The endocannabinoid system is a relatively newly discovered body system. Identified in the 1980s as an integral part of the physiology of all vertebrate animals, the past three decades has revealed there are but a few physiological processes in which the ECS is not involved in some capacity.
By interweaving through the immune, digestive and nervous systems the ECS is indisposable, with each of these systems codependent on the processes and function of ECS. Sounds pretty important right? Yet it has only been in the past decade that this information has seeped out from the academic sphere into the consciousness of physicians and the public in any meaningful way.
In saying that, there is still a dearth of education available to physicians within medical schools – if it is even covered at all. Given how essential this system is to the regulation of physiological processes occurring in every moment, widespread dissemination of education on the ECS is supremely important.
The ECS comprises receptors and endocannabinoids – cannabis-like substances the body innately produces. Receptors function as a ‘lock’, in which a ‘key’ (endo- or phytocannabinoids) can fit into, thereby exerting a physiological action.
The two G-coupled cannabinoid receptors, CB1 and CB2 can be found systemically throughout the body. CB1 receptors are abundant in the brain and nervous system and are primarily famous for their interaction with THC – facilitating the intoxicating effects of cannabis – though they engage in many other processes.
CB2 receptors do not modulate psychoactive effect but have a strong presence in the immune and reproductive systems. They are key mediators in the regulation of inflammation, pain and the enteric nervous system – the ‘brain’ of the gut.
There is one more receptor that gets honorary inclusion into the ECS and that is receptors of the TRP family, predominantly TRPV-1. This receptor is involved in the mechanisms of action of a whole host of botanical and pharmaceutical therapeutic treatments but does not interact with the primary intoxicating cannabinoid THC.
The ‘keys’ that fit into these receptors are referred to as endocannabinoids, endo- meaning they are endogenous or made within the body. There are two dominant endocannabinoids in human physiology, anandamide and 2-AG, both have a strong affinity with the ECS receptors.
The final component of the ECS is the compounds involved in regulating its function. The enzymes that build and breakdown endocannabinoids not only modulate this system but also have therapeutic potential in their own right. Given how sophisticated the ECS and its regulatory measures are, it’s a wonder we weren’t aware of this system earlier.
The dynamic interplay between the receptors, endocannabinoids and their influence on other systems is implicated in an extensive array of body functions and pathological presentations.
Homeostasis is a state of dynamic equilibrium the body is constantly attempting to maintain. Homeostatic processes aim to keep the bodies functions in a steady-state; never too hot, cold, dry, acidic or viscous etc. This dynamic dance is sustained inside such a narrow range within each body system and within each cell, it is a wonder our bodies manage to keep the environment just right all the time.
The ECS plays a crucial role in human development from conception, and even prior with dysregulated endocannabinoid homeostasis potentially having an effect on uterine receptivity and implantation. The fetal ECS is establishing from 14 weeks and is key in the initial formation of neuronal connectivity and ongoing signalling throughout the body.
CB1 receptors contribute to maintaining homeostasis via processes in the nervous and endocrine systems, regulating the distribution of information via neurons and hormones around the body. In managing the interactions between these systems the ECS plays both a direct and indirect role in mood, sleep, appetite and stress, to name but a few aspects.
Cannabinoid receptors are also found in the cardiovascular, reproductive and skeletal systems. In the heart, CB1 receptors moderate dilation and contraction of vessels thereby maintain blood pressure, while in the skeletal system CB2 receptors are thought to maintain bone density through supporting bone cell building and degradation processes.
By supporting and contributing to the delicate balancing act of homeostasis, the ECS and its components are integral to the body in numerous and fundamental ways.
Prominent cannabinoid researcher Ethan Russo and other scientific thought-leaders in the cannabinoid community are beginning to unveil connections between the functioning of the ECS with a number of conditions and syndromes. Syndromes are not specific to a particular disease but are usually a collection of symptoms often without a known cause. In some cases, syndromes have a psychosomatic component (which readily accompanies a degree of stigmatisation) and are commonly treatment-resistant.
Researchers have found a common denominator in many syndrome presentations – including migraine, chronic pain conditions and gastrointestinal disturbances – that being medical cannabis treatments regularly provide relief. This has led to the theory that many difficult treat and otherwise idiopathic conditions may be related to deficiency or dysfunction in the ECS.
Chronic migraine is one instance where researchers postulate dysfunction in the ECS to negatively impact symptoms. Individuals who regularly experience migraines had their cerebrospinal fluid examined in an Italian study. When compared with controls, chronic migraine sufferers exhibited decreased levels of the endocannabinoid anandamide, present in their cerebrospinal fluid.
In the same study, individuals who scored highly in depression scores also showed significantly lower anandamide levels than control subjects. The authors also examined headaches related to other potential causes and concluded that lowered anandamide level could be associated with head pain more broadly.
In relation to fibromyalgia, sufferers experience some characteristic and some unique symptoms. This is a painful condition that often affects individuals in vastly different ways, but one commonality is that it is often debilitating. There’s some understanding that fibromyalgia may be due to hypofunction of the ECS, particularly in the spinal cord, leading to uncontrollable sensations of pain.
Numerous trials have investigated the use of medical cannabis in fibromyalgia cases, certain studies have shown benefits in pain scores, sleep patterns and quality of life. Yet, further human and experimental research into the specific cannabinoids helpful in re-establishing ECS function will go a long way to discovering appropriate medical cannabis formulations for these patients.
Other conditions where it is postulated endocannabinoid dysfunction or deficiency may play a part include; Multiple Sclerosis, where lower levels of endocannabinoids have been found to be present in spinal fluid; Parkinson’s disease, with patients exhibiting unusually high levels of anandamide; mood disorders and even diabetic neuropathy may have ECS dysregulation as part of their etiology.
Much like factors that determine the health of other systems of the body the ECS is affected by a wide range of environmental, physiological and psychological variables. Recently links have been drawn between the ECS and the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis dominants how our bodies respond to stress and can directly influence the digestive system.
Chronic stress persistently activates the HPA axis resulting in, protracted reductions in anandamide and CB1 receptors as well as increases in cortisol and 2-AG. It is this disharmony between HPA processes and ECS components that is thought to contribute to gastrointestinal dysfunction.
Additionally, the ECS’s interactions with HPA pathways and regions of the brain such as the cortex, amygdala and hippocampus could account for some of the positive effects cannabis medicines have on anxiety, appetite and nausea.
Genetics also play a big part in the functioning of the ECS and therefore impact overall homeostasis. Gene variations in the codes relating to the enzymes that build or degrade endocannabinoids are implicated in psychological disorders, where low anandamide synthesis may contribute to mood and subjective anxiety.
More broadly, the same practices that are likely to benefit the cardiovascular and immune system are also thought to affect the overall health of the ECS. A balanced diet, filled with lots of fresh fruit and vegetables and healthy exercise habits are likely to be of benefit, just as much as psychological stress and environmental toxins may be detrimental.
There are numerous ways in which physicians can target the ECS in the treatment of disease. The tactful application of medical cannabis prescriptions has the capacity to engage and nourish the ECS, with the potential to bring about therapeutic benefits and symptom reduction.
There are both pharmaceutical and nutritional substances that can be used to encourage the production endocannabinoids, antagonise or upregulate receptors to illicit therapeutic action. These kinds of applications are still confined to experimental and preclinical research, yet results thus far are indicative of great growth in this area.
There is a huge range of conditions that might benefit from the thoughtful engagement of the ECS. Cannabinoid therapy may be beneficial to cardiovascular health by interacting with the ECS and reducing oxidative stress. In animal and experimental studies by activating cannabinoid receptors on the heart there is the possibility of decreasing risk factors and adverse effects for some cardiovascular diseases, particularly of ischemic or atherosclerotic origin.
Laboratory investigations into the interplay of medicinal cannabis applications and the ECS in relation to cancers are happening all over the world, with promising results being seen in Israel, Spain and human trials underway in Australia by leaders such as the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney.
Again, the potential for targeting the ECS in conditions of the gastrointestinal tract is a promising area. There is a complex relationship between the gastrointestinal, nervous and endocannabinoid system that we are yet to fully comprehend.
From what we understand so far, the ECS has just as much influence over the processes of the gastrointestinal tract as the nervous or endocrine system. It modulates secretions, motility and inflammation, lending it to interesting and novel treatment options for sufferers of irritable or inflammatory bowel conditions.
Both animal and human studies have shown amelioration of symptoms with cannabinoid treatments. It is posited this may be through activation of cannabinoid receptors, regulating motility and decreasing visceral hypersensitivity that is manifesting as pain.
The endocannabinoid system is an exciting medical frontier and we can assume our current understanding is but the tip of the iceberg. It goes without saying that much more research is needed, particularly in the UK. This system holds great promise in the application of treatments across numerous body systems and has the potential to improve the quality of life for patients with difficult to treat conditions in the UK and around the globe.
Whilst researchers continue to focus their efforts into new ways of combating COVID-19, a number of researchers are looking into whether cannabis or cannabis derived CBD (cannabidiol) or THC (tetrahydrocannabinol) might offer support for those suffering from severe forms of this infection.