Updated March 21, 2016 Three million Americans live with epilepsy. One-third of these people have ongoing treatment-resistant seizures. As the leading organization of clinical and research professionals specializing in the treatment of this challenging spectrum of disorders, the American Epilepsy Society (AES) supports all well-controlled studies that will lead to a better understanding of the disease and the development of safe and effective treatments for epilepsy. The anecdotal reports of positive effects of the marijuana derivative cannabidiol (CBD) for some individuals with treatment-resistant epilepsy give reason for hope. However, we must remember that anecdotal reports alone are not sufficient to support treatment decisions. Robust scientific evidence for the use of marijuana is limited. The lack of information does not mean that marijuana is ineffective for epilepsy. It merely means that we do not know if marijuana is a safe and effective treatment for epilepsy, which is why it should be studied using the well-founded research methods that all other effective treatments for epilepsy have undergone. There is great interest within the professional community to explore the potential of CBD and there are several clinical and basic research studies now underway. Every case of epilepsy is different and the disease is highly variable. Scientific studies help the entire epilepsy community to understand how and why various treatments work and for whom they are effective. Research also helps us understand the correct dose, side effects, and potential interactions with other medications. AES is highly supportive of these rapidly advancing research efforts. AES calls on government and private funders to support well-designed clinical research into all promising treatments for epilepsy. To increase clinical research into the effectiveness and safety of marijuana as a possible treatment for resistant epilepsy, the American Epilepsy Society urges that marijuana’s status as a Federal DEA Schedule 1 controlled substance be reviewed. AES’s call for rescheduling is not an endorsement of the legalization of marijuana, but is a recognition that the current restrictions on the use of medical marijuana for research continue to stand in the way of scientifically rigorous research into the development of cannabinoid-based treatments. The American Epilepsy Society is very sympathetic to the desperation of parents whose children have severe, treatment-resistant epilepsy. Our members, face these families daily at the clinic and at their bedside and are highly attuned to the need for compassionate use of promising new therapies in appropriate and controlled circumstances. AES urges all people touched by epilepsy to consult with an epilepsy specialist and explore the many existing treatment options, so that they can make informed decisions with their specialist that weighs the risks and benefits of the different treatment options. About the American Epilepsy Society The American Epilepsy Society is a medical and scientific society whose members are engaged in research and clinical care for people with epilepsy. For more than 75 years, AES has provided a dynamic global forum where professionals from academia, private practice, not-for-profit, government and industry can learn, share and grow.

July 13, 2015 Governor Butch Otter State of Idaho Office of the Governor P.O. Box 83720 Boise, ID 83720 Dear Governor Otter, As Idaho reconsiders enacting new cannabis legislation, I write to offer the perspective of the American Epilepsy Society (AES), the leading U.S. organization of clinical and research professionals specializing in the treatment and care of people with epilepsy. Epilepsy is the most common and potentially devastating neurological disease that affects people across the lifespan. In America, one in 26 people will be diagnosed with epilepsy at some time in the course of their life - more will experience an isolated seizure. Epilepsy is associated with significant morbidity and mortality and is associated with many co-morbidities including depression, cognitive dysfunction, and autism. Today between 2.2 and 3 million Americans, including almost 400,000 children, live with epilepsy, with one third living with treatment-resistant seizures that do not respond to current medications. The American Epilepsy Society position on medical marijuana as a treatment option for people with epilepsy is informed by the current research and supported by the position statements from the American Academy of Neurology, the American Academy of Pediatrics and the American Medical Association. Additionally, a 2014 survey of practitioners published in the journal Epilepsy Currents found that the majority of epilepsy practitioners agreed with and supported the AES position. Specifically, AES has called for more research, for the rescheduling of marijuana by the DEA to ease access for clinical studies, and has supported the compassionate use program of GW Pharmaceuticals, where a purified and uniform preparation of cannabidiol (CBD) called Epidiolex is being administered under the guidance and close monitoring of an appropriate medical professional. AES has also been highly supportive of the double-blind clinical trial now underway by GW Pharmaceuticals and of the forthcoming clinical trial by INSYS Therapeutics. These clinical trials utilize a vastly different substance than the artisanal cannabis products that are being considered for use in Idaho, and that have been used in Colorado. As you likely know, medical marijuana and its derivatives are legal in Colorado, but you may not realize that the content of these products is not regulated for purity or uniformity. A study by a team from Children’s Hospital Colorado that was presented during the AES Annual Meeting in December 2014 and has recently been accepted for publication in the journal Epilepsy & Behavior, found that artisanal “high CBD” oils resulted in no significant reduction in seizures in the majority of patients

and in those for whom the parents reported improvements, these improvements were not associated with improvement in electroencephalograms (EEGs), the gold standard monitoring test for people with epilepsy. Additionally, in 13% of cases reviewed seizures worsened with use of cannabis and in some patients there were significant adverse events. These are not the stories that you have likely heard in your public hearings, but they are the reality of practitioners at Children’s Hospital Colorado who have cared for the largest number of cases of children with epilepsy treated with cannabis in the U.S. The families and children coming to Colorado are receiving unregulated, highly variable artisanal preparations of cannabis oil prescribed, in most cases, by physicians with no training in pediatrics, neurology or epilepsy. As a result, the epilepsy specialists in Colorado have been at the bedside of children having severe dystonic reactions and other movement disorders, developmental regression, intractable vomiting and worsening seizures that can be so severe they have to put the child into a coma to get the seizures to stop. Because these products are unregulated, it is impossible to know if these dangerous adverse reactions are due to the CBD or because of contaminants found in these artisanal preparations. The Colorado team has also seen families who have gone into significant debt, paying hundreds of dollars a month for oils that do not appear to work for the vast majority. For all these reasons not a single pediatric neurologist in Colorado recommends the use of artisanal cannabis preparations. Possibly of most concern is that some families are now opting out of proven treatments, such as surgery or the ketogenic diet, or newer antiseizure medications because they have put all their hope in CBD oils. AES is sympathetic to the desperation parents of children with severe, treatment-resistant epilepsy feel, and understand the need for compassionate or promising new therapies in in appropriate and controlled circumstances. We are however opposed to the use of artisanal preparations of unregulated compounds of cannabis that contain unverified content and are produced by people with no experience in pharmaceutical production. That is what is currently happening in Colorado and may soon be happening in multiple states across the country as they legalize the use of medical marijuana products. The products currently provided in Colorado do not meet the FDA definition of expanded or compassionate use. The FDA requires compassionate use therapies to meet the same criteria as an investigational new drug which require standard purity, content and content uniformity testing of the product. None of these criteria are met in the products being given to people with epilepsy in Colorado and we are seeing the distressing results noted above. And yet, these and other similar products are being considered for use in Idaho. It is also worth noting that in late February 2015, the FDA issued several warning letters to firms that claim that their products contain CBD. The FDA has tested those products and, in some of them, did not detect any CBD as claimed on the label. Because there is no standard for these products, the market is increasingly flooded with a wide variation of products and states which

approve access to these preparations will bear the burden of monitoring for quality and controlling for the continuity of supply. In sum, there simply is no clinical, controlled research to support the adoption of new CBD legislation for epilepsy such as your state is considering. The anecdotal results of a few families in Colorado, shared in the media, should not be the basis for law making. The rush by states to pass CBD legislation has created an unusual situation where people with epilepsy and their families are demanding access to a highly variable homegrown substance that may or may not be beneficial and the medical and scientific community lacks the necessary efficacy and safety data to make good treatment decisions regarding cannabis for people with epilepsy, especially in children. The new legislation in most states places epilepsy practitioners in an untenable situation where they are expected, or in some states directed by law, to respond to requests for these highly variable artisanal products with no protocols, no research and no clinical guidelines regarding dosing or side-effects, and no assurance that the cannabis products that are to be recommended are pure, safe or uniform, making it nearly impossible to know if we are truly “Doing No Harm.” We need to accelerate the clinical research and wait to act until we have results to support decisions. If there are components of cannabis with specific therapeutic values we need to know this and we need to develop pharmacy grade compounds that utilize these components to help the nearly one million people living with drug resistant epilepsy. And if the harmful aspects of cannabis outweigh the therapeutic benefits, we need to find out now, before more medically fragile children have been exposed to cannabis products that are not effective and may risk damage to vital organs, brain development, or worse. We urge you and your fellow committee members to delay adoption of new cannabis legislation and to continue to support and encourage new research. If we can be of additional help please contact our Executive Director, Eileen Murray, at [email protected]. Thank you for your consideration of our position. Sincerely,

Amy Brooks-Kayal, MD President, American Epilepsy Society Chief and Ponzio Family Chair, Children’s Hospital Colorado Professor of Pediatrics and Neurology, University of Colorado School of Medicine

Robert T. Wechsler, MD, PhD, FAAN Owner, Consultants in Epilepsy & Neurology, PLLC Medical Director, Idaho Comprehensive Epilepsy Center March 5, 2015

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As a private practice neurologist in our community, Medical Director of the Epilepsy Center at St. Luke’s, Board President of the Epilepsy Foundation of Idaho, the only full-time epileptologist in Idaho, and an active clinical researcher, I have followed with great interest the process seeking access to CBD for children with severe epilepsy both here in Idaho and across the nation. While I treat patients with severe epilepsy every clinic day, often with some success, I cannot imagine how difficult it must be to be the parent of one of these kids. Just watching the process has been heart wrenching and my thoughts and prayers are with them. However, the emotions surrounding these terrible circumstances should not be allowed to cloud our thinking regarding good clinical care. As physicians, one of the first things we are taught in medical school is that physicians should not treat themselves or their immediate family members because good judgement can be clouded under such emotional circumstances. This is of particular concern when parents of desperately ill children are enticed by unproven therapies. In the United States, the FDA requires that therapies must be proven superior to a placebo or other comparator in order to gain approval. They must also show a favorable safety and tolerability profile. Such studies are conducted under carefully controlled circumstances, often involving hundreds and sometimes thousands of patient volunteers. These studies are organized by the companies, but are conducted by trained independent physicians with close oversight from institutional review boards, ethics committees, study monitors and, sometimes, FDA monitors, with all observed safety and efficacy data reported to the FDA. CBD has not been tested in this way. Much of the “evidence” of its efficacy comes from retrospective questionnaires completed by desperate parents of children with dire illnesses or through retrospective physician chart reviews. These two approaches have revealed an interesting pattern. While most physician retrospective reviews report a success rate of about 30% on average with CBD for epilepsy, parent questionnaires report a success rate closer to 80%. A similar pattern was recently reported in a retrospective study of children being treated with CBD for severe epilepsy in Colorado. Families who moved to Colorado to gain access to CBD for their ill children were three times more likely to report being positive responders than families who were already living in Colorado when treatment was started. I cannot imagine that families in such dire circumstances would deliberately provide false information. Nor does it seem likely that the mere act of moving to Colorado resulted in improved seizure control. It seems more likely that the emotional nature of such a relocation clouded their perception. At best we can say that an unbiased review of currently available studies suggests that CBD may work in some cases, with an overall chance of success on par with other currently approved therapies. It is important to study it further because not every therapy will work in every patient, so the more therapies we have available the greater our chance of success. However, CBD should be studied in a controlled way to better define its safety and efficacy

Robert T. Wechsler, MD, PhD, FAAN Owner, Consultants in Epilepsy & Neurology, PLLC Medical Director, Idaho Comprehensive Epilepsy Center March 5, 2015

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profile before being made widely available. Does it really work? Does it have long-term negative cognitive consequences, as some studies have already suggested? Does it have interactions with other medications? Is it safe to use on its own or is it better in combination with existing therapy? These questions must be answered. I have seen several instances of desperate parents and the media referencing the “dangerous side effects” posed by pharmaceutical agents. I would urge everyone to keep in mind that pharmaceutical medications and unapproved supplements are all chemical agents. The difference is that the pharmaceutical medications are chemicals that have been carefully tested whereas supplements are chemicals that have not been carefully tested. It is only with careful testing that side effects can be identified. CBD has not been tested carefully. This does not mean that it does not have side effects, it just means the side effect profile has not been fully defined. My fear is that, if CBD is made widely available in an uncontrolled way, families will run to it because of the hype, often using it to replace rather than augment current therapy. Some children might benefit. But it will not work for everyone and, if it is used as a stand alone therapy in children for whom it does not work, then some of those children will die. These children need to be protected from uncontrolled seizures but they also need to be protected from unproven therapies. Sadly, the good intentions of their desperate, loving parents have the potential to put some of these children in harm’s way. At least two different pharmaceutical companies have undertaken controlled clinical trials of purified CBD. These trials are being expedited, in part due to the media attention that has come to bear on this issue in the past year. Results are months, not years, away. The epilepsy research community is fully committed to getting good data published as quickly as possible. While I cannot speak for the legislature, our governor or the FDA, I am certain we all want to do everything we can to help these kids. But when it comes to CBD, wishing does not make it so. We need the data. If the legislature choses to allow access to CBD in the absence of data, then my hope is that is will be in a carefully controlled and regulated way, under the care of a skilled and licensed physician who can weigh the risks and benefits of therapy and can ensure that all other appropriate, approved therapeutic avenues have been exhausted before this unapproved therapy is undertaken.

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Respectfully,

Robert T. Wechsler, MD, PhD, FAAN

Contact: Natalie Judd, 203-389-5223 or [email protected] or Ellen Cupo, 203389-5223 or [email protected]

Three Studies Shed New Light on the Effectiveness of Cannabis in Epilepsy New Research from University of Colorado and Updates on Development of Epidiolex West Hartford, Conn., October 14, 2014 – In advance of the American Epilepsy Society’s (AES) Annual Meeting in December, the organization has offered highlights of groundbreaking research being studied at a number of institutions regarding the effectiveness of cannibidiol (CBD) and its derivatives as a viable treatment for people with epilepsy. The first of three studies (Abstract#1.326) to be presented in full at the Annual Meeting is from Colorado, where much of the nation’s attention has been captured by issues surrounding cannabis. The physicians and researchers at Children’s Hospital Colorado and the University of Colorado have a unique perspective on CBD given the large number of cases they have treated. In addition to the many children already in their care, these professionals are now caring for many of the patients who have ventured to Colorado in search of cannabis treatment. Dr. Kevin Chapman, associate professor of pediatrics and neurology at the University of Colorado, and his colleagues conducted a retrospective review of the 58 children and adolescents (average age of 7) who had catastrophic forms of epilepsy and were receiving artisanal oral cannabis extracts when they came under the care of the hospital-based team. Chapman’s team found that in only one-third of patients did the parents report a seizure reduction of 50% or more, and this did not correlate with an improvement in their electroencephalograms (EEGs). Of the sixteen patients who had baseline EEGs prior to and during treatment with cannabis, only two showed any signs of improvement. The researchers also noted that the response rate did not change with various strains of cannabis. Notably, families who moved to Colorado for CBD treatment were three times as likely to report a reduction greater than 50% than families who were already in Colorado. Adverse effects occurred in 47% of patients, with increased seizures or new seizures in 21%, somnolence/fatigue in 14%, and rare adverse events of developmental regression in 10% with one patient needing intubation, and one death. “This substantial gap between the clinical observations and various anecdotal reports highlighted in popular media underscores the desperate need shared by the entire epilepsy community for robust scientific evidence regarding the potential benefit and risks of marijuana in people with epilepsy,” said Dr. Chapman. Two additional studies that will be featured at the Annual Meeting provide updates on the development of Epidiolex (GW Pharmaceuticals), a purified and formulated form of CBD. The first study (Abstract #3.303) explores initial data from an efficacy and safety study, a precursor to a randomized clinical trial. Twenty-three patients with treatment-resistant epilepsies, especially Dravet Syndrome, with an average age of 10, were enrolled in two sites at New York University and the University of California San Francisco. After establishing a 4-week baseline of frequency, type of seizures and existing antiepileptic

drug (AED) regimes, patients received a purified 98% oil-based CBD extract, of known and constant composition at a dose of 5mg/kg/day in addition to their baseline AED regimen. The daily dose was gradually increased until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved. After three months of therapy, 39% of patients had a greater than 50% reduction in seizures with a median reduction of 32%. Seizure freedom occurred in 3/9 Dravet patients and 1/14 patients with other forms of epilepsy. Adverse effects were mostly mild or moderate and included somnolence, fatigue, AED level increases, decreased appetite, weight gain, diarrhea, increased appetite and weight loss. "These results are encouraging, especially since they involved a group of children and young adults with very treatment-resistant epilepsy. However, we await the planned double-blind study to truly assess the safety and efficacy of Epidiolex,” said Orrin Devinsky, M.D., director of the NYU Comprehensive Epilepsy Center and professor of neurology, neurosurgery and psychiatry at the NYU School of Medicine. The second abstract related to Epidiolex (Abstract #2.309) examined the drug interactions between existing AEDs and the CBD extract Epidiolex. In this study, 33 patients (with an average age of 10) were taking an average of three different AEDs including clobazam (54.5% of patients), valproate (36.4%) and levetiracetam (30.3%), felbamate (21.2%), Lamotrigine (18.2%) and zonisamide (18.2%). Baseline AED concentrations were established and then taken again after the addition of CBD. Patients were given a purified 98% CBD extract, of known and constant composition at a dose of 5mg/kg/day in addition to their baseline AEDs. The study found that in patients on multiple AEDs, the addition of CBD may be associated with changes in serum concentrations of some concomitant AEDs. A subset of patients experienced an increase in clobazam concentrations requiring a dose adjustment and suggesting CBD’s effects on the major metabolic pathway of clobazam. “These results support experimental findings that CBD can affect metabolism of some common antiepileptic drugs though the effects may not be seen in all patients. More studies are needed to understand the potentially complex interactions between CBD and other drugs but in the meantime, frequent monitoring of drug levels is warranted in children taking CBD-containing products, including medicinal cannabis,” Daniel Friedman, M.D., epileptologist and a clinical neurophysiologist at the NYU Comprehensive Epilepsy Center. All three of these research studies will be provided in full at the American Epilepsy Society Annual Meeting in Seattle December 5-9. Abstracts referenced above can be found on the American Epilepsy Society’s Annual Meeting Page. Editor’s Note: The authors of these studies will be available for comment during a press briefing at the Annual Meeting at the Washington Convention Center room 304, level 3. Press can also join by phone. About the American Epilepsy Society The American Epilepsy Society (AES) is a non-profit medical and scientific society. Our individual members are professionals engaged in both research and clinical care for people with epilepsy from private practice, academia and government. For more than 75 years, AES has been unlocking the potential of the clinical and research community by creating a dynamic global forum where professionals can share, learn and grow. AES champions the use of sound science and clinical care through the exchange of knowledge, by providing education and by furthering the advancement of the profession. ###

March 11, 2016 Representative Matthew Baker and the Pennsylvania Legislature 213 Ryan Office Building PO Box 202068 Harrisburg, PA 17120-2068 Dear Representative Baker, On behalf of the American Epilepsy Society I am writing in opposition to Pennsylvania SB-3 and to share the position of our organization and highlight some of the experience of our members in other states, especially those in Colorado who have seen the most epilepsy CBD cases in the U.S. We applaud your measured approach and for giving this issue thoughtful consideration. The American Epilepsy Society is the leading U.S. organization of clinical and research professionals specializing in the diagnosis and treatment of people with epilepsy, with more than 3,800 members engaged in all aspects of epilepsy. For nearly 85 years, the members of the American Epilepsy Society have led nearly every medical and scientific advance in epilepsy. Each year, the American Epilepsy Society hosts a scientific meeting on epilepsy more than 1,500 scientific studies are presented, making this the world’s largest and most respected epilepsy meeting. This year’s meeting in Philadelphia attracted over 5000 attendees from around the world. Epilepsy is the most common and potentially devastating neurological disease that affects people across the lifespan. In America, one in 26 people will be diagnosed with epilepsy at some time in the course of their life - more will experience an isolated seizure. Epilepsy is associated with significant morbidity and mortality and carries an increased risk of many co-morbidities including depression, cognitive dysfunction, and autism. Today between 2.2 and 3 million Americans, including almost 400,000 children, live with epilepsy, with one third living with treatment-resistant seizures that do not respond to current medications. The large number of treatment resistant cases emphasizes the urgency of bringing forth new treatments for epilepsy, but those treatments must be proven safe and effective in order to be truly helpful to people with epilepsy. Despite the pressure of anecdotal evidence prevalent in the popular press and social media, for the past two years the American Epilepsy Society has been opposed to the expanded use of medical marijuana and its derivative, cannabidiol or CBD, in the treatment of children with severe epilepsy. At this time there is no evidence from controlled trials that strongly supports the use of marijuana for treatment of epilepsy. Our position is informed by the lack of available research and supported by the position statements from the American Academy of Neurology, the American Academy of Pediatrics, and the American Medical Association. The American Epilepsy Society has consistently advised states against acting on anecdotal evidence alone and has called for more research. The need for more research is a consistent theme from nearly every medical society in the U.S. To help advance research, the American Epilepsy Society has requested that the Federal Drug Enforcement Agency reschedule marijuana to ease access for clinical studies.

The well intentioned law makers who have enacted laws in many states have done so without the benefit of any scientific evidence for people with epilepsy. This has created an uneasy situation where the laws are ahead of the science because we do not understand how and why various treatments work and for whom they are effective. Research also helps us understand the correct dose, side effects, and potential interactions with other medications. At present, the epilepsy community does not know if marijuana is a safe and effective treatment nor do we know the long-term effects that marijuana will have on learning, memory and behavior, especially in infants and young children. AES has consistently been supportive of the compassionate use program of GW Pharmaceuticals, where a purified and uniform preparation of cannabidiol (CBD) called Epidiolex is being administered under the guidance and close monitoring of an appropriate medical professional. The lead investigator for this clinical trial, AES member Dr. Orrin Devinsky, released results of a phase II study during the December 2015 Annual Meeting of the American Epilepsy Society held in Philadelphia. While Dr. Devinsky called the findings promising, he cautioned that “these results are from an uncontrolled study. Further study is needed before results can be confirmed. Randomized controlled studies are now underway to help us better understand the effectiveness of the drug.” The results of this phase II study have just been published in Lancet Neurology in the March 2016 issue. Phase III of this study is now beginning and this is a placebo controlled study. AES supports this critical step to help our whole community better understand the potential role of CBD in treatment of epilepsy. It is also important to note that in these studies Epidiolex was added to current antiepileptic drug (AED) treatment regimes. A pharmaceutical grade marijuana extract of purified cannabidiol, Epidiolex is being rigorously tested in several types of epilepsy in FDA authorized trials that are ongoing at dozens of US epilepsy centers. Many have already been completed or at least finished enrollment. Because the trials enrolled so quickly it is possible that an FDA approved product could be on the market sometime in 2017. Once an FDA approved product is on the market and available to people with epilepsy throughout the US, there is much less urgency for individual states to pass complex legislation about regulation and distribution of medical marijuana. It is also a very important distinction that the CBD oil Epidiolex used in the clinical trials is a vastly different substance than the artisanal cannabis products that are being considered for use in Pennsylvania, and are being used in other states like Colorado. In states like Colorado where medical marijuana and its derivatives are legal the content of these products is not regulated for purity or uniformity. Pharmacy-grade products like Epidiolex have followed Good Manufacturing Processes, meaning that the CBD content is measured by rigorous standards, that it is carefully monitored for additives or contaminants and that even the equipment used for manufacturing meets rigorous standards. None of this is true for the artisanal products. The artisanal products currently provided in Colorado do not meet the FDA definition of expanded or compassionate use. The FDA requires compassionate use therapies to meet the same criteria as an investigational new drug which require standard purity, content and content uniformity testing of the product and adherence to good manufacturing processes. None of these criteria are met in the products being given to people with epilepsy in Colorado and we are seeing the distressing results noted below. And yet, these and other similar products are being considered for use in several states. An observational study by a team from Children’s Hospital Colorado that was published in the April 2015 issue of the journal Epilepsy & Behavior found that artisanal “high CBD” oils resulted in no significant reduction in seizures in the majority of patients and in those for whom the parents reported improvements, these improvements were not associated with improvement in electroencephalograms (EEGs), the gold standard monitoring test for people with epilepsy. Additionally, in 13% of cases reviewed seizures worsened with use of cannabis and in some patients there were significant adverse events. These are not the stories that you have likely heard in your public hearings or have read in popular press, but they are the reality of AES members who are practitioners at Children’s Hospital Colorado who have cared for the largest number of cases of children with epilepsy treated with cannabis in the U.S.

Unlike the product used in the GW Pharmaceutical study, the families and children moving to Colorado are receiving unregulated, highly variable artisanal preparations of cannabis oil prescribed, in most cases, by physicians with no training in pediatrics, neurology or epilepsy. As a result, the epilepsy specialists in Colorado have been at the bedside of children having severe dystonic reactions and other movement disorders, developmental regression, intractable vomiting and worsening seizures that can be so severe they have to put the child into a coma to get the seizures to stop. Because these products are unregulated, it is impossible to know if these dangerous adverse reactions are due to the CBD or because of contaminants found in these artisanal preparations. The Colorado team has also seen families who have gone into significant debt, paying hundreds of dollars a month for oils that do not appear to work for the vast majority. For all these reasons not a single pediatric neurologist in Colorado recommends the use of artisanal cannabis preparations. Possibly of most concern is that some families are now opting out of proven treatments, such as surgery or the ketogenic diet, or newer antiseizure medications because they have put all their hope in CBD oils. Epilepsy specialists in Colorado are now conducting a state-funded observational study to monitor children with CBD. The study is going to consist of analyzing the results from 150 medical marijuana patients who consume cannabis products regularly. This is just one of many studies now underway with CBD for people with epilepsy. There is great interest within the professional community to explore the potential of CBD but the research needs to be conducted before new laws are enacted. It is also worth noting that in February 2016 and February 2015, the FDA issued several warning letters to firms that claim their products contain CBD. The FDA has tested those products and, in some of them, did not detect any CBD as claimed on the label. Because there is no standard for these products, the market is increasingly flooded with a wide variety of products. Should Pennsylvania approve access to these preparations it will bear the burden of monitoring for quality and controlling for the continuity of supply. This requires a level of new administrative oversight and the associated budget impact. The well-intentioned law makers in the states that have passed CBD laws are now coming to grips with the substantial financial and administrative burdens of developing, maintain and running a CBD access program. In reality, these programs could be abandoned as quickly as they are established should an FDA approved drug be available within the next 18-24 months. The American Epilepsy Society is very sympathetic to the desperation of parents whose children have severe, treatmentresistant epilepsy. Our members, face these families daily at the clinic and at their bedside and are highly attuned to the need for compassionate use of promising new therapies in appropriate and controlled circumstances. We are however, opposed to the use of artisanal preparations of unregulated compounds of cannabis that contain unverified content and are produced by people with no experience in pharmaceutical production. That is what is currently happening in Colorado and other states across the county as they legalize the use of medical marijuana products. In sum, there simply is no clinical, controlled research to support the adoption of new CBD legislation for epilepsy such as your state is considering. The anecdotal results of a few families in Colorado, shared in the media, should not be the basis for law making. The rush by states to pass CBD legislation has created an unusual situation where people with epilepsy and their families are demanding access to a highly variable homegrown substance that may or may not be beneficial and the medical and scientific community lacks the necessary efficacy and safety data to make good treatment decisions regarding cannabis for people with epilepsy, especially in children. It has also created a heavy financial and administrative burden on states. Don’t let Pennsylvania move in this direction, vote no on SB-3. Sincerely,

Michael D. Privitera, MD President American Epilepsy Society Director, Epilepsy Center University of Cincinnati Neuroscience Institute

This is the current position of the American Epilepsy Society, as written in a letter from Dr. Brooks-Kayal to a Pennsylvania legislator: March 22, 2015 Dear Representative, As Pennsylvania considers enacting new cannabis legislation (HB 193), I write to offer the perspective of the American Epilepsy Society (AES), the leading U.S. organization of clinical and research professionals specializing in the treatment and care of people with epilepsy. Epilepsy is the most common and potentially devastating neurological disease that affects people across the lifespan. In America, one in 26 people will be diagnosed with epilepsy at some time in the course of their life - more will experience an isolated seizure. Epilepsy is associated with significant morbidity and mortality and is associated with many co-morbidities including depression, cognitive dysfunction, and autism. Today between 2.2 and 3 million Americans, including almost 400,000 children, live with epilepsy, with one third living with treatment-resistant seizures that do not respond to current medications. The American Epilepsy Society position on medical marijuana as a treatment option for people with epilepsy is informed by the current research and supported by the position statements from the American Academy of Neurology, the American Academy of Pediatrics and the American Medical Association. Additionally, a 2014 survey of practitioners published in the journal Epilepsy Currents found that the majority of epilepsy practitioners agreed with and supported the AES position. Specifically, AES has called for more research, for the rescheduling of marijuana by the DEA to ease access for clinical studies, and has supported the compassionate use program of GW Pharmaceuticals, where a purified and uniform preparation of cannabidiol (CBD) called Epidiolex is being administered under the guidance and close monitoring of an appropriate medical professional. AES has also been highly supportive of the double-blind clinical trial now underway by GW Pharmaceuticals and of the forthcoming clinical trial by INSYS Therapeutics. These clinical trials utilize a vastly different substance than the artisanal cannabis products that are being considered for use in Pennsylvania, and that have been used in Colorado. As you likely know, medical marijuana and its derivatives are legal in Colorado, but you may not realize that the content of these products is not regulated for purity or uniformity. A study by a team from Children's Hospital Colorado that was presented during the AES Annual Meeting in December 2014 and has recently been accepted for publication in the journal Epilepsy & Behavior, found that artisanal "high CBD" oils resulted in no significant reduction in seizures in the majority of patients and in those for whom the parents reported improvements, these improvements were not

associated with improvement in electroencephalograms (EEGs), the gold standard monitoring test for people with epilepsy. Additionally, in 20% of cases reviewed seizures worsened with use of cannabis and in some patients there were significant adverse events. These are not the stories that you have likely heard in your public hearings, but they are the reality of practitioners at Children's Hospital Colorado who have cared for the largest number of cases of children with epilepsy treated with cannabis in the U.S. The families and children coming to Colorado are receiving unregulated, highly variable artisanal preparations of cannabis oil prescribed, in most cases, by physicians with no training in pediatrics, neurology or epilepsy. As a result, the epilepsy specialists in Colorado have been at the bedside of children having severe dystonic reactions and other movement disorders, developmental regression, intractable vomiting and worsening seizures that can be so severe they have to put the child into a coma to get the seizures to stop. Because these products are unregulated, it is impossible to know if these dangerous adverse reactions are due to the CBD or because of contaminants found in these artisanal preparations. The Colorado team has also seen families who have gone into significant debt, paying hundreds of dollars a month for oils that do not appear to work for the vast majority. For all these reasons not a single pediatric neurologist in Colorado recommends the use of artisanal cannabis preparations. Possibly of most concern is that some families are now opting out of proven treatments, such as surgery or the ketogenic diet, or newer antiseizure medications because they have put all their hope in CBD oils. AES is sympathetic to the desperation parents of children with severe, treatment-resistant epilepsy feel, and understand the need for compassionate or promising new therapies in in appropriate and controlled circumstances. We are however opposed to the use of artisanal preparations of unregulated compounds of cannabis that contain unverified content and are produced by people with no experience in pharmaceutical production. That is what is currently happening in Colorado and may soon be happening in multiple states across the county as they legalize the use of medical marijuana products. The products currently provided in Colorado do not meet the FDA definition of expanded or compassionate use. The FDA requires compassionate use therapies to meet the same criteria as an investigational new drug which require standard purity, content and content uniformity testing of the product. None of these criteria are met in the products being given to people with epilepsy in Colorado and we are seeing the distressing results noted above. And yet, these and other similar products are being considered for use in Pennsylvania. It is also worth noting that in late February 2015, the FDA issued several warning letters to firms that claim that their products contain CBD. The FDA has tested those products and, in some of them, did not detect any CBD as claimed on the label. Because there is no standard for these products, the market is increasingly flooded with a wide variation of products and states which

approve access to these preparations will bear the burden of monitoring for quality and controlling for the continuity of supply. In sum, there simply is no clinical, controlled research to support the adoption of new CBD legislation for epilepsy such as your state is considering. The anecdotal results of a few families in Colorado, shared in the media, should not be the basis for law making. The rush by states to pass CBD legislation has created an unusual situation where people with epilepsy and their families are demanding access to a highly variable homegrown substance that may or may not be beneficial and the medical and scientific community lacks the necessary efficacy and safety data to make good treatment decisions regarding cannabis for people with epilepsy, especially in children. The new legislation in most states places epilepsy practitioners in an untenable situation where they are expected, or in some states directed by law, to respond to requests for these highly variable artisanal products with no protocols, no research and no clinical guidelines regarding dosing or side-effects, and no assurance that the cannabis products that are to be recommended are pure, safe or uniform, making it nearly impossible to know if we are truly "Doing No Harm." We need to accelerate the clinical research and wait to act until we have results to support decisions. If there are components of cannabis with specific therapeutic values we need to know this and we need to develop pharmacy grade compounds that utilize these components to help the nearly one million people living with drug resistant epilepsy. And if the harmful aspects of cannabis outweigh the therapeutic benefits, we need to find out now, before more medically fragile children have been exposed to cannabis products that are not effective and may risk damage to vital organs, brain development, or worse. We urge you and your fellow committee members to delay adoption of new cannabis legislation and to continue to support and encourage new research. If we can be of additional help please contact our Executive Director, Eileen Murray, [email protected]. Thank you for your consideration of our position. Sincerely, Amy Brooks-Kayal, MD President, American Epilepsy Society Chief and Ponzio Family Chair, Children's Hospital Colorado Professor of Pediatrics and Neurology, University of Colorado School of Medicine