Cannabis Patient Care - August 2021


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26 research focus cannabis patient care | vol. 2 no. 2 A Brief Overview of the History, Efficacy, and Safety of Cannabis for Epilepsy R U T H F I S H E R E PILEPSY IS A chronic disease characterized by over- active neuronal activity—abnormal electrical discharg- es—in the brain. Most new cases are diagnosed either in children or the elderly. The cause of primary epi- lepsy is unknown, while secondary epilepsy may result from a number of different conditions, including injury or stroke (1). With an incidence of about 50 cases per 100,000 peo- ple per year, epilepsy is one of the most common neurologi- cal diseases. Notably, roughly one-third of patients are drug resistant (refractory), meaning their seizures have not been controlled after using at least two different antiepileptic med- ications (2). Refractory patients suffer from intractable sei- zures, and treatment is often invasive (1). The severest forms of epilepsy are the developmental and epileptic encephalopa- thies (DEEs), each of which is relatively rare, but with a non- trivial overall incidence of one in 2000 births. DEEs are de- fined by frequent seizures, together with severe cognitive and behavioral impairment, morbidity, and mortality (3,4). Cannabis for Epilepsy: Historical Use Written records of cannabis use for epilepsy date back as far as 1800 BC. Cannabis was introduced to Western medicine during the 19th century by an Irish physician, William O′Shaughnessy, who had studied medicine in India, from where he brought back knowledge of therapeutic uses for cannabis to Europe. O′Shaughnessy's own case reports note cannabis uses for "infantile convulsions." By the late 19th century, cannabis ap- peared in Western pharmacopeias and was widely used to treat a variety of illnesses. During the early 20th century, however, Western medicine turned away from natural extracts to focus on chemical isolates, and eventually cannabis use was prohibit- ed internationally (5). Much anecdotal and pre-clinical evidence had been amassed that clearly suggested the efficacy of cannabis for epilepsy. Yet, the lack of scientists' clear understanding of cannabis's mechanisms of action for its pro-therapeutic ef- fects for epilepsy deterred scientific interest in further re- search. It wasn't until the early 1990s that the discovery of the endocannabinoid system revived interest in researching the therapeutic effects of cannabis for epilepsy, among other health conditions (5). Cannabis for Epilepsy: Mechanism of Action One role of the endocannabinoid system (ECS) is to dampen overactivity in the central nervous system (CNS), including pre- venting seizures. More specifically, endocannabinoids (eCBs)— cannabinoids produced by the body—act on endocannabinoid receptors (CBRs) located in central and peripheral neurons (CB1) and in receptors located in immune cells (CB2) (2). The two most studied phytocannabinoids—cannabinoids produced by cannabis plants—are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC causes greater psychoactivity and serves as an agonist primarily for CB1, but also for CB2. CBD, on the other hand, is nonintoxicating and has lower affinity for CBRs, where it serves as a weak antagonist (6). Both THC and CBD have been shown to be promiscuous, that is, they have affinities for dozens of different molecular targets (3,7). Both THC and CBD have been shown to have anticonvulsant properties. There is also increasing evidence of ECS involve- ment in the process of epileptogenesis. However, the mecha- nisms of action (MOA) of THC and CBD for epilepsy have only been partially understood (6). Studies show CBD blocks the uptake and hydrolysis of an eCB, anandamide (ANA), which increases ANA's potential to activate the CBRs. Other potential MOAs include activation of transient receptor potential of: vanilloid type-1 receptors (TRPV1); G protein-coupled receptor 55 (GPR55); voltage-de- pendent anion channels 1, CaV3.x, 5-HT1A; glycine receptor; adenosine modulation; and sodium channels of GABAergic in- hibitory interneurons (3,6).

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