Rationale:
Cannabidiol (CBD) inhibits CYP2C19, a pathway for N-desmethylclobazam and phenytoin (PHT) clearance. A CBD interaction has been well documented for patients taking clobazam (CLB) but not for PHT. We report two cases with such interactions.Methods:
The data was obtained through direct care. Laboratory tests were conducted at Yale New Haven Hospital except CLB and metabolite done at Mayo Clinic.
Results:
Case 1
A boy with Lennox-Gastaut Syndrome (LGS) had tonic and atonic seizures (szs) almost daily and occasionally had more intense tonic-clonic (TC) szs. On presentation, he was taking levetiracetam, clonazepam, and PHT (which mom reported minimized the frequency and severity of his tonic-clonic seizures).
He was crossed from clonazepam to CLB with modest improvement but continued to have szs most days. Epidiolex (CBD) was initiated according to the standard titration. The follow up was telehealth and, six weeks after starting the CBD, mom reported her son had been sz free for 38 days, the longest since developing epilepsy and she saw no adverse effects!
A month later lab results indicated the PHT level had risen from 14.5 before initiating CBD to 44, and N-desmethyllclobazam 3,400.
We were concerned that he could be experiencing significant PHT toxicity and brought him into clinic. His exam was unchanged from prior. He was alert and smiling, had no nystagmus or finger to nose ataxia. Liver enzymes and ammonia were slightly elevated but unchanged from prior to initiating CBD. The mother refused to change anything! Over the next year his levels remained unchanged (free PHT was about 10% of the total).
After one year had passed, his medical doctors persuaded us to lower the dose of PHT due to the liver function elevation. When his PHT level decreased to 25ug/ml, he had few recurrent TC szs over two weeks. The LFTs were unchanged. The mother requested restoring the higher PHT dose and once his levels came up into the 30s, sz control was regained.
Case 2
A man with LGS has almost daily tonic and atonic szs and occasional TC and focal szs with head version and staring. Although no drugs controlled his szs, PHT decreased the frequency and severity of TC szs.
After titration of Epidiolex (CBD) according to the standard protocol he became increasingly dizzy and ataxic leading to falls unrelated to szs. He was admitted to a local hospital where marked ataxia and incoordination were observed. A PHT level was 36, a marked increase from his levels prior to CBD (usually in the mid-teens). The evening dose of 130 was held and the next morning’s dose lowered from 130 to 100. His PHT levels decreased to 20 and the symptoms of ataxia resolved. No benefit on szs was seen.Conclusions:
These two cases show CBD inhibition of PHT metabolism can lead to significant increases in levels and meaningful clinical changes (in one case sz control and in the other drug toxicity). In case 1, clinical benefit may also relate to the increase in CLB metabolite and direct effect of CBD. However, the recurrence of seizures on lowering the PHT dose and the resumption of improved control once PHT was restored suggests the elevated PHT was most significant.
Funding: none