Posts Tagged CBD

[ARTICLE] Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment – Full Text

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 ”.

LEGISLATION

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 indicaruderalis, 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.

PRODUCT LABELLING

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.

ADVERSE EVENTS

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).

CBD may exhibit numerous interactions with AEDs (Johannessen Landmark and Patsalos, 2010; Johannessen and Johannessen Landmark, 2010; Johannessen Landmark et al., 2012, 2016; Patsalos, 2013a, 2013b) including both potent enzyme inducers (such as carbamazepine and phenytoin) and inhibitors (such as stiripentol, felbamate and valproate) (table 2), however, the clinical significance of these interactions may not be meaningful. The most obvious and clinically significant interaction between CBD and other concomitantly used drugs, based on clinical trials, is that with clobazam. CBD, via enzyme inhibition (CYP2C19), may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam (Geffrey et al., 2015; Devinsky et al., 2018a), leading to toxicity (principally manifesting as sedation [Gaston et al., 2017]), which may occur at even low levels (1 mg/kg/day) (unpublished observations; Johannessen Landmark). In addition, concurrent clobazam may lead to increased 7-hydroxy-cannabidiol (an active metabolite of CBD) (Morrison et al., 2019), which arguably may lead to better seizure control by boosting the effect of CBD, however, studies with and without clobazam are needed to confirm this. Other AEDs with a similarly increased effect, concomitant with CBD, may include topiramate, rufinamide, zonisamide and eslicarbazepine (Gaston et al., 2017; Franco and Perucca, 2019). There are therefore still a number of unanswered questions regarding the pharmacology of CBD (Johannessen Landmark and Brandl, 2020; Brodie and Ben-Menachem, 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.

With these very encouraging results, shortly after the initial launch of this programme, controlled trials for Epidiolex were established for Dravet syndrome (Devinsky et al., 2017) and Lennox-Gastaut syndrome (Thiele et al., 2018; Devinsky et al., 2018b). For further details regarding these trials, refer to Nabbout and Thiele (2020).

Lennox Gastaut syndrome

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).

Dravet syndrome

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.

Other syndromes

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.

ADVERSE EFFECTS

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.

CONCLUSIONS

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.

DISCLOSURES

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 Collaborators, Members of The Cannabinoids International Experts Panel: Stéphane Auvin (France), Mar Carreno (Spain), Richard Chin (UK), Roberta Cilio (Belgium), Vincenzo Di Marzo (Italy), Maria Del Carmen Fons (Spain), Elaine Hughes (USA), Floor Janssen (The Netehrlands), Reetta Kalvilainen (Finland), Tally Lerman-Sagie (Israel), Maria Mazurkiewicz-Bełdzińska (Poland), Nicola Pietrafusa (Italy), Georgia Ramantani (Switzerland), Sylvain Rheims (France), Rocio Sánchez-Carpintero (Spain), Pasquale Striano (Italy), Ben Whalley (UK).

via John Libbey Eurotext – Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment

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[WEB PAGE] Study shows that cannabis combats stress, anxiety and depression

© iStock/OlegMalyshev

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.

via Study shows that cannabis combats stress, anxiety and depression

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[BOOK Chapter] Medication: Epilepsy – Abstract References Resources

Abstract

This chapter covers the use of medication in epilepsy, specific information about antiepileptic medication and what to do if there are issues or concerns about an individual’s medication.

References

  1. Berg A (2008) Risk of recurrence after a first unprovoked seizure. Epilepsia 49(Suppl 1):13–18CrossRefGoogle Scholar
  2. Brodie M, Barry S, Bamagous G, Norrie J, Kwan P (2012) Patterns of treatment response in newly diagnosed epilepsy. Neurology. 15:78(20)1548–1554Google Scholar
  3. Epilepsy Action (2019) Travel advice for people with epilepsy. https://www.epilepsy.org.uk/info/daily-life/travelling-abroad. Accessed 03 Jan 2019
  4. Epilepsy Society (2019) Generic and branded anti-epileptic drugs. https://www.epilepsysociety.org.uk/generic-and-branded-anti-epileptic-drugs. Accessed 03 Jan 2019
  5. House of Commons and Social Care Committee (2019) Drugs policy: medicinal cannabis. https://publications.parliament.uk/pa/cm201719/cmselect/cmhealth/1821/1821.pdf. Accessed 03 Jan 2019
  6. Medicines and Healthcare Products Regulatory Agency (2018) Valproate use by women and girls. Updated 2019. https://www.gov.uk/guidance/valproate-use-by-women-and-girls. Accessed 02 Jan 2020
  7. Medicines for Children (2017) Frequently asked questions (FAQs). https://www.medicinesforchildren.org.uk/frequently-asked-questions-faqs. Accessed 03 Jan 2019
  8. Mohanraj R, Brodie M (2006) Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13(3):277–282CrossRefGoogle Scholar
  9. National Institute for Health and Care Excellence (NICE) (2012) Epilepsies: diagnosis and management. Clinical Guideline CG137. Updated 2019. https://www.nice.org.uk/guidance/cg137. Accessed 02 Jan 2020
  10. National Institute for Clinical Excellence (NICE) (2016) Controlled drugs: safe use and management. NICE Guidance NG46. https://www.nice.org.uk/guidance/ng46. Accessed 02 Jan 2020
  11. Shakespeare J, Sisodiya S (2019) Guidance document on valproate use in women and girls of childbearing years. https://www.rcog.org.uk/globalassets/documents/guidelines/valproate-guidance-march-2019.pdf. Accessed 02 Jan 2020

Resources

  1. British National Formulary (BNF); Children’s British National Formulary (BNFC). https://bnf.nice.org.uk/
  2. Epilepsy Society (2016) Contraception and Epilepsy. https://www.epilepsysociety.org.uk/contraception-and-epilepsy#.XiwkV2j7TIU. Accessed 25 Jan 2020
  3. Medicines for Children (2017) Helping your child to swallow tablets. https://www.medicinesforchildren.org.uk/sites/default/files/contenttype/leaflet/pdf/Guide%20to%20swallowing%20tablets%2030.11.17.pdf. Accessed 25 Jan 2020
  4. Medicines Healthcare products Regulatory Authority (MHRA) (2017) Branded anti-seizure medication information. https://www.gov.uk/drug-safety-update/antiepileptic-drugs-updated-advice-on-switching-between-different-manufacturers-products
  5. NHS (2018) What is a controlled medicine (drug)? https://www.nhs.uk/common-health-questions/medicines/what-is-a-controlled-medicine-drug/. Accessed 02 Jan 2020

via Medication: Epilepsy | SpringerLink

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[Abstract + References] Cannabinoids for the Treatment of Epilepsy: a Review

Abstract

Purpose of review

Treatment-resistant epilepsy (TRE) is associated with severe morbidity and mortality and affects over 30% of epilepsy patients. Despite advances in epilepsy management over the last 30 years, this rate has largely remained unchanged. Through a largely patient driven movement and despite federal regulations, cannabidiol (CBD) emerged as a candidate drug for improving the management of treatment-resistant epilepsies. This review highlights the available research on CBD and its therapeutic role in the treatment of TREs.

Recent findings

Randomized controlled trials have established CBD as an add-on treatment option for the management of seizures in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), and there is a growing body of additional literature supporting CBD’s use as an add-on therapy in other TREs. Several studies have shown CBD to be a safe anti-seizure medication with dose-dependent mild-moderate adverse events which resolve with treatment de-escalation. CBD does affect toxicity with other anti-seizure medications including clobazam and valproate.

Summary

CBD is a safe and efficacious adjunctive therapy in the management of treatment-resistant epilepsies.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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    Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern J, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hock task force of the ILAE commission on therapeutic strategies. Epilepsia. 2010;51(6):1069–77.

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    Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78:1548–54.

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    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.

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    Racoosin JA, Feeney J, Burkhart G, Boehm G. Mortality in antiepileptic drug development programs. Neurology. 2001;56(4):514–9.

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    Sabaz M, Lawson JA, Cairns DR, Duchowny MS, Resnick TJ, Dean PM, et al. Validation of the quality of life in childhood epilepsy questionnaire in American epilepsy patients. Epilepsy Behav. 2003;4:680–91.

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    O’Shaughnessy WB. On the preparations of the Indian hemp, or gunjah (Cannabis indica). Transactions of the medical and physical society of Bengal; 1840:71–102.

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    Reynolds JR. Therapeutical uses and toxic effects of Candida indica. Lancet. 1868(1):637–8.

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    Gowers WR. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881.

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    Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften. 1978;65:174–9.

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    Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29(3):574–7.

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    Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783–6.

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    US Food and Drug Administration. Warning letters and test results. 2015–2019. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products (Accessed July 6th, 2019).

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    Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules. 2019;24:1459–74.

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    Pertee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol, and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2006;152(2):199–215.

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    Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta 9-tetrahydrocannabinol and cannabidiol. J Biol Chem. 2008;283:16124–34.

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    Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70:313–8.

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    Patel RR, Barbosa C, Brustovetsky T, Brustovestsky N, Cummins TR. Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain. 2016;139:2164–81.

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    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–51.

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    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al. Randomized, dose ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14).

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    •• Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20. This pivotal clinical trial provided evidence of CBD efficacy as adjunctive therapy in Dravet syndrome assisting its eventual Federal Drug Administration (FDA)-approved indication for adjunctive therapy in this patient population.

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    •• Devinsky O, Patel AD, Cross JK, Villanueva V, Wirrell EC, Previtera M, et al. Effects of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378:1888–97. This pivotal clinical trial provided evidence of CBD efficacy as adjunctive therapy for the treatment of drop seizures in Lennox Gastaut Syndrome assisting its eventual Federal Drug Administration (FDA)-approved indication for adjunctive therapy in this patient population.

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    Thiele EA, March ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–96.

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    Szaflarski J, Bebin E, DeWolfe J, Dure L, Gaston T, Harsanyi K, et al. Seizure response to cannabidiol in a state-sponsored open-label program (S14.006). Neurology. 2016;86(16).

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    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.

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    Szaflarski JP, Bebin EM, Cutter G, DeWolfe J, Dure LS, Gaston TE, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018;87:131–6.

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    • Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8). The results from this expanded access open-label program provide the largest published cohort to date of CBD use in a population of both children and adults with TREs providing important long-term safety and treatment effect data.

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    Sands TT, Rahdari S, Oldham MS, Caminha Nunes E, Tilton N, Cilio MR. Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US. CNS Drugs. 2019;33(1):47–60.

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    Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2018:60(2).

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    Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvn LA, Bruno PL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis. Epilepsia. 2016;51(10):1617–24.

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    Devinsky O, Verducci C, Thiele EA, Laux LC, Patel AD, Filloux F, et al. Open-label use of highly purified CBD (Epidiolex) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018;86:131–7.

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    Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32(1):35–40.

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    Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D. Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia. 2017;58(8):96–100.

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    Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol. 2017;71:18–23.

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    Morrison G, Crockett J, Blakey G, Sommerville K. A phase 1, Open-Label, Pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Am Coll Clin Pharmacol. 2019.

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    Gaston TE, Beben EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9).

via Cannabinoids for the Treatment of Epilepsy: a Review | SpringerLink

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[WEB PAGE] The ABCs of CBD: Separating fact from fiction – NIH MedlinePlus Magazine

CBD. Cannabidiol. No matter what you call it, you may have heard health claims about this little-known part of the marijuana plant, which comes from the plant’s flowers. Some say it treats muscle aches, anxiety, sleeping troubles, chronic pain, and more.

But what does the science say?

We spoke to NIH expert Susan Weiss, Ph.D., to learn more and find out why consumers should be careful. Dr. Weiss is the director of the division of extramural research at the National Institute on Drug Abuse (NIDA).

What is CBD?

CBD (or cannabidiol) comes from the cannabis (or marijuana) plant.

The chemical compound THC [tetrahydrocannabinol] is the part of the cannabis plant that most people are familiar with because that is the part that makes people “high.” Most effects of marijuana that people think of are caused by THC.

Most recreational marijuana has very little CBD in it. CBD products are available through dispensaries, health food and convenience stores, and the internet. It’s a widely used product that’s not regulated—and is not legal to sell for its largely unproven health benefits.

How does CBD work?

Nobody really knows what is responsible for the mental and physical health benefits that have been attributed to it. CBD affects the body’s serotonin system, which controls our moods. It also affects several other signaling pathways, but we really don’t understand its mechanisms of action yet.

How much do we know about CBD as a potential treatment?

There are over 50 conditions that CBD is claimed to treat.

We do know that CBD can help control serious seizure disorders in some children (e.g., Dravet and Lennox-Gastaut syndromes) that don’t respond well to other treatments. Epidiolex is an FDA [Food and Drug Administration] approved medication containing CBD that can be used for this purpose.

There’s also data to suggest the potential of CBD as a treatment for schizophrenia and for substance use disorders. But these potential uses are in extremely early stages of development.

Are there side effects?

We don’t know of any severe side effects at this time. But there were mild side effects reported in the epilepsy studies, mostly gastrointestinal issues like diarrhea. There were also some reported drug-to-drug interactions. That’s why, for safety reasons, it’s important that CBD or any cannabis product go through the FDA review process.

Are there any specific CBD studies that you are focused on?

We are interested in CBD as a potential treatment of substance use disorders.

There is some research looking at it for opioid, tobacco, and alcohol use disorders. If CBD can help prevent relapse in those areas, that would be really interesting. We’re also interested in it for pain management. Trying to find less addictive medications for pain would help a lot of people.

What else would you like people to know?

Buyer beware.

We are concerned about the health claims being exaggerated or incorrect. The FDA issued warning letters to several companies because of untested health claims. And the CBD products themselves didn’t always contain the amount of CBD that they were reported to have—some actually had THC in them.

Another concern is that people are using CBD to treat ailments for which we have FDA-approved medications. Thus, they may be missing out on better treatments. And when they’re using CBD or other cannabis products for conditions we don’t know very much about, that’s worrisome.

via The ABCs of CBD: Separating fact from fiction | NIH MedlinePlus Magazine

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[Abstract + References] Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

References

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    Russo EB. Cannabis and epilepsy: an ancient treatment returns to the fore. Epilepsy Behav. 2017;70(Pt B):292–7.CrossRefPubMedGoogle Scholar
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    Friedman D, Sirven JI. Historical perspective on the medical use of cannabis for epilepsy: ancient times to the 1980s. Epilepsy Behav. 2017;70(Pt B):298–301.CrossRefPubMedGoogle Scholar
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    O’Shaughnessy WB. On the preparations of the Indian hemp, or Gunjah (Cannabis indica): their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov Med J Retrosp Med Sci. 1843;5:363–9.PubMedCentralGoogle Scholar
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    Gowers W. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881.Google Scholar
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[Abstract + References] Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Abstract

Background

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

Objective

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

Results

Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

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[Abstract + References] Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Abstract

Background

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

Objective

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

Results

Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Supplementary material

40265_2018_992_MOESM1_ESM.doc (31 kb)

Supplementary material 1 (DOC 31 kb)

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[REVIEW] Epilepsy and Cannabis: A Literature Review – Full Text PDF

Abstract

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).[…]

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[WEB SITE] Medical Marijuana for Epilepsy: What We Know

Rahul Guha, MD, July 26, 2018

Earlier this year, the Virginia State Legislature voted to expand the medical cannabis oil program in the Commonwealth. I have patients ask me about medical marijuana during every clinic visit. Here are a few talking points that will help guide the discussion with your patients.

Patients usually start the conversation by saying, “I read on my cousin’s Facebook wall that smoking marijuana can treat my epilepsy.”

Let’s take a step back and talk about the clinically important compounds in marijuana. The first is tetrahydrocannabinol (THC). It exerts its effect through a pair of G protein-coupled cannabinoid receptors named, conveniently, CB1 and CB2. The effect of THC on synapses produces the typical “high” that allows you to tolerate 11-minute guitar solos and most items on Taco Bell’s late-night menu. Early animal models showed mixed effects of THC on epilepsy and, in some cases, worsening seizures. This is different from cannabidiol (CBD), which interacts with a variety of other receptors. More promising effects reported in early animal models and anecdotal evidence from case reports spurred the movement towards clinical trials measuring the effect of CBD on epilepsy.

Will medical marijuana help my epilepsy?

We don’t know which epilepsy syndromes are most responsive to CBD. We don’t know the long-term effects of CBD or THC in the brains of patients with epilepsy. We have not agreed on the best dosing strategy for these medications. The best evidence for CBD in epilepsy comes from two recently published trials studying the effect of the drug in patients with Lennox-Gastaut syndrome and Dravet syndrome.[1,2] These diseases develop in childhood or infancy due to underlying genetic changes and are resistant to treatment.

In the studies, patients who were taking an average of six other antiepileptic medications received CBD as an add-on therapy to conventional medications. At 3 months’ follow-up, patients who received the CBD experienced a statistically significant decrease in average seizure frequency compared with placebo.

Can I use commercially available CBD?

Unfortunately, many of the products that are available online or over the counter at your local vape shop are not consistent with labeling. Simply put, there’s no guarantee that you are getting what’s advertised. In addition to unknown dosing and concentrations of THC and CBD, there is a possibility of contaminants, such as pesticides or other drugs, in the product. We can only guarantee the safety and efficacy of US Food and Drug Administration (FDA)-approved products.

How will CBD affect my other medications?

CBD is metabolized by the liver and inhibits cytochrome P450 (CYP) isoenzymes. This inhibition leads to increased levels of topiramate, zonisamide, eslicarbazepine, rufinamide, clobazam, and valproic acid.

Is it legal?

The FDA recently approved a CBD formulation, but there is currently no formulation of CBD that can be prescribed with a Drug Enforcement Administration (DEA) license. Under federal law, cannabis is still considered a Schedule I drug. It is only available through clinical trials and rare compassionate-use exceptions. Patients and providers should familiarize themselves with local laws before recommending CBD for the treatment of epilepsy.

 

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