Four pivotal randomized placebo‐controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox‐Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4‐ to 5‐fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD‐treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD‐CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta‐analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.

中文翻译：

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大麻二酚是否具有独立于其与氯巴占相互作用的抗癫痫活性？随机对照试验的证据评估

四项关键的随机安慰剂对照试验表明，大麻二酚 (CBD) 的辅助治疗可改善 Dravet 综合征 (DS) 和 Lennox-Gastaut 综合征 (LGS) 患者的癫痫发作控制。在这些试验中分配到 CBD 治疗的患者中有 47% 至 68% 正在接受氯巴占 (CLB)，这表明与 CBD 的复杂相互作用导致活性代谢物去甲氯巴占的血浆浓度增加 3.4 至 5 倍. 这引起了人们对这些相互作用在确定 CBD 治疗患者癫痫发作频率降低方面所起的作用的关注，以及 CBD 本身是否具有临床明显的抗癫痫作用的问题。我们评估了关于 CBD-CLB 相互作用的临床后果的可用证据，根据欧洲药品管理局公共评估报告的规定，重点关注关键 CBD 试验中使用和不使用 CLB 联合用药的患者癫痫发作结果的亚组分析。对个别试验结果的评估清楚地表明，将 CBD 添加到 CLB 时比将其添加到其他药物时，对癫痫发作控制的改善更大。然而，CLB 患者的癫痫控制也得到了改善，尽管样本量很小，但在两项 LGS 试验之一中，10 mg/kg/d 剂量与安慰剂的差异具有统计学意义。对未接受 CLB 药物治疗的 LGS 和 DS 患者合并人群癫痫结果的荟萃分析，提供了更强有力的证据，证明 CBD 的抗癫痫作用独立于与 CLB 的相互作用。尽管需要考虑到方法学限制来解释这些结果，但它们提供了迄今为止最好的临床证据，证明 CBD 对癫痫患者发挥治疗作用，而这种作用独立于其与 CLB 的相互作用。当 CBD 与 CLB 结合时，观察到更大的抗癫痫作用和更大的不良反应负担。