January 2015
Emily Knezevich, PharmD, BCPS, CDE and Yunuo Wu, PharmD Candidate
Abstract
Cannabis, the substance more commonly known as marijuana, has gained interest in recent years for its potential use as an antiepileptic agent. The two main components of marijuana are delta-9-tetrahydrocannabinol, which has had mixed effects in epilepsy, and cannabidiol, which has shown more consistent anticonvulsant effects. Data supporting the use of marijuana for this purpose are limited, as the majority of clinical trials were conducted before 1990. There are case reports showing promising results; however, the data are inconsistent and cannot be generalized. The legal issues surrounding marijuana in the United States also may limit the use of this substance as an antiepileptic.
Epilepsy is defined as recurrent and ongoing seizures caused by changes in neuronal firing in the brain. Whereas nonepileptic seizures are not associated with neurophysiological changes, 3% of the population is predisposed to otherwise unprovoked, recurrent epileptic seizures.1 Current pharmacotherapy for epilepsy aims to restore normal neuronal function and decrease seizure frequency. Prospective, randomized trials estimate that individuals experiencing a first, unprovoked seizure have a 40% to 50% chance of seizure recurrence at 2 years. The risk of recurrence, which diminishes with time, is highest immediately following the first seizure, with 80% to 90% of patients experiencing recurrent seizures within the first 2 years.2,3 Despite available treatments, about 30% of patients remain resistant to therapy (fail two or more antiepileptics), resulting in poorly controlled and recurring seizures.4,5 This review discusses the current research on, rationale for, and limitations to the use of marijuana for the treatment of seizure disorders.
Historical Medical Use of Cannabis
The earliest documented use of cannabis (marijuana) occurred in about 2,700 bc in China, where it was used for a variety of medical ailments, including gout, malaria, constipation, menstrual disorders, and absentmindedness. Western medicine adopted the use of cannabis as a common analgesic in the 19th century.6
Cannabis was available in U.S. pharmacies as an OTC product until the 1937 Marihuana Tax Act limited its accessibility. Subsequently, the passing of the Controlled Substances Act in 1970 gave cannabis a Schedule I classification, making its use illegal.7 Since 1970, there has been increasing interest in the use of marijuana for its possible antiepileptic properties.4
Pharmacology
Cannabis sativa and Cannabis indica are two species of the Cannabis genus of flowering plants. Both of these species have a long history of use as an antiepileptic, with sativa strains causing more psychotropic and stimulating effects and indica strains causing more sedation.6 Compounds contained in the cannabis plant are known as cannabinoids.
Cannabis contains two main components: the psychoactive portion of marijuana known as delta-9-tetrahydrocannabinol (THC) and the nonpsychoactive portion known as cannabidiol (CBD). What makes cannabis an attractive agent for epilepsy is the presence of cannabinoid type 1 receptors in the hippocampus and amygdala, both of which are associated with partial seizures.8 The THC component of cannabis is a partial agonist at these receptors.9 Conversely, CBD interacts with other nonendocannabinoid signaling systems, reducing the psychotropic activity of THC while increasing tolerance.6 Recent trials of CBD have shown more consistent anticonvulsant properties, and this cannabinoid has gained interest as a possible agent for epilepsy.9,10
There are many potential routes of administration for synthetic CBD, the only non–delta-9-THC phytocannabinoid assessed for its anticonvulsant effects in clinical trials.6 The most common delivery route is by inhalation, either recreationally or for medicinal purposes. Because of the highly lipophilic nature of CBD and its high volume of distribution, the lungs are an effective route of medication delivery, with rapid distribution into the brain, adipose tissue, and organs. Cannabinoids are extensively metabolized by the liver, predominantly by CYP3A2, CYP3A4, CYP2C8, CYP2C9, and CYP2C19. Owing to significant first-pass metabolism through the liver, CBD is only about 6% bioavailable, thus rendering oral, oral-mucosal, and sublingual routes of delivery less desirable. The transdermal route of administration has also been considered; however, this route may be economically impractical, since special delivery systems are needed to prevent excessive accumulation of CBD in the skin.11,12
Conclusion
There is insufficient evidence to form a reliable conclusion regarding the efficacy of marijuana as an antiepileptic agent. Despite case reports demonstrating efficacy in reducing seizure frequency and severity, limited clinical studies have been published on its use for this indication. Additionally, the studies conducted were inadequately powered, lacked complete information, and used small sample sizes. There are few studies of long-term administration of cannabis and its safety profile. Currently, legal restrictions on cannabis make it difficult to conduct large-scale clinical trials, as the FDA has classified marijuana as a Schedule I controlled substance. The utility of marijuana for the therapeutic treatment of epilepsy cannot be determined at this time; more large-scale studies are needed that assess the efficacy and safety of treatment with either high CBD-THC ratio marijuana or isolated CBD compounds.
