The Science

Background

Endocannabinoid System

The endocannabinoid system (ECS) is a neuromodulatory lipid signalling system (1). The ECS has several components including endogenous cannabinoids (termed endocannabinoids), G-protein coupled receptors (GPCR) termed cannabinoid receptor type 1 and 2 (CB1 and CB2 respectively) and enzymes responsible for the degradation and synthesis of the endocannabinoids (e.g. DAG lipase and NAPE) (2).

CB1 is the most abundant GPCR in the brain and is also highly expressed throughout the central nervous system (CNS). CB1 is expressed in virtually all peripheral tissues and subtypes, albeit at lower levels (3). In contrast, CB2 is predominantly expressed in immune tissues and cells, but is also present in neuronal and non-neuronal cells in the brain at low levels. CB2 has also been shown to be expressed in other peripheral tissues such as the gut and skeletal muscle (Figure 1) (4).

Figure 1: Schematic of the distribution of CB1 and CB2 receptors throughout the body. Figure modified from (5).

Anandamide (AEA) was the first endocannabinoid identified by Ralph Mechoulam’s group in pig brain (Figure 2) (6). Another endogenous cannabinoid, 2-Arachidonoylglycerol (2-AG), was subsequently identified (Figure 2) (7). These endocannabinoids were determined to be derived from the 20-carbon chain fatty acid precursor, arachidonic acid (8).

Figure 2: Chemical structures of the endocannabinoids, 2-Arachidonoylglycerol (2-AG) and Anandamide (AEA).

 

The ECS functions in the body to modulate appetite, pain processing, learning and memory (9). It has been hypothesized that the dysregulation of the ECS is potentially responsible for a plethora of human diseases including cancer, inflammatory bowel disease, as well as several neurodegenerative disorders, including multiple sclerosis (MS) and Huntington’s disease (10). With this in mind, the exogenous manipulation of the ECS with phyto or synthetically derived cannabinoids may have broad therapeutic applications. Considering the regulation of the ECS to promote homeostasis in the body, more research needs to be conducted to understand the long-term health effects that the exogenous administration of phyto-cannabinoids may have.

Medical and Therapeutic Benefits

Cannabinoid Compounds:

The first evidence for the medical use of cannabis dates back to approximately 5000 years ago, where plant extracts were used to ameliorate symptoms of pain and cramps. To date, the two must studied cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD). All of the cannabinoid formulations that currently have market approval for specific indications contain either one (or both) of these compounds, either plant derived or synthetic.

Cannabidiol (CBD)


Figure 3: Chemical structure of cannabidiol (CBD)

In contrast to THC, CBD is known to have low psychoactive potential (Figure 3). From a pharmacological perspective, CBD displays lower binding affinity for both CB1 and CB2 receptors, relative to THC. CBD has been shown to have affinity for several other receptor types such as transient receptor potential vanilloid 1 (TRPV-1), serotonin 1A receptor (5-HT1A) and G protein-coupled receptor 55 (GPR55) (11, 12).

Epidiolex® (developed by GW Pharmaceuticals), was the first FDA-approved CBD isolate formulation (with a CBD purity of at least 98 % (w/w)) and is used for the treatment of two rare and severe forms of childhood epilepsy; Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).

Tetrahydrocannabinol (THC)

THC is one of the main psychoactive compounds of the cannabis plant (Figure 4) (13).


Figure 4: Chemical structure of tetrahydrocannabinol (THC)

It has been shown to exert its psychoactive effect, mainly via the CB1 receptor. Currently, THC is undergoing clinical trials for a variety of indications including chronic non-cancer pain [NCT03215940], Tourette’s syndrome [NCT03247244], as well as the symptoms of Alzheimer’s disease [NCT02792257] and Parkinson’s disease [NCT03773796].

In addition, there is a growing body of preclinical evidence that THC may be effective in a wide range of indications including cancer and ALS (14, 15). However, further studies are required in these areas to validate the claims.

Nabilone (Cesamet™) and dronabinol (Marinol® and Syndros®) are synthetic forms of THC that are marketed for various indications including loss of appetite in patients with AIDS and nausea and vomiting in patients undergoing chemotherapy. In addition, Sativex® (CBD:THC oral mucosal spray) has been sold in almost 30 countries for the treatment of neuropathic pain, MS-related spasticity and cancer pain.

Other Cannabinoids

Aside from THC and CBD there are a wide range of cannabinoids with untapped potential, with very little research conducted on these compounds so far;

  • Cannabichromene (CBC)
  • Cannabidiol – Acid (CBDA): precursor for CBD
  • Cannabigerol – Acid (CBGA)
  • Cannabigerol (CBG)
  • Cannabinol (CBN)
  • Tetrahydrocannabinol – Acid (THCA): precursor for THC
  • Tetrahydrocannabivarin (THCV)

References

  1. Mouslech Z, Valla V. Endocannabinoid system: An overview of its potential in current medical practice. Neuro Endocrinol Lett. 2009;30(2):153-79.
  2. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-25.
  3. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389-462.
  4. Svízenská I, Dubový P, Sulcová A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review. Pharmacol Biochem Behav. 2008;90(4):501-11.
  5. Cannabinoid Pharmacology http://medipurepharmaceuticals.com: Medipure Pharmaceuticals; 2019 [Available from: http://medipurepharmaceuticals.com/physicians/cannabinoid-pharmacology.
  6. 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.
  7. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215(1):89-97.
  8. Rouzer CA, Marnett LJ. Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem Rev. 2011;111(10):5899-921.
  9. Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: an overview. Front Behav Neurosci. 2012;6:9.
  10. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease–successes and failures. FEBS J. 2013;280(9):1918-43.
  11. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.
  12. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.
  13. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147 Suppl 1:S163-71.
  14. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget. 2014;5(15):5852-72.
  15. Fernández-Ruiz J, Moro MA, Martínez-Orgado J. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics. 2015;12(4):793-806.