Mechanism of Action

Cannabinoids in General

For a more comprehensive guide to all cannabinoids, their potential therapeutic targets and the mechanisms by which they are thought to operate please visit our R&D mechanism of action section by clicking here.

Sativex

The way in which cannabinoids such as THC exert their effects on the human body is known as their “mechanism of action”. This has recently become clearer with the discovery of two cannabinoid receptors CB1 and CB2 together with that of a chemical called “anandamide”. Anandamide is an endogenous ligand, which literally means that it occurs naturally within the body (endogenous) and is a binding agent or “ligand”. The full name of anandamide is arachidonoyl ethanolamide but it was nicknamed anandamide after the Sanskrit word for bliss “ananda”ⁱ . Anandamide has its effect by inhibiting cyclic AMP (part of the cellular energy gerneration process), through G-protein coupling in target cells, which cluster in areas of the central nervous system that mediate painⁱⁱ , memoryⁱⁱⁱ , and other key functions.

Preliminary tests of pharmacology and behavioural activity support the similarity of anandamide to THC^iv . Both anandamide and THC bind weakly to the cannabinoid type one (CB1) receptors, which are found in the brain and are called partial agonists^v,vi.In contrast, cannabidiol (CBD) has little activity at CB1 but greater activity at the cannabinoid type 2 receptors (CB2) that are mostly located in the periphery, in lymphoid tissues^v. CB1 receptor distribution and THC binding affinity at CB1 differ between humans and rodents, which underscores the importance of conducting human clinical trials^vii. Both THC and CBD are neuroprotective antioxidants that have been shown to inhibit NMDA-mediated excitotoxicity under conditions of traumatic head injury, stroke and degenerative brain diseases^viii.

The discovery of the endocannabinoid system^viii has provided new insights into a neuromodulatory scheme that may provide better explanations of, and treatments for, a wide variety of previously poorly treatable, often painful disorders^vi,x.

It has recently been demonstrated that CBD also stimulates vanilloid pain receptors (VR1), inhibits uptake of the anandamide, and weakly inhibits its breakdown^xi. These new findings have important implications in elucidating the pain-relieving, anti-inflammatory, and immunodulatory effects of CBD.

The combination of THC, CBD and essential oils in cannabis-based medicinal extracts may produce a therapeutic preparation whose benefits are greater than the sum of its parts^xii.

References

i. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258(5090):1946-9.

ii. Herkenham MA. Localization of cannabinoid receptors in brain: relationship to motor and reward systems. In: Korman SG, Barchas JD, editors. Biological Basis of Substance Abuse. London: Oxford University; 1993. p. 187-200.

iii. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002;418(6897):530-4.

iv. Fride E, Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 1993;231(2):313-4.

v. Showalter VM, Compton DR, Martin BR, Abood ME. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 1996;278(3):989-99.

vi. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001;63(5):569-611.

vii. McPartland JM, Glass M, Pertwee RG. 2007. Meta-analysis of cannabinoid ligand binding affinity and cannabinoid receptordistribution: interspecies differences.  British Journal of Pharmacology 152:583-589.

viii. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998;95(14):8268-73.

ix. Di Marzo V. 'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim Biophys Acta 1998;1392(2-3):153-75.

x. Russo EB. Role of cannabis and cannabinoids in pain management. In: Weiner RS, editor. Pain management: A practical guide for clinicians. 6th ed. Boca Raton, FL: CRC Press; 2002. p. 357-375.

xi. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;134(4):845-52.

xii. McPartland JM, Russo EB. Cannabis and cannabis extracts: Greater than the sum of their parts? Journal of Cannabis Therapeutics 2001;1(3-4):103-132.