Department of Neurology, University of Alabama at Birmingham Epilepsy Center, Birmingham, AL, USA.
312 Civitan International Research Center, 1719 6th Avenue South, CIRC 312, Birmingham, AL, 35294, USA.
Curr Neurol Neurosci Rep. 2018 Sep 8;18(11):73. doi: 10.1007/s11910-018-0882-y.
For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.
While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.
几千年来，人们一直对大麻治疗癫痫的作用感兴趣。然而，直到最近，才完成了适当功率控制研究。在本次综述中，我们介绍了调查使用大麻非精神活性成分大麻二酚（CBD）治疗癫痫的研究进展。
尽管 CBD 的抗惊厥作用机制尚未完全阐明，但我们讨论了最新的数据，包括其对内源性大麻素受体的低亲和力以及通过阻断花生四烯酸酰胺的分解来可能间接调节这些受体。其他靶点包括激活香草素瞬时受体电位 1 型（TRPV1）、GPR55 拮抗剂作用、靶向异常钠通道、阻断 T 型钙通道、调节腺苷受体、调节电压依赖性阴离子选择通道蛋白（VDAC1）和调节肿瘤坏死因子 α 释放。我们还讨论了最近在美国和国际上对癫痫患者进行的各种手工 CBD 产品的研究。虽然这些研究中的大多数患者报告癫痫发作有所改善，但这些研究要么是回顾性的，要么是通过调查进行的。在这些研究中，CBD 的剂量/制剂要么未知，要么没有得到控制。最后，我们展示了美国食品和药物管理局（FDA）最近批准用于治疗癫痫的高纯度口服 CBD 制剂的开放标签扩展访问计划（EAP）和随机安慰剂对照试验（RCT）的数据。在 EAP 中，许多患有各种难治性癫痫的患者的癫痫发作频率明显改善。与安慰剂相比，RCT 显示 CBD 可显著减少癫痫发作。最后，我们描述了与高纯度 CBD 相关的不良反应和药物相互作用的现有数据。虽然该产品总体上耐受性良好，但最常见的副作用是腹泻和镇静，镇静在同时服用氯巴占的患者中更为常见。在服用 CBD 的同时，天冬氨酸转氨酶和丙氨酸转氨酶升高的发生率也有所增加，许多出现这些异常的患者也同时服用丙戊酸。CBD 与氯巴占有明确的相互作用，在几项研究中显著增加其活性代谢物 N-去甲基氯巴占的水平；这被认为是由于 CBD 抑制 CYP2C19。EAP 数据表明，与鲁非酰胺、佐尼酰胺、托吡酯和依立替康可能存在其他相互作用。此外，有一例报告表明，与 CBD 同时使用需要调整华法林剂量。在过去的几年中，对 CBD 治疗 TRE 的疗效和安全性的认识有了显著提高。需要对各种 CBD 和 THC 比例进行对照研究，因为这些化合物对癫痫患者可能具有进一步的治疗潜力。
