It is now well established that Delta9-THC is a cannabinoid CB1 and CB2 receptor partial agonist and that depending on the expression level and coupling efficiency of these receptors it will either activate them or block their activation by other cannabinoids. Further research is now required to establish in greater detail the extent to which the in vivo pharmacology of
Delta9-THC is shaped by these opposing actions both in healthy organisms, for example following a decrease in cannabinoid receptor density or signalling caused by prior cannabinoid administration, and in animal disease models or human disorders in which upward or downward changes in CB1/CB2 receptor expression, CB1/CB2-receptor-coupling efficiency and/or in endocannabinoid release onto CB1 or CB2 receptors have occurred in cells or tissues that mediate unwanted effects or determine syndrome/disease progression. The extent to which the balance between cannabinoid receptor agonism and antagonism following in vivo administration of Delta9-THC is influenced by the conversion of this cannabinoid into the more potent cannabinoid receptor agonist, 11-OH-Delta9-THC, also merits investigation.
Turning now to CBD, an important recent finding is that this cannabinoid displays unexpectedly high potency as a CB2 receptor antagonist and that this antagonism stems mainly from its ability to induce inverse agonism at this receptor and is, therefore, essentially non-competitive in nature. Evidence that CB2 receptor inverse agonism can ameliorate inflammation through inhibition of immune cell migration and that CBD can potently inhibit evoked immune cell migration in the Boyden chamber raises the possibility that CBD is a lead compound from which a selective and more potent CB2 receptor inverse agonist might be developed as a new class of anti-inflammatory agent. When exploring this possibility it will be important to establish the extent to which CBD modulates immune cell migration through other pharmacological mechanisms. There is also a need for further research directed at identifying the mechanisms by which CBD induces signs of inverse agonism not only in CB2-expressing cells but also in brain membranes and in the mouse isolated vas deferens.
Important recent findings with ?Delta9-THCV have been that it can induce both CB1 receptor antagonism in vivo and in vitro and signs of CB2 receptor activation in vitro at concentrations in the low nanomolar range. Further research is now required to establish whether this phytocannabinoid also behaves as a potent CB2 receptor agonist in vivo. Thus, a medicine that blocks CB1 receptors but activates CB2 receptors has potential for the management of certain disorders that include chronic liver disease and also obesity when this is associated with inflammation. The bases for the ligand and tissue dependency that Delta9-THCV displays as an antagonist of CB1/CB2 receptor agonists in vitro also warrant further research. In addition, in view of the structural similarity of Delta9-THCV to Delta9-THC, it will be important to determine the extent to which Delta9-THCV shares the ability of Delta9-THC, and indeed of CBD, to interact with pharmacological targets other than CB1 or CB2 receptors at concentrations in the nanomolar or low micromolar range. It will also be important to establish the extent to which CB1- and CB2-receptor-independent actions contribute to the overall in vivo pharmacology of each of these phytocannabinoids and give rise to differences between the in vivo pharmacology of Delta9-THC or Delta9-THCV and other cannabinoid receptor ligands such as CP55940, R-(+)-WIN55212 and SR141716A.
Finally, cannabis is a source not only of Delta9-THC, CBD and Delta9-THCV but also of at least 67 other phytocannabinoids and as such can be regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further preclinical and clinical research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove' (Mechoulam, 2005). As well as leading to a more complete exploitation of Delta9-THC and CBD as therapeutic agents and establishing the clinical potential of Delta9-THCV more clearly, such research should help to identify any other phytocannabinoids that have therapeutic applications per se or that constitute either prodrugs from which semisynthetic medicines might be manufactured or lead compounds from which wholly synthetic medicines might be developed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/
so it appears that THC AND CBD can be antagonists to binding CB1 AND CB2 receptor sites...which is news to me. they may also inhibit endogenous agonists re immune cell receptor.
Delta9-THC is shaped by these opposing actions both in healthy organisms, for example following a decrease in cannabinoid receptor density or signalling caused by prior cannabinoid administration, and in animal disease models or human disorders in which upward or downward changes in CB1/CB2 receptor expression, CB1/CB2-receptor-coupling efficiency and/or in endocannabinoid release onto CB1 or CB2 receptors have occurred in cells or tissues that mediate unwanted effects or determine syndrome/disease progression. The extent to which the balance between cannabinoid receptor agonism and antagonism following in vivo administration of Delta9-THC is influenced by the conversion of this cannabinoid into the more potent cannabinoid receptor agonist, 11-OH-Delta9-THC, also merits investigation.
Turning now to CBD, an important recent finding is that this cannabinoid displays unexpectedly high potency as a CB2 receptor antagonist and that this antagonism stems mainly from its ability to induce inverse agonism at this receptor and is, therefore, essentially non-competitive in nature. Evidence that CB2 receptor inverse agonism can ameliorate inflammation through inhibition of immune cell migration and that CBD can potently inhibit evoked immune cell migration in the Boyden chamber raises the possibility that CBD is a lead compound from which a selective and more potent CB2 receptor inverse agonist might be developed as a new class of anti-inflammatory agent. When exploring this possibility it will be important to establish the extent to which CBD modulates immune cell migration through other pharmacological mechanisms. There is also a need for further research directed at identifying the mechanisms by which CBD induces signs of inverse agonism not only in CB2-expressing cells but also in brain membranes and in the mouse isolated vas deferens.
Important recent findings with ?Delta9-THCV have been that it can induce both CB1 receptor antagonism in vivo and in vitro and signs of CB2 receptor activation in vitro at concentrations in the low nanomolar range. Further research is now required to establish whether this phytocannabinoid also behaves as a potent CB2 receptor agonist in vivo. Thus, a medicine that blocks CB1 receptors but activates CB2 receptors has potential for the management of certain disorders that include chronic liver disease and also obesity when this is associated with inflammation. The bases for the ligand and tissue dependency that Delta9-THCV displays as an antagonist of CB1/CB2 receptor agonists in vitro also warrant further research. In addition, in view of the structural similarity of Delta9-THCV to Delta9-THC, it will be important to determine the extent to which Delta9-THCV shares the ability of Delta9-THC, and indeed of CBD, to interact with pharmacological targets other than CB1 or CB2 receptors at concentrations in the nanomolar or low micromolar range. It will also be important to establish the extent to which CB1- and CB2-receptor-independent actions contribute to the overall in vivo pharmacology of each of these phytocannabinoids and give rise to differences between the in vivo pharmacology of Delta9-THC or Delta9-THCV and other cannabinoid receptor ligands such as CP55940, R-(+)-WIN55212 and SR141716A.
Finally, cannabis is a source not only of Delta9-THC, CBD and Delta9-THCV but also of at least 67 other phytocannabinoids and as such can be regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further preclinical and clinical research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove' (Mechoulam, 2005). As well as leading to a more complete exploitation of Delta9-THC and CBD as therapeutic agents and establishing the clinical potential of Delta9-THCV more clearly, such research should help to identify any other phytocannabinoids that have therapeutic applications per se or that constitute either prodrugs from which semisynthetic medicines might be manufactured or lead compounds from which wholly synthetic medicines might be developed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/
so it appears that THC AND CBD can be antagonists to binding CB1 AND CB2 receptor sites...which is news to me. they may also inhibit endogenous agonists re immune cell receptor.