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The Endocannabinoid System

picture of cannabis leaf caduceus

The endocannabinoid system (ECS) is a neuromodulating network found both in the central nervous system (brain, spinal cord) and in the peripheral nervous system in humans and other vertebrates.  The role of the ECS as a whole is to achieve balance in each part of the body such that no system (nervous system, cardiovascular system, immune system) is imbalanced/unstable and therefore causing detrimental physiologic effects.  It consists of cannabinoid receptors (CB1, CB2), endogenous cannabinoids (ECs) and enzymes (fatty acid amide hydrolase, [FAAH] and monacylglycerol lipase [MAGL]) which regulate the levels and activity of receptors and ECs as necessary to maintain a stable system (homeostasis).  Early work on the therapeutic effects of exogenous cannabinoids (CBs) derived from cannabis (THC, CBD etc.) led to the discovery of the endocannabinoid system.  This, in turn, led to the discovery of ECs that are naturally synthesized in the body as part of the ECS.

The known cannabinoid receptors CB1 and CB2 are G-protein coupled receptors (GPCRs) and function as cell transmembrane proteins.  These receptors detect molecules outside of the cell and, in turn, activate signal transduction pathways inside the cell and ultimately cellular responses.  Thus, molecules (ECs, CBs) outside of the cell that are capable of binding to these receptors can influence cellular responses as a result.  Approximately one-third of all modern medicinal drugs target GPCRs, and therefore molecules that bind these receptors possess potential therapeutic value (Hauser, A. S.; Attwood, M. M.; Rask-Andersen, M.; Schiöth, H. B.; Gloriam, D. E. Nature Reviews. Drug Discovery 2017, 16, 829–842).  CB1 and CB2 receptors are widely distributed throughout the body as shown below.  CB1 is primarily expressed in the brain but is also found in the lungs, liver, and kidneys and is involved in retrograde signaling (feedback mechanism) to achieve balance in neurotransmission at nerve synapses.  CB2 is primarily expressed in the immune system (T cells, stem cells) and in the peripheral nervous system where it plays a role in antinociception (relief of pain).         

Endogenous cannabinoids (ECs) are small molecules synthesized by the endocannabinoid system (ECS) which are responsible for feedback mechanisms in various types of cells to achieve balance (homeostasis).  The chemical structures of 5 of the most prominent ECs known to date are shown below.  Each of these naturally occurring ECs binds CB1 and/or CB2 to varying degrees and thus modulates the cellular responses associated with these receptors.   Two of the most well-studied ECs are anandamide (AEA, the “bliss molecule”) and 2-arachidonoylglycerol (2-AG).  AEA binds selectively to CB1 with high affinity and is a partial agonist of this receptor.  Alternatively, 2-AG is a full agonist for CB1 and CB2 but binds these receptors with moderate affinity.  Together, these ECs function to achieve homeostasis through modulation of cellular signals throughout the body.  The ECS is ubiquitous in the body and is involved in many crucial functions including regulation of body temperature, serum pH, modulation of stress, pain, appetite, inflammation, motor coordination, hormone levels, heart rate, response to presence of toxins, memory, pleasure/reward, sleep, mood etc.    

Crystal structure of human CB1 receptor (purple ribbon) bound to a synthetic antagonist in yellow (Hua, T.; Vemuri, K.; Pu, M.; Qu, L.; Han, G.W.; Wu, Y.; Zhao, S.; Shui, W.; Li, S.; Korde, A.; Laprairie, R.B.; Stahl, E.L.; Ho, J.H.; Zvonok, N.; Zhou, H.; Kufareva, I.; Wu, B.; Zhao, Q.; Hanson, M.A.; Bohn, L.M.; Makriyannis, A.; Stevens, R.C.; Liu, Z.J. Cell 2016, 167, 750-762)

Structure of Endogenous Cannabinoids (ECs)

Parent 19-carbon chain

Differentiating R group

EC name

Anandamide (AEA)

2-Arachidonoylglycerol (2-AG)

Noladin ether



For an elegant visual description of the human endocannabinoid system (ECS) and how exogenous CBs (e.g. CBD) interact with the ECS to provide potent therapeutic effects and wellness benefits, please click here.  It’s one of the best visuals we’ve seen!  For a layman’s terms explanation of the ECS and how exogenous CBs can provide powerful therapeutic benefits on a systems level (not a symptoms level), click here.  

Therapeutic Potential of CBs

Given the multi-faceted role of the ECS in regulating numerous parameters to achieve homeostasis in biological organisms, it is not surprising that a plethora of research continues toward understanding the role of naturally-occurring cannabinoids (CBs) targeting ECS receptors and their potential therapeutic effects toward numerous ailments and disease conditions (Pertwee, R. G. Phil. Trans. R. Soc. B 2012, 367, 3353-3363; Kaur, R.; Ambwani, S. R.; Singh, S. Curr. Clin. Pharmacol. 2016, 11, 110-117).  

There are currently 4 medicines in clinic that activate (are agonists of) CB1 and CB2 receptors of the ECS.  Nabilone (a synthetic cannabinoid that mimics THC) is indicated for chemotherapy-induced nausea/vomiting (CINV) and offers modest relief of fibromyalgia and multiple sclerosis symptoms.  Dronabinol (delta 9-THC) is indicated for HIV/AIDS induced anorexia and for CINV.  Sativex (mixture of delta 9-THC and CBD) is indicated for non-controllable pain in cancer patients and for neuropathic pain and spasticity in MS patients.  Epidiolex (pure CBD) is indicated for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome in children.

It has been proposed that subjective pain syndromes such as migraines, fibromyalgia, irritable bowel syndrome (IBS), and post traumatic stress disorder (PTSD) which lack objective signs and are resistant to traditional therapeutic treatments may be attributable to an endocannabinoid deficiency, as the ECS mediates symptoms of these conditions and exogenous CBs have provided symptomatic benefit for these conditions (Russo, E. B. Cannabis Cannabinoid Res. 2016, 1, 154-165).   

Future research on cannabinoid receptor agonists will likely focus on additional potential therapeutic applications of CBs for pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders.  Additionally, research efforts will likely focus on improving efficacy through the development of strategies for the selective targeting of cannabinoid receptors outside the blood brain barrier, in particular types of tissue, and those receptors that are upregulated (McPartland, J. M.; Guy, G. W.; Di Marzo, V. PLoS One 2014, 9, e89566).  

 FDA Disclaimer


**These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.**

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