humulene and Epileptic-Syndromes

Severe paediatric epilepsies such as CDKL5 Deficiency Disorder (CDD) are extremely debilitating, largely due to the early-onset and refractory nature of the seizures. Existing treatment options are often ineffective and associated with a host of adverse effects, causing those that are affected to seek alternative treatments. Cannabis based products have attracted significant attention over recent years, primarily driven by reports of miraculous cures and a renewed public preference for 'natural' therapies, thus placing intense pressure on health professionals and the government for regulatory change. This study provides a comprehensive overview of the potential role for cannabis in the treatment of CDD. Key areas discussed include the history, mechanism of action, efficacy and safety of cannabis based preparations as well as the burden related to CDD. The evidence supports the use of cannabinoids, especially cannabidiol, in similar forms of refractory epilepsy including Dravet and Lennox-Gastaut syndromes. Evidence for cannabinoids specifically in CDD is limited but growing, with multiple anecdotal reports and an open-label trial showing cannabidiol to be associated with a significant reduction in seizure activity. This review provides the first comprehensive overview of the potential role for cannabis based preparations in the treatment of CDD and provides justification for further clinical and observational research.

Topics: Anticonvulsants; Cannabinoids; Cannabis; Drug Resistant Epilepsy; Epileptic Syndromes; Humans; Spasms, Infantile

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.. While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. U

Topics: Anticonvulsants; Cannabidiol; Cannabis; Drug Resistant Epilepsy; Endocannabinoids; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Randomized Controlled Trials as Topic; Retrospective Studies; Seizures; Spasms, Infantile; Treatment Outcome; TRPV Cation Channels

CDKL5 Deficiency Disorder (CDD) is a severe treatment-resistant form of early-onset epilepsy. Current treatment options are often ineffective and associated with adverse effects, forcing families to seek alternative therapies for their children including products derived from cannabis. Reportsof miraculous cures and a public preferencefor 'natural' therapies have resulted in considerable public interest, and so this study aimed to characterize the use of cannabis in these individuals, as well as compare caregiver perceptions of efficacy and safety to objective evidence of seizure control and number of antiepileptic drugs used.. Families from the International CDKL5 Disorder Database were invited to complete questionnaires which included data relating to their child's current and past treatments, including use of any cannabis-derived preparations. Perceived effects on seizure control, as well as additional benefits and adverse effects were reported. Seizure frequency and number of antiepileptic drugs were compared between those actively using cannabis products and those who were not. Longitudinal analysis was performed on a subset of the study population to compare these same variables at pre-treatment and post-treatment time points.. Three hundred and twelve caregivers answered questions regarding their child's use of antiepileptic medications. Of these, 82 (26%) described use of cannabis preparations either at present, or in the past, with the most common being cannabidiol. Of 70 caregivers that described their perceived effect on seizure control, more than two thirds reported an improvement in seizure control, either temporary (16%) or lasting (54%). Additional benefits included improvements in attention, cognition, and sleep. The majority of responses (78%) described adverse effects as 'none', though some reported an increase in sedation and gastrointestinal upset. There was no reduction in the median seizure frequency nor the number of different antiepileptic drugs, for those who were actively using cannabis products compared to those who were not. Similarly, individuals who were not using cannabis products at an initial time point had no differences in seizure frequency nor number of antiepileptic drugs at a second timepoint when they had started using this treatment.. Although this is an observational study, limited by potential participation bias and the unreliable nature of unblinded self-assessment, it suggests that caregivers perceive cannabis products, especially cannabidiol, to have a tolerable adverse effect profile and adequate efficacy. Despite this, cannabis was not associated with a reduction in seizure frequency nor number of antiepileptic drugs when compared to non-users or when compared to pre-treatment. Randomized controlled trials are urgently needed to more reliably assess this treatment's safety and efficacy.

Topics: Cannabis; Child; Drug Resistant Epilepsy; Epileptic Syndromes; Humans; Protein Serine-Threonine Kinases; Seizures; Spasms, Infantile