Mary's Cannabis Primer Issue #6: Cannabis & Epilepsy

CANNABIS PRIMER ISSUE #6

CANNABIS & EPILEPSY Edited by: Alice O’Leary Randall Contents Include: Introduction to Epilepsy & Cannabis The Importance of Knowing Epidiolex — FDA Approved CBD Down Under - A Southern Hemisphere Perspective

CANNABIS PRIMER ISSUE #6

CANNABIS & EPILEPSY

Editor-in-Chief: Alice O’Leary Randall Design: Jesica Clark Editor: Jane Banks Contributors: Ayesha Akhtar, Jason Bryan, Tim Byars, Heather Jackson, Eloise Theisen, and Lisa Todd.

Special Thanks to: Realm of Caring.

Published by: Mary’s Medicinals This publication was produced by Mary’s Medicinals and Mary’s Nutritionals in consultation with research scientists and medical professionals. Readers should keep in mind that our understanding of cannabis medicine is constantly evolving. We can only share the research that is currently available and what we have learned from patient observations and interviews. Each patient has individual reactions to different treatments, so readers should not assume that they will respond in the same way as another patient. Use of this information is not intended to be a substitute for professional medical judgment; before beginning any treatment, you should contact your own health care provider regarding your medical conditions or medical questions that you have.

Mary’s Cannabis Primer is published as an educational resource about the benefits of cannabis. It is part of Mary’s commitment to educating the general public about this remarkable plant. For further information please visit: www.maryspubs.com.

Copyright © 2019

Mary’s Medicinals • Denver, CO • MarysMedicinals.com • www.MarysPubs.com

EDITOR’S NOTE Welcome to the sixth issue of Mary’s Cannabis Primer. Our focus in this issue is epilepsy and cannabis, a topic that exploded onto the public scene in 2013 when Dr. Sanjay Gupta, in the CNN special “Weed,” highlighted the remarkable properties of cannabidiol (CBD) and spotlighted the case of young Charlotte Figi and treatment with CBD medicine produced in Colorado by the Stanley Brothers. Some observers regard Gupta’s documentary as the tipping point for medical cannabis. Not only did he introduce much of the world to CBD, he also apologized for not taking medical cannabis seriously enough in the past and stated flat out that the U.S. Drug Enforcement Administration (DEA) has lied about about the medical properties of cannabis.

While it may seem novel to use cannabis for treatment of epilepsy, this particular medical use of the plant is among the oldest recorded.

As Tim Byars and Eloise Theisen note in their article “Cannabis and Epilepsy,” the documented use of cannabis for this ailment has been found on stone Assyrian tablets dating to the second millennium B.C.E. Like the term “cancer,” epilepsy refers to a spectrum of disorders with many different causes. Recently, intractable pediatric epilepsy has been the focus of public attention, but epilepsy can strike at any age. Cannabis can be used to treat a large number of different types of epilepsy, including organic varieties as well as epilepsy caused by traumatic brain injury. Similarly, many different cannabis cultivars (strains) can be useful for treating epilepsy. That said, some are not efficacious, and some patients have reported that cannabis actually caused seizures (possibly due to high levels of delta-9 THC). In one case, a patient who had been successfully treating epileptic seizures for several years with a specific cultivar suddenly experienced seizures again. When the cannabis was analyzed, the only change was in terpene content. These stories demonstrate once more, the need for empirical research.

Nevertheless, for those patients with epilepsy that are unresponsive to conventional medications, cannabis can be a critical adjunct to their medical treatment. This issue pulls together observations from many who have been on the front line of the battle to secure adequate medicine including a parent, an educator from Chicago, and a nurse from Australia. We hope you find this issue of Mary’s Cannabis Primer educational and helpful.

Alice O’Leary Randall Editor-in-Chief, Mary’s Publications

Table of Contents INTRODUCTION TO EPILEPSY & CANNABIS. . . . . . . . . . . . . 1 THE IMPORTANCE OF KNOWING. . . . . . . . . . . . . . . . . . . . . 5 A PROSPECTIVE NATURAL HISTORY STUDY OF CANNABINOID USE AMONG PATIENTS WITH EPILEPSY . . . . . . . . . . . . . . . . 11 EPIDIOLEX — FDA APPROVED CBD. . . . . . . . . . . . . . . . . . . 13 WILEY’S STORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 DOWN UNDER - A SOUTHERN HEMISPHERE PERSPECTIVE. 18 RESOURCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

INTRODUCTION TO EPILEPSY & CANNABIS

By Timothy Byars & Eloise Theisen, AGPCNP-BC Radicle Health, Concord, California www.radiclehealth.com

Epilepsy describes a class of neurological disorders characterized by recurring seizures, which can vary dramatically in frequency and intensity. Approximately 3.4 million people in the U.S. suffer from epilepsy,1 and most of these patients can achieve seizure control using antiepileptic drugs such as valproate or carbamazepine.2 However, while there are more than two dozen anti-seizure drugs currently available3, twenty to

thirty percent of people with epilepsy have a condition that is drug-resistant—meaning that approximately one million Americans suffer from seizures that cannot be controlled with conventional medicine. Severe epilepsy has a major impact on the quality of life for patients, families, and caregivers. For instance, patients suffering from severe epilepsy frequently sustain injuries from seizures. For them, new therapies are required to reduce seizure frequency and severity and to improve the quality of life for everyone concerned.4 Cannabis has been used to treat epilepsy throughout history, possibly spanning four thousand years.

Some researchers suggest that the first documented evidence of cannabis use for epilepsy can be found on stone Assyrian tablets, dating to the second millennium B.C.E.5 In India, cannabis use for epilepsy

1 https://www.cdc.gov/epilepsy/about/fast-facts.htm 2 Stockings E, Zagic D, Campbell G, et al Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence J Neurol Neurosurg Psychiatry 2018;89:741-753.

3 https://www.epilepsysociety.org.uk/list-anti-epileptic-drugs#.W-oYP3pKjOQ 4 Romy Mahrer-Imhof, Sabina Jaggi, Armanda Bonomo, Hannele Hediger, Priska Eggenschwiler, Günther Krämer, Erich Oberholzer, Seizure, March 2013, pages 128-135.

5 Russo, Ethan. (2016). Cannabis and epilepsy: An ancient treatment returns to the fore. Epilepsy & behavior : E&B. 70. 10.1016/j.yebeh.2016.09.040.

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treat epilepsy patients with cannabis. This treatment would soon make its way across the Atlantic, and prior to the US prohibition of the use of cannabis, it became a common treatment for epileptic patients.7

can be traced back to the first millennium B.C.E. In one documented example, patients were instructed to insert the juice of cannabis leaves into their nostrils, a route of administration that is appropriate during acute attacks when an oral preparation can be difficult to administer and dangerous to the patient. It is also interesting to consider that the raw preparation would contain THCa (or the non-decarboxylated version of THC).6 The first modern investigations of cannabis as a treatment for epilepsy began in the nineteenth century, when William O’Shaughnessy studied the uses of cannabis in Ayurvedic therapies while working on the sub-continent of India. After returning to England, O’Shaughnessy reported success when using cannabis to treat his own patients and subsequently inspired other physicians to

Medical cannabis began to decline in the early twentieth century, and cannabis prohibition restricted patients from accessing this treatment modality for more than six decades.

However, new research, increased legalization of cannabis, high profile cases with pediatric epilepsy patients, and anecdotal evidence from patients experimenting with cannabis have all generated intense interest in cannabis-based medications for people with refractory epilepsy.

In fact, the use of cannabis as a treatment for pediatric epilepsy has made a significant impact on the public perception of legal cannabis. In 2013, CNN produced a cannabis documentary with chief medical correspondent, Dr. Sanjay Gupta. The documentary illustrated how cannabis virtually cured five-year-old Charlotte Figi, who suffered with Dravet syndrome.

Figi was wheelchair-bound, on a feeding tube, and suffering around from 300 grand mal seizures a week.

6 Russo, Ethan. (2016). Cannabis and epilepsy: An ancient treatment returns to the fore. Epilepsy & behavior : E&B. 70. 10.1016/j.yebeh.2016.09.040.

7 Russo, Ethan. (2016). Cannabis and epilepsy: An ancient treatment returns to the fore. Epilepsy & behavior : E&B. 70. 10.1016/j.yebeh.2016.09.040.

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When her parents started experimenting with high-CBD cannabis oil in 2012, her seizures were reduced to approximately four per month.

After the initial story, three additional CNN cannabis documentaries followed, and in 2014 The New York Times published a week of editorials in support of medical cannabis.

Ten states now have legal adult-use cannabis, and all but five states have some type of medical cannabis laws.

It’s impossible to deny the impact that Figi’s story—and others like it—has had on the legalization of cannabis in the United States.

As more data becomes available, it appears that cannabis as a therapeutic treatment for epilepsy has promise, especially for patients who do not respond to FDA-approved anti-epileptic drugs.

In an observational study8 with two hundred and seventy-two epileptic patients in California, Washington, and Maine, physicians reported seizure reduction in 235 of the patients using cannabis preparations.

Most patients used preparations consisting primarily of CBD, though some patients also used preparations that included a small amount of THC or THCa.

Of the 235 patients who experienced some relief, 26 patients had complete seizure remission, 75 patients had at least a two-thirds reduction in seizures, and 45 patients had at least a 50 percent reduction in seizures.

Thirty-seven patients (about 14 percent) had no seizure relief using cannabis preparations. In this study, more than half the patients experienced—at minimum—50 percent fewer seizures using cannabis.

Patients and families reported that adverse effects were mild, infrequent, and well tolerated. Some patients reported side effects that were beneficial, such as increased alertness.

Recently, the US FDA approved Epidiolex,9 an oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. Epidiolex is the first FDA-approved drug that contains a purified compound— CBD—that is derived from a cannabis plant. Epidiolex was studied in three randomized, double-blind, placebo-controlled clinical trials with a total of 516 patients. Epidiolex, when used as an adjunct medication to other conventional medications, demonstrated efficacy in reducing

8 Sulak, Saneto, and Goldstein, “The current status of artisanal cannabis for the treatment of epilepsy in the United States,” Epilepsy & Behavior , Volume 70 , 328 - 333 9 FDA news release, “FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy,” June 25, 2018.

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seizure frequency when compared with a placebo.10 Despite these advancements, challenges remain for patients using cannabis.

Many patients live in states where it’s impossible to procure safe, tested products. Often, these patients must reply on hemp-derived products that are unregulated and can contain heavy metals, pesticides, mold, bacteria, and other toxins. Even in states with legalized medical cannabis, products can often contain toxic additives such as propylene glycol, ethylene glycol, flavor additives like corn syrup, and artificial colors. Sometimes it is difficult to find information about how cannabis ingredients are extracted, and many products contain residual amounts of hydrocarbons (such as butane, hexane, and propane) or isopropyl alcohol.

Even in states like Colorado and California, consistently obtaining the same medication can be challenging, and given that most of these medications are artisanal, inconsistencies often occur among batches.

Labeling can be misleading, incorrect, or incomplete in terms of what patients require. There are few healthcare professionals available to guide cannabis patients, and many patients must rely on retail workers and product manufacturers for medical

advice. And, incredibly, families using cannabis for pediatric patients can face legal retribution from child protective services and other government agencies, even when those families comply with all state laws.

Despite these challenges, many families are considering cannabis as a treatment option. Given the side effects of many anti-seizure drugs, which can include blindness, liver damage, and increased risk of death with long-term use, it is easy to understand their motivation. While cannabis can certainly have adverse side-effects (such as fatigue, lethargy, and euphoria), these reactions are mostly dose dependent. Overall, cannabis has a much higher safety profile than many prescription medications used to treat epilepsy.

Of course, patients and families pursuing cannabis as a treatment modality should always get medical advice from a healthcare professional (HCP), especially when treating a condition as serious as epilepsy.

A competent HCP can conduct a comprehensive intake meeting to review the condition of the patient and assess current prescription medications to identify potential contraindications with cannabis. HCPs can help patients learn how to administer medicines and use devices, and they can discuss the benefits and potential side-effects of products. Finally,

10 FDA News Release, “FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy,” June 25, 2018.

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HCPs can provide ongoing support to help patients navigate the complexities of cannabis treatment, local laws, and access issues.

The medical community needs to accept that patients are currently using and will continue to use cannabis to treat a broad range of conditions and disease, regardless of a healthcare professional’s personal opinion about cannabis. Cannabis must be treated like any other medication,

Timothy Byars

and the medical community must assume the responsibility of caring for patients so that they do not need to get healthcare advice from unlicensed retail workers. With the release of the FDA-approved product Epidiolex, perhaps more healthcare professionals will pursue education about the endocannabinoid system and cannabinoid-based medicines. î‚?

Eloise Theisen, AGPCNP-BC

THE IMPORTANCE OF KNOWING

By Ayesha Akhtar, MPH Director of Education Epilepsy Foundation of Greater Chicago

The rate of chronic disease is on the rise, with care and treatment options becoming costlier, more heavily scrutinized by insurance companies, and cost-prohibitive when not covered. Most patients with chronic disease can be effectively treated with medication, but for some patients, nothing works at all. Increasingly, complementary therapies are brought into the conversation between healthcare providers (HCPs) and patients at the time of diagnosis, 5

whether it is dietary (as in the case of many auto-immune diseases), acupuncture (to treat back pain), and now more than ever, medical cannabis (as a treatment for epilepsy).

Epilepsy is a chronic brain disorder marked by two or more unprovoked seizures. The incidence of epilepsy is increasing. It is now the fourth most common brain disorder, behind Alzheimer’s, Parkinson’s, and migraines. In August 2017, the Centers for Disease Control and Prevention (CDC) issued an updated Morbidity and Mortality Weekly R ep or t ( M M W R) which stated that t he preva lence of epi lepsy has increased to more than three million Americans (over two percent of the population) and that there are more than thirty types of seizures.

Because not all seizure types are recognizable, raising awareness about this brain disorder is extremely important.

Some patients have seizures that manifest as staring off into space, other patients experience hallucinations, and about thirty percent experience convulsions.

I hear from nurses within the Chicago Public Schools that there is an uptick in reporting seizures. The question 6

is whether seizures have become more common or whether there is greater awareness of seizure disorders? Some days in the span of an hour, I may receive three separate training requests from school teachers for Seizure Recognition and First Aid (one of our signature education programs). There are other days when I am teaching groups of people with no experience or education about epilepsy. As Director of Education for the Epilepsy Foundation of Greater Chicago, my priority in an educational setting is making sure that the audience knows that the lifetime risk of developing epilepsy is about one out of twenty-six, that one in ten people will have a single seizure in their lifetime, and that not all seizures are convulsive. What stands in my way are attitudes like the stigmatization of seizure disorders and the public’s general lack of awareness of seizure disorders. The media tends to equate epilepsy with scary-looking convulsive seizures, but not all seizures are convulsive.

Effects range from what you typically see in the media, to a moment of staring off into space, to auditory, olfactory, or visual hallucinations, which is why some people mistake epilepsy for mental illness. Seizures may cause a

CBD molecule

person to smell oranges or hear ringing bells; there is a wide spectrum of seizure types.

How do people manage their epilepsy?

It is important to know that anti-epilepsy medications do not work for everyone. I spoke with a woman who was taking a seizure medication that caused her teeth to fall out (she subsequently stopped taking it). She was then advised to go on anxiety medication because “maybe that would help her control her seizures better.� Sadly, neither medication helped to control her seizures. About seventy percent of people living with epilepsy can effectively manage their seizures with medication. So what do the remaining thirty percent of people living with epilepsy do in order to have a positive quality of life? Complementary therapy has brought about significant improvements in the management of

epilepsy that is not well-controlled with conventional medications alone.

We are now in an era where a child has the ability to have her fifty daily seizures reduced to perhaps five per week. A young adult can reduce the pain from a head injury and control his seizures without unwanted side effects from a cocktail of medications (no one wants dentures at age 20). These success stories are being made possible with medical cannabis. The young child can take a daily dose of CBD oil in conjunction with a lesser dosage of anti-epilepsy medication and have a greater reduction in seizures. We have a number of clients who are ready to provide this treatment option for their children, when medication alone is not working. A young adult once told me about his sledding accident in the second grade.

The resulting head injury triggered Continued on page 10 7

CBG

reduces blood sugar levels & treats psoriasis

ENDOCRINE & IMMUNE RESPONSE

treats fungal infections

CBG

CBD, CBC, CBN & THC

reduces or eliminates pain

kills or slows bacteria growth

CBD & CBG

inhibit cell growth & cancer cells

CBD, CBG, CBC & THC

WHOLE BODY RELIEF & PROTECTION

CBD & THC

increases cerebral blood flow

THE NERVOUS SYSTEM

CIRCULATORY SYSTEM

CBD

reduces risk of artery blockage & anti-ischemic

CANNABIS MAN

suppress muscle spasms

CBD, CBC & THC

reduce inflammation

CBD, CBN & THC

promote bone health

CBD, CBG, CBC & THC-V

MUSCULAR & SKELETAL

CBD

CBD & THC-V

tranquilizes & relieves anxiety

CBD

THE DIGESTIVE SYSTEM

appetite stimulant

THC

reduces seizures & convulsions

reduces contractions in the small intestines

appetite suppressant

THC-V

CBN

aids in sleep

Continued from page 7

seizures that were difficult to control.

Today he is able to control his seizures with one strain of CBD, which allows him to enjoy his youth.

It is important to recognize that both anti-epilepsy medication and medical cannabis are not one size fits all and may not work for all seizure types. It is important that patients meet with their physicians to discuss whether

CBD would be effective and what type of CBD would work best. Most important is that every person living with epilepsy understands all the options on the table, and learns what works best for them to help manage their epilepsy as effectively as possible. î‚?

BIO Ayesha Akhtar is the current Director of Education with the Epilepsy Foundation of Greater Chicago and is a Master Trainer in Diversity & Cross Cultural Awareness. Ms. Akhtar is a graduate of Loyola University Chicago, where she earned a B.B.A. in accounting. In 2010 she earned her Masters of Public Health from the University of Illinois-Chicago, focusing on culturally sensitive approaches to health care. She has more than ten years of experience as a health educator in a variety of settings and is passionate about community education and bringing health information to individuals so they can live informed and empowered lives.

Her service area spans a fifteen-mile radius from her home base of Oak Park, where she lives with her husband and two sons. Ayesha’s specialty programs include trainings for school personnel, students in grades K-12 and collegeaged persons. She also specializes in trainings for African-American, Hispanic American and other diverse communities looking for culturally sensitive approaches to learning about epilepsy. Ayesha is fluent in English, Spanish, and Urdu.

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A PROSPECTIVE NATURAL HISTORY STUDY OF CANNABINOID USE AMONG PATIENTS WITH EPILEPSY

By Heather Jackson, et al.*

INTRODUCTION

Epilepsy is a group of serious neurologic disorders that is difficult to treat.

Many epilepsy patients use cannabis, cannabinoid extracts, or other cannabinoids for symptom relief based on anecdotal accounts, and more recently, clinical trials of cannabidiol (CBD). Little systematic data has been collected about the naturalistic use of cannabinoids for epilepsy.

METHODS

Patients or adult caregivers registered with the Realm of Caring Foundation, a non-profit focused on education related to the use of hemp products for epilepsy and other health conditions, were invited to participate in a web-based survey study that assessed demographic and health-related outcomes. Participants completed a baseline assessment and were then asked to complete follow-up surveys every three months. Analyses compared patients using cannabinoids to those who were not at baseline, and evaluated changes from baseline in patients who were not using cannabinoids at baseline but initiated their use during the follow-up assessments.

T-tests and Chi-Square tests were

used and significance was determined at p<0.05.

RESULTS

At baseline, one hundred and sixtyeight patients were using cannabinoids and one hundred and five were contemplating use, but had not yet done so. Products high in CBD, rather than those high in THC, were predominant among those who had initiated cannabinoid use, and use was typically either an adjunct to traditional treatments or used as a last resort when other treatments failed.

On average, cannabinoid users were significantly older than non-users, but did not differ with regard to gender, race/ethnicity, or educational attainment. Cannabinoid users reported significantly better health satisfaction and sleep quality, as well as lower anxiety and depression compared with non-users on validated assessments. Non-users were more likely to report past month outpatient hospital, inpatient hospital, or emergency room visits, and were more likely to have had a sick day from work or school in the past month compared with cannabinoid users. There were no differences between groups on self-reported quality of life or number of prescription or OTC medications used.

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Of the one hundred and five patients not using cannabinoids at baseline, thirty-five initiated use prior to completing a follow-up assessment.

Compared with the baseline, individuals who initiated cannabinoid use experienced improved self-reported health satisfaction, a reduction in the number of prescription medications taken, and reduced depression after initiating cannabinoid use. Children in this cohort also reported improved sleep following initiation of cannabis or cannabinoid products. One patient stopped use of cannabinoids due to an increase in seizure activity observed after initiating use.

CONCLUSIONS

In a convenience sample of epilepsy patients enrolled in an observational research registry, current users of cannabinoids reported better outcomes across a number of health-related measures compared with a demographically similar group

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of epilepsy patients not using cannabinoids. Among non-users at baseline, initiation of use was associated with improvements in health and a reduction in the use of prescription medications. This prospective natural history study indicates an overall clinical benefit of cannabinoid use among epilepsy patients using products high in cannabidiol, indicating the need for additional drug development and controlled clinical research in this area. î&#x201A;? *Complete author list: Heather Jackson, Realm of Caring Foundation, Colorado Springs, CO; Nicolas J. Schlienz, Johns Hopkins University School of Medicine, Baltimore, MD; Marcel O. Bonn-Miller, Zynerba Pharmaceuticals, Devon, PA and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Natalie A. Lembeck, Johns Hopkins University School of Medicine; Joel Munson, Realm of Caring Foundation and Ryan Vandrey, Johns Hopkins University School of Medicine.

EPIDIOLEX — FDA APPROVED CBD The development of pharmaceutical-grade medical cannabis products got a huge boost in 2018. The UK-based G.W. Pharmaceuticals, together with its US subsidiary Greenwich Biosciences, received approval from the US Food and Drug Administration (FDA) to market Epidiolex, a purified CBD product derived from the cannabis plant. The drug has been rigorously tested under the watch of FDA and other US drug agencies. Its approval marks the first time a cannabis-derived drug has been approved by the FDA. It started shipping in late October.

Epidiolex is particularly effective for children with Dravet Syndrome or Lennox-Gastaut Syndrome (LGS). These relatively rare pediatric conditions cause intractable seizures that limit development of the child and vastly reduce the child’s (and family’s) quality of life.

The use of CBD to treat intractable pediatric epilepsy first gained public attention with the case of Charlotte Figi which led to the development of Charlotte’s Web, a CBD product produced in Colorado by Stanley Brothers.

Charlotte’s Web was prominently featured in the 2013 CNN special “Weed” with Dr. Sanjay Gupta. In 2014 G.W. Pharmaceuticals filed for orphan drug status for Epidiolex and began testing after the first child was treated in 2012. According to the FDA: The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.

By focusing on Dravet Syndrome and LGS—rather than the broader categorization of pediatric epilepsy—G.W. was able to fast-track the drug’s development. Even so, it took four years of meticulous research and significant expense to get the drug approved.

The cost of Epidiolex is one big area of concern. Some news reports place the annual cost to the patient at $32,000, based on patient weight and dosing assumptions. Health insurance may pick up some of the cost, and there are 13

some who say this cost is in keeping with the cost of other epilepsy drugs which can range from $1,000 to $3,000 a month.

Maryâ&#x20AC;&#x2122;s Cannabis Primer asked the folks at Greenwich Biosciences a few questions about Epidiolex and its development. Our thanks to Dr. Jan Anderson, associate director at Greenwich, for her help.

PLEASE EXPLAIN WHAT IS EPIDIOLEX?

Epidiolex is an FDA-approved plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD). It is a standardized, consistent, reproducible liquid formulation of CBD. Epidiolex is approved for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) or Dravet Syndrome (DS) in patients two years of age or older. It is marketed and distributed in the US

by Greenwich Biosciences, the US subsidiary of GW Pharmaceuticals plc (Cambridge, UK).

YOU SAID THAT EPIDIOLEX IS PLANT-DERIVED. CAN YOU TELL US MORE ABOUT THAT?

The selectively bred plants from which Epidiolex is made are high in CBD and grown in accordance with Good Agricultural Practice (GAP).

The finished product is then manufactured under Good Manufacturing 14

Practice (GMP). Stability, purity, batch-to-batch consistency and compliance with US Pharmacopeia standards are monitored by the FDA. IN WHAT FORM IS IT AVAILABLE?

Epidiolex is an oral solution with a concentration of cannabidiol at 100 mg/mL. HOW LONG HAS IT BEEN RESEARCHED?

Ca n n a bi s - b a s e d me d ic at ion s have been actively researched by Greenwichâ&#x20AC;&#x2122;s parent company, GW Pharmaceuticals plc, for more than twenty years, and formal clinical research on Epidiolex began with FDA approval of an Investigational New Drug (IND) application in 2014.

CAN YOU SUMMARIZE THE FINDINGS?

Greenwich Biosciences and GW Research have now completed three randomized double blind, placebo-controlled clinical trials. Two of

these trials addressed Lennox-Gastaut Syndrome (LGS) and one addressed Dravet Syndrome (DS). A fourth clinical trial addressing DS is ongoing. In all three completed trials, Epidiolex met its primary endpoint, which was significant reduction of either drop seizures (LGS) or convulsive seizures (DS), when compared to placebo.

Statements regarding the efficacy of an FDA-approved drug must be accompanied by safety information.

The most common adverse events (incidence of at least ten percent and greater than the placebo) with Epidiolex-treated patients, included somnolence; decreased appetite; diarrhea; transaminase elevations (an indicator of liver damage); fatigue, malaise, and asthenia; rash; insomnia; sleep disorder, and poor quality of sleep; and infections (refer to United States Prescribing Information, USPI for adverse events of special interest, warnings and precautions, and contraindications).

WHEN AND WHY DID GW PHARMACEUTICALS DECIDE TO DEVELOP EPIDIOLEX? WAS THERE A PARTICULAR STORY OR EVENT?

Our research into cannabidiol, which eventually became Epidiolex, began in 2012 with a first-of-its-kind Expanded Access Program (EAP, also known as compassionate use) for a single child suffering from debilitating seizures. This physician-led EAP

has continued to enroll a total of more than 1,000 patients. In 2014, a rigorous Phase Three clinical trial program began for patients with LennoxGastaut Syndrome (LGS) and Dravet Syndrome (DS). The results of these trials were submitted to the FDA in a New Drug Application (NDA) which led to FDA approval of Epidiolex in June 2018.

EPIDIOLEX IS NOW AVAILABLE IN THE US. IS IT AVAILABLE IN OTHER COUNTRIES?

Not yet. In February 2018, the European Medicines Agency (EMA) accepted for review a Marketing Authorization Application (MAA) for Epidiolex for adjunctive treatment of seizures associated with LennoxGastaut Syndrome (LGS) and Dravet Syndrome (DS). The outcome of the MAA review by the EMA is expected in 2019.

WHAT OTHER CANNABINOID PRODUCTS DOES GREENWICH BIOSCIENCES HAVE?

For Epidiolex, a Phase 3 clinical trial in tuberous sclerosis complex (TSC) is currently underway with data from this trial expected in the first half of 2019. Beyond Epidiolex, we believe that our cannabinoid platform has potential utility in a variety of therapeutic indications including multiple sclerosis, schizophrenia, autism spectrum disorders, and glioblastoma. î&#x201A;?

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WILEY’S STORY

by Jason Bryan

Our baby boy Wiley suffered from infantile spasms, a type of refractory epilepsy. If left untreated this syndrome can completely debilitate a child. His infantile spasms began increasing in frequency and intensity, clustering near the times of waking and sleeping, and numbering in the hundreds throughout a single day.

For over six months we treated our son with Vigabatrin (Sabril) somewhat successfully. Although his development was stalled, the medicine did remove the outward appearance of the spasms that had wracked his little baby brain and body just months before.

We understood that long-term use of this drug in adults can cause permanent damage to patients’ peripheral vision, so the plan was to wean Wiley off the drug eventually and titrate up on another drug if needed. As we feared, when we started to wean him off Sabril, Wiley began to have breakthrough spasms. I had already conferred with the neurologist about CBD oil and while his doctor agreed that it would be fine to try CBD the initial response was, “First let’s try this other drug.”

So we started to titrate Wiley up on another anti-convulsant called Keppra (Levetracetam), and right away he had adverse reactions. He became 16

unusually fussy and clingy. He was not eating nor sleeping as well as he had been. And then my wife, Ryna, witnessed something very alarming, something we had never seen before—Wiley was having spasms in his sleep. Ryna called and told me “He’s having spasms in his sleep now.

I am not going to give him the pills, I am just going to give him the oil,” We decided that it was time for CBD. We based the dosage of CBD on his bodyweight; for every pound we gave Wiley 2.5mg of CBD. He weighed twenty pounds at the time, so we gave him 50mg of CBD daily.

Fortunately for us, we live in California, a state that has had a medical marijuana program since 1996, so unlike some parents, we did not have to uproot our family to get Wiley’s medicine. The group that produced the CBD we used for our son was an ethical patients’ collective that used organic farming practices and full flower extraction methods. For cannabis to truly qualify as medicine it must be both pure and potent. We were lucky to be in touch with a team of farmers who happily shared their knowledge. Later in our journey I began to produce my son’s medicine myself from resinous cannabis plants that graced our backyard garden.

Wiley’s oil was an infused olive oil preparation of a California cultivar

named ACDC. This lovely 20:1 CBD to THC strain has amazing neuroprotective, anti-epileptic and anti-inflammatory properties and was the right medicine for my son at the right time.

After we administered the first therapeutic dose of the oil to Wiley, we never looked back. He became spasmfree with the energy of a normal two year-old, tearing up the house faster than I could fix it. Truly, what a blessing cannabis has been for my family!

Conventional anti-seizure medication uses chemical compounds in an attempt to knock out and replace the function of an over-excited brain.

But plant-based medicines—rich in hundreds of phytochemicals —tend to work with the body’s natural systems.

Further research revealed that the cannabinoids actually traverse the synaptic cleft retrograde––calming the electrical over-activity by inhibiting glutamate and regulating other neurological activity. Wiley’s previous medications—single compound anti-convulsant pharmaceutical drugs—knocked out the body’s function really well… sometimes relegating him to a complete stupor… but what did they actually replace? The answer, of course, is nothing.

Full-flower extracts of CBD-rich cannabis controlled my son’s seizures and allowed Wiley to outgrow his syndrome. His brain began to heal and his development got back on track, all without side effects. Of course we surrounded our son with the best services and therapists we could. In large part it was the effort of a team that helped him to progress to where he is today, but none of their work would have been effective if his spasms had not been controlled. After two years of taking the cannabis oil Wiley no longer has seizures and does not require his medicine . . . although, I still keep a jar or two of CBD oil handy, just in case. 

BIO Jason Bryan is a documentary film producer and a fine art portrait photographer, but having witnessed the amazing healing that cannabis afforded his son, Jason has also become a cannabis medicine advocate and consultant.

He believes that through proper education, society will be able to reveal

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the truth of cannabis medicine. His mission is to elevate the therapeutic utility of cannabis in the public consciousness and help usher in a time when cannabis—one of the most efficacious substances known to humankind— will become available to everyone seeking its benefits.

Jason continues to work to empower patients with their own healing and seeks to expand his network of patient-centric professionals and advocates as he embarks on his next venture––Patient Led Discovery.

DOWN UNDER - A SOUTHERN HEMISPHERE PERSPECTIVE

By Lisa Todd Clinical Governance Manager Epilepsy Action Australia

Medicinal cannabis has been a contentious issue in Australia for more than 30 years with multiple attempts to open the conversation— in political circles and parliamentary forums— regarding the legalization of cannabis for therapeutic purposes.

Numerous attempts at both state and federal levels to de-schedule cannabis via the Poisons Act had failed, and a 2012 review of the Use of Cannabis for Medicinal Purposes by the New South Wales Legislative Council was dismissed by the Federal Health Minister who stated that “there was limited evidence on the clinical efficacy of cannabis for medicinal purposes.”

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A draft of Regulator of Medicinal Cannabis Bill 2014 was introduced to the ACT Parliament to open discussion seeking the creation of a new independent regulatory body to oversee cannabis cultivation, manufacture and distribution in Australia. It was rejected.

However, with the advent of the internet and social media the populace was able to access information and share their experiences regarding medical cannabis, thus raising the consciousness of the wider community. In particular, having seen social media reports of positive effects of CBD dominant strains of cannabis on seizure frequency and levels of function, parents of children with medication-resistant epilepsy who had exhausted all conventional therapies, sought “the right to try.” Parents

were realistic about the chances of medicinal cannabis working for their children because the chance of a fifty percent reduction in seizure activity in medication-resistant epilepsy is approximately four percent with each new anti-epileptic drug (AED).

Nevertheless, parents wanted the right to give it a try.

Some parents tentatively ventured into this arena with little to no support from medical specialists, often unaware of the potential drug-to-drug interaction, yet reporting reductions in seizure frequency and improved behavioral and cognitive f u nc t ion. When parents accessed i l l icit ca n nabinoid-based products from the recreational black market or from compassionate artisan suppliers or nutraceuticals on the internet, the issues of quality, composition, concentration, and purity always remained a concern.

Parents did not like being on the wrong side of the law, risking prosecution and removal of their children

by Childrenâ&#x20AC;&#x2122;s Services, and they desperately lobbied state and federal politicians, ministerial advisors, health department administrators, and medical personnel.

In the meantime, recognizing that changing legislation was the only way

to proceed, Mr. Dan Haslam (who was diagnosed with bowel cancer at the age of 20) and his parents Lucy and Lou Haslam became prominent legislative advocates. Meeting with the New South Wales (NSW) Premier, Mike Baird, they shared Danâ&#x20AC;&#x2122;s personal experience of having severe chemotherapy-related nausea and vomiting relieved by cannabis. Baird ultimately introduced and committed $9 million toward medicinal cannabis clinical trials for children with epilepsy, terminally ill adults, and patients living with cancer. NSW quickly int roduced t he Medicinal Cannabis Compassionate Use Scheme for patients w it h a ter m i na l illness which was administered by the Justice Department to protect those registered with the scheme from prosecution for the use of illicit cannabis products. Only a handful of people applied, with many concerned that disclosure to the Justice Department would draw attention to their illicit activity and their compassionate suppliers.

In June 2015, the Therapeutic Goods Administration (TGA), the Australian equivalent of the FDA, rescheduled cannabidiol (CBD), the non-psychogenic compound found in cannabis, from Schedule 9 Prohibited Substance to Schedule 4 Prescription Only Medicine. Sixteen months 19

• Lack of knowledge by medical practitioners about the endocannabinoid system and use of medicinal cannabis with few opportunities for them to learn

later in November 2016, nominated medicinal cannabis products were down-scheduled from Schedule 9 Prohibited Substances to Schedule 8 Controlled Drug, including those containing tetrahydrocannabinoil (THC), the psychogenic compound allowing the prescribing of these products. Cannabis and cannabis-derived products are still regarded as Schedule 9 Prohibited Substances if used for recreational purposes.

In Australia, unlike many other countries, the Federal Government opted to treat cannabinoid-based products just like any other unapproved unregistered medicine.The TGA provides pathways for access to medicines not currently approved or registered in Australia. Access options for medicinal cannabis include an Authorised Prescriber Scheme; the Special Access Scheme (SAS); or through clinical trial.

Unfortunately, despite removing many legislative barriers and streamlining the application process, patients trying to access legal forms of medicinal cannabis face many barriers including: 20

• The challenge of finding a medical practitioner willing to prescribe cannabinoid-based medicines, invest time to complete the required paperwork and provide an acceptable level of scientific evidence to support the application • Difficulty, in most instances, of gaining a letter of support from the treating specialist • Difficulty identifying a suitable product that is permitted to be imported or held in bulk within Australia • Long delays in importing and exporting products from international markets • Problems identifying financially accessible products, because costs are prohibitive for the average Australian, and • Lack of locally cultivated and manufactured medicinal cannabis products because the industry in Australia is in its infancy.

Professor Iain McGregor, of the Lambert Initiative for Cannabinoid Therapeutics at The University of Sydney, estimates that over 100, 000 Australians are accessing illicit cannabis products to self-manage

their health conditions. In comparison, the TGA has approved only 1,204 SAS Category B applications for unapproved medicinal cannabis products. This statistic does not refer to individual patients; it accounts for approvals that could be repeats or multiple types of products for the same patient.

Although many legislative changes to legislation have occurred to remove legal barriers to accessing medicinal cannabis, from the consumer perspective access is no easier now than it was 4 years ago. Patients still have difficulty in finding a medical specialist or general Practitioner with the support of a treating specialist to write a prescription and submit the SAS B application, and also in finding an affordable legal product. For

these reasons as demand grows, so does the number of people turning to the black market to buy products where there is no quality control.

Many patients are hesitant to reveal their use to their general practitioner for fear of repercussions, so they are flying blind without the benefit of medical oversight. These patients are often unaware of the potential drugto-drug interactions via the CPY450 metabolic pathway in the liver, nor do they know the right questions to ask to assess if the product could be contaminated with pesticides, heavy metals, hydroponic chemicals, mould, bacteria, fungus etc.

The Australian medical cannabis program is maturing but it still has a long way to go. î&#x201A;?

BIO Lisa Todd has worked with Epilepsy Action Australia for the last 14 years, starting as an Epilepsy Nurse Specialist and Educator before moving into management, policy, advocacy, consumer consultation and research roles. She is currently the Clinical Governance Manager and Clinical Nurse Consultant in Epilepsy for the organization. She has also worked on a temporary assignment with East Timor Epilepsy Foundation and the George Institute for Global Health.

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RESOURCES The Realm of Caring provides a comprehensive library of research articles on cannabis and epilepsy with more than twenty scientific articles. You can access them here. https://www.theroc.us/research-library The Epilepsy Foundation of America has an excellent web page on the use of cannabis in epilepsy and the current status of the drug in the United States. http://m.aryspub.com/medice07cd For the UK perspective on this topic visit the Epilepsy Society website. http://m.aryspub.com/canna170c2 Epilepsy Action Australia has an excellent web page on the topic with many links to other sources of information. http://m.aryspub.com/bd78b.

Cannabis 4 Epilepsy is a project of Epilepsy Action Australia and MGCPharma of Australia. This website is devoted to the use of cannabis in epilepsy and has several videos. www.c4e.com.au

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