The therapeutic potential of cannabis-related products has been suggested for many years (Perucca, 2017), and interest in the subject in recent decades has fluctuated in parallel with perceptions of cannabis and changes in legislation. With the realisation that (-)-trans-Δ-9-tetrahydrocannabinol (THC) is a component with prominent psychoactive properties, attention shifted to the potential therapeutic value of cannabidiol (CBD). In recent decades, interest in the therapeutic value of CBD-containing products, as anti-inflammatory, anti-emetic, anti-psychotic, and anti-epileptic treatments, has emerged for a wide range of conditions. However, the supporting data is principally based on anecdotal or in vitro experiments with supraphysiological concentrations. In addition, other compounds that may be present in artisanal CBD preparations may have independent physiological effects, leading to inevitable confusion regarding the effectiveness and safety of the preparations.
It is only within the last two years that Class I evidence has become available for a pure form of CBD, based on placebo-controlled RCTs. In the light of this recent evidence, this review aims to provide information on the current status of what is known about CBD as a therapeutic option for epilepsy, which will likely be of value to neurologists and epileptologists. This paper contributes to the following competencies of the ILAE curriculum (Blümcke et al., 2019): “Demonstrate up-to-date knowledge about the range of pharmacological treatments for epilepsy ; Recommend appropriate therapy based on epilepsy presentation ; Demonstrate up-to-date knowledge about special aspects of pharmacological treatment ”.
Laws regarding the use of raw herbal cannabis, cannabis extracts and cannabinoid-based medicines differ between countries (Abuhasira et al., 2018; Specchio et al., 2020). Recreational use of cannabis has been legalised in Canada and Uruguay, as well as 11 states and the District of Columbia in the US. More restricted recreational use has been adopted in Georgia, South Africa, Spain, and The Netherlands. The use of herbal cannabis for medicinal purposes is now authorised in a number of countries, including Argentina, Australia, Canada, Chile, Colombia, Croatia, Ecuador, Cyprus, Germany, Greece, Israel, Italy, Jamaica, Lithuania, Luxembourg, North Macedonia, Norway, the Netherlands, New Zealand, Peru, Poland, Switzerland, and Thailand, as well as a number of states in the US.
Cannabis and cannabis extracts have not been approved by the FDA or the European Medicines Agency (EMA), although cannabinoid-based products have been approved by the FDA as well as by 23 European countries and Canada. In some cases, authorisation is specific to certain indications, while in others the choice of indication may be dictated by the physician (Abuhasira et al., 2018).
In the European Union, CBD, in contrast to THC, is not a controlled substance and according to EU law, CBD products must not contain more than 0.2% THC. Several companies within the EU produce and distribute CBD-based products obtained from inflorescences of industrial hemp varieties. No analytical controls are mandatory and no legal protection or guarantees regarding the composition and quality is required. An obligatory testing and basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life, and stability is also not required. Much of the ongoing confusion results from whether such products should be regulated as a food, a supplement, or medicine.
It is beyond the scope of this review to provide details for individual countries. However, physicians considering prescribing cannabis related products should be fully aware of the relevant legislation in relation to the heath care service for their specific geographical location. Since the situation can be complex, provision and use of guidelines from recognised national professional associations and or governmental bodies can be extremely helpful. For example, in the UK, such guidelines have been provided by the British Paediatric Neurology Association (BPNA, 2018) and the National Institute for Health and Care Excellence (NICE, 2019). In both, to prescribe a cannabis related product for medicinal use for epilepsy, the prescriber must be on the Specialist Register (Reference: Section 34D of the Medical Act 1983) and the prescription should be made by a consultant paediatric neurologist. Within the UK, responsibility for the prescribing and potential adverse effects of a cannabis related product remain with the prescribing clinician. Thus, clinicians are advised to be aware of the General Medical Council (GMC) guidance on prescribing unlicensed medication (GMC, 2019), and to investigate whether medical protection insurance and hospital indemnity will cover them for prescription of unlicensed cannabis related products. Should a doctor feel under pressure to prescribe a medication that they believe is not in the patient’s interests, then paragraph 5d of the GMC guidance “Consent: patients and doctors making decisions together” is relevant (GMC, 2008). It states: “If the patient asks for a treatment that the doctor considers would not be of overall benefit to them, the doctor should discuss the issues with the patient and explore the reasons for their request. If, after discussion, the doctor still considers that the treatment would not be of overall benefit to the patient, they do not have to provide the treatment. But they should explain their reasons to the patient, and explain any other options that are available, including the option to seek a second opinion”.
ARTISANAL PRODUCTS ADVERTISED WITH CBD CONTENT
The known physiologically active components of cannabis include cannabinoids, terpenoids, and flavonoids. Plant or phyto cannabinoids are unique to the cannabis plant. Over a hundred different cannabinoid compounds have been isolated from the cannabis plant, for which various chemovars exist (Cannabis indica, ruderalis, and particularly sativa being the most common). Of these compounds, only 16 exist in meaningful concentrations; these include THC, CBD, cannabichromene (CBC), and cannabigerol (CBG) (as both acid and varin forms). The majority of animal and in vitro studies have focussed on THC and CBD, and whereas the effect of THC is less clear and appears to exhibit both proconvulsant and anticonvulsant properties under different conditions, CBD demonstrates clear anti-convulsant properties, making it a focus as a potential treatment for epilepsy.
An abundance of CBD-related products is currently commercially available, ranging extensively in purity, content of effective compounds and price. The global market for these products is considerable and according to the Centre for Medicinal Cannabis (2019) in the UK, at the current rate, the market will be worth one billion pounds/year in 2025.
Importantly, the content of CBD-related products is dependent on the type of cannabis plant as well as the different parts of the plant and growing conditions. Hemp and marijuana may be considered as different varieties of the same cannabis plant; whereas hemp is low in all cannabinoids including THC (≤0.3%), marijuana has a higher THC content (>0.3%).
Hemp seed oils (from seeds) contain minimal cannabinoids (i.e. THC); this depends principally on the extent of washing prior to subsequent processing, as cannabinoids in the flowers and leaves appear to transfer to the outer coating or husk of the seed during harvesting and preparation. Cannabis oils (from flowers and leaves of marijuana) contain variable levels of CBD and THC, depending on the chemovars. CBD-enriched oils (from flowers and leaves of hemp) contain high levels of CBD and some THC. The maximum ratio of CBD to THC that can be achieved without subsequent purification, irrespective of the chemovar, is 20:1, however, it should be noted that THC is significantly more potent (50-100-fold) than CBD. Moreover, for CBD-enriched oils advertised as “high CBD/low THC” content, in order to obtain CBD at similar doses to those used in randomised controlled trials (see below), the meaningful amount of THC may be higher than expected. For a child of 18 kg taking 300 mg CBD/day, this equates to 15 mg THC/day, based on a 20:1 CBD:THC ratio in preparations, which is similar to the maximum daily dosage of marinol or dronabinol, a synthetic Δ-9-THC (prescribed for chemotherapy-induced nausea and vomiting as well as weight loss in cancer or AIDS/HIV patients).
Galenic products are available in the form of cannabis decoction filter bags and cannabis extracts as oils, creams, and supplement capsules. Supplements appear to be the most common form, often referred to as “CBD dietary supplements” or “CBD-enriched oils”, obtained from extraction of different Cannabis sativa L. chemovars with high CBD content. Of the CBD-enriched oils, there are six main varieties available on the market in Europe: Bedrocan, Bedrobinol, Bediol, Bedica, Bedrolite and Bedropuur (table 1).
It is important to emphasise that these products demonstrate significant variation with regards to content, which is dependent not only on the initial source of the plant (e.g. the use of fertilisers and pesticides) but also the method by which they are prepared (Carcieri et al., 2018; Pegoraro et al., 2019; Bettiol et al., 2019). There are a number of different methods to prepare such oils, the most common being “supercritical CO2 extraction”. This leads to an extract rich in lipophilic cannabis components plus waxes, however, different biologically active compounds can be isolated during subsequent procedures, including omega-3 fatty acids, vitamins, terpenes, flavonoids, and other phytocannabinoids such as CBC, CBG, cannabidivarin (CBDV), and cannabinol (CBN) as a degradant (according to how the fresh the materials is) (Calvi et al., 2018). Terpenes represent the largest group (with more than 100 different molecules) of cannabis phytochemicals; these can easily cross cell membranes and the blood-brain barrier. Moreover, a synergistic effect between cannabinoids and terpenes has been hypothesised, but not proven (Russo, 2011; Aizpurua-Olaizola et al., 2016; Santiago et al., 2019).
It is also worth mentioning that an adequate dose of CBD based on commercially available CBD-enriched oils (up to 10-20 mg/kg/day), similar to doses used in randomised controlled trials (see below), comes at considerable financial cost to the family; in excess of 500 euros per month.
When it comes to CBD-enriched oils, there are major concerns regarding THC, CBD and terpene concentration, as well as appropriate preparation methods and storage conditions. These may vary significantly (Carcieri et al., 2018; Pavlovic et al., 2018), leading to insufficient quality control. Moreover, laboratory analyses have shown that the cannabinoid content is often not reflected on the marketing label (Vandrey et al., 2015).
Based on a report by the Centre for Medicinal Cannabis (2019) in the UK, there is an urgent need for a move towards accurate labelling regarding CBD content, as many products are sold with quantities of CBD which are well below those used in clinical trials. In the study by Bonn-Miller et al. (2017), the label accuracy of 84 products was analysed. Overall, CBD concentration ranged from 0.10 to 655.27 mg/mL (median: 9.45 mg/mL; median labelled concentration: 15.00 mg/mL). Of the products tested, 42.85% (n = 36) products were under-labelled, 26.19% (n = 22) were over-labelled, and 30.95% (n = 26) were accurately labelled. The level of CBD in the over-labelled products in the study is similar in magnitude to levels that triggered a warning from the US Food and Drug Administration (FDA) to 14 businesses in 2015-2016, indicating that there is a continued need for federal and state regulatory agencies to take steps to ensure accurate labelling of these consumer products.
Under-labelling is of less concern, as CBD itself does not appear to be susceptible to abuse and there have been no reported serious adverse effects (AEs) at high doses, however, the THC content observed may be sufficient to produce intoxication or impairment, especially among children. Clear labelling regarding the exact concentration of CBD is not yet mandatory, and there is clearly a need to introduce stricter legislation regarding accurate content labelling.
EFFECTIVENESS AS A TREATMENT FOR EPILEPSY
Anecdotal reports have fuelled public interest and, understandably, have inspired families to seek CBD-related products for the treatment of drug-resistant epilepsy (Filloux, 2015). The most well-known report is that of Charlotte, a five-year-old girl in the US who was diagnosed in 2013 with SCN1A-confirmed Dravet syndrome, with up to 50 generalised tonic-clonic seizures per day. Following three months of treatment with high-CBD-strain cannabis extract (later marketed as “Charlotte’s Web”), her seizures were reported to have reduced by more than 90% (Maa and Figi, 2014). Other anecdotal reports suggesting that CBD may improve seizure control as well as alertness, mood and sleep have also been documented (Porter and Jacobson, 2013; Hussain et al., 2015; Schonhofen et al., 2018).
A number of studies have investigated the effect of oral cannabis extracts on intractable epilepsy, based on parental reporting. These include the study by Press et al. (2015) of 75 patients (23% with Dravet syndrome and 89% with Lennox-Gastaut syndrome) in the US and Tzadok et al. (2016) of 74 patients in Israel over an average of six months; 50% seizure reduction was reported in 33%, and 50-75% seizure reduction in 34% in the two studies, respectively. In a retrospective study by Porcari et al. (2018) of 108 children with epilepsy in the US, the addition of CBD oil over an average of six months resulted in >50% seizure reduction in 29% patients, with 10% becoming seizure-free.
Based on a meta-analysis (n=670), Pamplona et al. (2018) provide evidence in support of the therapeutic value of high-content CBD treatments (CBD-rich cannabis extract or purified CBD). The results indicated a favourable effect for both patients with CBD-rich extracts (6.1 mg/kg/day CBD) and purified CBD (27.1 mg/kg/day), which was in fact more pronounced in patients taking the CBD-rich extracts. This may provide evidence in favour of the inclusion of other components within CBD-rich extracts offering beneficial entourage effects.
Overall, the studies on CBD-enriched oils indicate a 50% reduction in seizures in roughly 30-40% patients. However, it should be emphasised that these are uncontrolled studies with heterogeneous CBD preparations, the CBD content of which varied significantly (estimated at Press et al. (2015), the effect of cannabis extracts was investigated in a cohort of paediatric patients with epilepsy in a single tertiary epilepsy centre in Colorado, where the law on cannabis-related products is more relaxed. Interestingly, the overall responder rate (47%) for patients who had moved to Colorado for treatment was greater than that (22%) of those who were already living in Colorado, indicating a possible positive reporting bias and the need for appropriately controlled studies.
The studies described above reported AEs in 40-50% patients, including increased seizure frequency, gastrointestinal disturbances/diarrhoea, appetite alteration, weight changes, nausea, liver dysfunction, pancreatitis and, particularly, somnolence and fatigue. More serious effects included developmental regression, abnormal movements and status epilepticus.
More long-term effects regarding cannabis-derived products have generally been gathered based on indirect evidence, however, no hard conclusions can be drawn, mainly due to methodological limitations (dosage of THC and other cannabis-derived products, duration of exposure, concordant addiction to other drugs, genetic factors, psychiatric comorbidity, etc.). Long-term data from studies on prenatal and adolescent exposure to cannabis products indicate, however, a possible negative and lasting effect on cognitive and, particularly, behavioural functions (Lagae, 2020). Moreover, the externalisation of behavioural problems and a decrease in IQ have been reported as a result of chronic cannabis use. Clearly, long-term studies using large childhood epilepsy cohorts are needed on the chronic use of CBD and cannabis-related products.
PURIFIED CBD (EPIDIOLEX/EPIDYOLEX®)
A purified preparation of CBD is available from GW Pharmaceuticals plc, under the name of Epidiolex/Epidyolex® (>98% CBD). Interest has so far largely focussed on Epidiolex as an add-on drug for cases of epilepsy. Another product, Sativex® (also known as Nabiximol) (51% THC, 49% CBD), made by the same company as a refined extract, has been approved for cases of neuropathic pain, spasticity, overactive bladder and other symptoms of multiple sclerosis in some countries.
Purified CBD has been shown to demonstrate positive effects against a wide spectrum of seizures and epilepsy based on animal models (Rosenburg et al., 2017a). While the precise mechanism of action of CBD in the control of epileptic seizures in humans remains unknown, recent evidence suggests a role in modulating intracellular Ca2+ (including effects on neuronal Ca2+ mobilisation via GPR55 and TRPV1) and modulating adenosine-mediated signalling (Gray and Whalley, 2020).
In 2017 and 2018, the first randomised controlled trials for pharmaceutically prepared Epidiolex were published for Dravet syndrome and Lennox-Gastaut syndrome, respectively (Devinsky et al., 2017; Thiele et al., 2018), and in June 2018, the FDA approved CBD as an add-on antiepileptic drug for patients with Lennox-Gastaut syndrome or Dravet syndrome over the age of two. Epidiolex was also later approved by the EMA in September 2019 for patients over two years of age with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam. However, accessibility to Epidiolex outside of Europe and the US remains variable (e.g. only patients involved in RCTs may be eligible), due to a lack of approval and legal reform by central agencies. While such reform is clearly welcomed, it cannot come fast enough for those who may benefit.
PHARMACOLOGY AND DRUG INTERACTIONS
As a therapeutic drug, the pharmacokinetic profile of CBD exhibits low bioavailability, significant protein binding (99% protein binding capability), and interactions with various metabolic pathways in the liver, including CYPs that are susceptible to pharmacogenetic variability and drug interactions. However, as CBD interacts with many enzymes, it is cleared quickly and is therefore less susceptible to modulation by drugs that affect metabolising enzymes. Moreover, the pharmacokinetic profile of CBD seems relatively unaffected by inhibitors and inducers or genetic background. The bioavailability of oral oil formulations is limited (<6%) due to extensive first pass metabolism in the liver (Bialer et al., 2017, 2018).
The clinical impact of such interactions in the individual patient is difficult to predict. Patients should be systematically questioned about efficacy, tolerability and adherence, and serum concentrations should be measured if possible and dosages adjusted accordingly to optimise each patient’s treatment.
EFFICACY AS A TREATMENT FOR EPILEPSY
The first trials for purified CBD (Epidiolex) were launched as an expanded access programme in 2014 for patients with significant medically refractory epilepsy in the form of an open-label, non-controlled trial for compassionate use (Devinsky et al., 2016). Patients (n=214) with intractable seizures (at least four weekly) were monitored over a 12-week period (relative to a four-week baseline) with initial CBD doses of 2.5-5 mg/kg/day, increasing weekly to 25 or 50 mg/kg/day. Overall, a 36.5% median reduction of motor seizures was reported (49.8% for Dravet syndrome patients), and five patients were free of all motor seizures (of the patients with motor and atonic seizures, 39% and 56% showed a >50% reduction of seizures, respectively). This programme was continued and interim data on >600 patients over a 96-week period were published in 2018 by Szaflarski et al., revealing a reduction of median monthly convulsive seizures by 51% (52% with ≥50% seizure reduction) and total seizures by 48% at 12 weeks, with similar results over the 96-week period.
In the two Lennox-Gastaut syndrome double-blind placebo-controlled trials, patients (n=171 and 225) were administered CBD at 20 mg/kg/day (GWPCARE4; Thiele et al., 2018) or 10 or 20 mg/kg/day (GWPCARE3; Devinsky et al., 2018b) over a 14-week treatment period (including a titration phase of two weeks starting with a dose of 2.5 mg/kg/day, titrated to 10 or 20 mg/kg/day), and data were compared relative to a four-week baseline observation period. CBD in an oral solution or placebo was administered as add-on to current AEDs. For CBD at 20 mg/kg/day, the median percentage reduction in total seizure frequency was 41% (vs 13.7% placebo) and 38.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was reported to be 44% (vs 22% placebo) and 42% (vs 17% placebo) in the two trials, respectively. At 10 mg/kg/day, the median percentage reduction in total seizure frequency was similar at 36.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was 37% (vs 17% placebo).
Lennox-Gastaut syndrome patients who enrolled in these RCTs were also invited to enter an open-label study (GWPCARE5; Thiele et al., 2019a). The interim data after 48 weeks of treatment revealed a 48-60% median decrease in drop seizure frequency and a 48-57% median decrease in monthly total seizure frequency relative to baseline (figure 1).
Based on the patient or caregiver Clinical Global Impression (CGI) scale, overall improvements were reported in patients of each trial: 58% patients (compared to 34% in the placebo group) in the study of Thiele et al. (2018), 57% and 66% in the 20 mg/kg/day and 10 mg/kg/day group, respectively (compared to 44% in the placebo group) in the study of Devinsky et al. (2018b), and 88% at 24 weeks (also similar at 38 and 48 weeks) in the open-label study of Thiele et al. (2019a).
For Dravet syndrome, two trials involved an initial double-blind placebo-controlled trial (n=120) (GWPCARE1B; Devinsky et al., 2017) and a later open-label extension programme (GWPCARE5; Devinsky et al., 2019). An additional trial has also recently been completed (GWPCARE2; Miller et al., 2019). For the former, similar to the Lennox-Gastaut syndrome trials, patients were administered 20 mg/kg/day CBD over a 14-week treatment period, and data were compared relative to a four-week baseline period. For the open-label extension programme, a subset of these patients together with participants from the recently completed GWPCARE2 trial were enlisted (n=189) and followed over 48 weeks. For the controlled trial, during the treatment period, the median percent reduction of convulsive seizures and total seizures was 39% and 29% in the CBD arm relative to 13% and 9% in the placebo arm, respectively. The difference in median percent reduction in non-convulsive seizures was not significant. During the open-label extension programme, the median percent reduction of total seizures continued at between 39% and 51% over a 48-week period (figure 2).
As part of the expanded access programme mentioned above, the long-term effect of add-on CBD at up to 25-50 mg/kg/day over a period of 144 weeks was reported for Dravet syndrome and Lennox-Gastaut syndrome patients (Laux et al., 2019). Monthly major motor seizures were reduced by 50% and total seizures by 44%, with consistent reductions in both seizure types across the treatment period, thus supporting CBD as a long-term treatment option.
Based on the patient or caregiver CGI scale, overall improvements were reported for both trials: 62% patients (compared to 34% in the placebo arm) in the study of Devinsky et al. (2017), and 85% at 48 weeks in the open-label study of Devinsky et al. (2019).
Tuberous sclerosis complex
A clinical trial (GWPCARE6) for Epidiolex as add-on treatment in patients with tuberous sclerosis complex (TSC) was completed earlier this year and has also revealed promising results (Thiele et al., 2019b). Patients were randomised into two groups with Epidiolex (25 or 50 mg/kg/day) or placebo. Of the 201 patients who completed the study, total seizure frequency was decreased by 48% (p=0.0013), 48% (p=0.0018) and 27%, and 50% seizure reduction in 36% (p=0.0692), 40% (p=0.0245), and 22% in the 20 mg/kg/day, 50 mg/kg/day and placebo groups, respectively. An overall improvement, based on the caregiver CGI scale, was reported for 69% (p=0.0074), 62% (p=0.580) and 40% in the three groups, respectively. In conclusion, Epidiolex significantly reduced seizures in TSC patients. The therapeutic effect of the lower 25 mg/kg/day concentration was similar to that of the higher 50 mg/kg/day dose, and since the latter was associated with more AEs (see below), the 25 mg/kg/day dose would therefore be indicated for these patients.
Based on an open-label trial for compassionate use, CBD was tested as a treatment for CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes over a 12-week period (n=55) (Devinsky et al., 2018c). The mean decrease in convulsive seizure frequency was 51.4% (n=35). Studies are underway to evaluate CBD efficacy for a broader range of epilepsy syndromes and more than 20 trials are currently listed at ClinicalTrials.gov.
Overall, evidence from open-label studies suggests a favourable effect of CBD as an add-on treatment for a number of severe epileptic conditions and the controlled trials for Lennox-Gastaut syndrome, Dravet syndrome and TSC provide a clearer picture of the positive effect of CBD, in some cases even correlating with seizure freedom. A general positive trend for quality of life (particularly in Lennox-Gastaut syndrome patients), sleep behaviour (particularly in Dravet syndrome patients) and adaptive behaviour was reported. There were also particular improvements in the socialisation domain and communication domain for Dravet syndrome and Lennox-Gastaut syndrome patients, respectively. In the prospective, open-label clinical study by Rosenberg et al. (2017b), in which caregiver-reported quality of life (n=48) was evaluated for a subset of patients treated with CBD for 12 weeks, improvements (in energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behaviour and global QOL) were not related to changes in seizure frequency or AEs, suggesting that CBD may have beneficial effects on patient QOL, distinct from anti-seizure effects, however, this should be confirmed in controlled studies.
In contrast to artisanal CBD-related products, the AEs associated with purified CBD have been more clearly demonstrated based on the open-label trials and, particularly, the randomised, double-blind placebo-controlled trials (Anciones and Gil-Nagel, 2020).
Based on the collective data from the controlled trials, AEs were frequently reported (86% in CBD groups and 76% in placebo groups), however, the vast majority of AEs were mild and moderate. These included somnolence, decreased appetite, pyrexia and diarrhoea, followed by other less frequent AEs such as vomiting, fatigue and upper respiratory infections (table 3). Most AEs appeared within the first two weeks of treatment. Serious AEs were far less common (affecting 19% of CBD groups and 9% of placebo groups). These included, in particular, somnolence, pyrexia, convulsion, rash, lethargy and elevated transaminases (>three times the normal upper limit). The latter occurred in 16% patients in the CBD groups and 1% in the placebo groups. Moreover, in >79-100% of the cases with elevated transaminases, patients were concomitantly taking valproate.
No seizure worsening, suicidal ideation or deaths related to the treatment were reported. It should be emphasised, however, given the novelty of Epidiolex, that long-term AEs are currently unknown.
In the recent TSC trial with the higher dose of 50 mg/kg/day CBD (Thiele et al., 2019b), AEs were common but similarly overall reported as mild and moderate (93%, 100% and 95% in the 25 mg/kg/day; 50 mg/kg/day and placebo groups, respectively). The most common AEs were diarrhoea, decreased appetite, and somnolence, and treatment discontinuation due to AEs occurred in 11%, 14% and 3%, respectively. Elevated liver enzymes were reported in 12% (n=9) and 25% (n=18) in the 25 mg/kg/day and 50 mg/kg/day, respectively (of those, 81% were also taking valproate).
RECOMMENDATIONS FOR USE
CBD is administered orally as an oil solution. In open-label studies, doses mostly up to 25 mg/kg/day were used, and in the controlled studies, higher doses up to 50 mg/kg/day were used. The studies on Lennox-Gastaut syndrome, however, show that a significant proportion of children respond to doses of as little as 10 mg/kg/day. Therefore a “start slow” and “increase on a case-by-case basis” strategy is recommended. A starting dose of 5 mg/kg/day, divided in two doses, would appear to be adequate. This dose should be increased to 10 mg/kg/day after two weeks of treatment. Thereafter, the individual’s response should be carefully observed. The required observation time strictly depends on baseline seizure frequency before the administration of CBD. If the drug is well tolerated but not sufficiently effective, the dose should be slowly increased in increments of 5 mg/kg/day, as long as it is tolerated, up to a maximum of 20-25 mg/kg/day (table 4).
As mentioned above, special care should be taken if both CBD and clobazam are administered, since the addition of CBD may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam. A toxic benzodiazepine level may manifest as fatigue, somnolence, ataxia, a decrease in cognitive function or behavioural changes. Clinically, these are difficult to distinguish from the possible AEs of CBD itself and monitoring of clobazam/N-desmethylclobazam levels is therefore recommended. Baseline therapeutic drug monitoring should be performed before administration of CBD and subsequently after each increase. If a significant increase in benzodiazepine level is observed, the dose of clobazam should be reduced (and then checked), according to an estimate based on linear kinetics. Like CBD, however, stiripentol inhibits the same P450 subtype 2C19 (CYP2C19), and an increase in benzodiazepine level may not, therefore, occur if the patient is already on stiripentol (Devinsky et al., 2018b). It is highly recommended to follow serum concentrations of all drugs when initiating CBD as a basis for appropriate dosage adjustment. This includes psychotropic drugs (mood stabilisers, antidepressants, and antipsychotics) in order to reveal possible pharmacokinetic interactions or reasons for poor clinical effects or observed AEs.
Pharmacogenetic testing for CYP2C19 could be performed if a poor metabolizer genotype is suspected based on unexpectedly high levels of CBD relative to the dose.
Finally, biochemical markers of toxicity should be measured, particularly regarding liver enzymes in conjunction with valproate (Gaston et al., 2017; Devinsky et al., 2018a). In the controlled studies, increased liver enzymes led to withdrawal of CBD if levels were more than three times the upper normal limit in the presence of any symptoms (fever, rash, nausea, abdominal pain or increased bilirubin) or eight times higher in the absence of such symptoms. In rare cases, an increase in enzymes was observed with 20 mg/kg/day CBD without concomitant use of valproate, but not with lower doses of CBD. Overall, the increase in liver enzymes was reversible in about half the cases, without taking any action; in the remaining cases, CBD was withdrawn, leading to normalisation of levels (Devinsky et al., 2018b). A mild increase in enzyme levels may be observed over a few weeks before taking any action, however, as levels become too high, CBD or valproate should be withdrawn or reduced, according to the benefit of each.
Given the range of, and easy access to CBD-enriched oils on the market, alongside the fallacious perception that “natural” products may be safer with fewer AEs than conventional AEDs, it is clear to see why such products are popular. However, analytical controls for CBD-enriched products are not mandatory, leaving consumers with no legal protection or guarantees about the composition and quality of the product they are acquiring. Currently, CBD-enriched products are not subject to any obligatory testing or basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life or stability. The content of these products is therefore highly variable and although components other than CBD are present which may even be beneficial, there is currently no way this can be ascertained or controlled.
In contrast, purified CBD, in the form of Epidiolex/Epidyolex, is a standardised pharmaceutical preparation that is subject to minimal variability. Based on controlled trials, Epidiolex appears to be an effective treatment option for patients with Dravet syndrome, Lennox-Gastaut syndrome and TSC and has a relatively good safety profile, although it should be emphasised that, at least from the controlled trials, CBD does not outperform other drugs and will by no means represent a silver bullet for everyone. It does, however, add to the arsenal of available add-on drugs against these severe forms of epilepsy, in some cases offering substantial benefits.
Given the range of different seizure types associated with Dravet syndrome, Lennox-Gastaut syndrome and TSC, CBD would appear to have a favourable effect on a large spectrum of convulsive (consistent with preclinical data), rather than non-convulsive seizures (Devinsky et al., 2017), namely clonic, myoclonic, myoclonic-astatic, and generalised tonic-clonic seizures. It should be noted, however, that the effect of CBD on specific types of seizures was not described in detail in the controlled trials and further studies will therefore be required to address this. Other forms of intractable epilepsy cases have been investigated in open-label trials (CDKL5 deficiency disorder and Aicardi, Dup15q and Doose syndromes; Devinsky et al., [2018c]), and more than 20 trials are currently listed at ClinicalTrials.gov (including Rett syndrome and other forms of intractable epilepsy). Although these syndromes collectively represent a small fraction of the epilepsy population, clinical trials in the future may lead to CBD or indeed other cannabinoids being indicated more broadly across the spectrum of epilepsy syndromes.
A. Arzimanoglou receives salary support from the University Hospitals of Lyon (HCL). His work is also partly supported by the European Union grant for the coordination of the EpiCARE European Reference Network. He has a mission of Editor-in-Chief for the ILAE educational journal Epileptic Disorders and of Associate Editor for the European Journal of Paediatric Neurology. He is an investigator on research grants awarded to HCL, France and Sant Joan de Deu Hospital Barcelona from the Caixa Foundation, GW Pharma and UCB; he has received travel expenses or consulting fees from Advicenne Pharma, Amzell, Arvelle, Biomarin, Eisai, GW Pharma, Lündbeck, Sanofi, Shire, Takeda, UCB Pharma, Zogenix. R. Nabbout receives salary from APHP and university Paris Descartes. She reports grants from EU (EJP-RD, Horizons 2020, and FP7), research grants from Shire, Livanova, Eisai and UCB, consulting and lecturer fees from Eisai, Advicenne Pharma, Takeda, Biomarin, Lundbeck, Zogenix, novartis, and GW pharma, outside the submitted work. Antonio Gil-Nagel has received support from Zogenix, Bilal, Stoke Therapeutics, GW, UCB, Arvelle Therapeutics, Sanofi, Marinus Pharma. Nicola Specchio has received grant support and fees for advisory board participation from GW Pharma. J. Helen Cross has acted as an investigator for studies with GW Pharma, Zogenix, Vitaflo and Marinius. She has been a speaker and on advisory boards for GW Pharma, Zogenix, and Nutricia; all remuneration has been paid to her department. Her work is supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital & University College London. U. Brandl, Lieven Lagae, Cecilie Johannessen Landmark, Oliver Gubbay, and EA. Thiele have no disclosures. The workshop was supported by an educational grant from the Fundació Sant Joan de Déu (Barcelona, Spain) and the Association ESEFNP (Lyon, France).
A Washington State University study has examined how cannabis combats stress, anxiety and depression by looking at different strains and quantities of cannabis being inhaled by patients at home.
The work, published in the Journal of Affective Disorders, suggests that inhaling cannabis can significantly reduce short-term levels of depression, anxiety, and stress but may contribute to worse overall feelings of depression over time.
This new study is one of the first attempts by United States scientists to assess how cannabis with varying concentrations of THC and CBD affect medicinal cannabis users’ feelings of wellbeing when inhaled outside of a laboratory.
Current research not sufficient
Previous research to see whether cannabis combats stress and anxiety has be done with THC only strains that have been put into a capsule – but this study looks at the impact of cannabis when it is inhaled.
Carrie Cuttler, clinical assistant professor of psychology at Washington State University (WSU) and lead author of the study, said: “Existing research on the effects of cannabis on depression, anxiety and stress are very rare and have almost exclusively been done with orally administered THC pills in a laboratory.
“What is unique about our study is that we looked at actual inhaled cannabis by medical marijuana patients who were using it in the comfort of their own homes as opposed to a laboratory.”
The team found that one puff of cannabis high in CBD and low in THC was optimal for reducing symptoms of depression, two puffs of any type of cannabis was sufficient to reduce symptoms of anxiety, while 10 or more puffs of cannabis high in CBD and high in THC produced the largest reductions in stress.
Cuttler continued: “A lot of consumers seem to be under the false assumption that more THC is always better. Our study shows that CBD is also a very important ingredient in cannabis and may augment some of the positive effects of THC.”
Cannabis combats stress, anxiety and depression
The results of the study showed that patients inhaling cannabis saw a significant reduction in their adverse feelings with depression symptom being reduced in 89.3% of sessions. However, the study also revealed that the symptoms of depression were exacerbated in a total 3.2% of sessions, and there was no change in 7.5% of sessions.
Symptoms of anxiety were reduced in a total of 93.5% of tracked sessions but were exacerbated in 2.1% of sessions, and there was no change in symptoms for 4.4% of sessions. Symptoms of stress were reduced in 93.3% of tracked sessions, increased in 2.7% of sessions, and there was no change in reported levels of stress for 4% of sessions.
The study also compared the impact of cannabis on these symptoms between the sexes and found that women perceived a greater reduction in symptoms of anxiety than men did.
Dosage and the interaction between THC and CBD
The study compared different strains of cannabis that had different levels of THC and CBD to see if there was any difference.
When studying the effects on depression, the study revealed a significant THC and CBD interaction and the greatest reduction in ratings of depression were reported after using cannabis with relatively low levels of THC and relatively high levels of CBD. There was also a nonsignificant effect of dose on change in symptoms of depression.
Contrastingly, when looking at anxiety the study showed that there was no significant interaction between THC and CBD, and neither THC nor CBD alone were predictors of change in anxiety ratings. Results of models testing change in ratings of anxiety across different doses also revealed a nonsignificant linear effect. However, the team tested several models to explore curvilinear relationships – finding a significant curvilinear relationship. Further contrasts revealed that one puff produced significantly smaller changes in ratings of anxiety than all other doses, but no other differences across doses beyond one puff were detected.
When looking at whether cannabis combats stress, however, the study revealed a significant THC and CBD interaction, whereby ratings of stress were reduced the most after using cannabis with relatively high levels of THC and relatively high levels of CBD. Doses In contrast, strains with high THC/low CBD, low THC/high CBD, or low THC/low CBD, showed no appreciable differences in symptom change. Varying doses revealed a significant linear effect of dose and significant reduction of symptoms when having up to ten puffs.
Collecting cannabis impact data
The study used data taken from an app which provides medical cannabis users a means of tracking how different doses and types of cannabis affect a wide variety of symptoms of wellbeing.
The users rate the symptoms they are experiencing before using cannabis on a scale of 1-10 and then input information about the type of cannabis they are using. Twenty minutes after inhaling, they are prompted to report how many puffs they took and to rerate the severity of their symptoms.
Cuttler and WSU colleagues Alexander Spradlin and Ryan McLaughlin used a form of statistical analysis called multilevel modelling to analyse around 12,000 anonymous app entries for depression, anxiety and stress. The researchers did not receive any of the app users personally identifying information for their work.
Cuttler said: “This is to my knowledge one of the first scientific studies to provide guidance on the strains and quantities of cannabis people should be seeking out for reducing stress, anxiety and depression. Currently, medical and recreational cannabis users rely on the advice of bud tenders whose recommendations are based off of anecdotal not scientific evidence.”
The study is among several cannabis-related research projects currently underway at WSU, all of which are consistent with federal law and many of which are funded with Washington state cannabis taxes and liquor license fees.
Although the lives of patients dealing with a traumatic brain injury have improved manifold in recent years, they find themselves vulnerable to a host of side-effects that come with the modern-day medicine such as opioid painkillers, antidepressants, mood stabilizers and anti-seizure medicines.
The good news, however, is that we can now make use of legal cannabis to treat a traumatic brain injury, without the fear of death and other side-effects (recall, marijuana consumption has never resulted in a single death thus far).
A study published in 2014 found that testing positive for THC while sustaining a traumatic brain injury was associated with decreased mortality – from 11.5% to down to just 2.4%. In this post, we’ll take a look at the available research and scientific evidence that may help us determine if (and how) marijuana could help improve the condition of a person battling TBI.
Symptoms of a traumatic brain injury
TBIs occur because of a severe blow to the head, typically during an athletic event or a road accident. The common symptoms include:
Difficulties while speaking
Loss of motor control
Loss of memory
How cannabis could prove to be a breakthrough
1) Relieving Symptoms
Cannabis-derived medicines are known to drastically reduce the intensity and frequency of some types of seizures, while at the same time also displaying potent anti-anxiety and antidepressant effects, and that too without any serious side-effects.
Interestingly, a 2017 survey of 271 medical marijuana patients found that nearly 63% of participants preferred cannabis over prescription medications for the management of pain and anxiety.
2) Protection against a TBI
In order to understand this point well, you first need to have a clear understanding of the term ‘endocannabinoids’. Just like a cannabis plant produces phytocannabinoids (CBD, THC), the human body naturally produces similar molecules named endocannabinoids, which are used by the nervous and immune system to communicate.
A number of pre-clinical studies like this have shown that endocannabinoids have neuroprotective properties, which helps the brain and nervous system to recover after a blow.
It has been seen in animal models that CBD works by boosting levels of the body’s own endocannabinoids; while THC — the compound responsible for the “high” — works by taking the place of natural endocannabinoids itself in the body.
Growth of new brain cells
A study from the University of Saskatchewan (2005) found that when rodents were administered with synthetic THC, the cannabinoid apparently boosted the growth of new brain cells in a region known as the hippocampus.
The hippocampus region is responsible for memory, learning and the autonomic nervous system; research has shown that patients battling anxiety and depression often have this portion of their brain adversely affected.
Hence, the growth of new cells, courtesy of cannabis, may help in tackling the situation.
Reduced Brain inflammation
It is a well-known fact that CBD has anti-inflammatory properties. Preclinical research has found that CBD treatment immediately after a loss of oxygen can significantly reduce brain damage.
This 2011 study found that CBD treatment administered to newborn pigs after an injury effectively reduced brain edema, seizures and improved overall motor skills and behavior within just 72 hours after the injury.
The power of cannabinoids should never be underestimated. It’s only a matter of time before cannabis replaces most of the opioid medicines in use for traumatic brain injury treatment.
The three-pound organ that serves as command central for the human organism is certainly a marvel, just by virtue of the fact that the brain can appreciate its own awesomeness, even if it hasn’t quite perfected the flying car or even self-driving cars. Yet. Companies developing brain-computer interface technology are enabling humans to do things like send commands to computers by just flexing a bit of muscle. Still, there is much we don’t know about ourselves, no matter how much telepsychiatry we do. And that applies especially to medical conditions that affect the brain like epilepsy, a neurological condition for which there is no cure.
What is Epilepsy?
While most of us are probably familiar with some Hollywood-ized version of epilepsy in which someone starts flailing around after being hit by strobe lights on the disco floor, the reality is that epilepsy refers to a large group of neurological disorders that generally involve chronic, spontaneous seizures that vary greatly in how they manifest. The causes of epilepsy are also all over the place, from traumatic brain injuries and stroke to viral and bacterial infections to genetics.
Not surprisingly, many of the companies developing therapies for neurodegenerative diseases are also working on treatments for epilepsy and vice versa. For example, a new, well-funded joint venture involving Pfizer (PFE) and Bain Capital called Cerevel, which we profiled in our piece on Parkinson’s disease, is also in advanced clinical trials for an epileptic drug. Its GABA A positive modulator drug candidate targets GABA (Gamma-Aminobutyric Acid) neurotransmitters that block impulses between nerve cells in the brain, helping keep the nervous system chill.
Impacts of Epilepsy
More than 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally, according to the World Health Organization (WHO). The CDC estimates about 3.4 million Americans live with the condition. Globally, an estimated 2.4 million people are diagnosed with epilepsy each year. Interestingly, the disorder seems to target those who can least afford it: WHO said nearly 80% of people with epilepsy live in low- and middle-income countries.
A 2015 study of a bunch of other studies that estimated the cost of epilepsy in the United States found that epilepsy-specific costs probably average out to about $10,000 based on the variety of ranges, which means epilepsy costs the United States healthcare system about $34 billion, though the numbers are widely debated. Conversely, WHO says low-cost treatments are available, with daily medication coming as cheaply as $5 per year, so another win for the U.S. healthcare system.
Treatments for Epilepsy
There are more than 20 antiepileptic drugs used to treat epilepsy, usually to help prevent or slow the occurrence of seizures. Other therapies include surgery and electroceutical treatment in which electrical stimulation is applied, usually to the vagus nerve, the longest cranial nerve in the body. While many find relief from one or more of these options, a third of those who suffer from epilepsy are not able to manage their seizures, according to the U.S. National Institutes of Health (NIH). Below we take a look at a range of innovative therapies designed to detect, stop, or find a cure for epilepsy.
Brain Stimulation Therapies
In our article on electroceutical treatments, we highlighted a London company called LivaNova (LIVN) that offers an implantable Vagus Nerve Stimulation (VNS) therapy that has been approved by the U.S. Food and Drug Administration (FDA) to help treat those with partial seizures who do not respond to seizure medications. A medical device company with a lengthy track record of returning value to investors, Medtronic (MDT) got FDA pre-market approval last year for its Deep Brain Stimulation (DBS) therapy for use in reducing partial-onset seizure for those who have proven to not respond to three or more antiepileptic medications. DBS therapy delivers controlled electrical pulses to an area in the brain called the anterior nucleus of the thalamus, which is part of a network involved in seizures. Yet another company offering a variation of brain stimulation therapy is NeuroPace, which markets its responsive neurostimulation device, or RNS system, as “the first and only brain-responsive neurostimulation system designed to prevent epileptic seizures at their source.”
Artificial Intelligence to Detect, Predict, and Control Epilepsy
The NIH is funding further research into implantable devices that can detect, predict, and stop a seizure before it happens, “working closely with industry partners to develop pattern-recognition algorithms,” which sounds an awful lot like artificial intelligence and machine learning will be at the forefront of some future diagnostics and treatment. AI in healthcare has been an ongoing theme around here, with a recent dive into AI and mental health. Back to AI and epilepsy: A group of neurologists at the Medical University of South Carolina developed a new method based on artificial intelligence to predict which patients will see success with surgical procedures designed to stop seizures. Sounds like a great idea to learn beforehand if it’s necessary to crack open your skull.
A Boston area startup called Empatica, spun out from MIT in 2011, has raised $7.8 million for a smartwatch that detects possible seizures by monitoring subtle electrical changes across the surface of the skin. Other methods normally rely on electrical activity in the brain that tracks and records brain wave patterns called an electroencephalogram. Empatica’s seizure detection algorithm, on the other hand, can detect complex physiological patterns from electrodermal activity that is most likely to accompany a convulsive seizure. Psychology Today reportedthat the device, Embrace Watch, received FDA approval earlier this year for seizure control in children after getting the green light for the technology for adults in 2018.
AI and drug discovery for better epileptic drug candidates is yet another application that we would expect to see grow in the coming years. Silicon Valley-based startup System1 Biosciences raised $25 million last year, which included Pfizer among its dozen investors. System1 builds a sort of brain model for testing drug candidates using stem cell lines derived from patients with brain disease. The company uses robotic automation to develop these three-dimensional cerebral organoids, allowing it to generate huge datasets in a relatively short amount of time, then applying “advanced data analysis” (also AI?) to detect patterns that might match the characteristics of a neurological disease (what it refers to as deep phenotypes) such as epilepsy with novel treatments.
Cannabis for Controlling Seizures
We’ve written extensively about the suddenly booming hemp CBD market, noting that the FDA approved a CBD-based drug for epilepsy last year in our recent article on the best certified CBD oils on the market. However, we’ve only briefly profiled the company behind Epidiolex for treating rare forms of epilepsy, GW Pharmaceuticals (GWPH). Sporting a market cap just south of $5 billion, GW Pharmaceuticals has taken in about $300 million in post-IPO equity since our article, bringing total post-IPO equity funding to about $568 million. Aside from its successful epileptic drug, GW also developed the world’s first cannabis-based prescription medicine for the treatment of spasticity due to multiple sclerosis that is available in 25 countries outside the United States.
Back on the epilepsy side, Epidiolex has been approved for two rare forms of epilepsy, with clinical trials underway for two more rare neurological disorders associated with seizures – tuberous sclerosis complex and Rett syndrome. Also in the pipeline is a drug dubbed CBDV (GWP42006) that’s also for treating epileptic seizures, though the results of a trial last year were not encouraging. The same compound is also being investigated for autism. Be sure to check out our article on Charlotte’s Web, a CBD company that came about because of epilepsy.
Helping Cells Get Their Vitamin K
Neuroene Therapeutics is a small startup spun out of the Medical University of South Carolina that recently picked up $1.5 million in funding to tests its lead drug compounds, which are analogous to the naturally occurring form of vitamin K that is essential for brain health. In particular, the lab-developed vitamin K protects the integrity of the cell’s mitochondria, which serves as a sort of power plant for brain cells, helping the neural circuit fire better. Unfortunately, you can’t get the effect from simply eating a bowl of Special K each morning covered in an organic sugar substitute, so the company is developing a method to deliver the effects directly to the brain.
A Nasal Spray to Stop Seizures
Founded in 2007 near San Diego, Neurelis licenses, develops, and commercializes treatments for epilepsy and other neurological diseases. It has raised $44.8 million in disclosed funding, most coming in a $40.5 million venture round last November. The company’s flagship product is called Valtoco, a formulation that incorporates diazepam, an existing drug used to control seizures and alcohol withdrawal, with a vitamin E-based solution that is delivered using a nasal spray when a sudden seizure episode occurs. The product uses an absorption enhancement technology called Intravail developed by another San Diego area company called Aegis Therapeutics that Neurelis acquired in December last year. Neurelis submitted Valtoco to the FDA for approval in September.
While many people with epileptic conditions can control their seizures with many of the current medications or other therapies available now, there’s a big chunk of the population that is living with uncertainty. Considering the strong link between neurological disorders like epilepsy and certain neurodegenerative disorders, expect to see some good synergies in the next five to 10 years, especially as automation and advanced analytics using AI start connecting the dots between genetics, biochemistry, and brain disorders.
Epilepsy is considered to be one of the most common non-communicable neurological diseases especially in low to middle-income countries. Approximately one-third of patients with epilepsy have seizures that are resistant to antiepileptic medications. Clinical trials for the treatment of medically refractory epilepsy have mostly focused on new drug treatments, and result in a significant portion of subjects whose seizures remain refractory to medication. The off-label use of cannabis sativa plant in treating seizures is known since ancient times. The active ingredients of this plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the latter considered safer and more effective in treating seizures, and with less adverse psychotropic effects.
Clinical trials prior to two years ago have shown little to no significant effects of cannabis in reducing seizures. These trials seem to be underpowered, with a sample size less than 15. In contrast, more recent studies that have included over 100 participants showed that CBD use resulted in a significant reduction in seizure frequency. Adverse effects of CBD overall appear to be benign, while more concerning adverse effects (e.g., elevated liver enzymes) improve with continued CBD use or dose reduction.
In most of the trials, CBD is used in adjunct with epilepsy medication, therefore it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications. Future trials may evaluate the efficacy of CBD in treating seizures due to specific etiologies (e.g., post-traumatic, post-stroke, idiopathic).[…]
Epilepsy drugs don’t work well, or at all, for about one-third of people with the condition. Unfortunately, these hard-to-treat epilepsies are associated with an increased risk of premature death.
Anecdotal evidence suggests that cannabis oil may help some of these people control their seizures and potentially save their lives. A small number of studies have shown that adding cannabis oil to existing medication may be effective in devastating, hard-to-treat epilepsy in children and adolescents.
One of those people is 12-year-old Billy Caldwell. Billy was in the UK news recently after the cannabis oil prescribed for him was confiscated at Heathrow airport by the authorities. Billy’s mother, Charlotte, was attempting to bring the cannabis oil into the UK from Canada, where cannabis oil is legal.
Billy was seizure-free for more than 250 days when taking the oil, but his seizures started again when his cannabis oil was withdrawn. The home secretary, Sajid Javid, was persuaded to intervene and one of the seven bottles of cannabis oil was returned, with a 20-day licence to administer the medicine.
In a similar case, six-year-old Alfie Dingle, who suffers from severe epilepsy, had been successful[ly] treated with cannabis oil in the Netherlands. Alfie’s mother, Hannah Deacon, has been campaigning to allow her son to be provided with cannabis oil in the UK.
The government has now also relented in Alfie’s case following the concerns raised around the confiscation and return of Billy Caldwell’s medicine.
What the evidence shows
So what do we know about cannabis oil and its effects on epilepsy seizures?
The two main constituents of cannabis oil are THC (tetrahydrocannabinol) and CBD (cannabidiol). Oil containing CBD alone (CBD oil) can be legally bought in the UK without a prescription because it contains only very low quantities of THC. But cannabis oil that contains THC at higher levels (more than 0.3%) is illegal. THC is a schedule 1 drug, that is to say, it is deemed to have no medicinal value.
The reason that Billy’s cannabis oil was seized at Heathrow airport was that it didn’t just contain CBD, it also contained THC at higher levels than legally permitted.
There is good evidence in robust human clinical trials that CBD is of benefit for specific epilepsies, such as Dravet syndrome and Lennox Gastaut syndrome. An advantage for the pharmaceutical industry is that these rare diseases with no cure can be fast-tracked for drug development. On this basis, the US Food and Drug Administration is widely expected to grant a licence for CBD (under the tradename Epidiolex) to treat these epilepsies. If so, Epidiolex is likely to be available in US by late 2018. European approval is likely to follow.
It should be noted that Epidiolex is designed as standardised oral solution of pure plant-derived CBD. It is not the same as the non-standardised, viscous CBD oils that contain varying amounts of CBD and can be purchased in health food shops. There is currently no good evidence that formulations of CBD oil (or indeed cannabis oil) are as effective on epilepsy seizures. Equally, there is no robust evidence – just anecdotal reports – that THC helps reduce epilepsy seizures human.
In [animal studies], THC has weak overall effects in reducing seizures and has also been shown to be a less effective anticonvulsant than CBD. THC, being a psychoactive substance, also has a number of side effects, including the well-known euphoric “high” associated with recreational use – which is a significant disincentive for the pharmaceutical industry to develop a medicine containing this compound.
We now need to decide if we should expand human trials with better defined THC-containing cannabis oil, or if we should focus on CBD. The fact that Epidiolex has progressed towards approval in the US may encourage the latter course. CBD lacks psychoactive effects associated with THC and, in general, is regarded as a safe compound.
If Epidiolex is granted regulatory approval, it will also need to be monitored in a larger number of patients – in what’s known as “phase 4 post-marketing surveillance” – to ensure that it is safe and effective in a broader population. For any cannabis-based product, only large-scale clinical trials can provide definitive answers about effectiveness and safety.
Description: Spectrum News presents a free webinar with Orrin Devinsky on cannabis compounds for epilepsy. He is professor of neurology, neurosurgery and psychiatry at New York University and director of the NYU Langone Comprehensive Epilepsy Center. Time: 3 p.m. Eastern Time.
An advisory panel from the United States Food and Drug Administration (FDA) has recommended the approval of a novel epilepsy drug that is made up of ingredients from marijuana. The agency normally follows the recommendations of the advisory panels regarding approvals and rejections of applications of new drugs. The recommendation statement came yesterday (19th April 2018).
If this drug gets a green light, it is expected to become the first cannabis-derived prescription medicine to be available in the US. The drug is named Epidiolex and is made by GW Pharmaceuticals from Britain. It contains cannabidiol or CBD that is derived from cannabis. However the drug is not seen to cause any intoxication among the users.
The use of only one of the components of cannabis also makes it different from medical marijuana that is approved for pain management and other conditions around the world and in the United States. Synthetic forms of chemicals in the cannabis plant are also used to treat nausea among cancer patients and in AIDS patients to prevent weight loss.
Dr. Igor Grant, director of the Center for Medicinal Cannabis Research at the University of California San Diego welcomed this new recommendation from the panel saying, “This is a very good development, and it basically underscores that there are medicinal properties to some of the cannabinoids… I think there could well be other cannabinoids that are of therapeutic use, but there is just not enough research on them to say.”
As of now the panel has recommended the use of this new drug for two types of epilepsy only – Lennox-Gastaut syndrome and Dravet syndrome. These are notoriously difficult to treat and most people continue to have seizures despite treatment. Multiple seizures may occur in a day and this makes the children with these conditions vulnerable for developmental and intellectual disabilities. Lennox-Gastaut syndrome can appear in toddlers at around ages 3 to 5 and Dravet syndrome is usually diagnosed earlier. Nearly 30,000 children and adults suffer from Lennox-Gastaut syndrome and similar numbers of people are diagnosed with Dravet syndrome. Due to the small population of diagnosed patients Epidiolex was filed and classified under orphan drug status.
An orphan drug is one that is developed for a relatively rare disease condition. The FDA provides special subsidies and support for development of orphan drugs and often speed tracks their approval process.
The recommendation from the advisory panel is based on the results of three randomized, double-blind, placebo-controlled trials that included patients of both these disease conditions. The agency statement says, “The statistically significant and clinically meaningful results from these three studies provide substantial evidence of the effectiveness of CBD for the treatment of seizures associated with LGS and DS.” They drug causes liver damage but the report says that this could be managed effectively.
The FDA will conduct a final vote for approval of this drug in June. Oral solution of the drug for a small group of patients with these conditions would be allowed.
Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5–55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.
The International League Against Epilepsy (ILAE) defines epilepsy as a disease of the brain, diagnosis of which requires: (a) at least two unprovoked seizures occurring >24 hours apart; (b) one unprovoked seizure and a probability for further seizures of at least 60%, occurring over the next 10 years or (c) the diagnosis of an epilepsy syndrome.1 Between 70% and 80% of patients with new-onset epilepsy achieve complete seizure control using antiepileptic drugs such as valproate or carbamazepine.2 In 20%–30% who are drug-resistant,3 4 there is great interest in investigating novel agents to reduce seizure frequency and severity. For the purposes of this review, the ILAE’s definition of drug-resistant epilepsy—the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (AEDs) schedules (as either monotherapies or in combination) to achieve seizure freedom5—is used. For the 30% of patients who experience drug-resistant epilepsy, the efficacy of alternative and adjunctive therapies is likely to be of great interest.
Preclinical studies suggest that naturally occurring cannabinoids (phytocannabinoids) have anticonvulsant effects which are mediated by the endocannabinoid system.6 Cannabidiol (CBD) and cannabidivarin have shown antiseizure effects in both in vivo and in vitro models. In contrast to tetrahydrocannabinol (THC), CBD does not produce euphoric or intrusive psychoactive side effects when used to treat seizures.7 Cannabinoids have been proposed as an adjunctive treatment for epilepsy7 and parents of children with epilepsy report using CBD products.8–10 There are a number of phase III human trials underway of CBD as an adjunctive therapy for treatment resistant paediatric and adult epilepsies.11 12
Recently Israel, the Netherlands, Germany and Canada have legislated to allow the use of cannabinoids for medicinal purposes. In Australia, Federal and state legislation that allows doctors to prescribe cannabinoids is being implemented. Systematic reviews are required to synthesise the evidence for individual conditions for which cannabinoids may be used to inform clinical practice and patient guidance.
This review considers evidence on the safety and efficacy of cannabinoids as adjunctive treatments for drug-resistant epilepsy. As previous reviews noted a lack of controlled studies,13 14 we synthesised evidence from randomised controlled trials (RCTs) and observational studies.[…]
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. (2017;7:61-76) […]