CBD in cannabis shows promise for severe epilepsy

Around the globe there is high interest in using CannaBiDiol (CBD), a type of cannabinoid, for the treatment of epilepsy, especially in children with treatment-resistant forms of the disorder such as Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS). Significant seizure reduction has been seen in studies using CBD in combination with AEDs

Wikipedia: Cannabidiol (CBD) is one of at least 85 active chemicals identified in cannabis that repress brain neurotransmissions. It is a major phytocannabinoid, accounting for as much as 40% of extract from cannabis and considered to have wider medical application than tetrahydrocannabinol (THC).

Three studies presented at the American Epilepsy Society's 69th Annual Meeting in Philadelphia highlight emerging efficacy and safety data of Epidiolex, a pharmaceutical liquid form of cannabidiol currently undergoing U.S. Food and Drug Administration (FDA) Phase 3 clinical trials in the United States (conducted by GW Pharmaceuticals).

A fourth study highlights possible interactions of CBD with existing anti-epileptic drugs (AEDs) in animal models of seizures.

The first and largest CBD study presented by GW Pharmaceutical on Epidiolex (cannabidiol) involved 261 people, predominantly children, who have severe epilepsy and did not respond adequately to other treatments. The average age of participants was 11. (abstract 3.034)

Over the course of 12 weeks, study participants were given Epidiolex in gradually increasing doses. In all cases, Epidiolex was added to current AED treatment regimes. On average, patients were taking approximately three other AEDs. Participants and their caregivers recorded the number of seizures prior to taking CBD and during their 12 weeks of treatment. Clinicians also tested blood, liver and kidney function as well as AED levels before treatment and during — at four, eight and 12 weeks into the study.

After three months of treatment, the frequency of all seizures was reduced by a median of 45 percent in all participants. Almost half (47%) of the participants in the study experienced a 50 percent or greater reduction in seizures and nine percent of patients were seizure-free. Among specific patient populations, DS patients had a 62 percent reduction in seizures and 13 percent were seizure-free. Patients with LGS experienced a 71 percent reduction in atonic seizures.

Adverse events occurred in more than 10 percent of participants with the most common being somnolence, diarrhea and fatigue and led to discontinuation in 4 percent of patients. Thirty-four percent of participants reported serious adverse events of which 5 percent were considered treatment related including altered liver enzymes (n=4), status epilepticus (n=4), diarrhea (n=4) and others. Twelve percent withdrew from the study for lack of efficacy.

"We are pleased to report these promising data on significant numbers of children. These data reinforce and support the safety and efficacy we have shared in previous studies. Most importantly it is providing hope to the children and their families who have been living with debilitating seizures."

However: "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. We very much look forward to the results from these studies during 2016."

Orrin Devinsky MD, New York University Langone Medical Center, Comprehensive Epilepsy Center, and lead author on the paper.

A related second study authored by Michael Oldham, M.D., MPH, formerly at the University of California San Francisco (UCSF) and currently at the University of Louisville, explored the long-term efficacy of Epidiolex. This study followed a subset of the first population at UCSF Benioff Children's Hospital San Francisco, with an average age of 9, for one year. (abstract 2.296)

The patients took CBD in addition to their regular AED regimen. After 12 months, treatment with CBD resulted in a 50 percent reduction in seizures for 10 participants (40%). One participant with DS remained seizure-free. Twelve of the participants discontinued CBD because the treatment did not work for them. One participant suffered a marked increase in seizure frequency due to CBD.

Oldham: "The CBD as an add-on therapy reduced seizures by half for a third of the patients in the first 12 weeks of the study. This substantial improvement was maintained by 40 percent of participants for the entire 12-month period showing strong promise that CBD can be effective in controlling seizures."

A third preclinical study explored anticonvulsant and tolerability of CBD in animals models. Using the Anticonvulsant Screening Program (ASP), researchers used four well-established acute seizure models to find CBD exerted significant anticonvulsant effects and was well-tolerated in rodents. This study was provided as a free service by the National Institute of Neurological Disorders and Stroke ASP, and was conducted at the University of Utah. (abstract 3.397)

A fourth study, led by Misty D. Smith PhD at the University of Utah , explored how CBD interacts with five different AEDs in animal models of seizure. That study helps substantiate the effects of CBD in combination with common AEDs, including carbamazepine, valproate, levetiracetam, clobazam and lacosamide. The interactions between these drugs could mean the drugs work well together. The drugs tend to enhance each other's effects (synergism); or antagonize, when the combinations reduce effectiveness. (abstract 1.215)

Smith compared three fixed dose ratio combinations of CBD in order to rapidly assess the effectiveness of each combination against limbic seizure. The work revealed significant synergistic interaction between CBD with levetiracetam and significant antagonistic interactions between fixed dose-ratio combinations of CBD with clobazam and CBD with carbamazepine.

Added Smith: "By identifying these ... interactions between CBD and other ASDs, we are gaining a better understanding of their natures, which will help optimize therapeutic safety and efficacy for CBD going forward."

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. Find out more at aesnet.org.

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