Cannabidiol May Negatively Interact With Antiepileptic Drugs

Deborah Brauser

August 18, 2017

Cannabidiol, a compound of cannabis that is being investigated as a potential treatment for epilepsy, may negatively interact with commonly used antiepileptic drugs (AEDs), new research suggests.

Analysis from an ongoing, open-label compassionate-use study included 42 children and 39 adults given the cannabidiol (CBD) Epidiolex (GW Pharmaceuticals, plc) to augment their epilepsy treatment. Results from the full group showed an increasing dose of CBD was associated with significant increases in serum levels of rufinamide, topiramate, and N-desmethylclobazam and a significant decrease in clobazam.

The adult-only subgroup also showed a significant association between increasing CBD dose and increased zonisamide and eslicarbazepine serum levels.

All these serum-level changes were considered to be within the accepted therapeutic range except for N-desmethylclobazam/clobazam.

However, increasing CBD dosing was linked to changes on liver function tests for the full study population receiving concomitant valproate.

Lead author Tyler E. Gaston, MD, assistant professor of neurology at the University of Alabama at Birmingham Epilepsy Center, told Medscape Medical News that the results highlight the importance of monitoring AED levels, as well as liver tests, when treating with CBD.

Dr Tyler E. Gaston

Also, if Epidiolex goes for US Food and Drug Administration approval, "this is something that clinicians will need to know about when counseling their patients," said Dr Gaston.

The findings were published online August 6 in Epilepsia.

Adjunctive Therapy

As reported by Medscape Medical News, previous research suggests CBD can reduce seizures in a variety of epilepsy disorders, including Dravet syndrome and Lennox-Gastaut syndrome.

However, "to date, there are few data on CBD's interactions with other AEDs," write the investigators.

The University of Alabama at Birmingham's prospective, compassionate-use study was created to assess CBD's safety and potential as an add-on therapy for treatment-resistant epilepsy. And it includes frequent monitoring of serum AED levels in case of any drug–drug interactions.

"Given what is known about CBD's mechanism of action and metabolism, it was suspected that other AEDs with metabolism hinging on similar enzymes would be affected," the researchers write.

All participants began taking 5 mg/kg per day of CBD. They were instructed to split it into two doses — one in the morning and one in the evening — and to take it along with their other AEDs.

The patients attended the clinic every 2 weeks, where CBD dose adjustments were made in 5 mg/kg per day increments, based on response and tolerability, up to a maximum of 50 mg/kg per day.

At each visit, patients were also weighed and underwent neurologic examinations and laboratory testing. Each patient's "seizure diary," which included possible adverse effects, was also reviewed. Aspartate aminotransferase and alanine aminotransferase levels were compared with liver function test findings at baseline in those taking concomitant valproate.

For the current analysis, the investigators examined first-year data for 39 adult participants (51% women; mean age, 29.1 years) and 42 pediatric participants (48% girls; mean age, 10.4 years). The mean age at seizure onset was 7.2 and 2.4 years, respectively, and the mean number of AEDs taken at enrollment was 3.2 and 3.0, respectively.

In addition, the most common type of seizures for the adults was partial only (n = 26), followed by generalized only (n=8). For the children, generalized-only seizures were the most common (n = 28), followed by partial only (n=8).

Drug–Drug Interactions

Results from the full group showed that increasing CBD dose was significantly associated with increased levels of the following:

  • N-desmethylclobazam (the active metabolite of clobazam, P < .001),

  • topiramate (P < .001), and

  • rufinamide (P = .004).

In adults only, increasing CBD dose was also significantly associated with increased eslicarbazepine (P = .04) and zonisamide (P = .02) levels.

"Of note, there were no pediatric participants enrolled in the study who were taking eslicarbazepine at the time of this analysis," report the investigators. "So we don't know if that level increase is the same for pediatric patients," added Dr Gaston.

There were no significant links between titrated CBD and the other AEDs assessed, including levetiracetam, clonazepam, lamotrigine, and lacosamide.

As for adverse events, 8 of 15 pediatric and 6 of 12 adult patients taking clobazam reported at least one occurrence of sedation, and there was a significant association between N-desmethylclobazam and total sedation frequency in the adult-only group (P = .02).

All patients receiving CBD and valproate had significantly higher mean aspartate aminotransferase levels compared with those who were not taking valproate (37.1 vs 23.97 U/L, respectively; P = .003), and they had higher alanine aminotransferase levels (35.3 vs 23.7; P = .03). All these mean levels were considered to be in normally accepted ranges.

However, both valproate and CBD "were discontinued in 4 of 14 children due to elevated liver function test results of greater than three times the upper limit of normal, and valproate only was discontinued in one of 8 adults due to...levels approximately two times the upper limit of normal," write the researchers.

They add that these levels quickly normalized after medication changes were made.

A Starting Point

The study "emphasizes the need for not only selected drug levels to be monitored during therapy with CBD, but also for routine liver function test analysis in those patients who are taking concomitant valproate," the investigators write.

"Going forward, formal pharmacokinetic studies under controlled conditions will be needed to further confirm these interactions," they add.

Dr Gaston noted in a press release that there is a perception that because CBD is plant based, it is natural and safe.

"While this may be mostly true, our study shows that CBD, just like other antiepileptic drugs, has interactions with other seizure drugs that patients and providers need to be aware of," she said.

"More research is needed because of our open-label design, but at least it's a starting point to give people an idea of what to look for," she told Medscape Medical News.

The study was funded in part by the State of Alabama, the University of Alabama at Birmingham Epilepsy Center, and Greenwich Biosciences. Dr Gaston received salary support from the State of Alabama, under "Carly's Law," for her work on this project. Disclosures for the other study authors are in the original article.

Epilepsia. Published online August 6, 2017. Abstract

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