Cannabidiol (CBD) interacts significantly with clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine, researchers said at the 70th Annual Meeting of the American Epilepsy Society. The study results underscore the importance of monitoring levels of antiepileptic drugs (AEDs) during treatment with CBD. “In the future, these data will need to be correlated with reported side effects or laboratory abnormalities to determine whether they are clinically significant,” said Jerzy P. Szaflarski, MD, PhD, Director of the University of Alabama at Birmingham Epilepsy Center.
Dr. Szaflarski and colleagues monitored serum AED levels during active titration of pharmaceutical grade CBD in patients with refractory epilepsy who were enrolled in an open-label safety study. The study was intended to investigate CBD as a potential adjunctive therapy. As part of the study protocol, researchers checked serum AED levels frequently to identify interactions between CBD and AEDs. Based on previous data and anecdotal observations, Dr. Szaflarski and colleagues hypothesized that they would find interactions between CBD and clobazam and valproate.
Participants received an initial CBD dose of 5 mg/kg/day. The dose was increased by 5 mg/kg/day every two weeks, provided that tolerability was maintained, to a maximum of 50 mg/kg/day. Baseline AED levels were drawn, and AEDs were required to have been at a stable dose for one month before enrollment. The researchers obtained AED levels at almost all study visits during dose titration and maintenance. AED doses were adjusted at the investigators’ discretion if an adverse effect, laboratory abnormality, or drug level change was considered related to a potential interaction between CBD and the AED. The researchers frequently adjusted doses of clobazam and valproate because of complaints of sedation and alteration in liver function tests, respectively. At the time of Dr. Szaflarski’s analysis, 81 participants were enrolled in the study (39 adults and 42 children). There were sufficient data to analyze potential interactions between CBD and 19 AEDs.
The researchers found increases in serum levels of topiramate, rufinamide, and desmethylclobazam (an active metabolite of clobazam), and a decrease in levels of clobazam, with increasing CBD dose in the pediatric and adult arms. In addition, they noted significant increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose in the adult arm. Dr. Szaflarski and colleagues observed no significant interactions between CBD and the other AEDs investigated, which included valproate, levetiracetam, lacosamide, and perampanel.
Pharmaceutical-grade cannabidiol (CBD) may reduce seizure severity in adults and children with medically refractory epilepsy, according to an open-label trial described at the 70th Annual Meeting of the American Epilepsy Society. A controlled trial to confirm the drug’s effect may be warranted.
Jennifer L. DeWolfe, DO, Associate Professor of Neurology at the University of Alabama at Birmingham, and colleagues conducted a state-sponsored compassionate-use study of CBD in patients with refractory epilepsy. Patients received Epidiolex (a CBD formulation developed by GW Pharmaceuticals) in addition to their antiepileptic drugs. Eligible participants were adults and children with epilepsy confirmed by video EEG. Participants were required to have failed four antiepileptic drugs and had to have had four countable seizures per month. Exclusion criteria included psychogenic nonepileptic seizures confirmed by video EEG and prior CBD use.
The investigators measured participants’ seizure frequency and used the Chalfont Seizure Severity Scale to measure seizure severity. The scale solicits information about various factors, such as whether the patient lost awareness, dropped an object, fell, or was injured. The total possible score on the scale is 178, and the score increases with seizure severity. Changes of 10 or more points were considered significant. The researchers particularly focused on participants’ most frequent seizure type, which the Chalfont Seizure Severity Scale names the Type 1 seizure.
Dr. DeWolfe and colleagues measured patients’ total seizure severity scores and severity scores for Type 1 seizures at baseline, three months, and six months. To compare the scores, the researchers calculated time-weighted average values. They also examined percent change in seizures; seizure severity in adults, children, and all patients; and severity in responders and nonresponders. Responders were defined as patients who had a reduction in seizure frequency of more than 50%. The analysis included 81 participants, approximately half of whom were children. At the time of the analysis, 57 patients had undergone evaluation at three months, and 47 patients had undergone evaluation at six months. At baseline, the majority of patients had at least two types of seizures.
The total change in Chalfont Seizure Severity Scale score at three months was significant for adults, children, and all patients. The change remained significant at six months. The difference in the percent change in seizure severity between responders and nonresponders was significant at three months, but not at six months.
The change in severity of Type 1 seizures was significant for adults, children, and all patients at three months and at six months. The difference between responders and nonresponders in change in severity of Type 1 seizures was significant at three months, but not at six months.
At three months, the majority of adults, the majority of all patients, the majority of responders, and the majority of nonresponders had a reduction in seizure severity of at least 10 points. Approximately one-third of children had a reduction in seizure severity of at least 10 points at three months. At six months, the majority of adults, children, all patients, responders, and nonresponders had a decrease in seizure severity of at least 10 points. Patients’ average seizure severity tended to increase at six months, compared with the three-month point, but was still significantly lower than at baseline.
“One of the things I find most exciting is [that] … even if you were considered a nonresponder, you still had improvement in seizure severity,” said Dr. DeWolfe. She and her colleagues plan to examine the data by seizure type (eg, absence or tonic-clonic), to identify which factors measured by the Chalfont Seizure Severity Scale contributed most to the reductions in seizure severity, and to examine whether the effect of CBD on levels of antiepileptic drugs contributed to the change in seizure severity. The findings of this open-label trial suggest that CBD may improve seizure severity in people with medically refractory epilepsy. Randomized placebo-controlled studies are needed to further evaluate the effects of CBD on seizure severity.