Dr. Colin Doherty:

I am a consultant neurologist from St. James’s Hospital in Dublin with expertise in treatment all forms of epilepsy. I am the national lead for the epilepsy programme in Ireland and senior lecturer at Trinity College school of medicine and a member of the International League Against Epilepsy, ILAE. I will give a brief review of the history of cannabis use for epilepsy and describe the science underlying its potential use a prescribed treatment and I will attempt to outline a pathway for developing a consensus around potential prescribing practice.

In the history of cannabis use for epilepsy, while there are references to medical uses of hemp going back 8,000 years in China, Irish physician, W.B. O'Shaughnessy is widely acknowledged to have written the first modern scientific paper on medicinal use of cannabis in theProvincial Medical Journalpublished in 1843. Mr. O'Shaughnessy was born in Limerick in 1809 and moved to Calcutta with the East India Company where he observed the local use of cannabis for various ailments. He is now considered the father of the medicinal cannabis movement. In 1851, following his paper, the US Dispensary classified cannabis compounds as useful treatments for neuralgia and convulsive disorders. By 1860, the Ohio medical society committee on cannabis declared efficacy for infantile convulsions, epilepsy and many other disorders. However, the narcotic effects of cannabis led to unregulated recreational use and medicinal cannabis was caught up in the prohibition movement that lead to the banning of alcohol and other drugs.

In 1911, Massachusetts became the first state to outlaw cannabis. Other states quickly followed with marijuana prohibition laws and they persisted throughout the 20th century such that, by 1970, the US Controlled Substances Act was passed, classifying marijuana as a drug with "no accepted medical use". Countries throughout the world now have stringent laws and punishments for the possession and distribution of cannabis.

Let us consider the botanical and chemical aspects of cannabis use. The herb and its extracts contain more than 100 chemically similar compounds, called cannabinoids. It also contains over 400 other non-cannabinoid compounds. As we know, cannabis remains best known as a drug of recreational use and is consumed by approximately 150 million people around the world each day. Recreational use implies the ingestion of leaves, resin and oils of the Cannabis sativa plant, which has large amounts of the psychoactive form of the cannabinoid tetrahydrocannabinol, THC. It is cannabis which is rich in THC that causes the "high" people commonly associate with the drug. However, the indica plant produces a more fibrous compound that has no psychoactive effects, and this was also probably the first non-food crop grown by man, for the production of hemp rope, sacks, etc. Hemp is rich in cannabidiol, CBD, which is the form that appears to be useful for treating convulsive disorders. While the pharmacology of THC is considered to be reasonably straightforward, the pharmacology of CBD is extremely complex. CBD is known as a multi-target drug whose action is not completely understood.

Over the past 50 years, there has been a growing community of campaigners for more widespread and regularised use of medicinal cannabis. Among the most popular indications are chemotherapy-induced anorexia and chronic pain in cancer and multiple sclerosis. Of course, there have also been reports of spectacular reversals in the treatment of epilepsy leading to a chorus of calls from patients, carers and parents for a more thorough evaluation of the drug for epilepsy, and if proved useful, its legalisation. In 1996, California became the first state in the United States to legalise cannabis, for medicinal use only. Now cannabis is legal in 26 states in the United States.

I wish to consider the growing evidence for the efficacy of CBD in treating epilepsy. The first scientific reports in recent times did not appear until the early 2000s. After a number of case reports of success in treating epilepsy, the issue came to the fore in 2013 when Dr. Sanjay Gupta, CNN's doctor, broadcast a two-part documentary called "Weed" on medicinal cannabis use. The series features Charlotte Figi, a young girl from North America with Dravet syndrome, a severe genetic form of epilepsy that is often resistant to anti-epileptic drugs and puts sufferers at risk of sudden unexpected death in epilepsy, SUDEP. Some 20% of people with Dravet syndrome will be dead by the age of 20. Charlotte began to have seizures at the age of three months, and by three years she was having more than 300 per month. She spent three years in and out of intensive care units. Her parents moved to Colorado having researched cannabis and obtained a high CBD content oil that had a sudden and dramatic effect on the seizures. The Figis noted that the amount of CBD in each preparation was important, and they worked with a local grower family, the Stanley brothers, to perfect the strain that worked best. The product has now become known as Charlotte's Web.

This and other stories like it have led to unprecedented co-operation in open-label studies in the United States of Epidiolex, a purified phytocannabinoid form of CBD derived from the whole plant in the United Kingdom which is produced by the pharmaceutical company GW Pharmaceuticals. Results from 213 children and young adults who received Epidiolex, which is 99% CBD, in an open-label study were presented first at the American Academy of Neurology in April 2015. They can be summarised as follows. Some 9% of patients, or one in ten, with an average age of 11, became seizure free. The average number of seizures per month was approximately 100 but this number reduced to zero. Some 50% of patients saw a decrease in the seizure rate of at least 50%, so the number decreased from 100 to 50. Patients who had Dravet syndrome responded more positively, with a 63% decrease in seizures over three months. CBD did not work for all and was associated with adverse events, including drowsiness, in 37% and fatigue in 16%.

Two phase III placebo-controlled studies on Epidiolex have recently been completed. These are the types of trials usually required for licensing. Preliminary results were posted in a press released on 26 September 2016 on GW Pharmaceuticals' website. From having spoken to the researchers, I know one of the studies has been accepted for publication. The other has yet to be published. Therefore, they have not been published yet in peer review journals.

Despite increasing evidence in the scientific literature of the value of this almost pure form of CBD, there are calls for other as yet unproven forms to be made not only legal but also available for medicinal use. These forms have various levels of THC that adherents claim will improve its antiepileptic effect. The evidence for this is based on anecdotal reports of benefit in some children. While there may be reasons to be optimistic that such claims may have validity, there are as yet no controlled or uncontrolled trials being run to endorse such a position. Furthermore, recreational forms of cannabis with high levels of THC have been associated with psychosis in susceptible populations. Extreme caution, and significant evidence, will be required in determining the safe level of this drug to give to sick children.

Let me address issues concerning the availability of CBD in Ireland. Under Irish law, cannabis is not recognised as having any medical benefits. The most recent Misuse of Drugs (Designation) Order lists cannabis, cannabis resin and its derivatives as Schedule 1 drugs under the Misuse of Drugs Acts of 1977 to 2016. As a consequence, the manufacture, production, preparation, sale, supply, distribution and possession of cannabis are unlawful for any purpose, except under license from the Minister of Health for the purposes of research. The availability of various formulations for use in cancer, multiple sclerosis and epilepsy has led to calls for a liberalisation of the law in regard to medicinal use. In the past few years, a form of medicinal cannabis called Sativex has been specially licensed in Ireland for use to reduce spasticity and pain in multiple sclerosis but this has not been reimbursed by Government payment schemes, which may explain its slow uptake. The main form of cannabis that appears to work for epilepsy - high CBD, low THC - can be considered an unscheduled drug only if the THC level is no more than "trace". Nevertheless, a number of forms of high CBD, low THC oils can be purchased in retail stores in Ireland and imported online. However, since the drug is not regulated or designated as a medicinal product it cannot yet be prescribed by Irish physicians.

The use of cannabis to treat epilepsy offers a tantalising new horizon for severe disabling seizures. There is an urgency created by the community of families with severe epilepsy to complete a proper, sober and reflective scientific evaluation of the efficacy and safety of this drug. Initial studies are encouraging but not definitive. Already, it is possible to state with confidence that this drug will not work for everyone and will cause intolerable, but probably not dangerous, side effects in a few. For those for whom it would work, however, it may be life-saving. Despite the short timescale for these hearings, I have already consulted widely with Irish and UK colleagues and international researchers, including one of the lead researchers in the US studies quoted. As of the last count, only ten countries in the world have legalised cannabis for medicinal use and only one that I know of, Australia, has a proper national framework for medicinal prescribing for children with epilepsy.

In conjunction with those behind the national epilepsy programme and the Irish section of the International League Against Epilepsy, whose president is Professor Norman Delanty of the Royal College of Surgeons in Ireland, and with representatives from the pharmacology and therapeutics committee of the Royal College of Physicians of Ireland, we propose to work with the Health Products Regulatory Authority to determine whether such a framework for limited prescribing of pure CBD oil is possible based on the current level of evidence, with particular focus on the safety for children.