How cannabinoids work

Publication: https://www.biorxiv.org/content/10.1101/569079v1

The ‘entourage effect’ is the notion that the pharmacological effects of cannabis are greater than the sum of individual cannabis chemical components. This project examines some possible pharmacological mechanisms responsible for the entourage effect. In this study, we assessed cannabinoid and terpenoid synergy through their interactions with cannabinoid CB1 and CB2 receptors as well as transient receptor potential (TRP) channels. We assessed whether various terpenoids enhance the actions of THC, CBD and endocannabinoids at these drug targets. This might provide a firmer rationale for undertaking human studies that clearly verify the existence of the entourage effect. 

Results: Our first study in this area of research showed that the terpenes b-myrcene, linalool, b-caryophylllene, ⍺-Pinene, b-Pinene and limonene do not modulate the actions of THC at cannabinoid CB1 and CB2 receptors. However, this is not a definitive rebuttal of the entourage effect. There are many other ways that these molecules could interact with cannabinoids to influence the overall therapeutic and subjective outcomes of cannabis administration. So the quest for entourage does not end here; in many ways it has only just begun!

This was a collaboration between the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney and Macquarie University.

Research Team: Professor Mark Connor, Dr Marina Santiago (Macquarie University); Professor Iain McGregor, Associate Professor Jonathon Arnold (Lambert Initiative, University of Sydney)

In this project we are screening a wide range of cannabinoids for activity against 241 G protein-coupled receptors (GPCRs) and then conducting subsequent follow-up validation to confirm any hits of interest. GPCRs are one of the most important targets for therapeutic compounds and there has been surprisingly little systematic examination of cannabinoid activities at GPCRs. This project will provide the most comprehensive and systematic functional screen of cannabinoids at GPCRs ever conducted.  This information will not only provide us with insights into mechanisms potentially driving known therapeutic activities of cannabinoids, but will also help us to identify potential new indications to explore.

Research Team: Dr Michael Bowen (Lambert Initiative, University of Sydney)

Despite the potential of cannabinoids to treat a broad range of diseases, the mechanisms driving many of their therapeutic actions remains largely a mystery. In this project we are using state-of-the-art supercomputing, computational chemistry, and biophysics to better understand how cannabinoids work. We are using these techniques to identify novel biological targets for cannabinoids, which will help us to be able to better predict which therapeutic indications specific cannabinoid compounds are more suited to treating particular disorders. These techniques are also being deployed to discover exactly where cannabinoids are binding at specific targets at the brain at the atomic scale, which will help guide us in tweaking their chemical structures to optimise binding at these sites, potentially unlocking new, even more effective classes of cannabinoid-based compounds for a range of disorders.

Research Team: Dr Michael Bowen, Dr Lewis Martin (Lambert Initiative, University of Sydney)

Neuromuscular junction disorders, such as myasthenia gravis and Lambert-Eaton myasthenic syndrome, are a class of diseases where normal signaling between nerve and muscle is disrupted resulting in severe muscle weakness and impacted quality of life. Current drugs used to treat these conditions have debilitating side-effects such as nausea, vomiting, abdominal cramping, and diarrhea. A recent finding suggests that several cannabinoids improve neuromuscular junction signaling by an entirely new mechanism. This project is focused on the development of new cannabinoids selectively targeting the neuromuscular junction, offering the possibility of new treatments for myasthenia gravis and Lambert-Eaton myasthenic syndrome with greatly improved tolerability.

Research Team: Associate Professor William Philips, Associate Professor Stephen Reddel, Dr Dengyun (Gordon) Ge (University of Sydney); Dr Samuel Banister, Dr Jia Lin Luo, Dr Marika Heblinski (Lambert Initiative, University of Sydney).