First Trial of Transdermal CBD for Adult Epilepsy Reports Mixed Results

Transdermal CBD gels could help reduce the number of seizures a person with epilepsy experiences, according to the world’s first randomized, double-blind, placebo-controlled clinical trial investigating the use of transdermal CBD in treating adult focal seizures.

While there was no difference observed between either the high- or low-dose CBD gels and a placebo in the double-blinded portion of the study, around 60% of the patients who chose to continue into an open-label extension (OLE) study reported a 50% reduction in seizure frequency by month six.

As a result of these findings on long-term seizure rate, the researchers say that additional randomized controlled trials on transdermal CBD for adult focal epilepsy are warranted.

Transdermal CBD is safe, but ineffective in blinded trial

Focal epilepsies are the most common form of epilepsy seen in adults and are characterized by seizures localized to one specific part or lobe in the brain. As a result, focal epilepsy symptoms can differ significantly from person to person, depending on which part of the brain is affected.

While the anti-seizure effects of CBD have been well-studied, these studies have tended to focus on children with Dravet syndrome or Lennox-Gastaut syndrome. As a result, there has been no real high-level evidence detailing the safety and efficacy of CBD as a treatment for focal seizures in adults, until now.

This new randomized, double-blind, controlled trial took place at 14 epilepsy trial centers located across Australia and New Zealand, enrolling a total of 188 patients. Each patient had some form of drug-resistant focal epilepsy and was on a stable regimen of anti-seizure medications that did not include clobazam, ethosuximide, felbamate, or vigabatrin.

Enrolled patients attended a screening visit where a complete medical history, physical exam, and blood samples were taken. The patients were also asked to keep a seizure diary for eight weeks in order to establish a baseline measurement of their normal seizure frequency.

After this period, the patients were randomly assigned to receive either a 195 milligram (mg) or 390 mg dose of transdermal CBD gel daily, or a placebo medication. For the next 12 weeks, patients continued to record their seizures in a diary, with additional neurological exams, electrocardiograms, and blood samples also taken regularly.

“This is the first randomized, double blind, placebo-controlled trial of a cannabidiol in this common group of adult patients, whose seizures currently cannot be controlled with currently available treatments,” said lead study author Professor Terry O’Brien, director of the Monash University Department of Neuroscience, in a statement.

“The original 12-week trial did not show any difference in effect of the gel between the experimental and placebo group, though the trial did show the gel was safe.”

During the double-blind phase of the study, adverse events were reported by approximately 50% of the groups given CBD, and 40% of the placebo group. The vast majority of events were considered mild or moderate, with the most common adverse event reported by the CBD groups being headache or fatigue. Overall, the transdermal CBD treatment was determined to be safe and well-tolerated.

Open-label study of transdermal CBD reports 50% reduction in seizures

Despite there being no difference in seizure frequency between the CBD groups and the placebo group at the end of the 12-week blinded study period, 98% of the trial participants chose to continue into an open-label extension (OLE) study where they would continue to receive the transdermal CBD.

The OLE lasted up to two years, with a seizure diary being required and checked at monthly intervals at first, and then every quarter. Blood samples were taken every two weeks at first, before also becoming quarterly. The patients were also given the opportunity to increase their daily dose of CBD to 585 mg (approximately 7.9 mg per kilogram) after five months, and again to 780 mg (approximately 10.5 mg/kg) after a further month at that increased dosage.

One month into the OLE, patients reported a median reduction in seizure frequency of 29%. By month six, this had increased to 49%, reaching a peak of a 67% reduction in seizure frequency at month 17.

“Importantly, the open label extension of the trial to six months showed a seizure reduction of at least 50% in more than half of the experimental group, making it a promising candidate for further larger and longer trials,” O’Brien said.

“This trial represents an internationally significant, landmark trial, to build an evidence base to support the availability and use of medicinal cannabis based treatments for adults with common forms of epilepsy.”

In their paper, the researchers noted that this decrease in seizure frequency may be explained by some form of placebo or expectancy effect, as the nature of the OLE makes it impossible to control for such placebo effects. However, they also believe that it is possible that the time of onset for transdermal CBD’s effect may just be longer than 12 weeks, and so there is a chance this reduction is clinically significant.

Given the demonstrated safety and tolerability of transdermal CBD, and the possibility of a positive effect on seizure frequency, the researchers behind the study believe that more clinical studies should be done to properly determine the long-term efficacy of transdermal CBD in adult focal epilepsy.

Cannabis for epilepsy

The oral CBD formulation Epidiolex has received approval in the United States and European Union to be used in the treatment of two rare forms of drug-resistant epilepsy: Lennox-Gastaut syndrome and Dravet syndrome. But despite this, the question of whether CBD can effectively prevent seizures is surprisingly unsettled.

In 2019, a study published in the British Journal of Clinical Pharmacology proposed that the effectiveness of CBD is perhaps less to do with CBD’s direct effects, but is perhaps more down to a drug-drug interaction where CBD indirectly raises the levels of another concomitant anti-epileptic drug, clobazam, in the patients’ blood.

“I went back to [two of the three cited] papers… and I thought, ‘let’s have a look.’ How many of those patients were actually using clobazam?” lead author Geert Jan Groeneveld, the chief scientific officer at the Centre for Human Drug Research in the Netherlands, told Analytical Cannabis at the time.

“I was flabbergasted when I saw that 50% in one study and 60% in the other study were actually using this other drug, clobazam.”

“I'm not saying that I know for a fact that cannabidiol does not have any anti-epileptic effects. What I am saying is, I can explain the effects that you've observed through elevated blood levels of clobazam,” Groeneveld said.

Notably, this new study of focal seizures in adults chose to exclude potential patients who were taking clobazam or similar medications. Additionally, a later study led by neurologists from the Stichting Epilepsie Instellingen Nederland found that while CBD may amplify the effects of clobazam, it appears to also have an anti-seizure effect of its own.