Abstract

Cannabis is fast gaining recognition in the media for its beneficial effects in the treatment of otherwise intractable epilepsy(1).  The United Kingdom government, consistent with international governments, has taken a slow and measured approach to the legalisation of medicinal cannabis(2).  Conversely, the USA has legalised the use of medicinal Cannabis in 33 states and the US FDA has recently licensed the use of Epidiolex(3).  Many paediatric neurology centres in the UK are currently running trials with the use of Epidiolex(4), and the National Institute for Clinical Excellence (NICE) is currently developing guidelines for medical practitioners on the use of cannabis-based products for medicinal use(5).  Studies used by the FDA show promising results, and further support the notion that there is a need for novel therapies in intractable epilepsy(3).  This article aims to highlight the international data and establish whether the concerns surrounding the use of cannabis in refractory epilepsy are credible. 

Cannabis is the most widely used recreational drug in the United Kingdom (6), despite carrying a five year prison sentence for possession (7).  The intoxicating effects of Cannabis are a well-known driver for the proliferation in recreational use over the last decade (8).  With only limited research done on the pharmacology of Cannabis and its effects on the human brain, along with the increasingly high profile cases of young children with otherwise intractable epilepsy being cured by Cannabis oil (9); the empirical evidence behind the success of cannabis as a treatment for epilepsy needs to be considered, and risks need to be examined.  The International League Against Epilepsy (ILAE) define refractory epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules to achieve sustained seizure freedom, defined as less than one seizure per year” (10)With some people having hundreds of seizures each day, some lasting as long as thirty minutes, it is almost impossible for them to live a healthy life (11).  The mortality rate with some forms of epilepsy is high, with around seventeen percent of children dying suddenly (12).  Most deaths occur during sleep, due to ‘sudden unexplained death in epilepsy’ (SUDEP) (13).  Dravet syndrome (14)Doose syndrome (15), Lennox Gastaut syndrome (16), and idiopathic early onset epilepsy (17) are all severe and potentially life limiting forms of epilepsy, characterised by frequent convulsions known to cause serious cognitive, behavioural, and motor delays.  These severe forms of epilepsy do not respond to anti-epileptic drugs (AEDs).  Whilst around 70% of all epilepsy cases can be managed well with AEDs (11), and many AEDs have been studied in great detail with their drug profiles becoming very well known; around 30% of epilepsy cases (11), often the most severe and debilitating, are completely incurable, and occasionally require invasive surgery with no guaranteed outcome (18).  The need for novel therapies for these intractable neurological conditions is clear.  This article aims to highlight the international data and establish whether the concerns surrounding the use of cannabis in refractory epilepsy are credible.  

 

Search Criteria  

PubMed was searched for articles which came under the search terms refractory epilepsy, Lennox-Gastaut syndromeDravet syndrome or Cannabis.  Any articles not in English were excluded.  As the results were limited, there was no time limit applied to studies, hence studies as far back as 1999 have been included.  

 

Current guidelines  

For any refractory cases of epilepsy, NICE lists a range of AEDs for treatment, and also recommends a referral to tertiary care providers (19).  Due to the range of conditions that can be classed as epilepsy, it is beyond the scope of this work to discuss them all in detail.  Whilst treatment is split into first line treatments, alternative first line treatments and adjunct therapy, the most common first line therapy s Sodium Valproate (19) as it can be used in most forms of epilepsy with good response (20).  However, the drug has multiple common side effects, including hepatic disorders, deafness, haemorrhage, memory loss, pancreatitis and many more (21).  Furthermore, the drug cannot be used in girls or women of childbearing age if there is a risk the woman may be or may become pregnant due to recent research which highlights the danger to unborn babies (20), including the risk of children developing attention deficit hyperactivity disorder by age fifteen (22).  Women in this position need to be been seen by a specialist, confirmed as non-responsive to other treatments, and commenced on effective contraception before beginning treatment and throughout the full duration of their treatment with Sodium Valproate (21).  Women who take Sodium Valproate during pregnancy have a 40% risk of developmental disability in their child and a 10% risk of birth defects (20). The Medicines and Healthcare products Regulatory Agency (MHRA have circulated this information widely among healthcare professionals so that patients can make more informed decisions about their care (23), however it is thought that a large proportion of woman taking Sodium Valproate are unaware of the risks. A survey done in 2017 of 2000 women with epilepsy showed that 18% didn’t know about the risks associated with using Sodium Valproate (24), despite the MHRA toolkit to raise awareness published in 2016 (25).  Documents from 1973 show that the risk of teratogenicity was known at the time of licencing the drug (26), but a decision was made not to publish them, nor warn patients.  This lead to millions of people being born with disabilities owing to their mothers using Sodium Valproate for control of seizures during pregnancy (26).  Whilst Sodium Valproate is an effective treatment for epilepsy, and it is licenced for use, it carries enormous risks which can cause generational problems and extreme side effects (21).  Sodium Valproate is now subject to additional monitoring and healthcare teams are required to report any suspected side effects to the MHRA (23). 

 

The future: Cannabis 

Cannabis has been used medicinally for centuries across the world (27).  Despite this, research is limited and negative side effects of cannabis are not documented (28).  It was made illegal in the UK in 1928 owing to lacking evidence of medicinal benefit, and it became illegal to grow cannabis in 1964 (28).  Ninety years after criminalisation of possession of the drug, in 2018 based on mostly anecdotal evidence, the UK government has acknowledged that medicinal cannabis can positively modify physiological responses in humans and as a result has legalised the use of medicinal cannabis in otherwise incurable cases of a range of neurological conditions (2).  High profile cases of children with severe epilepsy responding only to cannabis oil have illustrated the potential for prescribing cannabis more widely to treat epilepsy (1).  The pharmacology behind successful treatment with cannabis is presently largely unknown although it is thought to play a role in modulation of synaptic transmission (29).  The discovery of the array of compounds found in the cannabis plant, lead to the eventual discovery of the endocannabinoid system (ECS) in the human body (30).  Since its discovery, this system has been implicated in physiological conditions in the central and peripheral nervous system as well as peripheral organs (30).  This has established multiple possible therapeutic targets within the ECS for a range of health ailments; however studies are currently ongoing to assess the degree of therapeutic benefit that can be derived from using compounds found in the cannabis plant.  

 

Cannabis itself is a naturally occurring plant which grows in the Indian subcontinent (31).  It contains hundreds of different compounds known as cannabinoids (32).  The most well-known cannabinoids are Tetrahydrocannabinol (THC), which produces the well-known and recognised psychoactive effects; and Cannabidiol (CBD), which is thought to have therapeutic value (32).  Endogenous cannabinoid (endocannabinoid) receptors in the human body were discovered following the study of the plant based cannabinoids (32).  The two primary endocannabinoid receptors found in the body are CB1, which are mainly in the brain and vital organs, and CB2 which are found in the immune system and stem cells (32).  The discovery of the existence of these receptors, quickly lead to the discovery of endogenous cannabinoids such as anandamide, which is hypothesised to produce a response similar, although naturally occurring, to cannabinoids (32) post exercise.  Studies have shown that the ECS is heavily implicated in memory, nausea, fertility, pain modulation, cardiovascular disease and many more (32).   

 

Epidiolex 

It is important to note that pharmaceutical grade cannabis is very different to any other cannabis based products as pharmaceutical grade cannabis guarantees the content and level of purity. In June 2018, the United States food and drug administration (FDA) approved Epidiolex, which is a CBD oral solution licenced for use in Lennox-Gastaut syndrome and Dravet syndrome for patients aged 2 years or over (33).  This is the first FDA approved drug specifically for Dravet syndrome but also the first pharmaceutical grade drug derived from Cannabis (33).   In the UK, there is currently no licenced cannabis based product for epilepsy; however some groups expect Epidiolex to be licenced in the UK in 2019 (34).  The National Institute for Clinical Excellence (NICE) is currently developing guidelines for medical practitioners on the use of cannabis-based products for medicinal use (5).  Epidiolex is currently being extensively studied at paediatric neurology units across the country under home office licences (4). Studies and use commenced in the paediatric neurology units in 2014 and therefore there is now a growing body of evidence for efficacy (4). Initial use of the drug was due to promising anecdotal evidence, but use over the last few years has proven that the drug is effective and proves its suitability for patients with severe epilepsy (4)  There have been sporadic studies around the efficacy of cannabis for seizure control in the last decade, however due to legal status of the drug in the United Kingdom, good quality research is severely lacking.  The most substantial evidence has come from studies done abroad in the last two years.  In 2018, following the licencing of Epidiolex in the US, the FDA published a document detailing the evidence for treating seizures in Lennox-Gastaut and Dravet syndrome with CBD (3).  The FDA referenced four randomized, double blind, placebo controlled trials.  The trials consisted of 550 patients, where two trials focussed on patients with Lennox Gastaut syndrome, and the two other trials focussed on patients with Dravet syndrome.  In all trials, neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. For further information on the setup of the trials, see table one. The statistically significant findings and clinically meaningful reduction in seizure frequency with CBD, along with the low risk of side effects from these trials, lead to the FDA supporting the use of Cannabis based products in epilepsy (3).  Table two details the results of the trials.  The FDA concluded that although the risk of liver injury was high, this was manageable with regular blood tests and appropriate education of healthcare providers (3).  Similar findings were made by Rosenberg who reviewed literature across 34 studies and found that THC reduced anticonvulsant activity in 62% of cases and is capable of increasing the effects of phenytoin and phenobarbital (35).  Both CBD and THC have been shown to reduce seizure frequency either alone or as an adjunct to AEDs (35).  Since the licencing of Epidiolex in the US, McCoy et al carried out studies to establish dosing and tolerability of a cannabis plant extract containing 100mg/ml of CBD and 2mg/ml of THC in children with Dravet syndrome (36).  They found that the product they used was safe and well tolerated by the participants.  Although the study was small with only 20 participants, it does provide a catalyst for further studies and could even be the beginning of legalisation of medicinal Cannabis across the world. 

 

Whilst all the evidence suggests that Cannabis is an effective treatment for refractory epilepsy, it is important to remember that it is an illegal drug in the United Kingdom, and despite the coverage of the drug being largely positive, it is important to proceed with caution.  Many studies within the last decade have shown that Cannabis may cause several complications and even developmental abnormalities.  For example, a study carried out in the USA in 2015 highlighted that smaller brain sizes may be attributable to the use of cannabis (37) .  Although the authors recognised that the variation in brain size is within normal ranges of variation and recommend further investigation, the risk is still present.  Equally, other studies have highlighted the known risk of developing schizophrenia in men as well as effects on the maturation of the cerebral cortex which plays an essential role in normal function (38).  Ortiz-Medina et al reviewed the link between cannabis consumption and development of psychosis or schizophrenia (39).  They studied sixty six different papers and concluded that use of cannabis doubles the risk of developing psychosis in vulnerable patients.  They argue that vulnerable people are those who have depression and anxiety prior to cannabis use – there is no evidence amongst people with no pre-existing conditions (39).  Several studies, also argue that age is a crucial factor and claim that consumption of cannabis before the age of fifteen predisposes the individual to a greater likelihood of developing psychotic symptoms during adulthood (40).  The relation of psychotic symptoms with the initial age of consumption might be explained by interference of cannabis in neurological development during adolescence (40).  Use of cannabis in adolescence may predispose individuals to development of psychotic symptoms.  Moreover, according to these studies, the use of cannabis may expedite the onset of schizophrenia in genetically predisposed individuals.  Zammit (41) reasons that use of cannabis increases the risk of psychosis by 30% and that 13% of schizophrenia cases could be prevented by avoiding the use of cannabis altogether. It stands to reason that patients who are pre-disposed to developing psychosis are more susceptible to the effects of Cannabis; however those with no family history or pre-disposing factors could theoretically use the drug without the risk of such side effects. The question of whether cannabis is causing psychotic symptoms or whether the patient would have psychotic symptoms regardless of cannabis use warrants further investigation.   It is important to note that none of the studies mentioned discuss how the drug was delivered to participants or the level of purity of the substance usedCannabis absorption is known to be dependent on the route of administration (42) therefore many of the earlier studies are dubious in their reliability.  

 

According to the most recent data from the national office for statistics, smoking tobacco caused eighty thousand deaths in 2014 (43), and deaths related to alcohol were over eight thousand (44), compared to thirty one from cannabis in the same year (45), yet tobacco and alcohol can be bought freely from supermarkets, legally.  Whilst the data in this respect for cannabis may be skewed owing to its illegal classification and hence reporting may be lower, the fact that legal drugs are causing so many deaths is a cause for concern.  Furthermore, both tobacco and alcohol are known to precipitate health deterioration (46), whilst cannabis is used to relive pain in MS, nausea in cancer patients and even has a role in Crohns disease (47).  Ironically, the UK is the world’s main producer and exporter of legal cannabis (48), and yet there are people with refractory epilepsy in the UK being left unable to access the drug despite the recent change in law and evidence to suggest it can be used safely.  There are beneficial effects of Cannabis, and with legalisation of the drug for recreational purposes in some countries across the world including Canada and the USA (49), it stands to reason that the UK government has legalised medicinal use (2) Some groups argue that because cannabis can be grown at home, requires very little specialist knowledge and is not a synthetic drug; the million-dollar pharmaceutical companies would lose the opportunity to monetise the value of the drug if it was legalised for recreational use and therefore lose their market share (50).  Hence the government will also be hesitant to legalise use to avoid losing tax revenue from these companies despite evidence to suggest legalisation would boost the economy (51).   

 

A call to action 

Medicinal cannabis remains largely illegal all over the world (52).  Its use is currently only legalised in parts of the USA, Canada and Uruguay (53) and there are limited studies on the use of medicinal cannabis.  Whilst there is clearly insufficient evidence to establish any strong conclusions about the safety of cannabis use, there is mounting evidence to clearly show that cannabis is an effective anti-epileptic drug (35).  The known side effects are limited, and the potential benefits can be life changing.  The risks need to be discussed in a frank conversation between specialists and potential patients to establish the truth about where research currently is and no guarantees about treatment should be given (54).  All healthcare professionals have a responsibility to ensure patients are not harmed as a result of treatment (54) and all currently licenced medication in the United Kingdom have undergone stringent testing and evaluation as well as clinical trials (55), therefore it is crucial to remember that cannabis is no different and requires the same level of attention and careful consideration.  Before recommending the treatment, prescribers need to be fully aware of the risks and benefits of initiating and maintaining cannabis treatment in order to ensure patient safety (54).  It is also imperative that patient’s expectations are managed.  With access to social media, and positive depiction of cannabis oil use in epilepsy (1), patients may expect this to be a cure for their condition.  Therefore the concerns around the use of Cannabis in refractory epilepsy are indeed credible hence a careful and meticulous analysis of each patient requesting the drug should be at the forefront of every prescribing clinicians mind.   

 

This is evidently a fine balancing act which requires specialist input and warrants further investigation.  Studies are currently ongoing in the United Kingdom to assess the efficacy of cannabis use, but the road to full legalisation may be long.  If cannabis is found to be both safe and effective, this would establish a foundation for medicinal cannabis in the treatment of intractable epilepsy as well as pave the way for decriminalisation of the drugConversely, if the drug is decriminalised and made legal before the reported benefits are verified by scientific analysis and due testing; because of the high potential for abuse, the risks to wider the society need to be evaluated, along with managing required changes to policing and controlling supply.  Regardless of the outcome, 2018 saw law makers in the United Kingdom accept that cannabis does have medicinal benefit, and this is the first step in allowing more widespread study of the drug without risk of recrimination and highlights the inadequacy of synthetic medicines currently available to patients with debilitating epilepsy. 

Table 1:  Description of clinical trials for Epidiolex 

Patients with Lennox-Gastaut syndrome who were not controlled on their current treatment for seizures.  Patients with Dravet Syndrome that were not controlled on their current treatment for seizures 
Trial 1 (n=171)  Trial 2 (n=225)  Trial 3 (n=59)  Trial 4 (n=61) 
aged 2 to 55   aged 2 to 55   2 to 18 years   4 to 10 years 
Patients were randomly assigned to receive one of two doses of Epidiolex or placebo twice daily. To reach the desired dose, the dose of Epidiolex and placebo were gradually increased every other day for 2 weeks. Patients remained on this dose for 12 weeks.  Patients were randomly assigned to receive Epidiolex or placebo twice daily in addition to their usual treatment for seizures. Patients remained on this dose for 12 weeks.  Patients were randomly assigned to receive one of three different doses of Epidiolex or placebo twice daily for 3 weeks. 
The benefit of Epidiolex was evaluated by measuring the change in the number of drop seizures from baseline for the patients receiving Epidiolex in comparison to the patients who received placebo.   The benefit of Epidiolex was evaluated by measuring the change in the number of convulsive seizures from baseline for the patients receiving Epidiolex in comparison to the patients who received placebo.  Patients were evaluated primarily for side effects. 

 

Table 2Outcome of clinical trials.  Trials 1, 2 were used to measure the drop in seizure frequency in Lennox-Gastaut Syndrome during the treatment period.  Trial 3 measured the convulsive seizure frequency in Dravet Syndrome during the treatment period.   

Seizure Frequency (per 28 Days)  Placebo  Epidiolex 10 mg/kg/day  Epidiolex 20 mg/kg/day 
Trial 1  n = 85  N/A  n = 86 
Baseline Period Median   75  N/A  71 
Median Percentage Change During Treatment  -22  N/A  -44 
p-value compared to placebo    N/A  0.01 
Trial 2  n = 76  n = 73  n = 76 
Baseline Period Median   80  87  86 
Median Percentage Change During Treatment  -17  -37  -42 
p-value compared to placebo    <0.01  <0.01 
Trial 3  n = 59  N/A  n = 61 
Baseline Period Median   15  N/A  12 
Median Percentage Change During Treatment  -13  N/A  -39 
p-value compared to placebo    N/A  0.01 

 

Table 3: Adverse reactions in patients treated with Epidiolex in controlled trials.  Outcomes from trial 4. 

 

Adverse Reactions 

EPIDIOLEX  Placebo 
10 mg/kg/day   20 mg/kg/day  
N=75
% 
N=238
% 
N=227
% 
Hepatic Disorders 
Transaminases elevated  8  16  3 
Gastrointestinal Disorders  
Decreased appetite  16  22  5 
Diarrhoea  9  20  9 
Weight decreased  3  5  1 
Gastroenteritis  0  4  1 
Abdominal pain, discomfort  3  3  1 
Nervous System Disorders  
Somnolence  23  25  8 
Sedation  3  6  1 
Lethargy  4  8  2 
Fatigue, malaise, asthenia  11  12  4 
Insomnia, sleep disorder, poor quality sleep  11  5  4 
Irritability, agitation  9  5  2 
Aggression, anger  3  5  <> 
Drooling, salivary hypersecretion  1  4  <> 
Gait disturbance  3  2  <> 
Infections  
Infection, all  41  40  31 
Infection, viral  7  11  6 
Pneumonia  8  5  1 
Infection, fungal  1  3  0 
Infection, other  25  21  24 
Other  
Rash  7  13  3 
Hypoxia, respiratory failure  3  3  1 

 

 

 AUTHOR: WAJEEHA MIR MPharm

 

 

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