The Endocannabinoid System

By Dr Nicola Davies


The isolation of plant-based cannabinoids in the 1960s led scientists to investigate the mechanisms by which these chemical compounds interact with the brain’s neurons (or nerve cells).[1] Indeed, the lipid Δ9-tetrahydrocannabinol (THC), was different from other water-soluble neurotransmitters or neuromodulators known at that time, and the hypotheses was that the psychotropic effects of THC were made through membrane-related features.[2] However, it became clear that cannabinoids did indeed work through receptors, when, in 1988, a cannabinoid receptor was identified in a rat brain.[3] In the following decades further exploration was made on the constituents of the body’s own cannabinoid system.


Components of the Endocannabinoid System

The endogenous cannabinoid system (ECS) includes the cannabinoid receptors, endocannabinoids (eCBs), and enzymes (such as fatty acid amide hydrolase) that synthesize and degrade the endocannabinoids.[4],[5]


CB1 and CB2: The Body’s Cannabinoid Receptors:

The first endogenous cannabinoid receptor, CB1, was successfully cloned in 1990,[6] while the second one, CB2, was identified in the spleen and cloned in 1993.[7] Both receptors are part of the supergroup of G-protein-coupled receptors (GPCRs), which are a large and diverse set of membrane receptors that respond to a wide range of external signals, making them essential in regulating numerous bodily functions.[8],[9] Modern medicine has benefited from the more in-depth understanding of GPCRs, with some researchers estimating that up to half of marketed drugs work by binding to these receptors.[10]

The CB1 receptor was initially believed to be present primarily in the central nervous system and was known as a brain cannabinoid receptor. Currently, it is believed that CB1 is also found in peripheral organs, but only in very low levels in some places. In the brain, CB1 is the most common GPCR, with the highest concentrations (as seen in the brain of a rat) in the basal ganglia, hippocampus, cerebellum, substantia nigra, and globus pallidus. These receptors are believed to have an essential role in cognition and motivation, consistent with the high densities of CB1 in parts of the brain that govern sensory and motor functions.[11]

On the other hand, CB2 receptors were previously thought of as the peripheral receptor because it was mainly found in immune cells, but the second type of receptor has also been found within the central nervous system, although at lower densities compared to CB1. It has been proposed that CB2 is part of a general protective mechanism within the immune system of mammals. Subsequently, drugs that act by binding to CB2 are being explored for some diseases, such as liver, cardiovascular and neuropsychiatric conditions.[12],[13]


AEA and 2-AG: The Body’s Natural Cannabinoids:

The discovery of a network of cannabinoid receptors, activated by the plant-based THC (an exocannabinoid), suggested the possibility of naturally occurring lipid molecules (endocannabinoids, or eCBs) also being present inside mammals’ bodies. Since THC is lipophilic (or soluble in fat), the assumption was that endogenous cannabinoids would be lipophilic as well.[14],[15] Soon after the cloning of the cannabinoid receptors, two lipid neurotransmitters were discovered, namely, N-arachidonoylethanolamine or AEA (which is also known as anandamide, named after the Sanskrit word ananda, meaning “supreme joy”) and 2-arachidonoylglycerol, or 2-AG.[16]

AEA and 2-AG differ from other neurotransmitters, like serotonin and dopamine, in that they are not stored within nerve cells, but are created by the body as and where they are needed. The eCBs are also unlike many neurotransmitters in that their actions are pre-synaptic instead of postsynaptic. This means that the eCBs’ chemical messages are sent “backwards” through the network of neurons. Normally, most neurotransmitters are released from one neuron (the presynaptic cell), travel through a gap called the synapse, and bind to receptors on a neighboring neuron (the postsynaptic cell); it is the activated postsynaptic neuron which then starts the events that allow the chemical “message” to be spread. On the other hand, eCBs are created “on demand” from fat cells within an activated postsynaptic neuron, and travel back to the presynaptic neuron, where they bind to cannabinoid receptors.[17],[18],[19]


Enzymes in the ECS:

In the cell, eCBs are broken down by enzymes. Fatty acid amide hydrolase (FAAH) is responsible for breaking down AEA into arachidonic acid and ethanolamine. In addition, 2-AG is broken down by FAAH and monoacyl hydrolase. Endocannabinoids are quickly removed from the cell by a membrane transport mechanism that still needs to be further investigated. When these enzymes are suppressed, the effect of eCBs is prolonged.[20]


The Importance of Understanding the Endocannabinoid System

The ECS is now widely believed to be responsible for regulating a wide range of bodily functions. It is essential for the normal operation of the central and peripheral nervous system, and has a part in the regulation of pain, chronic stress, blood pressure, and gastrointestinal activities. It also plays an important role in cancer therapy, obesity management, reproduction, liver disease management, and numerous other health conditions.[21] Recently, eCBs have also been shown to be responsible for modulating affect (mood), motivation and emotions. Drugs targeting the ECS are being explored in the field of psychiatric disorders.[22]

Further research, however, is needed to gain more in-depth understanding of the complex mechanisms of this system. For instance, a third cannabinoid receptor has been hypothesized by researchers,[23] although its existence is yet to be fully demonstrated. Another example of a function of the ECS that requires more research is the membrane transport mechanism that is believed to remove eCBs from the cells.[24]

Unfortunately, cannabis research still faces numerous barriers and challenges. In a January 2017 report on the state of marijuana research, the National Academies of Sciences, Engineering and Medicine identified several obstacles. One of these is the lack of funding and support for the development of a national cannabis research agenda. Other challenges include the difficulty of obtaining a large enough supply of cannabis for scientific investigation, as well as securing approval to conduct studies. The drug is highly regulated by government agencies, since it is classified as a Schedule I substance. Additionally, a more rigorous set of tools and standards for research must be formulated by the cannabis-focused scientific community. Data collection methods, as well as public surveillance tools (such as national health surveys), are also in need of improvement.[25]

There is a necessity to address these barriers as they are impeding the advancement of evidence-based knowledge on cannabis and the endocannabinoid system. The emerging importance of the ECS is already being seen. The capability to identify the potential ways of modulating its components could lead to the future development of a wide array of therapeutic innovations. The investigation of this important system will aid the public in understanding the numerous medicinal claims for cannabinoid-related products, as well as gain more objective insights into the potential dangers or benefits of cannabis. ♦


[1] Gaoni, Y., & Mechoulam, R. (1964). Isolation, structure and partial synthesis of an active constituent of Hashish. Journal of the American Chemical Society, 86, 1646–1647

[2] Alger, B. E. (2013). Getting high on the endocannabinoid system. Cerebrum: The Dana Forum on Brain Science2013, 14

[3] Devane, W. A., Dysarz, F. A. 3rd, Johnson, M., Melvin, L. S. and Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology, 34, 605–613

[4] Pazos M.R., Núñez, E., Benito, C., Tolón, R.M., Romero, J. (2005). Functional neuroanatomy of the endocannabinoid system. Pharmacology Biochemistry and Behavior, 81 (2), 239–47DOI:10.1016/j.pbb.2005.01.030

[5] Murillo-Rodriguez, E. (Ed.) (2017). The endocannabinoid system: genetics, biochemistry, brain disorders, and therapy. London: Academic Press.

[6] Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564

[7] Munro S., Thomas, K.L., Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365, 61–65

[8] Mechoulam, R. & Parker, L. (2013). The endocannabinoid system and the brain. Annual Review of Psychology, 2013, 64, 21-47. DOI:10.1146/annurev-psych-113011-143739

[9] Scitable. (n.d.). GPCR. Retrieved from

[10] Ibid.

[11] Mechoulam, R. & Parker, L. (2013)

[12] Ibid.

[13] Cota, D., Marsicano, G., Lutz, B., Vicennati, V., Stalla, G.K., Pasquali, R., & Pagotto, U. (2003). Endogenous cannabinoid system as a modulator of food intake. International Journal of Obesity, 27, 289-301. DOI:10.1038/sj.ijo.0802250


[14] Alger, B. E. (2013)


[15] Mechoulam, R. & Parker, L. (2013)


[16] Ibid.


[17] Ibid.


[18] Howlett A.C., Barth F., Bonner T.I., Cabral G., Casellas P., Devane W.A., Felder C.C., Herkenham M., Mackie, K., Martin, B.R., Mechoulam, R., & Pertwee, R.G. (2002). International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacological Reviews, 54, 161–202. Retrieved from


[19] National Institute on Drug Abuse. (2011). The science of the endocannabinoid system: how THC affects the brain and the body. Retrieved from


[20] Mechoulam, R. & Parker, L. (2013)


[21] Griffing, G. & Thai, A. (2015). Endocannabinoids. Retrieved from


[22] Campolongo, P., & Trezza, V. (2012). The endocannabinoid system: a key modulator of emotions and cognition. Frontiers in Behavioral Neuroscience, 6, 73. DOI:10.3389/fnbeh.2012.00073


[23] Samson, M., Small-Howard, A., Shimoda, L., Koblan-Huberson, M., Stokes, A., & Turner, H. (2003). Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. The Journal of Immunology, 170 (10), 4953-4962. DOI:10.4049/jimmunol.170.10.4953


[24] Mechoulam, R. & Parker, L. (2013)


[25] National Academies of Sciences, Engineering, and Medicine. (2017). The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. DOI:10.17226/24625


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