Epilepsy

Publication: https://onlinelibrary.wiley.com/doi/10.1111/epi.16355

Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox‐Gastaut syndrome. However, a drug-drug interaction occurs between CBD and clobazam, a first line medication. This recognized interaction has led to repeated suggestions that the anticonvulsant efficacy of CBD is overstated and its efficacy simply reflects CBD augmenting clobazam exposure. This study aimed to address the nature of the interaction between CBD and clobazam using a mouse model of Dravet syndrome (Scn1a^+/- mice). 

Results

We explored both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam. Combination CBD‐clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a^+/- mice, but only when an anticonvulsant dose of CBD was used. A sub‐anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. Additionally, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA_A receptor activation.

This study re-affirms that CBD itself is anticonvulsant and demonstrated that combination CBD-clobazam treatment promoted a greater anticonvulsant effect than either of the drugs alone. The increased anticonvulsant efficacy of combined CBD and clobazam, however, required intrinsically anticonvulsant doses of both drugs. This study supports the view that the clinical efficacy of CBD may not simply be explained by CBD increasing clobazam exposure, as the presence of a pharmacokinetic interaction was not sufficient to augment anticonvulsant effects. Importantly, our study highlights involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Research Team: Dr Lyndsey Anderson, Dr Nathan Absalom, Sarah Abelev, Ivan Low, Peter Doohan, Lewis Martin, Professor Mary Collins, Associate Professor Jonathon Arnold, Professor Iain McGregor, 

The Lambert Initiative is committed to the discovery and development of phytocannabinoid anticonvulsants. Using a genetic mouse model of Dravet syndrome, we have discovered four cannabinoids with more potent anticonvulsant properties than CBD. In this preclinical project funded by the National Health and Medical Research Council (NHMRC) (2019-2021) we aim to further characterise the efficacy of the phytocannabinoids in this innovative drug discovery platform. This will help clarify which cannabinoid has the most versatile efficacy and, therefore is the best to take forward. In an additional aim we will structurally modify our lead molecules to improve their pharmacokinetic properties and efficacy. We have preliminary evidence suggesting components of the endocannabinoid system are dysregulated in Dravet syndrome, which provides insight into potential drug targets. Our final aim is to validate the functional role of these putative drug targets and determine the mechanism of action of our lead phytocannabinoids.

This is a collaboration between the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney, and Northwestern University, Chicago.

Research Team: Associate Professor Jonathon Arnold, Dr Samuel Banister, Professor Iain McGregor, Dr Lyndsey Anderson, Dr Melissa Benson, Dr Jia Lin Luo (Lambert Initiative, University of Sydney); Dr Jennifer Kearney (Northwestern University)

Publication: https://www.nature.com/articles/s41598-018-28127-0

Our PELICAN study examined the experiences of parents using cannabis oils and tinctures to treat their child with epilepsy, as well as interviews with families who have tried and stopped using medicinal cannabis, families who had never used cannabis-derived treatments, and analysed cannabis extracts that have not been effective. For those using cannabis, extracts were analysed for cannabinoid and terpenoid content, with specific comparison of samples rated by families as “effective” versus those rated “ineffective”. Participants had the option to receive individual feedback on the cannabinoid and terpenoid content of their cannabis product.

Results: Results showed that children given cannabis products tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. At the time of the study, most families were accessing (illicit) cannabis products of unknown composition for their child’s epilepsy, with most reporting that their child’s seizure frequency had reduced since starting the cannabis product. There was high variability in the cannabinoid content and profile of cannabis extracts rated as “effective”, with no clear differences between extracts perceived as “effective” and “ineffective”. Contrary to family’s expectations, most samples contained low concentrations of cannabidiol (CBD), while tetrahydrocannabinol (THC) was present in nearly every sample. The study threw a spotlight onto the world of families who are resorting to the use of illicit cannabis products to manage their child’s seizures, underlining the huge unmet clinical need in the management of treatment-resistant epilepsy in children.

This was a collaboration between the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney; Epilepsy Action Australia; Queensland Department of Health; and Epilepsy Queensland.

Chief Investigator: Professor Iain McGregor (Lambert Initiative, University of Sydney); Professor Nick Lintzeris (South East Sydney Local Health District)

Project Coordinator: Anastasia Suraev (Lambert Initiative, University of Sydney)

In this project, cutting-edge molecular biology techniques have been developed that are allowing us to gain a better understanding of how cannabinoids may act to help children with specific forms of severe and intractable epilepsy. Recent advances have unearthed new genetic mutations in GABA-A receptors that cause severe childhood epilepsies that are unresponsive to traditional anticonvulsant medications. So far, this project has helped explain why the traditional anticonvulsant drugs are not working in children with these mutations and has identified cannabinoid-based therapeutics that may provide an effective treatment.

This is a collaboration between the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney, and the Ion Channel Drug Discovery Group, Brain and Mind Centre at the University of Sydney.

Research Team: Professor Mary Collins, Dr Nathan Absalom (University of Sydney); Dr Michael Bowen (Lambert Initiative, University of Sydney)

Only scant information is available concerning the mechanism of action and the network, neuronal and molecular scales of phytocannabinoids. Such knowledge can be pivotal in the process of selecting which particular phytocannabinoid from which species of plant has the greatest promise for clinical efficacy. To fulfill the promise of cannabinoid therapy in Dravet syndrome it is critical that we increase our knowledge base of the mechanisms of action. We propose to undertake such studies using a range of models that span studies of target engagement, single neuron patch clamp and multiunit recording in cultured neuronal networks. The latter will be done using organoids (disease in a dish model). Here we can take from a patient with a rare form of epilepsy, grow up their brain cells in culture and see if we can reduce signs of epilepsy in that dish.

This is a collaboration between the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney and the Florey Institute.

Research Team: Professor Steve Petrou (Florey Institute); Professor Iain McGregor, Associate Professor Jonathon Arnold, Dr Michael Bowen (Lambert Initiative, University of Sydney)

Our target validation research in Dravet syndrome mice has revealed that the G-protein coupled receptor GPR55 plays a permissive role in seizure generation and reduced lifespan. The present project will explore structure activity relationships (SAR) between cannabinoid chemotypes and their ability to antagonise GPR55 receptors (once thought to be the 3^rd cannabinoid receptor). GPR55 ligands are renowned for their limited brain uptake and cannabinoids offer great promise in the development of new brain penetrant GPR55 ligands for the treatment of epilepsy. Novel brain penetrant GPR55 ligands will be developed and then tested for their anticonvulsant efficacy in mouse models of epilepsy.

Research Team: Associate Professor Jonathon Arnold, Dr Samuel Banister, Dr Jia Lin Luo, Dr Marika Heblinski, Dr Lyndsey Anderson (Lambert Initiative, University of Sydney)