Sunday, October 28, 2018

Cannabis, cannabidiol, and epilepsy

 Adrian L. Turner, M. Scott Perry.  Cannabis, Cannabidiol, and Epilepsy. A new frontier brings new questions and old dilemmas. Practical Neurology   (no abstract)

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.  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.  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’s mechanism 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 anti-inflammatory effects. CBD is highly lipophilic and becomes distributed in the brain rapidly.

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, δ-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV], δ-8-tetrahydrocannabinol [δ-8-THC], and cannabinol [CBN].4 Only time and additional scientific effort will help discern their potential as medications…

A large analysis of expanded access to pharmaceutical-grade CBD included 607 patients and 25 institutions.  Of these patients, 76% continued treatment at a mean of 48 weeks. Of those who discontinued therapy, 15% withdrew because of lack of efficacy and 5% withdrew due to adverse effects. With adjunctive CBD therapy, the number of median monthly convulsive seizures was reduced by 51% at 12 weeks and this was largely sustained through 96 weeks. Likewise, the total number of seizures per month was reduced by 48% at 12 weeks and similarly sustained through 96 weeks.11

Many other studies examining both artisanal and pharmaceutical-grade CBD show efficacy in patients with LGS, DS, and convulsive and atonic type seizures .  Current data strongly support that pharmaceutical-grade CBD is efficacious for seizures classified as convulsive or drop type. Data are lacking for nonconvulsive seizures, which are more difficult to quantify; the studies discussed in this article were not designed to assess this endpoint…. 

In the study that included 607 patients at 25 centers, 88% experienced some sort of side effect.11 Severe side effects were reported in 33% of patients, the most common being convulsion (9%), status epilepticus (7%), pneumonia (5%), and vomiting (3%). Milder side effects included somnolence, fatigue, diarrhea, and reduced appetite.  Other reports validate these findings and report statistically significant instances of somnolence, decreased appetite, fatigue, and diarrhea in patients receiving pharmaceutical-grade CBD. More specifically, somnolence occurred in 22% to 36% of patients, diarrhea in 29% to 31%, decreased appetite in 20% to 28%, and fatigue in 20% to 22%.  Other notable side effects include convulsion, respiratory tract infections, weight loss, status epilepticus, irritability, and pyrexia, which appear to be dose-related and can be therapy-limiting.

Hepatotoxicity has emerged as an adverse effect of CBD treatment of particular concern. Many antiepileptic drugs (AEDs) carry some risk of hepatotoxicity, but with a clear monitoring plan, this concern could be reduced. The manufacturer of pharmaceutical-grade CBD recommends discontinuation if liver function test (LFT) levels rise to 3 times the upper limit of normal (ULN) and bilirubin levels are twice or more the ULN.  If patients experience sustained LFT elevation more than 5 times the ULN, CBD treatment should be discontinued. Elevation of LFTs appears to be most common in the first 2 months of treatment but has also been observed in later stages of treatment. Liver monitoring is recommended at months 1, 3, and 6 after initiating treatment with pharmaceutical-grade CBD or monthly after dose changes or addition of another AED that interacts with CBD.

The hepatotoxicity risk of pharmaceutical-grade CBD appears to be more common if there is polypharmacy with valproic acid products or clobazam, although LFT elevation has also been shown to occur without these concomitant drugs.  Some have postulated that interaction with liver enzymes may contribute to the positive therapeutic effects seen in clinical trials of pharmaceutical-grade CBD.  There are several other pertinent interactions to consider when implementing CBD treatment for patients with epilepsy. Varying reports of alterations in serum concentration of rufinamide, topiramate, zonisamide, and eslicarbazepine have also been noted. Topiramate and rufinamide both appear to have dose-related increases in serum concentrations in the presence of CBD whereas the serum increases of zonisamide and eslicarbazepine were present to a lesser extent…

Cannabis and CBD have a long history of use for medical purposes throughout human history. Until recently, standardized studies with large datasets have been lacking. Now, with the change in social climate and attitude towards the potential of cannabis and CBD, data are amassing to provide much-needed insight into the practical application of CBD in patients with seizures and epilepsy.

In patients with refractory epilepsy syndromes—especially in those characterized by convulsive and “drop attack” seizures—CBD is a promising adjunctive alternative treatment. More studies are needed to determine the exact mechanism of therapeutic efficacy (ie direct antiepileptic target vs. optimization of concomitant medications), but in the meantime appears to be reasonably safe and efficacious.

Practitioners still must be cognizant of individual patient factors because CBD is not a benign entity. Vigilance for concomitant hepatotoxic antiepileptics, potential interactions, and side-effects must be maintained and cost and variability between different formulations considered. New options are on the horizon and expanding potential medical treatment with CBD. Governmental acceptance of a CBD-based product is helping to open doors for many families and patients with previously limited options. The CBD safety and efficacy profiles combined with the great need for better treatment options in refractory epilepsy make this a promising therapy for patients and practitioners alike. We are likely experiencing the first among many therapies to be derived from the cannabis plant in the coming years.

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