Epigraph Vol. 20 Issue 1, Summer 2018

The medical marijuana and epilepsy debate comes to Bali

At the 12th Asian & Oceanian Epilepsy Congress in Bali, Indonesia, Helen Cross (UK) and Rhea Salonga-Quimpo (Philippines) debated the pros and cons of medical marijuana and cannabis-derived products for epilepsy. Ingrid Scheffler, from the Florey Institute of Neuroscience and Mental Health, moderated the debate, which drew an audience of more than 400 epilepsy specialists and neurologists.

Marijuana (cannabis) has been used for medicinal purposes for more than 4,000 years; the oldest known written record of its use comes from China, in 2727 BC. Cannabis was originally used mostly for pain relief, but also to treat malaria and boost memory. For as long as it has been used, there’s been controversy over its safety and effectiveness.

In 1843, an article appeared in the Provincial Medical Journal outlining cannabis’ medical benefits. The article caused a sensation, particularly in Europe and America, where physicians began prescribing it for a wide variety of conditions. The article’s author, William O’Shaughnessy, was an Irish physician who had already tackled cholera—his work led to the first use of IV therapy for the disease—and would later help build a 4,000-mile trans-India telegraph system.

As a basis for the article, O’Shaughnessy conducted what were likely the first clinical trials in people with several conditions, including epilepsy. He presented a case of a 40-day-old baby with “convulsions” who responded instantly to a tincture of “Indian hemp.” The baby went from “near death” to “robust health” in less than 3 weeks.

Charlotte and the web of medical marijuana

Nearly two centuries later, the effect of cannabis on a young girl in Colorado would re-focus the spotlight on medical marijuana for treating epilepsy. Charlotte Figi, a 5-year-old with Dravet syndrome, had up to 300 seizures a week and could no longer walk or talk. Her family had exhausted all treatment options; then, they learned of medical marijuana.

THC (tetrahydrocannabinol) chemical diagram
THC (tetrahydrocannabinol)
Cannabidiol Chemical diagram (CBD)
CBD (Cannabidiol)

They purchased a strain of cannabis low in the high-inducing component, THC (tetrahydrocannabinol), and rich in cannabidiol (CBD), the component associated with anti-seizure activity. They had the oil extracted from the plant and gave Charlotte a few drops. Her seizures stopped. On daily doses of CBD oil, she has only two or three seizures a month, usually in her sleep. (The strain of cannabis was named after her: Charlotte’s Web.)

Epidiolex and CBD

Five years after Charlotte’s family discovered CBD oil — and five days before the AOEC debate! — the U.S. Food and Drug Administration approved Epidiolex (GW Pharma), a liquid form of CBD, after it showed moderate efficacy for Dravet syndrome and Lennox-Gastaut syndrome. Epidiolex is formulated at 100 mg/ml of CBD and less than 0.1% THC in sesame oil.

The approval of Epidiolex brings some credence to the efficacy of CBD, but Epidiolex is pharmaceutical-grade, standardized and regulated. Given that more than one-third of people with epilepsy do not achieve seizure freedom on anti-epileptic drugs, many people and families are eager (and, understandably, sometimes desperate) to try any treatment option that shows promise. This leaves many clinicians struggling to balance questions and demands from their patients with the desire for evidence-based, safe recommendations about whether and how to use medical marijuana.

And, not trivially, marijuana is illegal in most of the world.

Yes: Cannabis-derived products have a place

Helen Cross
Helen Cross

Cannabis-derived products should be legal for epilepsy care, as long as certain conditions are met, said Helen Cross, of the Great Ormond Street Hospital for Children NHS Trust, London. Marijuana-derived products are “not a panacea or a miracle treatment,” she said. “There is a place for these products, but they must be carefully produced and monitored.”

Collectively, the trials that supported the approval of Epidiolex involved 516 people with either Dravet syndrome or Lennox-Gastaut syndrome. Cross was involved in the trials, and has received grant support from GW Pharma. She was careful to distinguish Epidiolex from unregulated CBD oils available online, as well as from whole-plant marijuana. She noted that many parents purchase CBD oils and give them to their children in hopes of stopping seizures, but there’s no way of knowing if or how the child is receiving any benefit. “There’s no evidence about dosing, and no consistency from batch to batch,” she said.


No: Medical marijuana should not be recommended

Rhea Salonga-Quimpo
Rhea Salonga-Quimpo

Rhea Salonga-Quimpo, from Manila Medical Center, Philippines, took the “con” position, arguing that under the legal definition — the use of the raw, unprocessed cannabis plant or any portion of it to treat a disease or symptom — medical marijuana should not be recommended for the treatment of epilepsy.

“It may work for some patients with Dravet syndrome and Lennox-Gastaut syndrome, but that doesn’t mean it will work for all patients,” she noted.

Salonga-Quimpo also emphasized that cannabis is a schedule 1 drug, which indicates a high potential for abuse and dependence. In the U.S. code, CBD also is listed as a schedule 1 drug because it’s a derivative of cannabis. (CBD is expected to be rescheduled within 90 days of the FDA approval of Epidiolex, to allow prescriptions to patients.)

Salonga-Quimpo also noted long-term effects of persistent cannabis use, such as neuropsychological decline. Use in children under 15 results in more deficits than use in adults. “There seem to be neurotoxic effects, but we don’t know which parts of [the plant] cause them,” she said.

Cost also is an issue for all types of cannabis products, she said. At the time of the debate, no price had been set for Epidiolex, though analysts estimated it could cost $25,000 per year. “This is higher than the average family income in at least 9 Asian countries,” she noted. Her calculations also found that artisanal CBD oil can cost $10,000 to $26,600 per year for a 10-kilogram child, depending on the formulation and the dose. Cross countered that many AEDs also are quite costly.

Congress consensus? Maybe

“I think there is no question that CBD can be effective” for Dravet syndrome and Lennox-Gastaut syndrome, conceded Salonga-Quimpo. However, she said that legalizing medical marijuana as a treatment for epilepsy is not a tenable solution, at least in most Asian countries. “More than the medical aspect, we should look at the social impact of promoting medical marijuana for use in our patients.”

During an audience vote at the conclusion of the debate, applause was louder for the “No” votes than the “Yes” votes, though there was clear support on both sides. The audience response suggests that among epilepsy specialists there is no consensus about the use of medical marijuana for epilepsy, but that the use of pharmaceutical-grade CBD oil is showing some benefit.

Further reading

Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results.
Interim results from an ongoing expanded access program for CBD (published 12 July 2018 in Epilepsia) showed that in people with treatment-resistant epilepsy, CBD as add-on therapy resulted in 50% or greater seizure reduction in 52% of participants, and seizure freedom in 11% of participants, after 12 weeks of treatment. The study involved 607 children and adults at 25 U.S. sites.

Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study.
An observational, longitudinal study (published August 2018 in Brain & Development) included 46 children and young adults treated with CBD for at least 3 months. Of these, 56% had at least a 50% reduction in seizure frequency. Children under 10, and those taking higher CBD doses (above 11 mg/kg/d) tended to respond better.

Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.
A systematic review (published online in March 2018 and in print July 2018 in the Journal of Neurology, Neurosurgery & Psychiatry) concluded that “Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency.” The review noted that randomized clinical trials are few, outside of pediatric samples involving rare epilepsy syndromes, and called for more research on epilepsy and cannabinoids.