Epilepsy in adults

Background Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regime...

/pdf/effect-of-cannabidiol-on-drop-seizures-in-the-lennox-gastaut-30u0weocvn.pdf

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system — known as the endocannabinoidome — that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma. In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the endocannabinoid system and the expanded endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease.

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

The endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa. The search for new therapeutics that target endocannabinoid signalling is both challenging and potentially rewarding, as endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the endocannabinoid network. The current development of drugs that alter endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article.

New approaches and challenges to targeting the endocannabinoid system.

Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2-5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.

/pdf/a-systematic-review-on-the-pharmacokinetics-of-cannabidiol-556uyzc5gf.pdf

Siddarth Kapoor

Papers

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial