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Running head: CANNABIS AS A THERAPEUTIC TOOL FOR EPILEPSY 2

CANNABIS AS A THERAPEUTIC TOOL FOR EPILEPSY 2

Cannabis A Therapeutic Tool For Epilepsy

Stephanie Petit-homme

ENC2201: Report Writing and Research Methods

Dr. Uliana Gancea

Miami Regional University

April 13, 2020

Abstract

Background: In recent years, there has been skyrocketing interest in cannabis-based products for treatment of refractory epilepsy. Purpose of the study/Objective: This paper concentrates on finding out if indeed cannabis is the solution to epileptic seizures and if it can be used as a therapeutic tool for epilepsy (Jaffe & Klein, 2018). Method: For this research, however, for the first time, there is a class one affirmation that the use of CBD ameliorates seizure control in clients with epilepsy. According to the available information at the present time, however, it seems uncertain regardless if the improved seizure control illustrate in these trials was associated to a straight movement of CBD, or was intervene by drug interactions with concomitant medications, specifically a marked increase in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Illumination of the comparable collection of CBD to upgrade seizure result or outcome stand in need of re-assessment of trial data for the subgroup of clients not co-medicated with clobazam, or the control of further studies conducting for the surprise results of the reciprocal action. Results: In the double-blind trial in Dravet syndrome there was reported a decrease of the frequency of the convulsive seizure from 12.4% to 5.9% in the CBD group and from 14.9% to 14.1% in the placebo group. Non convulsive seizures did not seem to significantly be affected by the CBD therapy. There was also a total of three patients who walked out of the treatment seizure free in the CBD group, but none from the placebo group. In the Double-blind trials in Lennox Gastaut syndrome the following results were collected; in the first trial, CBD treatment was associated with a greater median percent reduction in monthly drop seizures i.e. 44% and 22% and a greater proportion of patients with a less than 50% seizure reduction, 44% and 24%. Adverse results were recorded in the CBD group than in the placebo, 86% to 69%. Study found that a regulated dose of cannabis was effective for treating epilepsy.

Recommendations: Further researchers should ensure they determine the exact proportions of cannabis and proponents that are safe for creating an accurate treatment.

Keywords: Cannabis, epileptic seizures, therapy, treatment, syndrome.

Cannabis as A Therapeutic Tool for Epilepsy

Introduction

Hook : The use of cannabis plant by humans goes back to the dawn of humanity. Cannabis originated in Central Asia or the foothills of the Himalayas, was initially cultivated in China for seed production as well as fiber, in India it was used to produce resin.

Background Information : For centuries, European and East Asian societies have commonly used cannabis strains with low amounts of psychoactive principle THC, and their primary utilization as food and fiber. Conversely, African, Middle Eastern, South Asian, and Southeast Asian societies with strains containing more THC and have used them primarily for their psychoactive properties. The first modern and detailed description of the utility of cannabis-based products as an anti-seizure medication was published in 1843 by W.B. O'Shaughnessy, a physician in the Bengal Army and Late Professor of Chemistry and Material Medical at the Medical College of Calcutta. After trying the behavioral effects in healthy animals like fish, dog, horses, goats etc. He investigated the potential value of the plant's extracts in patients with different disorders, and there was reported remarkable anti-seizure effects in a 40 days old baby girl who suffered from recurrent seizures.

Problem Statement : The use of cannabis has declined in the twentieth century due to the illegalization of the plant's cultivation in many countries. Cannabis has been seen to be an effective drug used in the treatment of seizures. Epileptic patients need both tetrahydrocannabinol (THC) and cannabidiol (CBD) to manage episodes, which can be related to brain and muscular function. The use of medical marijuana has been a concern due to the illegalization of the plant (Cerda et al., 2018). Many epileptic patients around the world have thus been unable to access medication, notably since many countries completely prohibit the cultivation of the plant. The drug has also been outlawed in its medical form for fear of abuse in some situations, as it is commonly a recreation drug. It is for this reason that many doctors around the world have advocated for the legalization of medical marijuana, which can significantly save lives, especially for epileptic patients. Similarly, cannabis has been recommended as an appetite boosting drug for patients undertaking chemotherapy, often associated with cancer treatment (Cerda et al., 2018). The use of the drug for this purpose has also been associated with increased relaxation, minimization of mental and physical fatigue among patients, as well as a coping mechanism for the trauma associated with a terminal illness. The illegalization of marijuana thus significantly minimizes the options many of these patients have in dealing with their conditions.       

Hook Research Question(s) : What effect has the illegalization of marijuana had on the treatment of seizures in the past? What implications would be there for the medical profession if cannabis was legalized for medical use, especially for the treatment of epilepsy?

Hypothesis :  The use of marijuana for treatment of epilepsy is an effective method that can be of benefit to the medical profession if only the drug were legalized for widespread medical use around the world.

  Thesis Statement: In this paper, we will concentrate on finding out if indeed cannabis is the solution to epileptic seizures, and if it can be used as a therapeutic tool for epilepsy.

References

Cerdá, M., Sarvet, A. L., Wall, M., Feng, T., Keyes, K. M., Galea, S., & Hasin, D. S. (2018). Medical marijuana laws and adolescent use of marijuana and other substances: Alcohol, cigarettes, prescription drugs, and other illicit drugs. Drug and alcohol dependence, 183, 62-68.

Literature Review

Impressive research in the past has shown that, CBD has been found to be active in a variety of seizure models. Recently, the anticonvulsant profile of CBD was re-evaluated, but they used a refocused screening protocol which had been developed by the National Institute of Neurological Disorder and Stroke (NINDS) funded Epilepsy Therapy Screening Program. In the investigation, CBD administered intraperitoneally (i.p.) produced a dosed-pendent protection that was against maximal electroshock-induced seizures in mice and rats and was effective in the seizure model. These effects were recorded when the model received doses that did not cause motor impairment (Holtkamp & Hamerle, 2017).

From the findings, it can be concluded that the molecular actions involved in CBD anti-seizure activity was not directly mediated by the direct effect on cannabinoid receptors. However, this precise mechanism of action has not been ascertained. There is a range of activities that CBD is known to exhibit which suggest potential utility in other conditions. These include psychosis, trauma related conditions, tobacco and opioid addition, anxiety, mood disorders, neurodegenerative disorders. It is also used as tool of counteracting some undesired psychotropic effects that result from THC ("Cannabis drug," 2017).

            Epilepsy is said to be one of the most common non-communicable neurological diseases prevalent in low to middle income countries, with one-third of patients having seizers that are resistant to antiepileptic medications. The off-label use of cannabis sativa in treating seizures that are refractory to medication has been known since ancient times. Cannabis-derived drugs are very different from the cannabis that is available legally or illegally, in matters reliability of their content and purity, and also these derived medications differ from CBD oils. CBD trials reporting over the years have transitioned successfully the position of the drug from ‘anecdotal and promising’ to ‘proven to be effective’ ("Cannabis-derived," 2018).

            Studies and research methods have proven over the years that epileptic patients do not respond well to the conventional antiepileptic drugs. What is more, there are many side effects associated with these drugs such as ostemalacia and anemia. The use of CBD, therefore, has come in handy in many cases for centuries as it is considered by the general populace to have anticonvulsants properties.

However, these cannabis substances could not find a place in the current prescription regime to treat seizures related to epilepsy for two main reasons. One of the reasons is the insufficient number of trials done that could not prove their efficacy in treating or preventing seizure episodes. The other reason is the safety concerns of these substances in the long run (Szaflarski & Martina Bebin, 2016).

            Just like any other drug, medicinal cannabis; CBD or THC, have possible side effects. The most common effects of CBD include sleepiness, diarrhea, fatigue, and decreased appetite. Careful monitoring of its use is advised. However, CBD is still highly preferred and advocated for unlike THC which has intoxicating effects. Medical research is confident in using CBD for therapeutic purposes because it does not cause a high. Nonetheless, revisions ought to be done on the use of cannabis in epilepsy therapy as there is insufficient scholarship on the same in the few (Karler & Turkanis, 2019).

References

Cannabis drug cuts seizures in childhood epilepsy. (2017). Clinical Pharmacist.

cdoi:10.1211/cp.2017.20202978

 

Cannabis-derived treatment shows efficacy in rare form of epilepsy. (2018). Clinical Pharmacist.

doi:10.1211/cp.2018.20204455

 

Holtkamp, M., & Hamerle, M. (2017). Cannabis use in Epilepsy—Risks and Benefits.

Handbook of Cannabis and Related Pathologies, 431-438. doi:10.1016/b978-0-12-800756-3.00050-8

 

Karler, R., & Turkanis, S. A. (2019). Cannabis and Epilepsy. Marihuana

Biological Effects, 619-641. doi:10.1016/b978-0-08-023759-6.50052-4

 

Szaflarski, J. P., & Martina Bebin, E. (2016). Cannabis, cannabidiol, and epilepsy — From

receptors to clinical response. Epilepsy & Behavior, 41, 277-282. doi:10.1016/j.yebeh.2014.08.135

Method

The data was collected using a meta-analysis methodology. The researcher summarized the results of several studies to come up with their report. The information was collected from several scientific studies and journals, synthesized and compiled. Preference was given to studies that used randomized trial method. Different studies were assessed with the main focus being on those that did experiments (lasting a month or more) and recorded results before the study and compared them with the results after the study. For this study, the case study approach was used in which the researcher collected data from past researchers and did an analysis of the secondary data. The researcher was keen to focus only on qualitative and quantitative data that was collected firsthand from experiments and observations.

A meta-analysis method was preferred because it was both cost and time effective and provided deep insights on the topic of choice. During the collection of the data, a two-step approach was taken. First, the researcher identified credible sources of information relating to the topic from journals by filtering data using key words. The main key words of choice consisted of a combination of terms; “Epilepsy cure with cannabis” and “therapeutically cure of epilepsy with CBD.” After collecting studies that fitted into the key terms, the researcher then checked the year of publication with only recent studies qualifying (5 years). By reading the abstracts, relevant articles were chosen to be used as data for the study. The second approach entailed deriving data from the chosen sources, synthesizing and analyzing them to create new data. Emphasis was on the effects of CBD in the therapeutic cure of epilepsy by comparing the quantities and duration of CBD administration to the symptoms and effects in the patients after approximately two weeks.

Results

 Thus, In the double-blind trial in Dravet syndrome, there was reported a decrease of the frequency of the convulsive seizure from 12.4% to 5.9% in the CBD group, 14.9% to 14.1% in the placebo group. Non convulsive seizures did not seem to significantly be affected by the CBD therapy. 

          As a result, there was also a total of three patients who walked out of the treatment seizure free in the CBD group, but none from the placebo group. 

           Consequently, there were adverse events that seemed to be related to the study and were reported in 75% of patients in the CBD group and 36% in the placebo group. Diarrhea, somnolence and a decrease in appetite were recorded as the most common among CBD related adverse events. 18 of the 22 CBD treated patients who developed somnolence were on clobazam co-medication ("Marijuana and Medical Marijuana," 2016). 

            Appropriately, the events appeared mostly in the first 2 weeks of the treatment which lead to reduction of the dose of CBD or other medications. There was however no information stating the amount of concomitant clobazam that was reduced.

            In that event, eight patients in the CBD group discontinued with the trial prematurely due to adverse events (three cases the patients were found to have an elevation of liver enzymes), in comparison with one patient in the placebo group who also had an elevation of liver enzymes (Williams, Jones, & Whalley, 2018).

            In the Double-blind trials in Lennox Gastaut syndrome the following results were collected; In the first trial, CBD treatment was associated with a greater median percent reduction in monthly drop seizures i.e. 44% and 22% and a greater proportion of patients with a less than 50% seizure reduction, 44% and 24%. Adverse results were recorded in the CBD group than in the placebo, 86% to 69%. 

           The most common were diarrhea, pyrexia, decreased appetite, vomiting and somnolence. Treatment- related serious adverse events were recorded in 9 of the CBD group patients and one placebo patient ("Cannabis drug cuts seizures in childhood epilepsy," 2017).

            In the second trial, there was a significantly bigger reduction in the monthly frequency of drop seizures in the CBD 20 mg/kg/day group (42%) and 10 mg/kg/day (37%) than in the placebo group. There was also a similarly significant reduction in the proportion of patients with a more than 50% decrease monthly frequency of drop seizures. 

            Adverse events however were reported in 94% of the patients that took 20 mg/kg, 84% in those taking 10 mg/kg, and 72% of placebo patients too. Generally, the total seizures were significantly reduced in both CBD groups as compared to placebo.

           The most common were decrease in appetite and somnolence. Serious treatment-related adverse events occurred in five of the patients allocated 20 mg/kg group, 2 patients in the 10 mg/kg group, and zero patients in the placebo group. Of the 212 completers, 99% entered an open label extension study (Earleywine, 2003).

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Discussion

Article 1: Epilepsy and Marijuana

Paraphrase:

The use of cannabis by adults with epilepsy is widespread. This has led to the use of medicinal purposes common in many states. Various preparations of marijuana of varying content and strengths are now available. This is due to a study that proves that cannabis use by people with epilepsy reduces the intervals that they experience convulsions and seizures or even stops the seizures (Dantas, 2016). This has only been tested on animal models of epilepsy. Although cannabis has negative effects for a developing brain, the cases are reported to be extremely rare and mild. There are studies to find out the short time effects as well as long term effects of high CBD and low THC products in treatment of epilepsy in children and adults.

Summary

Due to the legalization of medical marijuana, there have been a rise in the therapeutic use of cannabis products in suppressing seizure in people, especially adults (Dantas, 2016). There has also been a lot of researches being carried out to figure out the effects to the brain that the use of cannabis products might have. Though it is recorded that these cases are not common, and at most times they are mild.

Dantas, F. G. (2016). Epilepsy and marijuana - a review. Journal of Epilepsy and Clinical Neurophysiology, 11(2), 91-93. doi:10.1590/s1676-26492005000200005

Article 2: Medical marijuana for epilepsy: Winds of change. 

Paraphrase:

Millions of people have been dealing with untreated epilepsy that have cause thousands to deal with experimental treatments in order to help alleviate their symptoms since no definitive treatments have been established. According to Sirven (2018), there have been a high amount of uncontrolled seizures affecting the lives of these individuals with epilepsy, and they are constantly struggling to find a personalized regimen to help them overcome their condition.

Summary

Social factors have been uncovered as a key driver of epilepsy care, disparities and outcomes. There is a clear evidence that THC acts via the cannabinoid receptor CB1. is suspected that the mechanism of action of CBD is likely polypharmacological (Sirven, 2018). There is scientific data that supports the roles of endocannabinoid system in seizure generation, maintenance as well as control.

Sirven, J. I. (2018). Medical marijuana for epilepsy: Winds of change. Epilepsy & Behavior, 29(3), 435-436. doi: 10.1016/j.yebeh.2013.09.004

Limitations and Implications

The results are subject to several limitations that have made it difficult for the study of Cannabis in Epilepsy to accurately answer its major research questions and risked the quality of findings and conclusion made. For starters, no information was reported on how often the dose of concomitant Clobazam was reduced. As a result, the conclusions made on how effective cannabis can be used for therapeutic epileptic treatment in this study are overgeneralized. Since this study does not answer the question of how to create an accurate dose of the treatment prescribed, future studies can and should focus on offering a detailed explanation of what specific doses or chemical combination make the accurate and optimal treatment for the syndrome.

Furthermore, the reports studied for this research did not clearly report on the changes that were happening to the plasma concentrations of concomitant AEDs and, most notably, N-desmethylclobazam and clobazam. In view of the fact that 66% of the patients in the CBD group were using clobazam co-medication and the irrefutable evidence from previous studies that indicated that N-desmethylclobazam levels increase by 500% on average when you add CBD, the data from the reports should have determined whether or not the reported improvement in seizure frequencies could be attributed to a direct action of CBD, or it is simply a consequence of increased plasma levels of comedication (KHAN, ABBAS, & JENSEN, 2018). The lack of clarity on what caused the cessation of seizures makes it difficult to accurately answer the research question and determine whether or not the cessation of seizures was because of the cannabis therapeutic treatment. Again, the overgeneralized conclusions provided as a result of the general findings also directly impact the quality of the conclusions of this study. Further researchers should however look into determining whether reduction of seizure frequencies could be attributed to a direct action of CBD, or it is simply a consequence of increased plasma levels of comedication in epileptic patients.

The third limitation of the study is that it further did not provide specific and accurate information on concomitant therapies, the most notable one being, whether and to what extent the clinical improvements on CBD therapy could be related to elevations in serum concentrations of other medications, especially N-desmethylclobazam and clobazam. As mentioned earlier, the lack of clarity on results possibly compromises the quality of conclusions. Future studies should determine whether the concomitant therapies and especially the clinical improvements on CBD therapy could be related to elevations in serum concentrations of other medications, especially N-desmethylclobazam and clobazam and how that impacted the use of cannabis in the therapeutic treatment of epilepsy.

Conclusion

To conclude, studies did not establish what researchers should look out for in a patient in order to make sure that one does not do more damage than good when trying to get rid of the convulsive seizures (Jaffe & Klein, 2017). The study offers no guidelines for practitioners who look forward to practicing and applying the cannabis therapy treatment on epileptic patients. As such, it would be difficult to have a controlled test of the proposed treatment in real life patients. Future researchers should therefore work on determining what practitioners should look out for in patients to point out whether the patients are responsive to the treatment or not. 

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References

Cerdá, M., Sarvet, A. L., Wall, M., Feng, T., Keyes, K. M., Galea, S., & Hasin, D. S. (2018). Medical marijuana laws and adolescent use of marijuana and other substances: Alcohol, cigarettes, prescription drugs, and other illicit drugs. Drug and alcohol dependence, 183, 62-68.

Cannabis drug cuts seizures in childhood epilepsy. (2017). Clinical Pharmacist.

cdoi:10.1211/cp.2017.20202978

 

Cannabis-derived treatment shows efficacy in rare form of epilepsy. (2018). Clinical Pharmacist.

doi:10.1211/cp.2018.20204455

 

Holtkamp, M., & Hamerle, M. (2017). Cannabis use in Epilepsy—Risks and Benefits.

Handbook of Cannabis and Related Pathologies, 431-438. doi:10.1016/b978-0-12-800756-3.00050-8

 

Karler, R., & Turkanis, S. A. (2019). Cannabis and Epilepsy. Marihuana

Biological Effects, 619-641. doi:10.1016/b978-0-08-023759-6.50052-4

 

Szaflarski, J. P., & Martina Bebin, E. (2016). Cannabis, cannabidiol, and epilepsy — From

receptors to clinical response. Epilepsy & Behavior, 41, 277-282.

doi: 10.1016/j.yebeh.2014.08.135

Dantas, F. G. (2016). Epilepsy and marijuana - a review. Journal of Epilepsy and Clinical Neurophysiology, 11(2), 91-93. doi:10.1590/s1676-26492005000200005

Sirven, J. I. (2018). Medical marijuana for epilepsy: Winds of change. Epilepsy & Behavior, 29(3), 435-436. doi: 10.1016/j.yebeh.2013.09.004