Should Cannabis Oil be used for Treatment-Resistant

Epilepsy?Name: Ishwarya Sivakumar

ContentsThe Problem……………………………………………………………………………………...……..2

Possible Solution…………………………………………………………………………………….….2

Ethical, Economic and Social Issues……………………………………………………………...…….5

Benefits and Risks……………………………………………………………………………………....7

Alternative Solutions…………………………………………………………………………….....…..8

Evaluation………………………………………………………………………………………….….10

Bibliography…………………………………………………………………………………………..11

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Fig.1: Structure of P-gp that causes anti-epileptic drug efflux by re-distribution or direct transport.

Should Cannabis Oil be used for Treatment-Resistant Epilepsy?

The ProblemAround one third of people with epilepsy are resistant to the current treatment - antiepileptic drugs (AEDs).[1]At some point of their condition, 20% of patients with generalized epilepsy and up to 60% of patients with partial epilepsy can develop resistance to drug therapy. Currently mechanisms underlying the drug-resistance are not fully understood. The cause is thought to be an increased number of P-glycoprotein (P-gp) pumps in the blood-brain barrier which move AEDs out of the brain to maintain a steady concentration; more of these pumps means that larger amounts of AEDs are transported out of the brain than usual making them ineffective (see fig.1).[17]

Resistance to AEDs results in debilitating, long-lasting and consecutive seizures,[2] causing cognitive and psychological dysfunction. There is a large amount of electrical abnormality in the brain during a seizure. Normal cell function is disrupted leading to cell death.[3] Resistance to treatment is also associated with a lower quality of life, social impairment and sudden unexpected death (SUDEP). So what is the solution to this unmet clinical need?

Possible Solution: Cannabis oilCannabis oil is being proposed by GW pharmaceuticals as the most effective treatment for treatment-resistant epilepsy.[29]It is known to significantly increase the life expectancy of patients with uncontrollable seizures[23] In rodent seizure models, 1, 10 and 100mg/kg CBD significantly lowered mortality and the percentage of animals experiencing tonic-clonic seizures. Numerous patients claimed that they are experiencing over 75% reductions in seizures after taking high CBD infusions and oils orally everyday.[36]

Unfortunately, it induces some side effects. The plant is bred so that it predominantly contains the non-psychoactive component ‘Cannabidiol’ (CBD) which has seizure-fighting properties and is low in Tetrahydrocannabinol (THC) - the psychoactive component of Cannabis. CBD is hydrophobic and lipophilic which makes it lipid-soluble so it is mixed with olive oil for people to consume.[9, 14]

2

Fig.2

Currently, little is known about the molecular mechanisms of CBD. There are two plausible theories which explain how CBD controls seizures via another route. One theory states that CBD works by reducing the Ca2+ oscillations under high-excitability in the hippocampal neurons adjusting the brain’s exchange of information; this in turn reduces the seizures. The other theory involves the protective effect of cannabinoids through receptor proteins known as NMDA which play a key role in memory and learning, cannabinoids can have a ‘special’ site of interaction on these receptors too.[15-16, 31] There is some evidence that CBD has controlled seizures in cases where AEDs have been ineffective (see fig.3).

To see just how effective CBD were, a parent survey of 19 patients was carried out on the use of cannabidiol-enriched use in pediatric treatment-resistant epilepsy for children with Dravet syndrome, Doose syndrome, Lennox-Gastaut syndrome and idiopathic early-onset epilepsy.[18] The survey consisted of children aged 2-16 years. All children aged above 2 years experienced no less than 3 years of treatment-resistant epilepsy before taking cannabidiol-enriched cannabis. Parents reported that the dosage of CBD-enriched cannabis given to their children ranged from 0.5 to 28.6 mg/kg/day. This cannabis only contained a range of 0-0.7 mg/kg/day of the psychoactive component.

According to two parents, their child became completely seizure-free after 4 months of CBD-enriched cannabis use. 84% of the 19 parents claimed that their child’s reduction frequency was minimized. As stated in the table, before CBD was given, the occurrence of seizures varied from 2/week to 250/day whereas after CBD was given the occurrence of seizures dropped to 0/week to 10/day. This data clearly signifies that CBD definitely prevents or greatly reduces the occurrence of epileptic seizures plus CBD is shown to be more effective and favourable over AEDs. An average number of 12 seizures (211/18=11.7) were noted before CBD administration. The average percentage decrease in seizure frequency after CBD was administered is 54.7%.

Other accounts of cannabidiol and seizure reduction support these results which makes the information about CBD both valid and reliable.[21] Data was collected by the Scientific Committee of ACT (Associazone Cannabis Terapeutica- Italy) in which children with drug-resistant seizures were given a 2.5% corn oil solution of CBD. The outcome of the CBD treatment was encouragingly positive. In 2001, only four of the 16 parents dropped the CBD treatment for their children and this was due to the treatment’s expensiveness. Nevertheless, they were very pleased about their child’s reduced seizures.

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Fig.3: Summary of the responses obtained from the parent survey.

In the results obtained so far1) No side effects of such severity were observed as to require CBD discontinuation.2) In most of the treated children, an improvement of the crises was obtained equal to,

or higher than, 25% in spite of low doses administered.3) In all CBD- treated children a clear improvement of consciousness and spasticity

(whenever present) was observed.

[21]

The ‘WEED’ documentary by Dr Sanjay Gupta consisting of a case study about Charlotte Figi from Colorado who is affected by Dravet syndrome justifies that CBD enriched oil is a medical breakthrough. Charlotte started to decline cognitively as her seizure frequency increased. On average, she had 300 seizures a week. After taking CBD-enriched cannabis oil, she didn’t get any seizures for the first seven days and now only has about one seizure a week which is a major improvement.[23] Her cognitive skills are increasing.

A study was carried out to check whether CBD was the real cause behind seizure reduction since epilepsy was found to be triggered by an increase in potassium current. The effect of potassium channels on the antiepileptic effect of CBD was studied by administering various doses of paxilline in electroshock-induced seizures of mice. Paxilline is a highly specific potassium channel antagonist which reduces the potassium current.

When CBD was administered to mice with electroshock-induced seizures, the seizure protection increased. This graph shows that there is a positive correlation between CBD administration and percentage of seizure protection. 100% seizure protection is achieved with only 200ng/mouse of CBD.

Cannabidiol (ng/mouse)

Paxilline (ng/mouse)

Seizure protection (%)

0 200 00 1000 800 2000 6020 200 4020 1000 3020 2000 60100 200 80

4

0 50 100 150 200 2500

20406080

100120

Effect of CBD on seizures without paxilline

Cannabidiol (ng/mouse)

Seizure protec-tion (%)

Fig.5 Data used from [31]

100 1000 10100 2000 100200 200 70200 1000 20200 2000 100

When paxilline was administered to the mice separately, the maximum seizure protection achieved was only 80% with 2000ng/mouse of paxilline (see Fig.6) whereas CBD gave 100% seizure protection when administered separately with a dosage of only 200ng/mouse (see Fig.5). Increasing the dosage of paxilline any further showed to decrease the seizure protection. Moreover, there seems to be no major interactions in the antiepileptic effects when CBD and paxilline were administered together. E.g. a 90% seizure protection was already achieved by administering 100ng/mouse of CBD, co-administering it with 2000ng/mouse of paxilline has only increased the seizure protection by 10%. CBD is clearly effective in reducing seizures. Dr Gupta claims that “It could potentially help people who really need it and it’s not being offered” and that he “couldn’t find a single confirmed overdose death.”[44]

Ethical, Economic and Social Issues

Despite the success stories in the use of CBD to treat epilepsy and the abundance of studies that support the claim, doctors are still claiming that there is insufficient evidence that CBD is effective for the treatment of epilepsy or if it’s safe in the long-term:

More randomized double-blind placebo-controlled trials and comparisons between other treatments should be carried for CBD oil to prove just how effective it is.

Additional data is needed to show that the reduction in seizures by CBD is not a placebo-effect- to see whether or not the results are caused by the oil mixed with CBD to make it consumable. CBD oil must go through the contemporary drug testing protocols to check whether the results achieved in studies are reliable.

A case-controlled study should be carried out to collect information about the risk factors people have been exposed to and see what has contributed to the development and prevention of epileptic seizures. This helps us see if there is causation in the link between CBD oil intake and seizure reduction.

Larger sample of people should be used to ensure that the data obtained from studies are reliable. Furthermore, other variables that have shown to cause or prevent seizures must be controlled to ensure the data is valid.

Since cannabis is illegal, scientists should try to produce a synthetic strain containing only the active ingredient CBD and no THC. This strain can be first tested in animal trials followed by clinical trials to see whether it’s as effective as the cannabis strain currently used.

Cannabis is a class B drug. So much of the data explaining the effectiveness of CBD comes from synthetic cannabinoids, rather than natural ones. According to the National Institute on Drug Abuse US Director, Dr Volkov, Cannabis is “an extremely important area of research” due to its health benefits.[24] More research should be done to determine the optimal dosage of CBD and to see whether it has any long-term effects.

In Colorado, producers are breeding cannabis to have a high THC content so that their customers are satisfied with the ‘high’ that they get from using the product. This has reduced the medicinal CBD

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Fig.6 Data used from [31]

component of cannabis with only a few non-profit organisations breeding cannabis strains with a high CBD content.

Many people around the world smoke cannabis illegally- this includes over 8% of the UK population. Legalizing cannabis would mean that more people would smoke cannabis and be exposed to carcinogens which cause lung cancer and more people will have mental illnesses and respiratory problems.[25]This will lead to an increased strain on the NHS, as a higher number of people will be in medical need due to drug abuse. The NHS is already spending £607million a year to treat problems related to alcohol and drugs.[27] Therefore, it would be appropriate if cannabis was legalized for only medicinal purposes.

Due to the rarity of strains of cannabis wit high CBD content, their prices remains very high in places where cannabis is being used to treat epilepsy. This makes it unaffordable for some parents to give their child CBD as treatment.

If cannabis is legalized for medicinal purposes, more CBD-enriched cannabis strains can be bred which will reduce their price. It would also mean that families wouldn’t have to travel around the world, leaving their jobs and relatives in order to stop their family member from having debilitating seizures.

Due to social or political reasons cannabis addiction remains as the focus of discussion worldwide, regardless of research that proves cannabis consists of components which have healing properties. More people should be educated about the positive effects of cannabis and that it has a non-psychoactive component that can be used treat seizures. Socially, it is unimaginative that a parent would willingly give their child cannabis oil, however this could be a matter of re-education.[25]

Benefits and Risks

6Fig.8

Fig.7 World map showing percentage of Cannabis abuse

Parents of a 16-year-old epileptic teenager in Lancashire are hoping to raise £30,000 to give their son treatment with cannabis oil which is being trialled in the US and has an astonishing

effect on other children like him.[28]

Since Cannabis is a class B drug in the UK, it is defined as a harmful substance and is illegal even for medicinal purposes.

[35]

Extracted CBD is the non-psychoactive component of cannabis plants so it does not initiate the unwanted psychotropic and hallucinogenic effects that are characteristic of other cannabis derivatives such as THC.[8-10] Cannabis oil used to treat seizures is very low in THC and high in CBD. Quality of life improves after taking CBD oil as it reduces the risk and fear of the onset of seizure.

Fig.9, taken from a parent survey about their children’s epilepsy illustrates that cannabidiol does not induce any terrible side effects. The only negative side effects were appetite decrease, fatigue and drowsiness which seems minor compared with all the benefits which include self-stimulation, better sleep, increased alertness and better sleep. On average, the percentage of benefits caused by CBD is higher than the percentage of negative side effects. Although the negative side effects such as fatigue and drowsiness don’t seem too bad, it can have a major impact on a busy person’s life. It may cause a person to stop doing what’s extremely important and rest instead leading to changes in their plans.

CBD should not be taken by epileptic people with diseases such as HIV, allergic inflammation in the lungs and tumour formation. This is because a study indicates that CBD worsens these diseases.[39]

A study has shown that taking CBD during pregnancy may alter the P-gp and Breast cancer Resistance Protein (BCRP) expression in the human placenta. The effect of long-term exposure of CBD to JAr cells (model of human trophoblast) was studied.

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Fig.9

Graph A shows that as the exposure time of the placental model to CBD increases from 48h to 72h, the BRCP protein level decreased. Graph B indicates that when the concentration of CBD increased from 10 µM to 15 µM, the BRCP protein level increases. Graph C shows that CBD reduces P-gp protein levels. As a result, it’s clear that it’s problematic for an epileptic women to take CBD during pregnancy as it may lessen placental protective functions and alter its morphological and physiological characteristics.[40] The stains also indicate that there is a gradual change in protein levels compared to the control protein when CBD is administered.

People may not want to take CBD to reduce their seizures. Reasons include fear of the potential side effects, not knowing much about its effectiveness and living in an environment where CBD is looked down upon due to lack of knowledge. This means more people have uncontrollable seizures leading to psychological dysfunction. It is important for doctors, carers and patients to weigh the potential benefits of using CBD to treat epilepsy against the potential side effects.

Alternate solutionsEpilepsy surgery

Epilepsy surgery can be performed if seizures are treatment-resistant. However, epilepsy surgery can only be performed when the part of the brain causing seizures is known. This is a major disadvantage since in many cases the area of the brain causing seizures is more than one or cannot be found. Undergoing epilepsy surgery is risky as it will cause permanent brain damage and it’s not definite that the seizures will stop.[12]

Some of the complications in epilepsy surgeries which involve removing a bone flap from the skull to access the brain include:

A study revealed that epilepsy surgery is also associated with SUDEP, an uncommon but significant risk of epilepsy.[43]

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StrokeSeizuresSwelling of the brain (requires another operation)Nerve damage, which may cause muscle paralysis or weaknessLoss of mental function [19]

Fig.10

Fig.11 implies that 3.6% of the surgically treated candidates died compared to only 2.2% that died without undergoing epilepsy surgery. This suggests that epilepsy surgery clearly increases the chances of death. When all the risks of epilepsy surgery are taken into account, it is clear that CBD is a safer and better alternative. CBD increases life expectancy rather than increasing the chances of death.[23] Moreover, CBD does not induce any disabling side effects or cause permanent brain damage.[29]

Ketogenic Diet

A ketogenic diet mimics the biochemical changes in the body during starvation; a person starves for 24 hours and then follows a strict regimen extremely rich in fats and very low in carbohydrates and proteins. It is mainly suggested for children and not recommended for teenagers. This diet is said to cause unwanted side effects such as gall stones, poor immune response, decreased bone density, raised blood cholesterol, constipation and low blood sugar.[12] Although doctors don’t know how a diet that burns fat for energy prevents seizures, it is known to work in some people.[13] Unfortunately, this diet isn’t successful for everyone. Fig.12 shows what a ketogenic diet consists of.

Ketogenic is linked with stunted growth and bone failure. The data from John Hopkins Hospital claims children are suffering from:

CBD is safer and better to use than ketogenic diet, since it does include any regimens that are difficult to implement and doesn’t have any negative effects on a child’s health.

EvaluationCBD has been found to reduce seizure frequency and show improvement in epileptic patients with none of the negative side effects induced by the vigorous AED medications tried to alleviate the symptoms of drug-resistant epilepsy. This information is from [18] Porter B. E., Jacobson C. (2013) Epilepsy & Behaviour: Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. 29(3), 574-577. This source is reliable, since it agrees with many other sources and showed similar results to a study about treatment with CBD for drug-resistant epilepsies

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Such a strict regimen is difficult to implement and maintain and requires close supervision by a dietician and physician. In addition to the practical complexities, concerns also exist about the

long-term effects of the diet on the child’s growth and overall health.[2]

Fig.11

Fig.12

Weak bones. Skeletal fractures occurred in 6 of 28 children following the ketogenic diet for 6 years; 4 children had fractures at separate locations and times.

Stunted growth. By the end of the 6 years, 23 of the 28 children were in the bottom tenth by height of their age group. 

[45]

[21]. The results from this survey were also funded by GW pharmaceuticals to advertise their CBD-enriched product for epilepsy which highlights that this source is considered to be valid and reliable by a prestigious pharmaceutical company [29]. Although there was bias in the sample population for the survey as it involved parents already supporting CBD-enriched cannabis after using it for their children, investigations were carried out to ensure that there were no leading questions. This was done by conducting a similar survey on a known AED (stiripentol). The results were consistent and matched stiripentol’s effects, concluding that the results from the parent survey are accurate to some extent. What’s more, the source is service of the US National Institutes of Health, National Centre for Advancing Traditional Sciences and National Centre for Research Resources which makes it reliable.

Another source I found very useful is 23, CNN: ‘WEED’ Documentary by Dr Gupta http://www.youtube.com/watch?v=hrVXRZY1_x0. It provided very helpful information as Dr Gupta is a neurosurgeon and CNN’s chief medical correspondent.[33] His profession highlights that he knows what he is talking about. The documentary also consists of personal accounts from family members of medical cannabis users and people using cannabis for medicinal purposes. These people are familiar with symptoms of epilepsy due to personal experiences and will therefore know how effective cannabis has been at reducing seizures. There is proof of how CBD oil has affected Charlotte Figi (an epileptic child) in the documentary; it gave worldwide recognition to CBD oil. Moreover, Smart Approaches to Marijuana (Project SAM), a non-profit organization that elucidates the future of cannabis-based medicine agrees with Dr Gupta’s decision in favouring the use of cannabis for medicinal purposes. This is because, despite having no proof, the drug-scheduling process in the US states that cannabis is a Schedule I drug, which describes it as one of the most unsafe drugs with no medical properties. But according to Dr Gupta and Project SAM, cannabis does have medicinal uses and more scientific evidence is needed to claim that it is dangerous to the human body.[34]

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