRPV1–3, transient receptor potential of vanilloid types 1–3; TRPV4, transient receptor potential of vanilloid type 4; TRPM8, transient receptor potential of the melastatin type 8; TRPA1, transient receptor potential of ankyrin type 1; 5-HT1a, serotonin receptor, subtype 1A; GPR55, G protein-coupled receptor 55; PPAR-γ, nuclear peroxisome proliferator-activated receptor γ; VDAC1, voltage-dependent anion-selective channel protein type 1.

Pharmacological profile in experimental models of seizures and epilepsy

Among the many active principles found in the cannabis plant, THC is the most widely investigated for its many actions, including its psychoactive effects and risks associated with overdose and abuse. THC shows some anticonvulsant effects in certain seizure models, but there have also been studies suggesting a proconvulsant effect.14,37 Although it is plausible that THC may contribute to the anti-seizure activity reported for medical marijuana and other cannabis preparations, its adverse psychotropic properties37 and inconsistent activity in seizure models render it undesirable for development for the treatment of epilepsy.38 Therefore, most cannabinoid research efforts in epilepsy have focused on the characterization of non-psycho-active agents, particularly CBD and cannabidivarin (CBDV), and the present review will focus especially on these compounds.

In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock39–41 and by pentylentetrazole in rats and mice,42–44 audiogenic seizures in rats45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid (but not strychnine) in mice.39,45,46 In addition, CBD shows protective activity in pilocarpine models of temporal lobe seizures and in the penicillin and cobalt models of focal seizures in rats,47–49 and increases the afterdischarge threshold while reducing afterdischarge amplitude and duration in electrically evoked kindled seizures in rats.50 CBD also inhibits epileptiform potentials induced by a Mg 2+ -free medium and 4-amino-pyridine in hippocampal brain slices.42

Recently, the anticonvulsant profile of CBD was re-evaluated using a refocused screening protocol developed by the National Institute of Neurological Disorders and Stroke (NINDS)-funded Epilepsy Therapy Screening Program.41 In this investigation, CBD given intra-peritoneally (i.p.) produced a dose-dependent protection against maximal electroshock-induced seizures in mice (ED50 83.5 mg/kg) and rats (ED50 88.9 mg/kg), and was also found to be effective in the 6 Hz 44 mA seizure model (ED50 164 mg/kg), and in the corneal kindling model (ED50 119 mg/kg) in mice. These effects were observed at doses that did not cause motor impairment. No protection, however, was attained in the lamotrigine-resistant amygdala kindled rat at doses up to 300 mg/kg.

As discussed above, the molecular actions involved in CBD anti-seizure activity do not appear to be mediated by a direct effect on cannabinoid receptors, but the precise mechanisms of action have not been ascertained. In various studies, CBD has been reported to exhibit a range of other activities which suggest potential utility in many other conditions, including anxiety, mood disorders, psychosis, fear, trauma-related conditions, tobacco and opioid addition, inflammatory diseases, neurodegenerative disorders, and as a tool to counteract the undesired psychotropic effects of THC.32,51–56

CBDV, another cannabinoid present in the cannabis plant, has been the focus of many recent studies. Like CBD, CBDV is virtually devoid of psychoactive effects and shows protecting activity in vitro against epileptiform potentials induced by 4-aminopyridine and Mg 2+ – free conditions in rat hippocampal slices and, in vivo, against seizures induced by maximal electroshock, pentylentetrazole, and audiogenic stimulation.57 In an early study, CBDV was not found to protect against pilocarpine-induced seizures at doses up to 200 mg/kg i.p., but potentiated the effect of valproic acid and phenobarbital in this model.57 In a subsequent study by the same group, however, inhibition of pilocarpine-induced seizures was observed after administration of a CBDV-rich cannabis extract.58 The mechanisms responsible for the anti-seizure effects of CBDV do not seem to involve an action on cannabinoid receptors.25,29 Like CBD, CBDV acts as an agonist for the transient receptor potential (TRP) channels TRPV1, TRPV2, TRPA1, and as an antagonist for TRPM8.28,30,59 These actions, however, have been considered unlikely to contribute to its anticonvulsant activity.29,36 CBDV also inhibits diacylglycerol lipase α, the primary enzyme involved in the synthesis of 2-arachidonoylglycerol.28 Again, the potential contribution of this effect to its anticonvulsant activity has not been established.

9-Δ-tetrahydrocannabinolinic acid

In the cannabis plant, most cannabinoids are synthesized in their acidic form. These acidic cannabinoids undergo decarboxylation to their neutral counterparts (e.g., CBD and THC) under the influence of auto-oxidation, light and heat. In most common extraction and delivery methods, plant materials are exposed to heat, resulting in the conversion of the acidic forms to the neutral constituents.60 However, some cannabis products may retain some content in acidic cannabinoids, particularly cannabidiolic acid (CBDA) and 9-Δ-tetrahydrocannabinolinic acid (THCA). THCA has been found to possess anticonvulsant activity in preliminary preclinical investigations, and be devoid of adverse psychoactive effects.61 Interest in THCA been rekindled recently by the fact that it is sometimes used for anti-seizure purposes in the USA, where it can be more readily available and/or affordable than CBD. One specific concern is that accidental exposure to heat of artisanal THCA preparations may result in partial conversion to THC.61

Pharmacokinetics and drug interactions

Following administration to healthy subjects of a single 400 mg oral dose encapsulated in gelatin capsules, CBD was found to be rapidly absorbed, with mean peak plasma concentrations of 114 to 181 ng/mL being attained at about 1.5 to 3 hours.62 Following oral administration, CBD shows a high interindividual pharmacokinetic variability. Its oral bioavailability is low, in the order of 6%37 or 10%,63 due in part to extensive first-pass metabolism.37 Bioavailability appears to be higher (in the range of 11 to 45%) after inhalation in cannabis smokers.64 In a study conducted with an oromucosal spray of nabiximols (a formulation containing THC and CBD in an approximately 1:1 ratio, which is approved in some countries for the treatment of symptoms of spasticity associated with multiple sclerosis), co-administration with food resulted in a mean 5-fold increase in CBD bioavailability.65 It is unclear whether a similar effect also occurs with oral formulations.

CBD is highly bound to plasma proteins (> 99%)63 and is extensively metabolized by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C19,66 and glucuronyltransferases.67 The major metabolic pathway involves hydroxylation and oxidation at C-7, followed by further hydroxylation in the pentyl and propenyl groups.68 The major oxidized metabolite identified is cannabidiol-7-oic acid containing a hydroxyethyl side chain. The elimination of CBD follows a biphasic pattern, with an initial half-life of about 6 hours which partly reflects distributive processes. Because of its very high lipophilic properties, CBD distributes extensively into tissues, from which it is slowly released, resulting in a late-phase terminal half-life of about 24 hours.63 In a safety and pharmacokinetic study in patients with Dravet syndrome, 27 children aged 4 to 10 years received CBD doses of 5, 10 or 20 mg/kg/day in addition to pre-existing antiepileptic drugs (AEDs).69 On treatment day 22, exposures to CBD and its major metabolites were found to increase dose-proportionally.

The clearance of CBD has been reported to be increased after co-administration with the enzyme inducer rifampicin.70 It would be expected that enzyme inducing AEDs such as carbamazepine and phenytoin also accelerate CBD metabolism and reduce CBD levels at steady state. Conversely, CBD levels have been found to be increased by the CYP3A4 inhibitor ketoconazole, but not by the CYP2C19 inhibitor omeprazole.70

In studies conducted on liver isozymes, CBD has been shown to inhibit the activity of CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4, and CYP2C19 enzymes.71–75 There is also evidence of CBD acting as an inhibitor of transporter systems, such as BCRP and the ABC transporter multidrug resistance-related protein 1.67 Some of these in vitro effects occur at concentrations above those found within the clinically used dose range. However, at least one clinically important interaction mediated by inhibition of drug metabolism has been reported. In a group of 13 patients with epilepsy aged 4 to 19 years, addition of CBD (initial dose 5 mg/kg/day, titrated up to a target dose of 25 mg/kg/day) resulted in an increase in the plasma levels of concomitantly administered clobazam by 60 ± 80% (mean ± standard deviation). More importantly, the plasma concentration of the active metabolite of clobazam, N-desmethylclobazam, increased by 500 ± 300% (95% confidence interval [CI]: +90 to +610%) at 4 weeks after starting CBD.76 Ten of the 13 patients experienced side effects, most commonly drowsiness, which resolved after lowering the clobazam dose. This interaction, which was considered to be mediated by inhibition of CYP2C19, is particularly relevant because clobazam is frequently used in epileptic encephalopathies for which CBD appears to be a promising new treatment. In a safety and pharmacokinetic study in children with Dravet syndrome, there were minimal changes in clobazam levels, but concentrations of N-desmethyl clobazam increased independently of CBD dose, except for patients on stiripentol in whom N-desmethyl-clobazam levels appeared to be unaffected by CBD.69 There were no demonstrable effects on other AEDs (valproic acid, topiramate, stiripentol, levetiracetam).69 Serum levels of concomitant AEDs were also measured in another study which assessed 39 adults and 42 children started on CBD at a dose of 5 mg/kg/day, increased according to clinical response up to a maximum of 50 mg/kg/day.77 In the latter study, increases in the levels of N-desmethyl-clobazam, topiramate, and rufinamide were reported with increasing CBD doses. In adults, there were also increases in serum levels of zonisamide and eslicarbazepine. The results of this study are difficult to interpret, because of the confounding effects of changes in the dose of comedications. Serum clobazam levels, for example, decreased during CBD coadministration, primarily due to a reduction in clobazam dose. In any case, assessment of the data suggested that changes in serum levels of concomitant AEDs during CBD administration were generally minor, with the exception of clobazam and N-desmethylclobazam levels.77 In fact, occurrence of sedation as a result of the interaction with clobazam often led to a decrease in clobazam dose.

CBD may also be involved in pharmacodynamic interactions, i.e. interactions which occur at the site of action. In particular, acutely administered CBD may antagonize some of the effects of THC at CB1 receptor sites,78–80 an observation which may explain why patients taking marijuana with higher CBD content are less likely to develop adverse THC-related psychotropic symptoms, and may tolerate high-ecr THC doses.37,81 Studies in animal models, however, suggest that after prolonged exposure molecular interactions between CBD and THC may be more complex than previously thought, and may involve superadditive effects on some measures.82 Terpenoids contained in cannabis extracts may also interact with the action of CBD and other cannabinoids.83

The observation has been made that elevations in liver enzymes associated with CBD treatment occur much more frequently among patients comedicated with valproate than among patients comedicated with other AEDs.77,84–86 It is unclear whether the mechanism underlying this interaction is pharmacokinetic or pharmacodynamic in nature.87

The pharmacokinetics of CBDV have not been reported in detail. In a recently completed Phase I study, healthy subjects were given single oral doses ranging between 25 and 800 mg, as well as multiple doses of 800 mg once daily over 5 days.36 Peak plasma concentrations and areas under the plasma concentration-time curve were found to be dose proportional. The 7-hydroxy- and 6-hydroxy-metabolites could be detected shortly after dosing.

Clinical evidence of efficacy and safety: exploratory studies

Marijuana and oral cannabis extracts

As discussed in the introductory section of this article, evidence of cannabis being used in the treatment of seizure disorders dates back thousands of years, and cannabis preparations had a role in the treatment of epilepsy by neurologists in the late nineteenth century. Although use of cannabis in epilepsy declined in the twentieth century due to legal restrictions and the gradual introduction of AEDs, observations suggesting anti-seizure activity continued to be reported. In 1975, Consroe et al.88 described a 24-year-old patient with seizures uncontrolled despite therapy with phenobarbital and phenytoin, who became seizure-free after starting to smoke marijuana. A few other reports suggestive of beneficial effects on seizures of marijuana smoking appeared in the subsequent decades,89–92 including an interesting epidemiological study which found a reduced risk of a first seizure among illicit cannabis users.93 There have been however, also reports of marijuana smoking precipitating or aggravating seizures.94,95

For medicinal use, oral intake provides a more easily controllable route of drug delivery than inhalation. Therefore, particularly during the last twenty years, users of cannabis for seizure control have generally preferred oral preparations. At the same time, increasing realization that CBD is superior to THC in safety and potential anti-seizure activity has resulted in preferential use of whole plant preparations or cannabis-based oil or liquid extracts enriched in CBD content. A number of such products are accessible in many countries and states under widely different legal and regulatory scenarios.87,96 In some settings, users obtain their cannabis from local growers, purchase it online or they grow the plant and process the product themselves.61 Therefore, it is not surprising that many preparations lack adequate quality validation, and that some marketed products when tested are found to have contents of individual cannabinoids wildly different from those stated in their label,97,98 and some may even contain potentially harmful contaminants.99 This situation raises concerns about consistency in dosing and risk of adverse effects, including toxic effects resulting from psychoactive constituents such as THC. In this regard, a recent report described two children with manifestations suggestive of THC intoxication, including seizure exacerbation, in whom clinical symptoms remitted after switching their treatment from a CBD-enriched edible cannabis preparation to a formulation of purified CBD.100 In some countries, well standardized products are accessible, which typically differ in their relative content of CBD and THC. In Israel, for example, available medical cannabis products approved for epilepsy have standardized CBD/THC ratios of 2:1, 5:1, and 20:1, with the latter being the preparation most commonly used.101

Evidence about the efficacy and safety of oral cannabis preparations is mostly based on surveys and case reports, including the widely publicized story of Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, who experienced a remarkable improvement in her seizures after being switched to a CBD-enriched extract.102 One of the first surveys targeted a Facebook group of approximately 150 parents in the USA supporting the use of CBD-enriched cannabis in their children with drug refractory seizures.103 There were only 19 respondents, with most of the children having a diagnosis of Dravet syndrome and Doose syndrome. Over 80% of parents in this small and possibly biased sample considered their child to have fewer seizures while on CBD-enriched cannabis, at estimated doses up to 25 mg/kg/day for CBD and up to 0.8 mg/kg/day for THC. Two children were free from seizures. Parents also reported other beneficial effects, including improved alertness, and improved mood and sleep. Side effects included drowsiness and fatigue. Another online survey was directed to parents who used CBD-enriched cannabis products for the treatment of their children’s epilepsy.104 There were 117 respondents (including parents of 53 children with infantile spasms and Lennox-Gastaut syndrome), with 85% reporting a reduction in seizure frequency in their children, and 14% reporting complete seizure freedom. The median duration of therapy was 6.8 months, and the median estimated CBD dosage was 4.3 mg/kg/day. Many responders reported that their children showed improved sleep, alertness and mood. In a very recent web-based survey from Australia targeting people with epilepsy nationwide, 137 of the 976 respondents reported to be using, or having previously used, cannabis products for the treatment of their seizures.105 Use of these products increased with increasing number of AEDs used in the past, suggesting that patients with the most drug resistant seizures were more likely to access cannabis therapy. Products were perceived as helpful in managing seizures in 71% of children and 89.5% of adults, and almost one half of respondents reported to have been able to reduce their concomitant AEDs. Interestingly, only 6.5% of responders stated that they used cannabis because it was recommended by their physician, and the majority of the products used were obtained from illegal suppliers, without knowledge of their precise composition. Positive results with cannabis use were also reported in another recent online survey directed to parents of children with refractory epilepsy in Mexico.106

In addition to web-based surveys, there have several reports based on chart reviews. In one such report from the USA, use of artisanal cannabis in 272 children and adults with a variety of seizure types was associated with at least 50% seizure reduction in 55% of cases, with 10% achieving seizure freedom, and there was no indication of improvement being preferentially associated with a specific seizure type or syndrome.61 In a retrospective survey of 75 children and adolescents with refractory epilepsy from Colorado, where use marijuana for medical purposes was legalized in 2,000, one third of patients experienced a > 50% seizure reduction after starting therapy with oral cannabis, with the highest apparent benefit being reported in those with Lennox-Gastaut syndrome.107 Adverse events were reported in almost one half of the cases and included increased seizures (13%) and somnolence/fatigue (12%), but there were also reports of improved alertness or behavior in one third of the cases. Comparable findings were reported in a similar report from Colorado, which included data from 119 patients (it is unclear whether this population partly overlapped with that described in the earlier report by the same group).108 In the latter study, the proportion of patients who showed >50% seizure reduction was 24% and, interestingly, one third of those who did not report any seizure improvement continued to take cannabis therapy, presumably because of other perceived benefits. The average duration of cannabis use in this cohort was 11.7 months (range 0.3 to 57 months) and overall 71% of patients discontinued cannabis therapy during the study period. Another report from Israel included 74 patients with highly drug resistant epilepsies secondary to various etiologies (mostly epileptic encephalopathies), treated with a CBD dose of 1 to 20 mg/kg/day using an oil product containing CBD and THC in a 20:1 ratio.109 Almost 90% of the patients were cognitively impaired and one half were less than 10 years of age. Unlike other studies, therapy in the Israeli setting was generally prescribed by a physician, and the fact that 81% of the patients received relatively low doses (less than 10 mg/kg/day) was attributed to the fact that most patients kept the oil drops sublingually for several minutes, which would be expected to result in higher bioavailability.102 About one half of the patients reported at least a 50% reduction of their seizures, but five reported seizure aggravation leading to treatment withdrawal. As in previous reports, many patients reported improvements in behavior, alertness, language, communication, motor skills and sleep. Thirty-four (45%) patients reported adverse events, including somnolence/fatigue (22%), seizure aggravation (18%), gastrointestinal symptoms and irritability (7%).

Overall, review of the available studies suggests that CBD-enriched cannabis may have anti-seizure effects, but the quality of the evidence does not allow to draw firm conclusions. Studies were generally retrospective, and based on patient or parenteral reports without adequately structured data collection. Many of the patients surveyed used unspecified products whose composition and dosage was unknown. Moreover, estimates of apparent efficacy could be affected by patients’ selection bias, reporting bias, and other confounders such as the natural course of the disease, regression to the mean phenomena, and placebo effects.110 In particular, placebo effects are known to be strongly influenced by expectations,111 and the broad media exposure associated with cannabis products is a strong generator of positive expectations. An indication that patient or parental expectations may have a strong impact on the outcome of cannabis treatment is provided by a comparison of perceived improvement among patients included in the Colorado surveys.107,108 Specifically, outcomes of cannabis therapy were significantly better when families moved their residence to Colorado in order to access the medication compared with families already residing in Colorado ( Fig. 3 ). Although there could be alternative explanations for this finding, it is plausible that patients with high expectations/motivations, leading them to relocate to another state, were those who responded best.

Proportion of patients reporting beneficial anti-seizure effects from cannabis products in relation to whether patients’ family resided originally in Colorado or moved to Colorado in order to access cannabis therapy.108

Purified cannabidiol

The first studies of pure CBD in the treatment of drug-resistant epilepsy date back to the late 70s and the 80s and explored oral doses in the range of 200 to 300 mg/day.112–115 Despite the fact that all four studies included placebo as a control, only one trial was truly double-blind, the largest sample size was only 15 patients, critical details were lacking, and there were other methodological shortcomings.37 These trials were evaluated in a Cochrane review which included a systematic literature search up to September 2013, and the conclusion was reached that ‘no reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy’.116 Similar conclusions were reached in a 2014 report of the Guideline Development Subcommittee of the American Academy of Neurology.117

To date, the largest exploratory study of the tolerability and anti-seizure activity of CBD relates to a recent physician-sponsored expanded-access programme at 11 epilepsy centres in the USA.84 A total of 214 patients aged 1–30 years with severe, childhood-onset, drug resistant epilepsy received an oil-based liquid formulation of 99% pure CBD at an initial dose of 2–5 mg/kg/day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day, depending on study site. Tolerability and safety were analysed for the group of 162 patients who achieved at least 12 weeks of follow-up–this included 33 patients with Dravet syndrome and 31 patients with Lennox-Gastaut syndrome. In this group, adverse events were reported in 128 (79%) patients, the most common being somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%), and convulsion (11%). Adverse events leading to discontinuation of treatment occurred in 5 patients (3%). An explorative assessment of efficacy was performed in a subgroup of 137 patients, after excluding patients with less than 12-week follow-up (n = 52), patients with no motor seizures (n = 21), and patients who were aged less than one year or had a severe progressive metabolic disease (n = 3). In those 137 patients, there was a median 35% decrease in total seizures, with the greatest seizure reduction being recorded in patients with focal seizures (−55%, n = 42) and atonic seizures (−54%, n = 32). Nine patients (7%) were free from all seizures during the last 4 weeks of follow-up. It is of interest that a reduction in motor seizures by 50% or greater was observed in 51% of patients comedicated with clobazam (n = 70), compared with 27% of those not receiving clobazam (n = 67). Patients on clobazam, however, were also more likely to develop adverse effects, particularly somnolence and fatigue. These differences in outcome in relation to type of comedication may be explained by the increase in plasma clobazam and N-desmethyl-clobazam levels caused by CBD.76 Additional analyses in the efficacy patient set showed that patients with Dravet syndrome (n = 32) had a 43% median reduction in all seizures, whereas for patients with Lennox-Gastaut syndrome (n = 30) median reduction in total seizures was 36%. In a subgroup of children evaluated with a care-giver-filled quality of life questionnaire, CBD therapy was associated with improved scores for energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life, which did not correlate with changes in seizure frequency.118 Outcome data from a larger cohort of 261 children and young adults from the same program (including 44 with Dravet syndrome and 40 with Lennox-Gastaut syndrome) have also been reported in summary form.36 Convulsive seizure rate for the whole cohort decreased by a median of 48% compared with baseline, whereas atonic seizures in patients with Lennox-Gastaut syndrome decreased by 71.1%. Overall, the main value of these studies is in providing a preliminary characterization of CBD safety profile. Data concerning improvement in seizure control, however, are difficult to assess in view of the uncontrolled nature of the observations.

Smaller uncontrolled studies and case reports have also suggested that CBD could be of value in the treatment of patients with drug resistant seizures associated with tuberous sclerosis complex,119,120 febrile infection-related epilepsy syndrome (FIRES),121 Sturge-Weber syndrome122 and malignant migrating partial seizures in infancy.123

Well controlled randomized trials

The recent flurry of research focused on the potential usefulness of cannabinoids in epilepsy has resulted in the completion of three well controlled randomized trials, all of which evaluated a liquid proprietary oral formulation of CBD.85,86,124 Of these trials, only one has been published in detail.85

Double-blind trial in Dravet syndrome

As an indication of the high interest of the medical community in the application of cannabinoids to epilepsy management, the first randomized placebo-controlled double-blind trial of CBD in Dravet syndrome was published in the New England Journal of Medicine in May 2017.85 In this trial, conducted at 23 centers in the USA and Europe, 120 patients with an established diagnosis of Dravet syndrome (mean age 9.8 years, range 2.3 to 18.4 years) were randomized to receive placebo or 20 mg/kg/day CBD in two divided daily administrations. All patients had at least 4 convulsive seizures during a preceding 4-week baseline, and CBD or placebo were added on to pre-existing medications, which included clobazam in 65% of cases. The duration of treatment was 14 weeks, including a 2-week-titration phase. Compared with baseline, the median monthly frequency of convulsive seizures (defined as the sum of tonic-clonic, tonic, clonic, and atonic seizures) decreased from 12.4 to 5.9 in the CBD group, and from 14.9 to 14.1 in the placebo group. Median percent changes in seizure frequency are shown in Fig. 4 . The adjusted median difference in change in seizure frequency between the CBD and the placebo group (primary endpoint) was −22.8% (95% CI: −41.1 to −5.4, p = 0.01). The proportion of patients with ≥ 50% reduction in convulsive seizures frequency was 43% in the CBD group compared with 27% in the placebo group. Non-convulsive seizures were not significantly affected by CBD therapy. Three patients (5%) became seizure-free during the treatment period in the CBD group, compared with none in the placebo group.

Median percent reduction in seizure frequency in the three randomized adjunctive-therapy placebo-controlled efficacy trials of cannabidiol (CBD) reported to date in patients with Dravet syndrome85 and Lennox-Gastaut syndrome.86,124 For patients with Dravet syndrome, seizure frequency refers to convulsive seizures. For patients with Lennox-Gastaut syndrome, seizure frequency refers to drop seizures. P values refer to comparisons between each CBD group and corresponding placebo group. n refers to number of patients randomized into each group. For further details, see text.

Adverse events deemed to be related to the study treatment were reported in 75% of patients in the CBD group and 36% of those in the placebo group. Somnolence, diarrhea, and decreased appetite were the most common CBD-associated adverse events ( Table 2 ). Eighteen of the 22 CBD-treated patients who developed somnolence were on clobazam comedication. Adverse events appeared mostly during the first two weeks of therapy, and there were instances in which the dose of CBD or other medications were reduced. No information, however, was reported on how often the dose of concomitant clobazam was reduced. Eight patients in the CBD group discontinued the trial prematurely due to adverse events (in three cases, marked elevation of liver enzymes), compared with one patient in the placebo group who also had a marked elevation in liver enzymes. Overall, elevated aminotransferases levels occurred in 12 patients in the CBD group and one in the placebo group, all of whom were on concomitant valproate therapy. In the nine patients with raised aminotransferases who did not discontinued treatment, liver enzymes reverted to normal on continuation of therapy.

Table 2

Adverse events most commonly reported in the randomized double-bind placebo-controlled trial of CBD in comparison with placebo in patients with Dravet syndrome85

Adverse event Percentage of patients with adverse event
CBD group (n = 61) Placebo group (n = 59)
Somnolence 36% 10%
Diarrhea 31% 10%
Decreased appetite 28% 5%
Fatigue 20% 3%
Vomiting 15% 5%
Fever 15% 8%
Lethargy 13% 5%
Convulsion 11% 5%
Upper respiratory tract infection 11% 8%

Only events occurring with a frequency > 10% in either group are listed.

Overall, this trial provides for the first time robust evidence that CBD added-on to pre-existing AED treatment reduces the frequency of convulsive seizures in children and young adults with Dravet syndrome. The data also emphasize the need for caution in interpreting results from previous uncontrolled trials–although median convulsive seizure frequency (primary endpoint) decreased by a statistically significantly greater extent in the CBD group compared with the placebo group, the proportion of patients with ≥ 50% reduction in convulsive seizure frequency did not differ significantly between groups, and more than one quarter of patients allocated to placebo had their seizure frequency reduced by one-half or more during the trial. Interestingly, no significant differences between groups were found in sleep scores, behavioral adaptation (Vineland-II) scores, and Quality of Life in Childhood Epilepsy scores, even though duration of treatment was relatively short and possibly insufficient to determine changes in these parameters. A major weakness in the presentation of the trial results is the failure to report changes in plasma concentrations of concomitant AEDs and, most notably, clobazam and N-desmethylclobazam. In view of the fact that 66% of patients in the CBD group were on clobazam comedication, and evidence from a previous study indicating that N-desmethylclobazam levels increase by 500% on average after adding CBD,76 the reported data do not allow to determine whether the reported improvement in seizure frequency can be ascribed to a direct action of CBD, or is simply a consequence of increased plasma levels of comedication.

Double-blind trials in Lennox-Gastaut syndrome

Two well controlled double-blind trials in patients with Lennox-Gastaut syndrome have been completed, but results to date have only been reported in summary form.86,124

In the first trial, 171 patients (mean age 15 years) with uncontrolled drop seizures (median baseline monthly frequency 74) were randomized to receive adjunctive treatment with CBD oral solution 20 mg/kg/day or placebo for a period of 14 weeks (2-week titration and 12-week maintenance).86 Fourteen patients (16%) in the CBD group and one patient (1%) in the placebo group withdrew prematurely. Compared with placebo, CBD treatment was associated with a greater median percent reduction in monthly drop seizures (44% vs. 22%; p = 0.0135, Fig. 4 ) and a greater proportion of patients with a ≥ 50% seizure reduction (44% vs. 24%; p = 0.0043). Adverse events were reported in 86% of CBD and 69% of placebo patients, the most common being diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. Treatment-related serious adverse events were reported in nine CBD patients and one placebo patient. Elevations in transaminases occurred mostly in patients on concomitant valproate therapy and all resolved.

In the second trial, 225 patients with Lennox-Gastaut syndrome (mean age 16 years, median number of drop seizures per month at baseline 85) were randomised to three groups and allocated to two doses of CBD (10 or 20 mg/kg/day) or placebo.124 Enrolled patients were receiving a median of 3 concomitant AEDs. Duration of the trial was 14 weeks (2-week titration and 12-week maintenance). The reduction in monthly frequency of drop seizures was significantly greater in the CBD 20 mg/kg group (42%) and 10 mg/kg group (37%) than in the placebo group (17%; p = 0.0047 and 0.0016, respectively, Fig. 4 ). The proportion of patients with a ≥ 50% decrease in drop seizure frequency was also significantly greater in the 20 and 10 mg/kg groups (40% and 36%, respectively) than in the placebo group (15%; p = 0.0006 and p = 0.0030, respectively). Total seizures were also significantly reduced in both CBD groups compared with placebo. Adverse events were reported in 94% of patients allocated to 20 mg/kg, 84% of those allocated to 10 mg/kg, and 72% of placebo patients, the most common being somnolence and decreased appetite. Serious treatment-related adverse events occurred in five patients in the 20 mg/kg group, two patients in the 10 mg/kg group, and no patients on placebo patients. Some elevations in transaminases were seen. Of 212 completers, 99% entered an open-label extension study.

Overall the results of these trials demonstrate that at dosages of 10 to 20 mg/kg/day CBD is superior to placebo in reducing the frequency of drop seizures in patients with Lennox-Gastaut syndrome. Published reports, however, provide no information on concomitant therapies, and most notably whether, and to what extent, the clinical improvement on CBD therapy could be related to elevation in serum concentrations of other medications, most notably clobazam and N-desmethylclobazam.

Conclusions and future perspectives

The interest in cannabis preparations in the treatment of epilepsies, particularly drug refractory childhood epilepsies, has skyrocketed in recent years. Marijuana and other cannabis products with moderate to high THC content utilized primarily for recreational purposes are generally unsuitable for this indication, not only because evidence for an anti-seizure activity of THC is equivocal and risk of seizure aggravation cannot be excluded,101 but also because THC is associated with many undesired effects, including addiction liability, psychiatric disorders, cognitive and motor impairment125–127 and, possibly, also cardiovascular toxicity.128 The maturing brain is also more vulnerable to the adverse of effects of marijuana,126,129,130 and there is evidence of THC impairing structural and functional connectivity during brain development.126,129,130 Discontinuation of THC after prolonged exposure can also lead to withdrawal manifestations131,132 and cases have been reported of seizure exacerbation after marijuana cessation in people with epilepsy.133

Compared with THC, CBD shows a better defined anticonvulsant profile in animal models considered to be predictive of efficacy against focal and generalized seizures. Moreover, CBD is largely devoid of adverse psychoactive effects, and is considered to lack the abuse liability associated with THC-containing products.134 In the last decade, this has led to an increasing use of CBD-enriched extracts as a potential treatment for epilepsy, particularly in children. Improvement in seizure control, often associated with additional benefits on sleep and behaviour, have been reported in a sizeable proportion of cases,87 but interpretation of these data is made difficult by the uncontrolled nature of the observations. Additionally, as discussed in this article, there are concerns about the quality and variability of many of the products used,98 particularly because cannabis treatment is often initiated spontaneously by patients or caregivers without adequate medical supervision.105

Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of the first high-quality placebo-controlled trials of a purified oil-based liquid CBD preparation in patients with Dravet syndrome and Lennox-Gastaut syndrome.85,86,124 The results of these studies demonstrate that, at a dosage of 20 mg/kg/day, CBD added on to pre-existing AED treatment is superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. In the latter patients, a dosage of 10 mg/kg/day treatment was also superior to placebo. Therefore there is now for the first time class 1 evidence that CBD improves seizure control when added on to other AEDs in patients with two difficult-to-treat epileptic encephalopathies. Available data, however, do not allow to conclude that CBD per se has anti-seizure activity. At least for the trial published in full,85 a majority of patients were receiving concomitant clobazam therapy, and it is unclear whether the reported seizure benefits, as well as adverse effects, were related to a direct action of CBD, or were mediated by a previously described 5-fold elevation in plasma N-desmethylclobazam levels. For the two studies in Lennox-Gastaut syndrome, the proportion of patients on concomitant clobazam therapy was not reported, but it is likely to have been significant because clobazam is a frequently used comedication in patients with this syndrome. Clarification of the independent effects of CBD would require re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies after excluding such patients or, alternatively, adjusting blindly clobazam dosages to maintain unaltered concentration of N-desmethylclobazam. Additional well controlled studies are also desirable to determine the potential value of CBD in other seizure types and epilepsy syndromes, including refractory focal epilepsies.

One of the reasons for the utilization of cannabis products to have become so popular among patients and their caregivers is that these products are generally regarded as causing fewer adverse effects compared with traditional AEDs, partly out of the misperception that remedies derived from natural products are unlikely to be harmful. In a survey carried out by Epilepsia, 96% of respondents among the general public felt that there was sufficient safety evidence about cannabis products, whereas only 34% of physicians considered this to be the case.135 In fact, in the randomized controlled trials conducted to date the tolerability profile of CDB was relatively benign, with somnolence, decreased appetite and gastrointestinal symptoms being the most common treatment-emergent adverse events. Although these results are encouraging, further studies are required to evaluate the safety profile of CBD and other cannabis products in greater detail, particularly after long-term exposure and whenever these products are used in subpopulations potentially at risk. Elevations of liver enzymes have been frequently observed, especially in patients comedicated with valproate, and although they were generally reversible, close observation for signs suggestive of hepatic toxicity is advisable. Nabiximols, an oromucosal spray formulation containing approximately equal amounts of THC and CBD, has been commercially available in several countries for a number of years and has a relatively extensive safety record.68 However, the maximum approved daily CBD dose in nabiximols is considerably lower than the CBD doses used in epilepsy trials, and experience of nabiximols in pediatric age is limited because the product is not recommended for use ‘below 18 years of age due to lack of safety and efficacy data’.68 As discussed above, prolonged exposure of the immature brain to THC has been shown to cause deleterious effects on brain connectivity, and there is some evidence of prolonged recreational use of marijuana in adolescence being associated with neuropsychological decline and lower academic performance scores.136,137 There are also special concerns for risks to the offspring of mothers who use marijuana during pregnancy.138,139 Although these findings may be specific for THC and other psychoactive cannabinoids, adequate safety data for young children exposed to long-term CBD therapy are not yet available.24 Another area where limited data is available relates to the risk of rebound seizures following abrupt or rapid discontinuation of treatment. Unlike THC, CBD is not associated with the development of tolerance after repeated administration in various seizure models, and there is no evidence of a withdrawal syndrome developing after CBD discontinuation.12

These are exciting times for research in cannabinoids. After almost four millennia of their documented medical use in the treatment of seizure disorders, we are very close to obtaining conclusive evidence of their efficacy in some severe epilepsy syndromes. The era of evidence-based prescription of a cannabis product is within our sight.

Acknowledgements

Emilio Perucca received speaker and/consultancy fees from Eisai, Biopharm Solutions, GW Pharma, Mylan, Sanofi, Shire, Sun Pharma, Takeda, an UCB Pharma.

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.

1. Introduction

Cannabis sativa L. is an ancient medicinal plant wherefrom over 100 cannabinoids are extracted [1]. Among them, the most studied are Δ 9 –tetrahydrocannabinol (Δ 9 –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).

Structure of CBD.

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 Ca 2+ . 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.

2. 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].

3. 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 (Ca 2+ ). The neuronal Na + and Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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].

4. 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 Ca 2+ 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 Ca 2+ , 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 Ca 2+ [63]. T-Type Ca 2+ , are another class of ion channels with which CBD interacts. These channels control Ca 2+ 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 Ca 2+ , in this way the T-Type Ca 2+ 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 Ca 2+ 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].

5. Cannabidiol: Clinical Trials for Epilepsy

In the last decades, some clinical studies were conducted in order to investigate the potential effects of the efficacy of CBD in the management of epilepsy. This review provides an overview of the studies recorded on http://clinicaltrial.gov, distributing them into complete trials (see Table 1 ) and ongoing trials. All trials test the use of CBD as an adjunct to common AEDs and most of them assess the efficacy and safety of CBD especially in infants, children and teenagers. Trials exploring the combination of CBD/Δ 9 -THC have been excluded. In addition, we included further studies that have been approved by local ethics committees (see Table 2 ). In the description of these clinical trials, attention was also paid to the possible interactions of CBD with other anti-epileptic drugs.

Table 1

Completed cannabidiol clinical trials in epilepsy (https://clinicaltrials.gov/). The table shows the efficacy and safety of CBD in different forms of epilepsy. In all studies, CBD is used as adjunctive therapy to conventional antiepileptic drugs.

Identifier Study Title Subjects Conditions CBD Dose Concomitant AEDs Efficacy Security Ref
<"type":"clinical-trial","attrs":<"text":"NCT02987114","term_id":"NCT02987114">> NCT02987114 A Study to Evaluate the Safety, Tolerability and Efficacy of Oral Administration of PTL101 (Cannabidiol) as an Adjunctive Treatment for Pediatric Intractable Epilepsy 16 children (2 to 15 years) Pediatric Intractable Epilepsy 25–450 mg/kg/day
<"type":"clinical-trial","attrs":<"text":"NCT02324673","term_id":"NCT02324673">> NCT02324673 Cannabidiol Oral Solution in Pediatric Participants With Treatment-resistant Seizure Disorders 61 children (1 to 17 years) Resistant Seizure Disorders 10, 20, 40 mg/kg/day Improvement of illness SAEs in 5% of patients with medium-dose and in 9.5% with high-dose
<"type":"clinical-trial","attrs":<"text":"NCT02551731","term_id":"NCT02551731">> NCT02551731 Cannabidiol Oral Solution for Treatment of Refractory Infantile Spasms 9 infants (6 to 36 Months) Refractory Infantile Spasms 20–40 mg/kg/day Complete resolution of spasm in 14.3% of children after 14 days of treatment No SAEs were recorded
<"type":"clinical-trial","attrs":<"text":"NCT02318602","term_id":"NCT02318602">> NCT02318602 Cannabidiol Oral Solution as an Adjunctive Treatment for Treatment-resistant Seizure Disorder 52 children and young adults (1 to 18 years) Treatment-resistant Seizure Disorder 10, 20, 40 mg/kg/day SAEs in 77.78% of infants, in 38.46% of children and in 0% of adults
<"type":"clinical-trial","attrs":<"text":"NCT02224703","term_id":"NCT02224703">> NCT02224703 GWPCARE2 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome 150 children and young adults (2 to 18 years) Dravet Syndrome 10, 20 mg/kg/day
<"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 Safety, and Tolerability of Epidiolex In Patients (Ages 1–19 Years) With Intractable Epilepsy 100 children and young adults (1 to 18 years) Intractable Epilepsy 5–50 mg/kg/day CLB, Valproate, Levetiracetam, Phenobarbital, Clonazepam, Phenytoin, Carbamazepine, Lamotrigine, Oxcarbazepine, Ethosuximide, Topiramate,
Vigabatrin, Zonisamide, Eslicarbazepine, Ezogabine,
Pregabalin, Perampanel, Rufinamide, Lacosamide
4 children with concomitant valproate showed elevate damage of liver function [78]
Reduction of seizures of 63.6% after 12 weeks of treatment Improvement of AE Profile [79]
<"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412 University of Alabama at Birmingham (UAB) Adult CBD Program 100 children and adults (15 to 99 years) EpilepsySeizures 5–50 mg/kg/day 4 children with concomitant valproate showed elevate damage of liver function [78]
Reduction of seizures of 63.6% after 12 weeks of treatment Improvement of AE Profile [79]
<"type":"clinical-trial","attrs":<"text":"NCT02224560","term_id":"NCT02224560">> NCT02224560 Efficacy and Safety of GWP42003-P for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults (GWPCARE3) 225 children and adults (2 to 55 years) Epilepsy Lennox Gastaut Syndrome 10, 20 mg/kg/day CLB
Valproate
Lamotringine
Levetiracetam
Rufinamide
The median percent reduction in seizures frequency from baseline was 37.2% in the 10 mg/kg/day CBD group; 41.9% in the 20 mg/kg/day CBD group SAEs were reported in 19.40% of patients at the dose of 10 mg/kg/day of the CBD and in 15.85% at the 20 mg/kg/day [75]
<"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206 A Dose-ranging Pharmacokinetics and Safety Study of GWP42003-P in Children With Dravet Syndrome (GWPCARE1) 34 children (4 to 10 years) Dravet Syndrome 5, 10, 20 mg/kg/day CLB
Valproate
Stiripentol
Levetiracetam
Topiramate
TEAEs in 5 patients; SAE in 10% of patients at the dose of 5 mg/kg/day, in 25% at the 10 mg/kg/day and in 11.11% at the 20 mg/kg/day dose.
6 patients with concomitant valproate had elevated ALT or AST
[73]
<"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375 Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1) 120 children, young adults (2 to 18 years) Dravet Syndrome 20 mg/kg/day CLB
Valproate
Stiripentol
Levetiracetam
Topiramate
The median frequency of seizures decreased from 12.4 to 5.9, compared to the placebo-treated group SAEs in 16.39% of patients [74]
<"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults (GWPCARE4) 171 children and adults (2 to 55 years) Lennox-Gastaut Syndrome 20 mg/kg/day CLB
Valproate
Lamotrigine
Levetiracetam
Rufinamide
The monthly frequency of seizures decreased by a median of 43,·9% from baseline in the CBD group Serious TEAEs occurred in 4 patients;SAEs in 23.26% of patients. 16 of the 36 patients on valproate had transaminase elevations [76]
<"type":"clinical-trial","attrs":<"text":"NCT02224573","term_id":"NCT02224573">> NCT02224573 GWPCARE5 – An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet or Lennox-Gastaut Syndromes 264 children, and adults (2 years and older) Dravet Syndrome Lennox-Gastaut Syndrome CLB
Valproate
Stiripentol
Levetiracetam
Topiramate
The monthly frequency of seizures decreased by a median ranged from 38% to 44% SAEs in 29.2% of patients [77]
<"type":"clinical-trial","attrs":<"text":"NCT02565108","term_id":"NCT02565108">> NCT02565108 A Randomized Controlled Trial to Investigate Possible Drug-drug Interactions Between Clobazam and Cannabidiol 20 adults (18 to 65 years) Epilepsy 20 mg/kg/day CLB All participants reduced the maintenance dose of CBD from 10% for the day 2 patients withdrew from the study due to SAEs (seizure cluster)
<"type":"clinical-trial","attrs":<"text":"NCT02564952","term_id":"NCT02564952">> NCT02564952 An Open-label Extension Study to Investigate Possible Drug-drug Interactions Between Clobazam and Cannabidiol 18 adults (18 to 65 years) Epilepsy Initial 20 mg/kg/d titrated to maximum dose of 30 mg/kg/day CLB SAEs in 11% of patients

CBD: Cannabidiol; TEAEs: Treatment-emergent adverse events; SAEs: serious adverse events; AST: aspartate transferase; ALT: alanine transferase.

Table 2

Data obtained from trials authorized by local ethics committees (https://www.ncbi.nlm.nih.gov/pubmed/). The table shows the efficacy and safety of CBD in different forms of epilepsy. In all studies, CBD is used as adjunctive therapy to conventional antiepileptic drugs.

Study Design Subjects Conditions CBD Dose Concomitant AEDs Efficacy Safety Ref
A prospective, open-label, expanded access study 214 children and adults (1 to 30 years) Drug Resistant Epilepsy Initial 2–5 mg/kg/day titrated to maximum dose of 50 mg/kg/day CLB
Valproate
The median reduction in monthly motor seizure was of 36.5% Treatment-related SAEs were recorded in 20 patients;
SAEs were reported in 30% of patients. Thrombocytopenia and elevated liver function test in patients with concomitant valproate
[83]
A prospective, open-label study Children and adults (1 to 30 years) Drug Resistant Epilepsy Initial 2–5 mg/kg/day, titrated to maximum dose of 50 mg/kg/day Overall quality of life significantly improved in 48 patients, The median monthly seizures frequency was 13.9 [86]
A prospective, multicentre, open-label study 55 children and adults (1 to 30 years) Epilepsy Dravet Syndrome CDKL5 deficiency disorder Aicardi Doose syndromes Dup15q syndromes Initial 5 mg/kg/day titrated to maximum dose of 50 mg/kg/day CLB
Valproic acid
Levetiracetam
Rufinamide
Felbamate
Topiramate
Median monthly convulsive seizure frequency decreased from baseline by 51.4% at week 12 and by 59.1% at week 48 A serious treatment-emergent AEs such as status epilepticus (9%) and respiratory infection (5%) [87]
A prospective, open-label study 40 children (1 to 17 years) Drug Resistant Epilepsy Initial 5 mg/kg/day titrated to maximum dose of 25 mg/kg/day 12 patients reported substantial improvement of the condition 4 patients withdrew from the study because of AEs;
SAEs were reported in 15 patients
[88]
A prospective, multiple center, open-label study 607 children (average age 13 years) Drug Resistant Epilepsy Initial 2–10 mg/kg/day to maximum dose of 50 mg/kg/day A median monthly seizure frequency of 51% was recorded after 12 months of treatment and maintained at weeks 96 SAEs were reported in 33% of patients; [89]
Expanded access program 5 infants (1 to 45 months) Sturge-Weber Syndrome 2–25 mg/kg/day Levetiracetam
Valproic acid
Felbamate
CLB
Rufinamide
Perampanel
Clorazepate
Oxcarbazepine
Lacosamide
Topiramate
50% of seizures reductions in all patients; Improvements in quality of life in all patients AEs were recorded during the study [85]
Retrospective study 210 children (≤ 19 years) Epilepsy 2.9, 5.8 mg/kg/day CLB 50% in seizures reduction in 33% of patients in the CBD group; in 44% of CBD + CLB and in 38% of CLB group AEs in 36% of patients in the CLB group and in 7% of patients in CBD + CLB group [80]
Expand access investigational new drug (IND) trial 13 children and young (4 to 19 years) Refractory Epilepsy 5–25 mg/kg/day CLB 50% of reduction in seizures in 69.23% of patients No serious AEs in 77% of patients [72]
Open-label, fixed-sequence trial 78 healthy subjects 750 mg twice daily CLB
Stiripentol
Valproate
Moderate AEs in 8 patients; mild AEs in most of patients [81]
Expanded access study 18 children and adults (2 to 31 years) Tuberous Sclerosis Complex 5–50 mg/kg/day CLB
Lacosamide
Levetiracetam Lamotrigine
Valproic acid
Rufinamide
4 patients recorded a reduction in seizure rate greater than 80%; 1 patient became seizures-free AEs in 66.7% of patients [82]
Expanded access program 26 children (1 to 17 years) Refractory epilepsy 5–25 mg/kg/day CLB A 50% reduction in seizures SAEs in 23.1% of patients [84]

CBD: Cannabidiol; TEAEs: Treatment-emergent adverse events; SAEs: serious adverse events.

5.1. Completed Clinical Trials

All clinical studies (phases 1, 2 and 3) reported below assess the safety and/or efficacy of CBD in addition to common AEDs. Most of these studies enrolled pediatric patients (0.5 to 17 years) with diagnoses of genetically based epilepsy, LGS, DS and WS, resistant to common antiepileptic treatments. The following trials collect data on administration short-term CBD (from 10 days to 3 months).

A phase 1/2 clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02324673","term_id":"NCT02324673">> NCT02324673 has evaluated efficacy and safety of the CBD oral solution at three different doses (10, 20 and 40 mg/kg/day) administered for 10 consecutive days in sixty-one children (1–17 years) with drug-resistant forms of epilepsy. It was to assess the plasma concentration of the CBD and its metabolite (7-hydroxycannabidiol, 7-OH-CBD) in blood samples collected at baseline, at day 1 and at day 10 post-treatment at different time points (1, 2, 4, 8, 12, 24, 48, 72 h). On day one, the plasma concentrations of CBD and its metabolite increase in a dose-dependent manner. These levels, instead, decrease at the 10th day. Moreover, both at the first and at the tenth day CBD concentrations are double those of its metabolite. A negative change in clinical global impression of severity score at the end of treatment has shown an improvement of illness in all dosage. An improvement, in a dose-dependent manner, has also been observed in daily seizure activity. Serious Adverse Events (SAEs) such as apnoea, skin eruption and thrombophlebitis, were observed in 5% of patients that received medium-dose CBD and in 9.5% that received high-dose. Further no-serious Adverse Events (AEs), such as anaemia, gastrointestinal disorders (diarrhoea, flatulence, constipation, gastroesophageal reflux disease, nausea), nervous system disorders (somnolence, psychomotor hyperactivity, seizure, ataxia) were respectively observed in 65% of patients treated with low-dose CBD, in 45% treated with medium dose and in 80.95% treated with high-dose. The results of this study showed that CBD can be considered safe and tolerable even at high concentrations.

A phase 2, multi-center clinical trial ( <"type":"clinical-trial","attrs":<"text":"NCT02551731","term_id":"NCT02551731">> NCT02551731) enrolled 9 children (6 months to 36 months) with a diagnosis of WS (Infantile Spasms) who have not responded to first-line therapies. CBD in oral solution was administered at the initial dose of 20 mg/kg/day or 40 mg/kg/day. The protocol provided the division of the study into two parts: Part A and Part B. In Part A was evaluated the efficacy, defined as complete resolution of spasms and hypsarrythmia (if present at baseline) confirmed by video-electroencephalogram (EEG) and safety at day 14 of treatment. Instead, in Part B was evaluated the efficacy and the long-term safety up to 64 weeks of treatment. In Part A, 14.3% of children showed complete resolution of spasms and hypsarrhythmia (when present at baseline) on day 14. Only in 33% showed AEs, while no SAEs were recorded. No results of Part B of the clinical trial were recorded because only one subject has completed the study. Then, these results confirm the efficacy and safety of the CBD oral solution after 14 days of treatment.

The patients that concluded the clinical trials <"type":"clinical-trial","attrs":<"text":"NCT02324673","term_id":"NCT02324673">> NCT02324673 and <"type":"clinical-trial","attrs":<"text":"NCT02551731","term_id":"NCT02551731">> NCT02551731 have been involved in the completed phase 3 open-label clinical-trial <"type":"clinical-trial","attrs":<"text":"NCT02318602","term_id":"NCT02318602">> NCT02318602. The participants were divided for an age range into three groups: infants (1 to <2 years of age), children (2 to <12 years of age) and teenagers (12 to <17 years of age). All individuals continued the treatment with CBD at the same dose of trials <"type":"clinical-trial","attrs":<"text":"NCT02324673","term_id":"NCT02324673">> NCT02324673 (10, 20 and 40 mg/kg daily) and <"type":"clinical-trial","attrs":<"text":"NCT02551731","term_id":"NCT02551731">> NCT02551731 (20 mg/kg daily) for 48 weeks. The first outcome of this clinical trial was to evaluate the safety of CBD as adjunctive therapy for children with treatment-resistant convulsive disorders. Patients following treatment with established AEDs were continued uninterrupted, dose adjustments were allowed if necessary based on safety concerns or changes in seizure control. SAEs such as seizures, status epilepticus and mental status changes occurred in 77.78% of infants, in 38.46% of children and 0% of teenagers. No serious AEs (anemia, diarrhoea, constipation, vomiting, infection of the upper respiratory tract, nasopharyngitis, otitis media and influenza) occurred in 88.89% of infants, in 92.31% of children and 88.24% of teenagers. In all patients, no significant changes were observed as respect to baseline in laboratory values or in vital signs. These results show that while the administration of CBD cannot be considered safe in infants, but it was generally well tolerated in adults.

The multicenter, open-label clinical trial, <"type":"clinical-trial","attrs":<"text":"NCT03196934","term_id":"NCT03196934">> NCT03196934, is an extension of the <"type":"clinical-trial","attrs":<"text":"NCT02318602","term_id":"NCT02318602">> NCT02318602 trial. The aim of this study is to assess the long-term safety of CBD oral solution as an adjunctive treatment for pediatric subjects with a treatment-resistant seizure. No result is available today.

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.

The first clinical trial GWPCARE1 was divided into two parts: Part A ( <"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206) and Part B ( <"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375). <"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206, a double-blind randomization study (phase 2), to evaluate the safety of multiple doses of the CBD oral solution (GWP42003-P) in 34 children (4 to 10 years) with DS. All patients before enrolment had to have stabilized all AEDs at least 1 month before and the therapy stability had to be maintained during the study. Participants were randomized to one of the three doses (5, 10 and 20 mg/kg/day) of active drug or placebo at a 4:1 ratio. In addition, patients had to take their usual dose of antiepileptic drugs 2 h before CBD administration. The primary outcome was to assess the incidence of Treatment-Emergent AEs (TEAEs). A pharmacokinetic evaluation was also performed by measuring the plasma concentrations of CBD and its metabolites 7-OH-CBD and 7-carboxycannabidiol (7-COOH-CBD), and of the most common antiepileptic drugs taken by patients. Serious TEAEs, such as pyrexia and convulsions, occurred in five patients: one at the dose of 5 mg/kg/day, two at the dose of 10 mg/kg/day, one at the dose of 20 mg/kg/day and one in the placebo group. No serious TEAEs (such as pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia and abnormal behaviour) reported in 80% of patients at 5 mg/kg/day of CBD, in 62.5% at the 10 mg/kg/day dose, in 77.78% at the 20 mg/kg/day dose and in 85.71% of placebo group. SAEs such as status epilepticus, convulsion, parvovirus infection, rash maculopapular, occurred in 10% of patients who received 5 mg/kg daily of CBD, in 25% at the 10 mg/kg daily, in 11.11% at the 20 mg/kg daily and in the 14.29% in placebo group. CBD was generally well-tolerated at the 5–20 mg/kg/day dose range. Elevated transaminases (ALT or AST) were only reported with concomitant use of valproate. The study showed that exposure to CBD and its metabolites increased in a dose-dependent manner, and 7-COOH-CBD was the most abundant circulating metabolite at all doses and times. In fact, at the end of treatment, 7-COOH-CBD levels were 13–17 times higher than those of CBD. The results also showed a pharmacokinetic interaction of CBD with CLB, resulting in an increment of the metabolite N-desmethylclobazam [N-CLB] in plasma exposure of the patients. An elevation in N-CLB, was absent in patients co-administered with stiripentol, possibly reflecting prior inhibition of the CYP2C19 isoenzyme [73].

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.

Subsequently, GW launched a second Phase 3 trial, GWCARE2 ( <"type":"clinical-trial","attrs":<"text":"NCT02224703","term_id":"NCT02224703">> NCT02224703), to evaluate DS patients’ responses to either a low (10 mg/kg/day) or a high dose (20 mg/kg/day) of GWP42003-P for 14 weeks. The study, still recruiting, plans to enroll 150 participants, both children and adults (2 to 18 years). The results are not available.

The phase 3 clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02224560","term_id":"NCT02224560">> NCT02224560 (GWPCARE3) included 225 patients with LGS (2 to 55 years) with two or more seizures/week. This study was to evaluate the safety and efficacy of the CBD oral solution (GWP42003-P) as an adjunctive treatment of other antiepileptic drugs. The patients were divided into 3 groups and treated with CBD at the dose of 10 mg/kg/day or 20 mg/kg/day or with placebo for 14 weeks. During the treatment, SAEs such as pneumonia, status epilepticus, elevated aspartate aminotransferase concentration, elevated alanine aminotransferase concentration and elevated γ-glutamyltransferase concentration, occurred in 19.40% of patients treated with 10 mg/kg/day of CBD, in 15.85% treated with 20 mg/kg/day and in 10.53% of the placebo group. Increases in serum aminotransferase concentrations occurred only in patients treated with placebo. While, non-serious AEs (diarrhea, vomiting, decreased appetite, pyrexia, fatigue, somnolence, upper respiratory tract infection, nasopharyngitis) have been observed in 53.73% of 10 mg/kg daily group, in 76.83% of 20 mg/kg/day group, and in 52.63% of the placebo group. A median percent reduction from baseline in drop-seizure frequency was 37.2% in the 10 mg/kg/day CBD group, 41.9% in the 20 mg/kg/day CBD group, and 17.2% in the placebo group. The results reported by the authors show that the addition of the CBD to conventional antiepileptic therapy reduces the frequency of seizures in a dose-dependent manner [75].

The phase 3 clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690 (GWPCARE4) included 171 patients (aged between 2 and 55 years) with a diagnosis of LGS. Participants had to have taken one or more antiepileptic drugs (the most used was lamotrigine, valproate and CLB) at a stable dose for at least 4 weeks prior to screening as well as interventions for epilepsy. The first endpoint was to aim the efficacy of the CBD oral solution (GWP42003-P) as adjunctive treatment in reducing the number of drop seizures when compared to the placebo. The secondary endpoint was to assess the safety of CBD by measuring AEs using standard severity measures. Individuals were divided into two groups: 85 received placebo and 86 received a CBD at a dose of 20 mg/kg/day for 14 weeks. SAEs (pneumonia, viral infection, alanine aminotransferase increased, aspartate aminotransferase increased, γ-glutamyltransferase increased) occurred in the 23.26% of CBD group and in 4.71% of patients in the placebo group. Serious TEAEs (increased levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase) occurred in four patients in the CBD group. Instead, the most common no serious-AEs (vomiting, diarrhoea, loss of appetite and drowsiness) occurred in the 61.63% of CBD group and in 50.59% of patients in the placebo group. After 14 weeks of treatment, the monthly frequency of seizures decreased by a median of 43·9% from baseline in the CBD group. A reduction in seizures frequency of 50% or more, was reported in 44% of patients in the CBD group and in 24% of patients in the placebo group. The study found that in many patients treated with antiepileptic drugs that included CLB, a higher onset of somnolence was observed. High levels of transaminases were recorded in patients treated with valproate. Nevertheless, the high rate of AEs, the results showed that the administration of long-term CBD oral solution in patients with LGS determines the reduction in seizure frequency compared to placebo [76].

Subsequently, all patients who completed the treatment period in <"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206, <"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375, <"type":"clinical-trial","attrs":<"text":"NCT02224703","term_id":"NCT02224703">> NCT02224703, <"type":"clinical-trial","attrs":<"text":"NCT02224560","term_id":"NCT02224560">> NCT02224560 or <"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690 were included in the sixth clinical trial GWPCARE5 ( <"type":"clinical-trial","attrs":<"text":"NCT02224573","term_id":"NCT02224573">> NCT02224573). The results of this study will help to understand the safety of CBD administered over long periods. Patients received an oral solution of CBD (100 mg/mL), titrated from 2.5 to 20 mg/kg/day over a 2-week period, in addiction with their existing treatment. The median treatment duration was 274 days. SAEs such as status epilepticus and convulsion occurred in 29.2% of patients. Commonly reported AEs (diarrhoea, pyrexia, decreased appetite and somnolence) occurred in 93.2% of patients. 17.2% of patients from GWPCARE1 that taking valproic acid, had liver transaminase elevations. In patients from GWPCARE1 Part B, the monthly frequency of seizures from baseline decreased by a median of ranged from 38% to 44% in 12-week periods up to week 48.85% of patients reported an improvement in the overall condition after 48 weeks of treatment. This trial showed that long-term CBD treatment was safe and efficacy to reduce seizure frequency in patients with treatment-resistant DS [77].

A randomized controlled trial <"type":"clinical-trial","attrs":<"text":"NCT02565108","term_id":"NCT02565108">> NCT02565108 (phase 2) included twenty patients (aged 18 to 65 years) with diagnosed epilepsy treated with CLB. This study examined the possible drug-drug interactions between CLB and CBD. Participants before enrolment followed a stable therapy for at least a month with antiepileptic drugs, including CLB. Patients received CBD oral solution (GWP42003-P) at a dose of 20 mg/kg/day after taking CLB for 21 consecutive days. 75% of patients in the CBD group and 50% of patients in the placebo group showed non-serious AEs (diarrhea, nausea, vomiting, dizziness, somnolence, sedation, dermatitis). Results showed that all participants reduced the maintenance dose of CBD of 10%/day.

Eighteen participants who completed trial <"type":"clinical-trial","attrs":<"text":"NCT02565108","term_id":"NCT02565108">> NCT02565108 were transferred to the open-label extension (OLE) trial <"type":"clinical-trial","attrs":<"text":"NCT02564952","term_id":"NCT02564952">> NCT02564952. The OLE phase was a safety study. Initially, all participants received CBD at a dose of 20 mg/kg/day, thereafter the dose was decreased or increased to a maximum of 30 mg/kg/day. All individuals during the study continued to receive CLB. In addition to CLB, participants could not take more than two other AEDs during the study. Only seven of the 18 participants completed the study, 11.11% showed SAEs (status epilepticus, seizure, alanine aminotransferase abnormal, aspartate aminotransferase abnormal γ-glutamyltransferase abnormal). While, 94.44% of patients presented no-serious AEs such as diarrhoea, vomiting, headache, hyponatraemia, dizziness, seizure, somnolence, irritability, respiratory tract infection. The high rate of AEs in the concomitant use of the CBD and CLB for prolonged periods of time may be unsafe.

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.

A clinical trial of phase II <"type":"clinical-trial","attrs":<"text":"NCT02987114","term_id":"NCT02987114">> NCT02987114, is an open-label, single-center trial, that recruited 16 children (aged 2-15 years), with intractable epilepsy. The aim of this trial was to evaluate the safety, tolerability and efficacy of oral administration of PTL101 (formulation of seamless gelatin matrix green beads containing CBD) as adjunctive therapy for pediatric intractable epilepsy. Patients at least 4 weeks before enrolment had to have stabilized the doses of antiepileptic drugs. This clinical trial has included 4 weeks of observation of clinical parameters and 13 weeks of CBD treatment at an initial dose of 25 mg/kg daily up to the maximum dose of 450 mg/kg. Subsequently the patients were monitored for 2 weeks. The results of this study, not yet available.

The results obtained from all the completed studies show that CBD is a safe compound when combined with common AEDs. An aspect of particular interest concerns the association of CBD with valproate and CLB. In particular, some studies have shown that the association between CBD and valproate leads to a reduction in liver function related to an increase in transaminases. This alteration has been shown to be reversible and not to cause permanent liver damage. Pharmacokinetic studies have shown that CBD determines, as associated with CLB, a plasma increase in the metabolites of this benzodiazepine. All trials reporting efficacy data show that CBD is able to reduce the frequency of seizures.

5.2. Ongoing Clinical Trials

In the last 4 years, various tests have been started to evaluate the efficacy and safety of CBD as an antiepileptic. In this subsection, we have collected the trials that to date have not yet available results as they are still in the patient recruitment phase.

Two phase 2 clinical trials <"type":"clinical-trial","attrs":<"text":"NCT03355300","term_id":"NCT03355300">> NCT03355300 and <"type":"clinical-trial","attrs":<"text":"NCT03336242","term_id":"NCT03336242">> NCT03336242 are expecting to recruit about 30 pediatric patients (3 to 17 years), with treatment-resistant childhood absence seizure. Both studies will include three experimental treatment cohorts (20, 30 and 40 mg/kg/day). <"type":"clinical-trial","attrs":<"text":"NCT03336242","term_id":"NCT03336242">> NCT03336242 will assess efficacy, safety, tolerability and pharmacokinetics of CBD oral solution after 4 weeks of treatment. This study will include a 4-week screening period and a 5 or 10 day titration period (depending on study cohort), a 4-week treatment period followed by 5-day tapering for doses >20 mg/kg/day and a 4-week follow-up period. Instead, <"type":"clinical-trial","attrs":<"text":"NCT03355300","term_id":"NCT03355300">> NCT03355300 will evaluate the long-term (up to approximately 54 weeks) safety and tolerability of the CBD oral solution, monitoring the incidence of SAEs and AEs during and after treatment. For both trials, the final data collection and the results are expected by the end of the year 2019.

In the clinical trial <"type":"clinical-trial","attrs":<"text":"NCT03676049","term_id":"NCT03676049">> NCT03676049, CBD will be administered as an adjunct to all current AEDs in 5–10 patients (aged between 5 and 19) with refractory epilepsy. The CBD oral solution used for treatment, with prior approval from the National Institute on Drug Abuse was prepared at the University of Mississippi, and subsequently received FDA approval for compassionate use. A dosing titration period will start with 100 mg/day, and will be titrated monthly as tolerated based on clinical response, up to 300 mg/day. During the treatment period the patients will be subjected to control visits at the baseline, at the fourth, at the eighth and at the twelfth weeks. During these visits the efficacy of the treatment will be evaluated, observing the laboratory tests, quality of life of the patient, the profile of the side effects and the crisis count. Patients who after 3 months of treatment show stability could continue the use of CBD for another 3 months.

The clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02461706","term_id":"NCT02461706">> NCT02461706 will assess the safety and efficacy of CBD when administered as adjunctive therapy in 50 children (2 to 16 years) who have resistant to AEDs. Patients treated with AEDs were to have stabilized doses at least 4 weeks prior to enrolling. The study established the starting dose of 25 mg/kg/day. Maximum dose titration should be achieved in most patients within 5 weeks. The patients will be clinically evaluated at baseline, once a month for three months and once every three months thereafter. In addition, to ensure the safety of the study, all patients who reached the maximum dose (more than 600 mg of daily) of the CBD will be monitored at least once a month until the steady state of the maintenance dose was reached.

A double-blind, randomized, placebo-controlled phase 3 trial ( <"type":"clinical-trial","attrs":<"text":"NCT02783092","term_id":"NCT02783092">> NCT02783092), is intended to evaluate the efficacy of the adjuvant use of CBD oral solution (200 mg/ml dissolved in corn oil), in patients with epilepsy. The estimated 126 patients (2 to 18 years) will be treated with CBD at the initial dose of 5 mg/kg/day, up to a maximum dose of 25 mg/kg/day. The primary outcome is to evaluate whether CBD treatment resulted in a 50% reduction in seizure frequency compared to treatment with antiepileptic drugs after 30 days. The results of this study (estimated final data collection in August 2020) will make it possible to clarify the efficacy of CBD at different doses.

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.

Two phases II clinical trials <"type":"clinical-trial","attrs":<"text":"NCT02607904","term_id":"NCT02607904">> NCT02607904 and <"type":"clinical-trial","attrs":<"text":"NCT02607891","term_id":"NCT02607891">> NCT02607891 want to verify the possible drug-drug interactions between GWP42003-P and two antiepileptic drugs, stiripentol or valproate in patients with epilepsy. Both trials will enroll patients between 16 to 55 years. In the trials <"type":"clinical-trial","attrs":<"text":"NCT02607904","term_id":"NCT02607904">> NCT02607904, patients will be treated up to a maximum dose of 30 mg/kg/day for 12 months. Instead, in <"type":"clinical-trial","attrs":<"text":"NCT02607891","term_id":"NCT02607891">> NCT02607891 trials, the participants will be randomized into a 4: 1 ratio to receive GWP42003-P or corresponding placebo. The hypothesis is that levels of stiripentol or valproate may be altered as a result of using GWP42003-P. During treatment, CBD will be administered at a maximum dose of 20 mg/kg/day for 25 days. Participants had to take stiripentol or valproate and no more than two other AEDs during the blinded period of the study.

Two phases III clinical trials <"type":"clinical-trial","attrs":<"text":"NCT02953548","term_id":"NCT02953548">> NCT02953548 and <"type":"clinical-trial","attrs":<"text":"NCT02954887","term_id":"NCT02954887">> NCT02954887 intended to evaluate the efficacy and safety of CBD oral solution (GWP42003-P; GW Pharmaceutical) in infants with WS (Infantile Spasms). These studies weredivided into 3 phases: a pilot safety phase; a randomized central controlled phase and an open-label extension phase. The <"type":"clinical-trial","attrs":<"text":"NCT02953548","term_id":"NCT02953548">> NCT02953548 will be described in the pilot phase. Two cohorts of five participants will be enrolled sequentially. GWP42003-P will be administered up to a maximum dose of 40 mg/kg/day for the 2-week treatment period. Instead, clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02954887","term_id":"NCT02954887">> NCT02954887 will be an extension trial that will recruit 202 infants (from 1 month to 24 months), for 1 year of treatment. The results expected from this study will allow observing if the administration of CBD will be effective in infants with WS.

Two phases III clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02544763","term_id":"NCT02544763">> NCT02544763 and <"type":"clinical-trial","attrs":<"text":"NCT02544750","term_id":"NCT02544750">> NCT02544750 (GWPCARE6) will evaluate respectively, in a double-blinded phase and in an open-label extension phase, the efficacy of the CBD oral solution (GWP42003-P) as adjunctive therapy by monitoring the frequency of seizures in patients with TSC. <"type":"clinical-trial","attrs":<"text":"NCT02544763","term_id":"NCT02544763">> NCT02544763 is expecting to recruit about 210 patients (1 to 65 years). All AEDs or interventions will be stabilized at least 1 month before the screening and the stability of the therapy will be maintained during the study. Patients will be treated with CBD at the dose of 25 or 50 mg/kg/day for 16 weeks. The efficacy of the CBD will be tested by evaluating the change in seizure frequency. Patients that will complete this blinded phase will be included in the <"type":"clinical-trial","attrs":<"text":"NCT02544750","term_id":"NCT02544750">> NCT02544750 trial. The safety of CBD administration will be measured based on the incidence of AEs. All participants will be dosed up to a maximum of 50 mg/kg/day. From these two trials the results, not yet available, will help to understand if the administration of CBD can lead to a decrease in the crisis in patients with TSC.

A phase 1/2 clinical trial <"type":"clinical-trial","attrs":<"text":"NCT03014440","term_id":"NCT03014440">> NCT03014440, aim to determine the safety and tolerability of CBD (Epidiolex) in addition to the anti-epileptic treatments in use, in patients aged 1 to 20 years with drug-resistant epilepsy. Antiepileptic therapy followed by patients had to be stable for at least 1 month. To date, there is no information available regarding the treatment, the doses used and the results.

The <"type":"clinical-trial","attrs":<"text":"NCT02660255","term_id":"NCT02660255">> NCT02660255 is an observational, open-label, flexible dose study. The aim of this trial is to evaluate the safety and efficacy of Epidiolex, in addition to common AEDs. The study will be recruited subjects aged 1-60 years with treatment-resistant epilepsy. Patients prior to enrolment will be treated with 1–4 AEDs on stable settings from least 1 month. Epidiolex will be administered for 1 year and 9 months. To date, no superior information and results are available, yet.

The clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02397863","term_id":"NCT02397863">> NCT02397863 is an open-label, multi-center study including patients (1 to 18 years of age) with drug-resistant epilepsy. Patients are treated with CBD (Epidolex), the daily dosage is up to 25 mg/kg/day with optional up-titration to a maximal daily dosage up to 50 m/kg/day until the end of treatment. Treatment was provided for a total of 52 weeks. For this study the results have not been published, yet.

Clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02332655","term_id":"NCT02332655">> NCT02332655 (phase 1/2) aims to assess the tolerability and optimal dose of CBD to be used as a treatment in children and young adults with SWS and drug-resistant epilepsy to define the optimal dose of Epidiolex. The study involving the recruitment of the 10 patients (aged 1 months to 45 years) already in treatment with antiepileptic drugs. Patients treated with 1–5 basic antiepileptic drugs had to have reached stable doses for a minimum of 4 weeks prior to enrolment. Treatment will start with 2 mg/kg/day. The dose will be increased by 3 mg/kg/day after seven days and then by 5 mg/kg/day every seven days up to a maximum dose of 25 mg/kg/day given for 48 weeks. From the expected results potential efficacy of CBD in refractory crises in patients with SWS will emerge.

An open-label observational study <"type":"clinical-trial","attrs":<"text":"NCT02556008","term_id":"NCT02556008">> NCT02556008 will evaluate the efficacy of pure CBD for the treatment of 25 children (1 to 17 years) with severe refractory epilepsy. The pure CBD used during treatment is not approved by the FDA, therefore, investigators conducted this study through the FDA’s expanded access mechanism for compassionate use. CBD will be administered as an adjunct to all current anti-epileptic therapies. Patients had to undergo therapeutic treatment with 1-3 basic antiepileptic drugs at stable doses for a minimum of 4 weeks prior to enrolment. The expected dosage of the study was 2 mg/kg/day for a first week, 3 mg/kg/day for the second week, 5 mg/kg/day for the third week up to a maximum dose of 25 mg/Kg/day. Seizure frequency will be assessed four weeks before the initiation of CBD, the next month, and at least every 3 months thereafter. The results of efficacy of CBD are not yet available. Data from these studies will be available soon, as the final data collection for many studies is expected by the end of 2019.

5.3. Clinical Trials Approved by Local Ethics Committees

In this subsection, clinical studies published in indexed journals have been described. Many of these manuscripts report the results obtained on long periods of treatment with CBD and provide important efficacy data. In addition, the common antiepileptic drugs taken by patients in association with CBD are detailed.

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.

The efficacy of the interaction between CBD and CLB was also seen in a study conducted by Porcari, et al. [80]. This study was approved by the Vanderbilt University Institutional Review Board. In this retrospective study, the aim is to define the efficacy of CBD alone or in association with CLB in 209 children (≤ 19 years) with epilepsy. The duration of treatment in patients receiving CBD was 1.1 years, while patients received CBD + CLB for 1.3 years, and for 2.5 years received CLB. The reduction of antiepileptic drugs was seen in 21% of the CBD group, in 26% CBD + CLB and in 18% of CLB group. No-seizures were observed in 14% of patients in the CBD group, in 9% of patients in the CBD + CLB group and in 11% of patients in the CLB group. The results reported by the authors show a reduction of the crises > of 50% in 33% of the CBD group, in 44% of the CBD + CLB group and in 38% of the CLB group. It was also observed that LGS was the most commonly observed syndrome in all cohorts, and in these patients, the response rate was 58% with CBD, 52% with CBD and CLB and 40% with CLB alone. The sedation was the most common AEs reported in 36% of patients in the CLB group, in 7% of patients in the CBD + CLB group and in 0% of CBD group. This retrospective study suggests that CBD is useful in the treatment of refractory epilepsy with benefits that cannot be attributed to the interaction with CLB and increased levels of its active metabolite.

Morrison, et al. [81] conducted a pharmacokinetic study that evaluated the possible drug-drug interactions between CLB, stiripentol or valproate and CBD (Epidiolex). This study was approved by the Independent Ethics Committee of the Foundation Evaluation of Ethics in Biomedical Research, Assen, The Netherlands. For this open-label phase I study, were enrolled 78 healthy subjects. The primary outcome was to evaluate the interaction of multiple CBD administration as a perpetrator drug with antiepileptic drugs (victim) at steady-state plasma concentrations: CLB (and its active metabolite, N-desmethylclobazam); stiripentol and valproate (and its potentially hepatotoxic metabolite, 4-ene-VPA). On the contrary, was also evaluated the interaction of CBD (victim drug) and its metabolites 7-OH-CBD and 7-COOH-CBD at steady-state plasmatic concentrations, with multiple doses of CLB, stiripentol or valproate as perpetrators drugs. CBD was given at 750 mg twice daily, CLB at 10 mg/kg/day, stiripentol at 750 mg and valproate at 750 mg twice a day. The results showed a significant interaction between CBD and CLB. When CLB was used as the victim drug, significant increases in its metabolite [N-CLB] were recorded. These increases are related to an inhibition of the CPY2C19. In addition, the concentrations of the active metabolite 7-OH-CBD increased when was co-administered with CLB. Stiripentol, however, increased by 28% when it is at steady-state plasma concentrations alone, and by 50% following co-administration with CBD. The 50% increase in stiripentol concentration may be caused by an inhibition of CPY2C19 by the CBD. Instead, co-administration of stiripentol with CBD not caused an increase in CBD concentrations, but caused a 29% increase of 7-OH-CBD and 13% of 7-COOH-CBD. The interaction of the CBD and valproate did not affect the pharmacokinetics of the two drugs. Regarding the safety study, six subjects were withdrawn due to adverse events; three when CLB was added to the steady-state CBD and three when the valproate was added to the steady-state CBD. Two subjects reported SAEs when CLB was co-administered to CBD. Moderate AEs were reported in eight subjects; instead mild AEs were reported in most subjects. The results obtained by the authors can be concluded by saying that the co-administration of drugs was moderately tolerated. Furthermore, the drug-drug bidirectional interaction noted when CLB was co-administered with CBD, suggests a dose reduction for CLB when administered with CBD.

Another study to evaluate the efficacy of the CBD oral solution (GWP42003-P) as a therapy for drug-resistant epilepsy in TSC was conducted by Hess, et al. [82] (approved by Massachusetts General Hospital Institutional Review Board and U.S. Food and Drug Administration). Of the 56 patients enrolled in this study, only 18 patients (aged 2 to 31 years) were evaluated because they were affected by TSC. At the time of enrolment, patients were taking between one and seven anti-epileptic drugs, such as lacosamide (n = 14), CLB (n = 10), levetiracetam (n = 7), lamotrigine (n = 5), valproic acid (n = 3) and rufinamide (n = 3). Treatment started at a dose of 5 mg/kg/day. This dose was increased by 5 mg/kg/day every week up to the initial maximum dose of 50 mg/kg daily, for 12 months. After the third month of treatment, doses of the CBD and concomitant AEDs could be adjusted monthly in almost all patients in order to optimize seizure control. 15 patients achieved the initial maximum dose of 25 mg/kg/day of CBD, while five achieved the highest dose of 50 mg/kg/day of the CBD, and at this dose, none reported CBD-related AEs. Instead, six patients decreased the dose of CBD during the study in order to alleviate AEs and interactions with concurrent AEDs. 66.7% of patients reported AEs and among them, drowsiness, ataxia and diarrhoea. Three months after the treatment, in four patients a reduction in seizure rate greater than 80% was recorded and one patient became seizure-free and he remained free until the twelfth month. The results also show that in patients took CBD and CLB the response rate after 3 months of treatment was 58.3% against 33.3% in patients who did not take CLB. Given the results reported by the authors in this study, the CBD can be considered valid and safe in the treatment of refractory epilepsy in the TSC.

Five patients enrolled in this study were included in another multicentre analysis of CBD expanded-access conducted by Devinsky, et al. [83] (in 11 epilepsy centers in the USA). The aim of this study was to assess safe, tolerated and effective of CBD (Epidiolex) in children and young adults with severe, intractable, treatment-resistant epilepsy (the most common epilepsy syndrome treated were DS and LGS). This study was approved by the institutional review boards at each study site. CBD was used in addition to anti-epileptic treatment. For this trial, 214 patients were enrolled (1 to 30 years); of these 162 patients after the first dose of CBD were monitored for 12 weeks and were included in the safety and tolerability analysis while 137 patients (64%) were included in the efficacy analysis. Patients started the treatment with CBD at the initial dose of 2–5 mg/kg daily up to a maximum dose of 50 mg/kg daily for 12 weeks. In the safety study, SAEs were observed in 30% of patients. Treatment-related serious AEs, such as status epilepticus, diarrhoea, pneumonia and weight loss were recorded in 20 individuals. Instead, in 79% of patients showed no serious AEs, the most common were decreased appetite, fatigue, somnolence, diarrhoea, convulsions, status epilepticus, sedation, lethargy. After 12 weeks of treatment, results showed a median reduction in monthly motor seizures of 36.5%. In the patients with DS (n = 32), the treatment led to a median reduction of monthly motor convulsions of 49%, in 16 patients a reduction of 50%. Instead, for patients with LGS (n = 30), an average reduction of 36.8% in motor crises was recorded. Findings obtained from this study showed that CBD seems to reduce the frequency of seizures and also shows an appropriate safety profile, even in patients with DS and LGS.

Another study conducted by Sands, et al. [84] assessed the long-term safety, tolerability and efficacy of CBD to children with refractory epilepsy. This study was approved by the Human Research Ethics Committee of the UCSF Benioff Children’s Hospital. The CBD oral solution (Epidiolex) was administered in addition to other anti-epileptic treatments in 26 patients (aged 1 to 17 years). The doses of concomitant antiepileptic drugs had to be stable during the 4-week of baseline period and had to remain stable during the first three months of treatment. CBD was administered at the starting dose of 5 mg/kg daily and subsequently, weekly dosage was measured in increments of 5 mg/kg daily up to a maximum dose of 25 mg/kg daily. The duration of therapy ranged from 4 to 53 months. The patients underwent blood tests performed during the baseline period, after 1, 2 and 3 months and thereafter every 3 months from treatment. Furthermore, the minimum concentrations of antiepileptic drugs were evaluated. The frequency of seizures and AEs was monitored during the treatment period. The primary outcome of the study was to test the efficacy of CBD in terms of > 50% reduction in the frequency of motor seizures. Fifteen of 26 patients discontinued treatment, one due to a status epilepticus, one for severe weight loss, all others for lack of efficacy. Instead, six patients showed SAEs as status epilepticus (n = 3), catatonia (n = 2) and hypoalbuminemia (n = 1). 21 out of 26 patients reported no serious AEs among which the most frequent were: reduced appetite (n = 10), diarrhoea (n = 9), and weight loss (n = 8). In patients showing significant weight loss, the doses of CBD were reduced. Changes in the concentrations of antiepileptic drugs were observed in four patients. Three of them reported increased CLB concentrations, one reported an increment in phenobarbital contractions. In three patients was observed an increment in aspartate aminotransferase and alanine transferase levels when CBD was co-administered with valproate. The reduction in the frequency of seizures > 50%, was rediscovered in 38.4% of patients after 3 months of treatment, in 56.7% after 6 months, in 42.3% after 9 months, in 38.4% after 12 months, 42.3% after 18 months and 34.6% after 24 months. In conclusion, after 24 months of treatment, of the 26 patients enrolled, only nine continued CBD as adjunctive therapy. Of these patients, seven had a 50% reduction in the frequency of motor crises, three of which remained completely free of seizures. Only seven of the nine patients who continued treatment showed a reduction in seizure frequency > 50% after 36 months. The results reported by the authors showed that long-term CBD results in a clinically significant reduction in seizure frequency, and a low percentage of SAEs. Moreover, because treatment was stopped after a few months in most patients, the number of patients exposed to CBD for a long time is low and the rate of adverse effects over time may be underestimated.

Using the same CBD formulation (Epidiolex) and the same administration doses Kaplan, et al. [85] conducted a study that was approved by the Federal Drug Administration for the use of Epidiolex in the treatment of pediatric medically refractory epilepsy in SWS. In this study, five patients (aged 1 months to 45 years) were enrolled. The maximum dose of 25 mg/kg daily was tolerated only by two patients, while in the other three the maximum tolerated dose was 20 mg/kg per day. Three participants withdrew from the study, two due to lack of efficacy (week 38 and week 9), while one due to the temporary increase in seizures during dose titration, but later re-enrolled. Three subjects remain in the extension phase of the study continued to take CBD for more than a year. All subjects reported at least one CBD-related adverse event during the study such as temporarily increased seizures, behavioral issues, increased aspartate aminotransferase and fatigue. All transient AEs resolved spontaneously after dose changes in concomitant anticonvulsants or CBD. Seizure reduction above 50% was seen in two patients at weeks 14 and in three patients with bilateral brain involvement. Instead, subjects reported improvements in quality of life during the treatment. As suggested by the results obtained from this study, CBD appears to be well tolerated and a valid candidate as adjunctive therapy for seizures management in individuals with SWS.

Rosenberg, et al. [86] belonging to the same research group of Devinsky, et al. [83] prolonged the study for evaluating the Quality of Life of Childhood Epilepsy (QOLCE) before and after treatment with CBD (Epidolex). The study was approved by the NYU Langone Medical Center institutional ethics board. For this study were enrolled patients (aged 1–30) with intractable treatment-resistant epilepsy. In addition to the baseline antiepileptic drugs, patients were given CBD at the initial dose of 2–5 mg/Kg daily up to the maximum dose of 50 mg/Kg daily for 12 weeks. After 12 weeks of treatment with CBD, the median monthly seizures frequency was 13.9 and the median percent change from baseline was –39.4%. In addition, the results indicated an improvement of 8.2 ± 9.9 points in patient QOLCE. In fact, patients showed an improvement in behaviour, in memory, in energy/fatigue, in control/impotence, in other cognitive functions and in global quality of life.

The same research group of Devinsky, et al. [87], conducted a study for evaluating the safety and efficacy of long-term CBD administration in patients with severe childhood-onset epilepsy, and with CDKL5 deficiency disorder and Aicardi, Doose syndromes and Dup15q syndromes. This study was approved by the IRB at each institution. For this study, 55 patients aged between 1 and 30 were enrolled (with 55 in the safety group and 50 in the efficacy group). Patients were given a pharmaceutical compound of Highly purified CBD (Epidolex). Treatment included 144 weeks of Epidiolex administration in addition to anti-epileptic therapies at the starting dose of 5 mg/Kg per day. During treatment, an increase of 2–10 mg/kg per day was carried out every two weeks up to the maximum dose of 50 mg/kg per day. The efficacy study showed that the percent change in median monthly convulsive seizure frequency for all patients after treatment decreased from baseline of 51.4% to week 12 and of 59.1% to week 48 with a no significant change between weeks 12 and 48. After 12 weeks of follow-up was reported a decrease of 50% or more of seizures in 50% of patients and in 57% at 48 weeks. The safety results of the drug showed that of the 55 patients,10 patients withdrew by week 48, including 5 by weeks 12 and 48 due to lack of efficacy (n = 4) and AEs (n = 1). A total of 15 (27%) participants withdrew by week 144 of extended follow-up. There were no deaths during the study. SAEs that occurred during treatment were convulsions (9%), status epilepticus (9%) and respiratory infection (5%). While other adverse events reported more frequently were diarrhea (29%), drowsiness (22%) and fatigue (22%). These results can demonstrate the safety and tolerability of long-term treatment with CBD and the reduction in seizure frequency in these four aetiologies of epilepsy.

Chen, et al. [88] conducted an open-label study, the aim was to assess the tolerability and safety of CBD (Epidiolex) in the treatment of drug-resistant epilepsy in children. Sydney Children’s Hospital Network Human Research Ethics Committee approved the protocol for this study. Children (n = 40; mean age 8.5 years) with drug-resistant epilepsy and uncountable daily seizures in focal/multifocal epilepsy, epileptic encephalopathy, LGD and DS, were enrolled. CBD was administrated in addition to anti-epileptic therapy at the initial dose of 5 mg/Kg daily for 12 weeks. The initial dose was increased every week by 5 mg/Kg daily up to a maximum dose of 25 mg/Kg daily. During the treatment five children withdrew from the study, two because he had an increase in the frequency of the seizures, one because has manifested significant somnolence, one for respiratory depression and one because their transaminase level was elevated. SAEs occurred in 15 out of patients, the frequent recurring to treatment were increased seizure number (in eight patients), intercurrent illness (in five patients), liver function disorder (in all patients), hyperlipidemia (in all patients), severe somnolence with anorexia and respiratory depression (in one patient). Over-therapeutic phenytoin levels are another SAEs manifested in two participants were considered related to treatment and occurred at doses of 10 mg/kg/day and 20 mg/kg/day. All participants showed AEs not all attributable to treatment. While, AEs that occurred frequently (15 individuals) and linked to the treatment was the drowsiness (AEs spontaneously resolved the 10 participants), and gastrointestinal disorders (nausea, vomiting, diarrhoea) in nine patients, somnolence (13 individuals) and increased seizures (two individuals). Instead, 12 children showed an improvement in health in general. The results reported in this study show that Epidiolex can be considered useful as adjuvant therapy. The presence of adverse events and possible interactions with antiepileptic drugs are important aspects to be taken into consideration.

Szaflarski, et al. [89] conducted an open-label, Expanded-Access Program (EAP) in 25 epilepsy centers in the USA, and it was approved by an institutional review board at each site. The aim of this study was to evaluate the safety and efficacy of CBD oral solution (Epidiolex), in addition to common AEDs in patients with different forms of treatment-resistant epilepsies (TREs). For the study, 607 patients with a mean age of 13 were enrolled. All patients were included in the safety study, while 508 were included in the efficacy study. Treatment involved a 4-week baseline period followed by a 96-week treatment period. During treatment, patients received Epidiolex at the initial dose of 2–10 mg/Kg up to a maximum dose of 25-50 mg/Kg daily. 146 patients (mostly due to lack efficacy [15%] or AEs [5%]) from the safety study group and 136 patients (mostly due to lack efficacy [15%] or AEs [4%]) from the efficacy group were withdrawn from the study. SAEs were found in 33% of patients such as convulsion (9%), status epilepticus (7%), pneumonia (5%), and vomiting (3%). Instead, AEs manifested in 88% of patients the most common were diarrhea (29%), somnolence (22%), and convulsion (17%). Already after 12 weeks of treatment, the median monthly frequency of seizure convulsions was reduced by 51% and by 48 % the frequency of total seizures. These reductions remained stable during the 96 weeks of treatment. Between weeks 12 and 96 the average dose of CBD was 25 mg/kg daily, 55% of patients at follow-up had reduced the dose. Half of the patients taking concomitant CLB and valproate reduced the dose compared to baseline during the study. While, most of those who take simultaneously levetiracetam, had remained at their basal doses. The data obtained from this study show that CBD as an adjunct treatment to common AEDs can be used in the long-term effective treatment in patients with TRE.

A very interesting data in these studies is the pharmacokinetics and interaction of CBD with common AEDs. The interaction of these drugs is very complex and is linked to the individual metabolites produced and to the possible metabolic pathways that are involved. Specifically, the study conducted by Geffrey, et al. [72] shows a bidirectional drug-drug interaction when CBD is administered with the CLB for long period of time. Therefore, CLB determines an increase in serum levels of the CBD metabolite (7-OH-CBD) and conversely, CBD causes an increase in the metabolite of CLB (n-CLB). CBD is an inhibitor of CYP2C19, an enzyme involved in the degradation of n-CLB, these explain how the CBD associated with CLB causes elevated plasma levels of this metabolite. In contrast, CBD does not influence the pharmacokinetics of valproate and stiripentol when co-administered, moreover, stiripentol causes a slight decrease in CBD metabolites (7-OH-CBD 7-COOH-CBD) while valproate causes a slight increase of 7-OH-CBD. The mechanisms by which these interactions take place are not yet known but do not cause clinically relevant effects. However, the CBD shows good safety profiles, the interaction with these two drugs does not require the interruption of therapy. The modulation of the dose of these AEDs will be sufficient to resolve the adverse events. In conclusion, the results of these studies show that the administration of CBD as an addition to the common AEDs for long periods of time leads to clinically significant reductions in the frequency of convulsive and total seizures in different etiologies of epilepsy. Furthermore, an improvement in the quality of life of these patients was also observed.

6. Conclusions

The CBD is a compound extensively studied for its potential efficacy for the treatment of epilepsy. In this review, we reported the studies conducted in infants, children and teenagers affected by epilepsy resistant to common AEDs.

To date, available safety data show that the administration of CBD associated with other AEDs causes non-serious adverse events, which can be resolved reducing the dose of CBD and/or common AEDs. In this context, particular attention should be paid when CBD is associated with valproate and CLB. Specifically, abnormal liver function was noted in participants taking concomitant valproate, therefore, it is necessary to monitor serum levels of these compounds and their respective metabolites. Instead, when CBD is associated with CLB it induces an increase in its metabolites. Since the adverse effects are not serious, this association can be considered safe.

The available results also highlight the efficacy of CBD as adjunctive to common AEDs. The mechanism by which CBD interacts with other AEDs is not yet fully known, as many metabolic pathways involved in this interaction are still unknown. In addition, not all the molecular targets used by the CBD to exercise its antiepileptic action are yet known. However, the results obtained to date encourage the use of CBD associated with AEDs.

Acknowledgments

This manuscript was supported by grants of the Italian Ministry of Health.

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