Initial Data on 'Pharma Grade' Cannabidiol in Epilepsy

October 23, 2014

Initial data from an open-label study in treatment-resistant epilepsy of pharmaceutical-grade cannabidiol — the nonpsychoactive ingredient in marijuana that is believed to be responsible for its antiepileptic action — suggest that it reduces seizure rate by about 30%.

The product, said to be 98% pure cannabidiol, in development under the brand name Epidiolex by GW Pharmaceuticals, which funded this study, was associated with a greater than 50% reduction in seizures in 39% of patients.

Lead investigator, Orrin Devinsky, MD, New York University School of Medicine, said he thought the results were "encouraging."

"There appears to be potential for real benefit," he told Medscape Medical News.

A second study of patients using many different types of medical marijuana has found not dissimilar results, with one third of patients reporting a seizure reduction of 50% or more.

The author of that study, Kevin Chapman MD, University of Colorado, Aurora, said this response rate was well below that expected from previous media reports. "There has been much discussion on the Internet and in the media about how medical marijuana is a miracle and children having the most intractable forms of epilepsy are becoming seizure-free," he said. "But our data suggests that it is not as effective as these reports have suggested."

The two studies will be presented at the American Epilepsy Society (AES) 68th Annual Meeting in December, but preliminary data have been released early by the organization.

Promising Results

Coauthor of the cannabidiol study, Daniel Friedman, MD, NYU Comprehensive Epilepsy Center, summarized the findings. "My feeling is that we still don't know for sure if cannabidiol it is an effective treatment but our results do look promising and support further studies. While it probably won't be the miracle that some advocates have claimed, I believe it will have a role for treating very difficult epilepsy cases."

Dr Devinsky added: "The populations we are testing this drug on are notoriously difficult to treat. Any drug that has a beneficial effect is potentially very helpful. Most current epilepsy drugs are ineffective and have serious side effects. There is a huge unmet need."

Dr Friedman pointed out that Dr Chapman's study was particularly difficult to interpret because there was a huge variability in what the patients were taking.

"They were using medical marijuana from various sources," he said. "This would be a very heterogeneous group of products. There are many different strains of medical marijuana. Some are claimed to have a high cannabidiol content but not all have independent laboratory verification or consistency from batch to batch. In contrast, in our study we were giving a pharmaceutical grade product — we know exactly what it contains and what dose the patient is getting. So our results are much more reliable."

Dr Chapman agreed with this comment but said his research was interesting because it was the first study to report any results with medical marijuana. "This is really an unknown area of research. Many people are using these products and we wanted to see if they are actually helpful or not."

All three investigators said they would much prefer patients to take the pharmaceutical-grade cannabidiol when it becomes available, rather than one of the unregulated medical marijuana products. But the pharmaceutical product, which is only now starting to be evaluated in placebo-controlled trials, is not expected to reach the market for at least 2 years.

And Dr Chapman points out: "Even then, the challenge will be cost. The unregulated medical marijuana products will be cheaper."

Epidiolex Study

The first study of the pharmaceutical-grade cannabidiol involves children and young adults with treatment-resistant epilepsies, such as Dravet syndrome.

After a 4-week baseline period to establish frequency and type of seizures on existing antiepileptic drug regimens, patients received the cannabidiol product at an initial dose of 5 mg/kg per day on top of their existing therapies. The daily dose was gradually increased until intolerance occurred or a maximum dose of 25 mg/kg per day was achieved.

Results from the first 23 patients (average age, 10 years) show that after 3 months of therapy, 39% of patients had a greater than 50% reduction in seizures with a median reduction of 32%. Seizure freedom (no seizures for the last month of treatment) occurred in three of nine patients with syndrome and one of 14 patients with other forms of epilepsy.

Adverse effects were mostly mild or moderate and included somnolence, fatigue, weight loss or gain, diarrhea, and increased or decreased appetite.

Drug Interactions

A second presentation is focusing on drug interactions between existing drug therapy and the cannabidiol product in the same study. Data so far are available on 33 patients taking the 5 mg/kg dose of cannabidiol with an average of three different antiepileptic drugs, including clobazam (54.5% of patients), valproate (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%).

Dr Friedman told Medscape Medical News that most of the common antiepileptic drugs used did not show major changes when the cannabidiol product was added in. The one main exception to this was with clobazam, which showed a median 10% increase in levels from baseline after Epidiolex was introduced. Further, 7 of 17 patients receiving clobazam (40%) had an increase above 40% and had to have the clobazam dose reduced.

"There were too few patients in this study to make any definitive statements about drug interactions but we can say that the biggest variability in drug levels was seen with clobazam, so I would recommend that cannabidiol containing products are used with caution in patients taking clobazam," Dr Friedman commented. "More studies are needed to understand the potentially complex interactions between cannabidiol and other drugs but in the meantime, frequent monitoring of drug levels is warranted in children taking any form of medicinal marijuana," he added.

The current data on the drug interactions relate just to the lowest dose of cannabidiol first introduced: 5 mg/kg per day. The dosage was subsequently increased and more patients enrolled and further data from the study will be presented at the Epilepsy Society meeting in December.

Medical Marijuana

For the study of medical marijuana, Dr Chapman and colleagues at the Children's Hospital Colorado retrospectively reviewed the 58 children and adolescents (average age, 7 years) who had catastrophic forms of epilepsy and were receiving artisanal oral cannabis extracts when they came under the care of the hospital-based team.

They found that the parents reported a seizure reduction of 50% or more for one third of patients. Of the 16 patients who had baseline electroencephalograms before and during treatment with cannabis, only two showed any signs of improvement. In addition, 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).

Anther observation in the study was that families who had moved to Colorado specifically to access medical marijuana reported higher efficacy rates than those who were already there. "We believe the fact that they had to jump through so many hoops to get the product made them more likely to report a positive effect because they wanted to justify their actions," Dr Chapman said.

"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," Dr Chapman concludes.

"Don't Expect Miracles"

He commented to Medscape Medical News: "I would say be cautious. Don't expect miracles. Families have been led to believe that marijuana products are more effective than anything else but our data do not suggest that this is necessarily true. If you are thinking about trying medical marijuana work closely with a neurologist."

Dr Chapman noted that some forms of medical marijuana are soon to be available over the Internet.

"You will no longer have to be resident in Colorado to get it. This raises concerns for me as many more patients may now try it without medical supervision," he said. "We don't know how it interacts with other drugs, what side effects may occur. There is very limited data on the appropriate dose. Different strains will have different effects, and there are still concerns about what these products may do to the brain, particularly the developing brain in children. It is being touted that cannabidiol has no psychoactive component but I'm not sure this has been proven," he added.

Abstracts can found on the American Epilepsy Society's Annual Meeting Page.

The cannabidiol study was funded by GW Pharmaceuticals.

American Epilepsy Society (AES) 68th Annual Meeting. Abstracts 203458, 2034648, and 2016808.


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