how does cbd work for epilepsy

December 15, 2021 By admin Off

A prescription for medicinal cannabis would only be given when all other treatment options have been tried or are considered unsuitable, and would only be given if the doctor considers it to be in your best interests.

The BPNA guidance states that non-licensed medicinal cannabis should only be considered for children who:

The recommended guidelines are still only draft and the consultation closes on 16 September. So there is still time for you to have your say and let them know what you think. Professor Sander will be doing the same. All comments received will be considered by NICE and final guidance is likely to be published in November 2019.

CBD does not contain any significant amount of THC, the component of cannabis associated with producing a ‘high’.

THC is the psychoactive compound in cannabis. It is responsible for the “high” people feel. The legal limit of THC content in a product, as stipulated by the Home Office, is 0.2%.

Getting a prescription for medicinal cannabis.

Guidance for other conditions is being drawn up the Royal College of Physicians with the Royal College of Radiologists (RCR) and the Faculty of Pain Medicine of the Royal College of Anaesthetists.

Concerns have also been raised about the effect of THC on the developing brain in children and young people. Evidence suggests that chronic exposure to THC can affect brain development, structure and mental health.

The BPNA states that the current best evidence for medicinal cannabis is CBD, a highly purified liquid, which has been licensed in the US by the Food and Drug Administration and is currently going through the application process for a licence from the European Medicines Agency.

“Clinicians should not feel under pressure to prescribe cannabis-based medicinal products until they have undergone proper clinical trials,” says the BPNA.

Although the label Lennox-Gastaut is often broadly attached to severe epilepsies with compatible seizure types and intellectual disabilities, it is important that there is a clear syndromic diagnosis.

People always have the option of seeking a second opinion.

The reason that the BPNA is only recommending CBD is that there is some evidence to show that this newly developed drug can be effective in reducing some type of seizures in Dravet and Lennox Gastaut syndromes.

CBD is not psychoactive and it is thought to be responsible for many of the medical benefits associated with cannabis.

Interim guidance from the ABN states that there is only published evidence for the use of medicial cannabis in Dravet syndrome and Lennox-Gastaut syndrome. Prescriptions should only be for cannabidiol.

The British Paediatric Neurology Association (BPNA) has drawn up interim guidance around epilepsy on behalf of NHS England.

Guidance from the Association of British Neurologists (ABN)

On 1 November 2018, the Government's landmark decision to reschedule some cannabis based products for medicinal use, came into force. The change in law means that specialist doctors in the UK can now prescribe medicinal cannabis to people with a limited number of conditions, including epilepsy. Here we explain what the change in law means for people with epilepsy.

The body also has concerns about the ‘viability of the economic model’ used by GW Pharma, the company that developed the drug, to establish the cost to be charged to the NHS for it. It concluded that Epidyolex would not, at this stage, be an effective use of NHS resources.

The Government has no plans to legalise the use of cannabis for recreational purposes. Possession of cannabis is illegal. This includes cannabis for medical use unless it has been prescribed for you.

“We recommend that these products undergo randomised clinical trials for efficacy and safety before they are routinely prescribed in the UK. We welcome the rescheduling of these products from Schedule 1 to Schedule 2 that will enable their investigation in clinical trials.”

“Is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative; is produced for medicinal use in humans and is a medicinal product, or a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product”.

Cannabis-based medicinal products can only be prescribed by a specialist. A GP cannot prescribe the medication but could refer you to a specialist.

The BPNA also recommends that where children are already taking other cannabis-based products that contain higher proportions of THC, they should be transitioned on to CBD until strong evidence for these products can be produced through clinical trials.

Guidance around prescribing cannabis-based products.

Three double blind randomised controlled trials of pure CBD in children and young people with these syndromes has shown a greater reduction in monthly seizures compared to placebos. There was also a greater reduction in drop seizures in people taking CBD compared to those on a placebo. Further open label studies have shown that it may also have an anti-epileptic effect in the epilepsies in general.

Dosing data for adults is currently very limited, although more information is expected shortly.

There is also a wide range of other cannabis products available on the internet and in some commercial outlets such as health food outlets and from cannabis ‘dispensaries’ internationally. These products are of unknown quality and contain CBD and THC in varying quantities and proportions.

Cannabis is made up of hundreds of different components. The most well known are two cannabinoids: CBD – cannabidiol – and THC – tetrahydrocannabinol. These are found naturally in the resin of the cannabis plant.

There is also no good scientific evidence to support suggestions that the addition of THC in combination with CBD increases the efficacy of cannabis-based medicinal products for children.

In August 2019, NICE – the National Institute of Health and Clinical Excellence – announced that it would not be recommending that cannabidiol, a medicinal cannabis in the form of Epidyolex, should be prescribed on the NHS for children with two severe forms of epilepsy. This is on account of the fact that its long-term effect remains unclear.

While some studies have also suggested that THC may have an anti-epileptic effect, animal studies suggest it can also trigger seizures. There is no evidence from randomised controlled clinical trials for products with higher proportions of THC (more than 0.2 per cent).

The Government has defined a cannabis-based product for medicinal use in humans as one that:

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.

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%).

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.

Chemistry and mechanisms of action.

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 G i/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.

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.

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.

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.

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.

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.

Purified cannabidiol.

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.

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

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.

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.

Conclusions and future perspectives.

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.

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.

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.

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.

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.