Cannabis, Cannabidiol, and Epilepsy. Clinical Considerations and Practical Applications. A new frontier brings new questions and old dilemmas.
Adrian L. Turner and M. Scott Perry
Practical Neurology, October 2018, 31-35
As early as 12,000 BCE, texts from central Asia reported human use of cannabis for nonmedical
indications including ropes, fibers, and cloth. Ancient Chinese manuscripts from approximately 10,000 years later give the first documented use of cannabis for medical purposes 1. Other early reports from ancient Mesopotamia, Persia, and India describe cannabis use for indications such as spasticity,
depression, anxiety, and epilepsy.1,2
Cannabis for medicinal purposes was not scientifically studied until the 19th century. In 1840, William O’Shaughnessy documented efficacy of cannabis for treating babies with infantile convulsions and studied cannabis’s effect in patients with epilepsy, spasticity, and arthritis. Cannabis and its various components, namely d-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have continued to be researched.3 In recent years, use of CBD for treating patients with refractory epilepsies has come to the forefront, increasing research and resulting in the first Food and Drug Administration (FDA)- approved CBD-based medication for patients with epilepsy.
With this new frontier in modern medicine, practitioners are faced with new questions and old dilemmas. Use of medical marijuana and CBD are becoming increasingly common, but there is still much to be discerned in the realm of evidencebased medicine. Several recent randomized controlled trials of CBD have shown efficacy in a standardized, controlled manner allowing the data to be adjudicated scientifically and applied practically. With solid data for physicians to justify therapeutic plans that include CBD, the horizons for our patients with epilepsy have expanded. Practitioners, then, must also look to the horizon and expect unforeseen hurdles before the place for CBD is ultimately found. Furthermore, CBD is one cannabinoid amongst more than 100 within the cannabis plant. We can expect subsequent research to broaden the indications and availability of other cannabis-based compounds in the future.
Mechanism of Action
The endocannabinoid system, which may play a role in epileptogenesis, includes 2 G-protein coupled receptors (cannabinoid type 1 [CB1] and cannabinoid type 2 [CB2]) and 2 endogenously synthesized, lipid-signaling endocannabinoids (anandamide [N-arachidonyl ethanolamide] and 2-arachidonoyl glycerol [2-AG]) that bind to CB1 and CB2. A presynaptic receptor, CB1 is highly expressed in the hippocampus, amygdala, cingulate, cerebral cortex, basal ganglia, midbrain, and medulla. Therapeutic effects of CB1 binding are via modulation of neurotransmitter release, including dopamine, GABA, glutamine, serotonin, norepinephrine, and acetylcholine. Concentrated in peripheral immune tissues (i.e. spleen, bone marrow, B-cells, macrophages), CB2 receptors have limited expression in the brainstem and hippocampus. In the context of seizures and epilepsy, although it seems CB1 would be a
likely target, that does not appear to be the case. Cannabis contains more than 100 unique compounds called phytocannabinoids, which are quite similar to lipophilic endocannabinoids— differentiated only by the origin of synthesis (ie, plants). The 2 primary phytocannabinoids are THC and CBD 3,5. A direct agonist of the CB1 and CB2 receptors, the psychoactive effect of THC is secondary CB1 activation. There are mixed reports of seizure treatment success and seizure exacerbation 3,5. Unlike THC, CBD does not directly agonize CB1 receptors and subsequently is not psychoactive. Some believe this is a benefit as it may have less potential for abuse. CBD’smechanism of action is not fully elucidated yet and appears to be related to its effects on serotonergic and GABAergic activity, intracellular calcium modulation, and potential antiinflammatory effects. CBD is highly lipophilic and becomes distributed in the brain rapidly 3-6.
Much remains to be ascertained regarding cannabis and its precise mechanism(s) of action in epilepsy. Evidence suggests that in addition to THC and CBD other components of cannabis may have anticonvulsant properties (eg, d-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV], d-8-tetrahydrocannabinol [d-8-THC], and cannabinol [CBN].4 Only time and additional scientific effort will help discern their potential as medications.