Medicalcannabis for epilepsy - is it really safe??

To understand the perspective, author is a Pediatric Neurologist and Epileptologist with experience of treating many children with drug resistant epilepsy in India and Australia.  

Why this blog?

In recent days, there has been tremendous publicity given to medical cannabis being “very effective in controlling seizures and epilepsy”. This is contrary to what is the available evidence shows, misleading many patients and families to resort to indigenous even illegal means to procure and take (give to one's near and dear ones) cannabis in the belief that it is the magical cure! Is it really effective and safe? This is a million dollar questions yet to be answered, worse you any not have clear answer for years to come. 

What is the real issue?

Question one should ask is not is it effective? but is it really safe? effective but at what cost? how is it effective? Available data shows that cannabis increases the blood levels of Clobazam and Valproate. Two most commonly taken anti seizure medications among patients with epilepsy. In some cases, the Clobazam blood level was increased up to 600% That is similar to raising the dose of Clobazam 6 times (for argument sake). So it comes at a steep cost! and along with associated adverse effects. Another important aspect to note is short term (12 weeks/16 weeks) effectiveness in controlling seizures that recent studies suggested for Cannabis are not long lasting (seizures come back), the same effect seen every time a new medication is added to the existing regime in  any patient with drug resistant epilepsy. Third factor is placebo effect. It is unbelievably high proportion of 25-35% of patients who have placebo effect (in any RCT comparing placebo versus a new anti seizure medication). So, the water is really murky and muddy ideal for those with vested interests to fish (recreational marijuana lobby, those who are growing cannabis and pharma companies)

Which cannabis molecule is effective?

The answer is we dont know yet. Cannabis is not a single chemical molecule, rather a mixture of many different agents with different safety concerns and long term effects. as of now there is no quality control of anything produced on the grey market, no way of knowing what and how much these contain? If we assume even one of these is effective in controlling epilepsy, the unsuspecting patient is taking the crude plant extract containing all other unwanted substances that may be harmful. Its like taking an antiseizure medication mixed with a known toxin (poison). It is poroven in studies that the medium/solvent used in the cannabis preparation is responsible for the adverse events. The only way out is to do more research to really understand which molecules are effective in controlling seizures so that these can be purified and produced as against those unwanted/harmful substances that can be removed from the final product. It takes some time. For those parents who promote cannabis in compassionate basis saying that they cannot wait any longer as their kids are running out of time (because severe epilepsy), my advice is that it is better not do any further harm to the child by administering potentially harmful agents that we do not know effective or not!
 
what about claims of dramatic effectiveness of cannabis in epilepsy?

Behind every success claim there are at least 20-30 patients that go unreported (or not pupublicized enough) because it was not effective, or it had to be ceased as there were problems, even worse there were cases of cannabis over dosage reported in Colorado, US! Again it is all about whipping up the frenzy, isn't it? This is exactly the problem if you go by lay press and anecdotal reports rather than waiting for the robust scientific evidence!

What about cannabis side effects (adverse effects)?

Many concerning short term and long term side effects are known to occur with intake of cannabis. The side effect profile depends largely on the actual molecule. As there is no way of knowing the actual composition of the unregulated products available in the market, there is no way of predicting side effect profile. Sleepiness, irritability and hallucinations. Long term side effects include memory and cognition problems, risk of addiction, schizophrenia in young people, psychosis, anxiety, etc. 

Can cannabis itself cause seizures?

Yes, of course. Some of the cannabis molecules are known to cause seizures (proconvulsants). In the Lancet Neurology study, 11% of patients who took cannabis had convulsions and 6% had status epilepticus (long seizures) without any other reasons being identified. It is concerning that such a high proportion of patients developed convulsive seizures or long seizures. 

Why drug trials on cannabis should not enroll children?

There is a dictum in medical science, if there are no randomized controlled trials (robust clinical research study) available on adults utilizing a particular medication, there cannot be an RCT commenced that enroll children for the same medication treatment. This is a prudent approach, as more often than not, there are unanticipated adverse effects that can occur with any trial medication, adults can handle many adverse effects better than children, because of higher safety margin. Another important point is that adults can articulate subjective sensations (cognitive and behavioral side effects) better than children. So it is all about safety. 

When there is no safety data on cannabis available or the available data points to serious concern, children should not be included in such drug trials. Cannabis with its potential side effects like hallucinations, psychosis, schizophrenia and many other cognitive and behavior related effects can never be tested in children without first being tested adequately in adults, period. The scariest thing is to enroll severely developmentally disabled kids like patients with Dravet’s syndrome and LGS in such trials, how are they supposed to articulate their mood and cognition related effects. It is unethical and unfair. For such kids with severe epilepsy and development delay, who do you think take decisions about commencing or ceasing the medications? Naturally, the next of the kin, parents and family. 

Keeping this in mind, how is it to fair to conclude a study (Recent open lebel trial on Cannabidiol, Lancet Neurology, 23 Dec 2015) “might be safe” just based on the fact that only 3% patients discontinued medications though 30% patients had severe adverse events!! Parents who are desperate to try and control their kid’s epilepsy and who is looking for a “magic medication” (and seeing one in cannabis), how are they expected to discontinue the same? It is natural for the family to think that the effects may be transient and to wait it out rather than to cease the “magic medication” that is doing some good (?!) to their kids. Credit cannabis for the good and blame the disease for the bad should not be the approach taken by medical community.

 

  

Role of medical cannabis in epilepsy-what is the evidence? is it really safe??

To keep the perspective, author is a Pediatric Neurologist and Epileptologist with experience of treating many children with drug resistant epilepsy in India and Australia.  

Why this blog?

In recent days, there has been tremendous positive publicity given to medical cannabis being “very effective in controlling seizures and epilepsy”. This is following the recent publication (Lancet Neurology, 23 Dec 2015) of first ever prospective trial on medical cannabis concluding that “…. cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy”. It may seem on the surface, so far so good. To make things clear, no prospective, open label, uncontrolled drug trial in 2015 can conclude “might be effective” and “might be safe” especially if not supported by the data and get published in any reputed Journal. This gets more interesting when you look in to the data presented in the study, showing that 30% of patients had serious adverse events and 12% patients had severe adverse events possibly related to cannabidiol use (including 6% had status epilepticus) and 3% discontinued cannabidiol due to severe adverse events! So much for “adequate safety profile”. 

The next line in the conclusion reads “Randomized controlled trials are warranted to characterize the safety profile and true efficacy of this compound”. This should have been the only reasonable conclusion of the study. Unfortunately, the first half of the conclusion has been promoted relentlessly in the media, online forums and tweets, conveniently forgetting the second half!! In my personal opinion, the conclusion of the study have been cautiously worded instead of resorting to clever word play to mislead patients and the public in general. There are three RCTs on cannabis compounds in epilepsy already underway, can we hope these RCTs show some “true” light? Prudence calls for waiting for more robust evidence to emerge from these RCTs keeping in mind primum non nocere.

Anyone can understand the contradictions and the way the conclusions were arrived at by reading the discussion that states “…….had an adequate safety profile in this patient population with highly treatment-resistant epilepsies. The safety and tolerability of cannabidiol was acceptable, with only five (3%) of 162 patients stopping treatment because of an adverse event.” and “adverse event profile of cannabidiol was favourable, with most patients tolerating the drug well despite its addition to a median of three concomitant antiepileptic drugs. However, the 20% rate of serious adverse events was higher than expected, with half these events deemed possibly related to cannabidiol.”

It is unfortunate that the conclusion of the study states the way it does, instead of a more cautious statement warranted of an open label, uncontrolled study with many methodological flaws! The reasonable conclusion for the data presented would read in lines of “though there is some seizure reduction observed in many patients in the short term, it needs to be evaluated in a randomized controlled trials before recommending this compound for clinical use. In addition, there are serious concerns raised about safety profile of this compound that needs further investigation especially over longer duration”.

Notably, the study was funded by GW pharmaceuticals, the leading pharmaceuticals company that produces Cannabidiol, the product studied in the research study. Sativex, the first (and only) natural cannabis plant derivative to gain full market approval in any country is produced by the same British company. 

This in conjunction with the recent revelations of Harvard Medical School’s Dr. Marcia Angell (Editor of NEJM, the reputed medical journal) about the rot that plagues pharmaceutical funded clinical research raises doubts about the credibility of clinical research in general and conclusions such as this does not help change that impression. Dr Angell states that “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.”

What is medical cannabis?

Medical cannabis a plant extract made from cannabis plant and is produced in many different formulations. Understandably, there are many different products available in the market (legal in some places and illegal in most others). As there is no quality control on preparation, concentration and storage, there is wide variation in the amount of various molecules and contaminants in any such preparations. So, most of the products available in the market may not contain any of the molecules claimed to be effective against seizures or in very small amounts.

Can natural products like cannabis harm the body?

Some people argue that as cannabis is a natural product (as against synthetic chemicals like most other medications), there is no harm done to the body. This is outright ignorance. There are many poisonous/toxic plants and plant products available in nature and natural products are not without harm. As far as human body is concerned, it reacts in a same way to naturally occurring chemicals (xenobiotics) or synthetic chemicals. Different cannabinoid molecules cause different side effects. Often, the medium used to keep cannabis as liquid is the culprit in causing bodily harm.  It is surprising, that usual patients who are worried about taking medications or increasing the dose of medications to control seizures are the ones that support and promote medical cannabis. This is due to the ignorance and popular belief that being a natural plant product, there are no side effects!

What is the effectiveness of medical cannabis in epilepsy?

In one simple sentence, till date there is no scientific evidence to show that medical cannabis is effective in controlling seizures. Though, there have been many claims of cannabis being effective in controlling epileptic seizures, most of these were based on anecdotal cases that apparently responded dramatically to this agent. The main problem with these type of evidence is that these were not scientifically verified and there is a possibility that the apparent effect of cannabis may have been due to multiple other factors such as interaction with other medications being taken concurrently and natural history of spontaneous remission in seizures.

What does the recent open label cannabidiol trial show in terms of efficacy?

It is too early to conclude that cannabidiol might reduce seizure frequency! There are many reasons for this, the first and fore most thing is, this study is only a short term one looking at effects on seizures for 12 weeks. Anyone who is suffering or who is caring for a person with drug resistant epilepsy will know, whenever a new medication is tried to control seizures, there is some reduction in seizure frequency for the first few weeks but seizures come back eventually. This along with well known “placebo effect” may account for reported efficacy in a large number of patients. Outcomes were assessed using seizure diary and there was not objective assessment of efficacy. Objective assessment such as seizure burden recorded in video-EEG over 48-72 hours before and after treatment is of critical importance. This is more relevant in cases like medical cannabis that is being very positively viewed by many patients and families taking part in such studies, there is bound to be subjective bias in outcome reporting. 

Moreover, in this study, cannabis was more effective in those who were concurrently taking Clobazam (Frisium) and valproate. So the efficacy in this group at least partly is due to cannabidiol causing elevated blood levels of these concurrent medications rather than by direct effect of cannabidiol itself. In simple words, it is like taking twice the dose of Clobazam or valproate. In most people with epilepsy, increasing dose of Clobazam can cause seizures control for few weeks. A recent study published in Epilepsia showed that cannabis can increase the blood levels of Clobazam up to 600% (ie, equivalent to taking six times the dose of Clobazam), no wonder that there is reduction in seizure frequency in many of these patients! 

What about cannabis side effects (adverse effects)?

Many concerning short term and long term side effects are known to occur with intake of cannabis. The side effect profile depends largely on the actual molecule. As there is no way of knowing the actual composition of the unregulated products available in the market, there is no way of predicting side effect profile. Sleepiness, irritability and hallucinations. Long term side effects include memory and cognition problems, risk of addiction, schizophrenia in young people, psychosis, anxiety, etc. 

Can cannabis itself cause seizures?

Yes, of course. Some of the cannabis molecules are known to cause seizures (proconvulsants). In the Lancet Neurology study, 11% of patients who took cannabis had convulsions and 6% had status epilepticus (long seizures) without any other reasons being identified. It is concerning that such a high proportion of patients developed convulsive seizures or long seizures. 

Why drug trials on cannabis should not enroll children?

There is a dictum in medical science, if there are no randomized controlled trials (robust clinical research study) available on adults utilizing a particular medication, there cannot be an RCT commenced that enroll children for the same medication treatment. This is a prudent approach, as more often than not, there are unanticipated adverse effects that can occur with any trial medication, adults can handle many adverse effects better than children, because of higher safety margin. Another important point is that adults can articulate subjective sensations (cognitive and behavioral side effects) better than children. So it is all about safety. 

When there is no safety data on cannabis available or the available data points to serious concern, children should not be included in such drug trials. Cannabis with its potential side effects like hallucinations, psychosis, schizophrenia and many other cognitive and behavior related effects can never be tested in children without first being tested adequately in adults, period. The scariest thing is to enroll severely developmentally disabled kids like patients with Dravet’s syndrome and LGS in such trials, how are they supposed to articulate their mood and cognition related effects. It is unethical and unfair. For such kids with severe epilepsy and development delay, who do you think take decisions about commencing or ceasing the medications? Naturally, the next of the kin, parents and family. Keeping this in mind, how is it to fair to conclude a study “might be safe” just based on the fact that only 3% patients discontinued medications though 30% patients had severe adverse events!! Parents who are desperate to try and control their kid’s epilepsy and who is looking for a “magic medication” (and seeing one in cannabis), how are they expected to discontinue the same? It is natural for the family to think that the effects may be transient and to wait it out rather than to cease the “magic medication” that is doing some good (?!) to their kids. Credit cannabis for the good and blame the disease for the bad should not be the approach taken by medical community.

What is the take of neurologists/pediatric neurologists on medical cannabis?

I, as a pediatric neurologist, will be the happiest person if cannabis or any other antiepileptic medication is proven more effective and safe in drug resistant epilepsy, after undergoing rigorous scientific trials. Till such date, clinical use of such a potentially harmful substance cannot be recommended. This is the take of many pediatric neurologists and neurologists worldwide. The process being followed for any newly developed medications should be followed in case of cannabis as well, the special concessions made for cannabis, makes one wonder what is going on behind the scenes? Let me point out, there are more effective antiepileptic medications under clinical trials waiting for approval for last many years, some of them are more effective than cannabis with much better safety profile. One classical example is Stiripental, even after observed efficacy over many years of use in Dravet’s syndrome in many European countries, the same is not approved by FDA and is not available in many other countries. Why are there no prospective trials or RCTs being conducted on such drugs? It is all about lobbying by the pharmaceutical industry! Scuttling the time tested drug approval process, special treatment for some medications, emotional and pharmaceutical lobbying cannot and should not make way for sound scientific reasoning, for the larger public good and the good of many voiceless children.

Thank you for your patient reading,

LN