HOUSTON -- Cannabidiol is likely to interact with more anti-epileptic agents than just clobazam, researchers reported here.

In an open-label study of 81 adult and pediatric patients, the cannabis derivative also showed drug-drug interactions with topiramate and rufinamide, Tyler Gaston, MD, of the University of Alabama at Birmingham, and colleagues reported at the American Epilepsy Society meeting here.

Cannabidiol appeared to interact with zonisamide and eslicarbazepine as well, but only in adults, the researchers reported.

"With marijuana, the general idea is that it's a safe product, and while that may be true, I think there are some caveats to that and I think that physicians need to be monitoring and managing this," Gaston told MedPage Today.

The cannabidiol-clobazam interaction has been well established, particularly with the active metabolite N-desmethylclobazam, the researchers said. However, there are no published human data on cannabidiol's potential interactions with other anti-epileptic drugs.

So Gaston and colleagues monitored patients who were enrolled in a state-based compassionate use study of cannabidiol for those who were refractory to at least four other anti-epileptic drugs. Over a year of monitoring, they collected data on 81 patients: 39 adults and 42 children.

Cannabidiol dosing was weight-based, starting at at 5 mg/kg per day, split into twice-daily dosing.

Overall, they found significant linear increases in serum levels of topiramate (P<0.001), rufinamide (P=0.004), and N-desmethylclobazam (P<0.001) with increasing cannabidiol dose in both adult and pediatric patients.

They also saw significant increases in serum zonisamide (P=0.017) and eslicarbazepine (P=0.039) in the adult arm only, though they noted there were no pediatric patients taking eslicarbazepine in this analysis.

There were no other interactions with other AEDs including levetiracetam, carbamazepine, or perampanel, they reported.

About half of patients taking concomitant clobazam complained of sedation at least once during the study, they added. In linear regression analysis, there was a significant effect of mean N-desmethylclobazam level on the total frequency of sedation in adult patients.

They did see a significant effect of valproate dose on AST levels (P=0.002) and on ALT levels (P=0.023) in both pediatric and adult patients.

The combination of valproate and cannabidiol was discontinued in four of 14 children due to liver function tests that were more than three times the upper limit of normal, and valproate alone was discontinued in one of eight adults due to liver function tests twice the upper limit of normal.

Liver enzymes normalized quickly in all cases, Gaston said.

She said that many of these relationships are "very easily explained by the known metabolic actions on the CYP enzymes, but some are less clear." For instance, CYP2C19 and CYP2C9 are key enzymes involved in AED metabolism, and CBD impacts these enzymes. "There are published data that desmethylclobazam is metabolized by CYP2C19, which is strongly impacted by cannabidiol," she said.

But for drugs like rufinamide and eslicarbazepine, the relationship is less clear. "Zonisamide and topiramate have some mild metabolism from the liver enzymes but they're mainly renally metabolized and excreted," she said.

Gaston added that it's very unclear as to why the interaction between valproate and cannabidiol raises liver enzymes: "It does seem to be the combination of these two medications, rather than each individually."

"Some interactions don't seem to be clinically significant," she concluded, "but more data needs to be collected in order to confirm that."