The dispute caused by the relatively recent surge in cannabis-related science (and pseudo-science) is one of the hottest topics of the 21st century, with many ramifications – from regulation and law to biochemistry and psychiatry. If you have brushed against any manifestation of this phenomena, there is a safe bet that you have come across the term “endocannabinoid system.” Many of the disputes around cannabis (and cannabinoids) would probably be settled if the intricacies of this system would be better understood, and if a minimum of consensus would exist within the academic community. The current state of affairs is, in our opinion, detrimental to everyone – scientists argue over the probity of each other’s studies, while the layman is more or less in the dark about if and how cannabis-related products are beneficial. In this article, we will try to provide an in-depth, yet terminologically accessible and eye-opening description of the endocannabinoid system, the biological structure responsible for the manner in which cannabinoids influence our bodies and minds. Just as no-one would dare to explain how a blood pressure medication works without a basic comprehension of the circulatory system, the same is true for cannabis, derived products, and the endocannabinoid system. We will start by painting a general picture of this entity (along with a bit of history, which partly explains the current under-researched state), then we will proceed to an analysis of its components, ending with the system’s possible impact on major physiological and psychological human functions.

The Endocannabinoid System – Overview

The modern history of cannabis-related studies began in 1964, with the chemical isolation of tetrahydrocannabinol  (chemical designation – Δ – 9 – tetrahydrocannabinol, or THC for short), the substance responsible for the psychoactive effects of marijuana consumption (botanical name – Cannabis sativa). Nowadays, the scientific community considers THC as a phytocannabinoid – a cannabinoid of vegetal origin.[1] In the wake of this discovery, scientists aimed to find out the exact pathways through which THC produced its physical and, particularly mental effects on the human body. This research trend led to the discovery of the endocannabinoid system (ECS for short, meaning self-produced or “endogenous” + “cannabinoid”) in the early 1990’s. Since this breakthrough, it has been argued that all vertebrates have such a system, with its influence being especially evident in mammals.[2] It is speculated that the endocannabinoid system’s influence is far-reaching, which should come as no surprise because experts have certified the existence of cannabinoid receptors in the nervous system (both central and peripheral), while also playing a part in the body’s immune function. Nevertheless, the social stigma associated even with just the allusion to cannabis has perpetuated the current under-researched state and may impede future efforts. At its most basic (cellular and tissue) level, the function of the endocannabinoid system (through its primary components – complex fatty acids, transformed by enzymes, which perform their roles when they get attached to cannabinoid receptors) is neuromodulation. Cannabinoids are thus an integral part of the system and, naturally, the types of cannabinoids and their concentration, influence the workings of the whole. Cannabinoids are usually classified into two groups: endocannabinoids (internally produced through the animal’s metabolism) and other cannabinoids (which can be phytocannabinoids such as THC and even synthetic cannabinoids like cannabicyclohexanol). Neuromodulation is a particular process consisting of chemical signals a nervous cell emits and has the possibility of regulating other such cells, be it one or even large numbers of neurons. Neuromodulation is one of several “methods of communication” between neurons. It is different than your schematic “middle-school biology lesson” synapse communication, where two neurons are linked through the small synaptic pathway. Neuromodulation is more of a diffuse and indirect means of communication. One could envisage the difference between interpersonal communication and mediated communication. Cannabinoids are but one of a number of substances classified as neuromodulators. With their localization, function, and effects not quite well understood yet, they are far less known than the major neuromodulators in the central nervous system such as serotonin, norepinephrine or dopamine. That being said, every (conscientious) high school student knows that elevated levels of serotonin aid sleep and that marijuana does so as well. Cannabinoids, in the tissues where enough receptors are located, are thought to work in concert with other neuromodulators by providing the “feedback” from the stimulated groups of neurons to the group that had provided the chemical stimulation, thus regulating future cellular behavior. You will often hear that the endocannabinoid’s system goal is homeostasis. This statement is a bit tautological as all the systems in our body (in case they are functioning properly) are designed to achieve homeostasis – more of a philosophical concept than a biological notion. Before moving on to the next section, it is useful to consider as an example the scenario in which homeostasis is lost, through the action of the strong cannabinoid tetrahydrocannabinol in the areas of the central nervous system where many cannabinoid receptors are located:

  • Spinal Cord – acting as the intermediary between the brain and the rest of the body – THC presence chiefly alters the perception of pain.
  • Nucleus Accumbens – though at least eight other neurotransmitters are affecting this part of the brain because it plays a major role in motivational salience, the euphoria caused by THC comes from modifications in each cerebral hemisphere’s nucleus accumbens.
  • Neocortex – the section which enables complex, distinctly human cognition, it leads to the characteristic poor judgment when under the influence of tetrahydrocannabinol.
  • Hypothalamus – reverting to more “animalistic” functions, THC’s actions on the hypothalamus lead to the often reported increase in appetite, but can also result in the anti-emetic properties of marijuana.
  • Hippocampus – presiding over short-term and spatial memory, explains the memory impairment associated with THC.
  • Cerebellum – explains why you should not drive under the influence.
  • Brainstem – linking the brain and the spine and responsible for many involuntary behaviors accounts for the anti-nauseating consequences of THC.
https://www.youtube.com/watch?v=PZYjJf0t2OQ

The Constituents of the Endocannabinoid System

A Glance at Endocannabinoids

The presence of cannabinoids elicits signals from the cannabinoids receptors in cells so that certain physiological processes can be regulated. This sequence is not unique to the functioning of the endocannabinoid system. In fact, it is only a particular manifestation of a general mechanism in biochemistry. Most biological responses are initiated through the action of ligands. By and large, biochemical processes have three components: a biomolecule that exists around a binding site (usually a complex protein), the protein itself, and another (somewhat foreign) substance that binds itself to the surface of the protein and forms another (more complex) biomolecule with the initial one, called the ligand. Ligands which act on nervous receptors and have the ability to signal important physiological changes are called agonists, a designation which is often encountered in pharmacology. Because endocannabinoids do not regulate physiological processes to a visible degree, they are often called non-classical neuromodulators, functioning as internal ligands for the cannabinoid receptors. It is widely believed that the body produces many compounds that act on the receptors, yet as there have been only two properly studied receptors, we only know of two properly studied endocannabinoids – anandamide and 2-arachidonoyl-glycerol.

Anandamide

Formally N-arachidonoylethanolamide (AEA, for short), acts as a ligand, not just for receptors in the ECS but is thought to stimulate other receptors along the central and peripheral nervous systems. An organic amide (one of the simplest chemical compounds found both in nature and in synthetic substances), anandamide is a derivative of the arachidonic acid, and (in the biochemical sequence) is transformed by the action of amide hydrolase enzyme (more on that later). In the initial stages of research into the endocannabinoid system, anandamide was thought to affect just a single type of cannabinoid receptor (the CB1 type). However, more recent studies discovered a wider-ranging action of AEA.[3] The role anandamide plays in the endocannabinoid system, as a ligand for the cannabinoid receptors, could explain the position of those who propose endocannabinoid deficiency as a bona fide medical condition. The precursor of AEA, arachidonic acid is one type of omega-6 fatty acid and serves as the building block for numerous biochemical compounds necessary for the correct functioning of the liver, brain, and muscle tissue. The metabolism of most animals produces arachidonic acid through the synthesis of linoleic acid, widespread in foods of both animal and plant origin. However, many species of mammals lack this characteristic. Therefore the necessary amount of arachidonic acid can only be obtained from foods of animal origin.[4] To conclude, a diet poor in meat, eggs or dairy products could lead to reduced anandamide synthesis causing decreased neuromodulation from the abnormal activity of the cannabinoid receptors. Nevertheless, there is a long road to asserting that this deficiency should be addressed through the administration of (Exo)cannabinoids.

2-Arachidonoylglycerol

(2-AG) is a substance that has much in common with anandamide. Their precursor is arachidonic acid (with the added contribution of glycerol in the case of 2-AG), yet there are also important differences. The fact that it has been far less researched than anandamide should also be taken into consideration. The current consensus is that 2-AG, in the context of the endocannabinoid system, is the chief internally produced compound that acts as an agonist for the CB1 cannabinoid receptor only. Studies on rodents revealed that 2-AG is one of the most common molecules present in the central nervous system. Therefore its importance is still being assessed. For 2-Arachidonoylglycerol to bind to the CB1 receptor, there needs to be a substantial growth in the concentration of calcium, meaning that 2-AG has a much more sophisticated sequence of formation, action, and degradation than anandamide. Its actions need the presence of the enzymes phospholipase and diacylglycerol lipase to provide the necessary local increase in calcium levels. 2-AG is degraded by two other glycerol-based lipases.[5]

Enzymes in the ECS and Endocannabinoid Enhancers

Enzymes are biological compounds which possess the property to accelerate biochemical reactions, being present in almost all complex organisms. Naturally, numerous enzymes play a part in the regulation of one (or more) physiological and psychological processes. The same goes for the actions of the endocannabinoid system, yet because of its relative novelty among researchers, only two enzymes have captured the limelight – anandamide amidohydrolase (fatty acid amide hydrolase being its official designation or FAHH) and monoacylglycerol lipase (MAGL, for short). FAHH is involved in the transformation of many other amide-based compounds. Cannabis-related research shows that the inability to degrade anandamide (either through a higher concentration of anandamide or an inability to produce FAHH) leads to a significantly reduced perception of pain in rodents, without serious side effects. Consequently, FAHH could be an important future direction for analgesic medication. Monoacylglycerol lipase works alongside other enzymes from its class to degrade monoacylglycerol (complex substances found in both animal and vegetable fat) into the basic fatty acid and the remaining glycerol molecule. Again, studies on rodents presenting chronic disturbances in monoacylglycerol production unearthed dramatic high levels of 2-arachidonoyl-glycerol explaining the similarly dramatic behavioral shifts in the subjects. Powerful modifications in the endocannabinoid system are not usually possible. They can be achieved through the actions of certain phytocannabinoids (as discussed in the case of THC) or through the manipulation of enzymes mentioned above. Substances that inhibit the functioning of these enzymes (scientifically called FAHH and MAGL inhibitors) are part of a larger class of substances called endocannabinoid enhancers. Obviously, there is no definite list of these enhancers, but one “everyday” example is the active compound in the paracetamol drug. Known as AM404, it (temporarily) slows the production of FAHH, leading to higher anandamide concentrations, and thus to pain relief.

The Cannabinoid Receptors

Cannabinoid receptors are part of cell membranes and considered to be part of the class known as G protein-coupled receptors. All receptors in this class follow the sequence described in the previous sections – after detecting the presence of an outside molecule, they trigger responses in the cell (or a whole group of cells). These receptors are also designated as 7TM (trans-membrane) receptors, owing to the number of times they pass through the cellular membrane. The importance this type of receptors has for the smooth functioning of the human body cannot be understated, with as many as 40 percents of current medication targeting some sub-type of G protein-coupled receptors. As is the case with the endocannabinoid system as a whole, the types of cannabinoid receptors and their inner workings are still very much a mystery. Here is a brief description of the two, fairly well-understood, cannabinoid receptors. Cannabinoid receptor type 1 (CB1), at the cellular level, produces a decrease in the amount of cAMP (cyclic adenosine monophosphate, one of the most important messengers involved in all biological processes of multicellular organisms), when activated. The density of CB1 receptors is at its highest in the brain, and to a lesser extent in the spine and adrenal, pituitary, and thyroid glands. The example cited in the first section of this article (involving the effects of tetrahydrocannabinol on the nervous system) is a byproduct of research involving the relationship between the cannabinoid and CB1 type receptors. Cannabinoid receptor type 2 (CB2) is quite similar in composition and structure to CB1 being made up of the same amino acids in a proportion of almost 70 percent. Knowledge of the CB2 receptor is not quite to the same standard as that of type 1. Initial hypotheses excluded the existence of these receptors in the nervous system, believing them to be restricted to the immune system. Nevertheless, more recent studies acknowledged that the largest concentration of CB2 receptors is indeed in spleen and thymus gland, with a smaller (but not insignificant) presence in other areas throughout the body – chiefly the brainstem, hippocampus, and the GI tract. Because many early investigations on the endocannabinoid system focused almost solely on the influence THC consumption has on it, the evidence of CB2 type receptors and their neuromodulating consequences was much lighter, compared with the first cannabinoid receptor discovered.

Major Biological Processes Influenced by the Endocannabinoid System

In the previous section, we learned that the major components of the endocannabinoid system exist in almost every tissue in the mammalian body. Therefore it is evident that it influences many biological processes (both physiological and psychological).[6] Closely detailing ECS’s action in each context is beyond the scope of this article, but a quick review of these processes may be useful for readers who wish to delve deeper into the more sophisticated aspects of the endocannabinoid system:

  • Memory and Mood – these markedly different aspects of the neurological function are often discussed together to indicate the scope (and unpredictability) of the influence exercised by the endocannabinoid system. The departure point was the anecdotal evidence of short-term memory impairment associated with the smoking of cannabis.

Serious, peer-reviews studies on rodents using a synthetic cannabinoid acting on CB1 receptors over a medium term resulted in serious spatial memory dysfunction, coupled with a steady elevation in overall mood. More complex memories were not taken into account. The researchers explained the elevated mood through abnormal neural growth in the hippocampus region of the central nervous system, yet the memory deterioration could not be accounted for through other observable changes.

  • Appetite – the endocannabinoid system clearly plays an important part in the brain reward mechanism associated with certain physiological acts, though this has been demonstrated chiefly through indirect methods. Both anandamide and 2-arachidonoyl-glycerol tend to increase dopamine levels in neighboring cells (remember the “diffuse” manner of action in the case of the ECS), during and immediately after so-called “pleasurable acts.” Furthermore, mice whose CB1 receptors were chemically disabled in infancy tend to become much thinner adults compared to the general population.
  • Metabolism – again, indirect evidence points to the endocannabinoid system regulating (to a degree) the metabolism through the ubiquity of CB2 receptors in specialized cells like hepatocytes and adipocytes, and in tissues associated with metabolism and the immune function (such as the pancreas and the small intestine). The implications of the exact mechanism of action are huge, potentially shedding further light into complex metabolic diseases like atherosclerosis and diabetes.
  • Immune System – the same goes for CB2 receptors and the immune function. However, there is another hypothesis among cutting-edge cannabis researchers. By analogy with the role of neuromodulator, (endo)cannabinoids expressed through CB2 type receptors may act as immunomodulators, and play a key role in at least two significant areas – inflammation and spasmodic disorders.
  • Sleep – the altering of sleep patterns by endocannabinoids is suggested through both direct and indirect methods. Increased endocannabinoid signaling has been linked with a reduction in waking hours. In rodent studies, the growth of anandamide levels saw an extension of sleep time well into the normal waking hours of mice.
The list could go on and on. Suggestions, clues, and in vitro experiments, however, do not compensate for serious, preferably human studies. These allusions and links indeed prove that there is infinitely more to the endocannabinoid system than what we have (modestly) covered in this article. The relationships between (endo)cannabinoids, the endocannabinoid system, and the psychological and physiological functions they influence have clear pharmacological applications. Nobody knows what future research holds, yet we hope to have sparked your interest in the (still pending) issue of the endocannabinoid’s system importance.

References   [ + ]