Virginia Thornley, M.D., Neurologist, Epileptologist
March 9, 2018
One of the most challenging therapeutic goals are to keep patients with epilepsy seizure free. Once a patient is found to be medically refractory, it is not unusual to find patients on 3-4 medications for seizure control. However, oftentimes, the means to the end is often wrought with its own challenges with patients suffering side effects placing their quality of life secondary to the medical control of their condition. More and more patients and their families are turning towards a more naturalistic approach including diet and cannabidiol use which has fewer side effects as a means to control seizures. The literature is fraught with a paucity of scientific data with small clinical trials, animal models, and anecdotal data. Larger clinical randomized control trials are pursued.
Mechanisms of Cannabidiol and THC
In the brain, there is the natural endocannabinoid system. Endocannabinoids are released after exercise referred to as the runner’s high which contributes towards our sense of well-being. In the endocannabinoid pathway, cannabidiol has a low affinity to the CB1 receptor and modulates THC tetrahydrocannabinol by blocking CB1 receptor. It is thought to modulate THC by blocking the CB1 receptor acting as an inverse CB1 agonist (2). This may be the mechanism behind combining CBD with THC, CBD modulates the side effects of THC making it less available to exert its effects. Delta9THC is found to work at the level of the CB1 receptors which are rich in the brain and CB2 receptor which is more predominant in the immune system. THC can bind to other targets exerting inflammatory properties. CBD has less binding capabilities to CB1 receptors and is thought to exert its effect by working through other mechanisms such as voltage-gated potassium and sodium channels and the GRP55 in controlling seizures. Cannabinoids are lipid binding or lipophilic making it less available within the system making it challenging to deliver (3).
Cannabidiol clinical trials
In one study, 216 patients were enrolled and followed 3 months after administration of the first dose cannabidiol. Initially, the dose was 2mg/kg which was titrated up to 50mg/kg. 76% were enrolled in the safety profile study and 64% were enrolled in the efficacy profile study. In the first group for safety, 20% had Dravet syndrome and 19% had Lennox-Gastaut syndrome. Side effects were noted in 79% of the patients in the safety group. These include somnolence, diarrhea, seizures (11%), fatigue and reduced appetite. Five disenrolled due to adverse effects, 30% had serious side effects including 1 death of consisting sudden death syndrome. 12% had serious side effects including status epilepticus which may have been related to cannabidiol use. The median reduction of seizures was 36.5%. The study concluded that cannabidiol may be an effective strategy for reducing seizures in medically refractory seizures. The flaw with the study is that the doses at the higher end may have been too high for the patients to tolerate, a lower titrated dose may have been equally effective in controlling seizures and minimizing side effects. Nevertheless, the results were promising as it proves to be beneficial in controlling some of the seizures.
- Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
- McPartland, et al, “Are cannabidiol and 9 delta tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review,” British Journal of Pharmacology, 2015, Feb., 172(3):737-53.
- Gaston, et al, “Pharmacology of cannabinoids in the treatment of epilepsy,” Epilepsy Behavior, 2017, May, 70(Pt B):313-318.