One of the fundamental aspects of biology is an organism’s evolutionary drive to maintain an innate physiological balance called “homeostasis”: the auto-regulation of an organism’s internal environment for optimal functioning of its biological systems that are needed to maintain life.
Furthermore, research is constantly unearthing the notion that this balance is also the basis for good health2.
The phenomenon of homeostasis, in part, is characterized by the production, metabolism and maintenance of chemical messengers called neurotransmitters, which act both centrally (in the brain) and peripherally (throughout the rest of the body).
Major neurotransmitters, like acetylcholine, dopamine and serotonin, for instance, play a role in multiple physiological and psychological processes, and aberrations in their equilibrium have been linked to a litany of brain disorders, such as Alzheimer’s, Parkinson’s and Depression, respectively 1,7.
The notion that a “chemical imbalance” in the brain may cause disorders like depression is much more mainstream among modern society than it was in the past.
The original commercial for Zoloft (Sertraline), a popular SSRI type antidepressant, relayed that message around the world.
In the case of synthesized drugs, like Zoloft, decades of research have allowed scientists to create a compound that will essentially push just the right buttons when consumed.
How is it though, that we can modulate this homeostatic balance (or the lack thereof) by using living, whole-plant medicines like cannabis and opium?
To unravel that mystery, first, a short lesson in pharmacology and physiology.
Physiology & Pharmacology: A Brief Summary
Essentially, we are born with the physiological machinery with which we naturally produce substances that are strikingly and coincidentally (depending on how you look at things) similar to the active compounds contained within a variety of plant species.
When we introduce exogenous (exo = “outside”) drugs like morphine (a derivative of the poppy plant) into our bodies, it dramatically affects our own endorphin and dopamine levels because the poppy plant just happens to produce chemicals (opiates) that are so incredibly similar in structure and function to our own endogenous opiates (endorphins and enkephalins).
Their pharmacological mechanisms mimic or modulate that of our own, endogenously produced neurotransmitters and their respective physiological mechanisms.
When humans noticed potent physiological and psychotropic effects from cannabis use, the implication was that there must be a system of neurotransmitters and receptors already in our bodies that the active compounds in the cannabis plant (cannabinoids) can also act upon.
The discovery of our endocannabinoid system turns out to be exactly that.
The Endocannabinoid System: What is it?
The endocannabinoid system (ECS) is composed primarily of the G-coupled endocannabinoid receptors (CB1 & CB2), the endogenously produced cannabinoids anandamide (N-arachidonoylethanolamide or “AEA”) and 2-AG (2-arachidonoyl glycerol) which stimulate them and the factors involved in their synthesis and degradation 2,5.
The distribution of EC receptors CB1 and CB2 are ubiquitous, that is to say, they’re distributed across various regions across the brain and body.
CB1 is largely located in the brain; while CB2 is mainly identified with being located in immune and hematopoetic cells (blood stem cells).
However, “functionally relevant expression” of CB2 has been identified in numerous other regions, such as the heart, gut, pancreas, bone, reproductive organs and even certain tumors 5.
Furthermore, it’s recently been uncovered that CB1 receptors also play an important and documented regulatory role in “virtually all peripheral tissues and cell types, albeit at much lower densities than in brain…” 5.
Adding to the overall complexity of this system is the evidence that the body uniquely produces bioactive lipid molecules (fatty acid or derivatives of fatty acid) that are agonists that also bind to and stimulate EC receptors, in addition to the bodies’ naturally produced endocannabinoids: AEA and 2-AG 5,7.
With so many different spinning cogs and wheels, it quickly becomes apparent the ECS plays a diverse and significant role in the maintenance of life and good health.
The question then becomes, how does it all work?
The Endocannabinoid System: How it Works
Naturally, dopamine activates dopamine receptors; serotonin activates 5HT (serotonin) receptors; and so goes the usual pairing of neurotransmitters and their respective receptors they normally activate.
This is commonly simplified by the “lock and key” analogy to describe the relationship between neurotransmitter ligands (keys) and their receptors (locks).
The biosynthetic pathway of EC production is largely dependent on intracellular calcium (Ca2+) levels.
In the brain, AEA and 2-AG are synthesized “on demand” to act as “retrograde transmitters” on CB1 receptors.
Essentially, these neurotransmitters travel “backwards” in the brain from the post-synaptic dendrite to the pre-synaptic axons 5.
Overall, AEA has a higher affinity for (is more attracted to) CB1 receptors, however, at higher concentrations can affect other receptors outside the ECS, such as TRPV1 5.
How does C. Sativa fit into all this?
In brief: THC, the major psychoactive constituent of the cannabis plant that is responsible for the “high” one experiences, is a partial agonist at CB1 in the brain.
In fact, CB1 receptors are the “most abundant GPCR (G-protein coupled receptors) in the mammalian brain 5.
Perhaps even more unique is the production of lipid molecules that act on this same receptor system that our endocannabinoids do.
Using the (very simplified) “lock and key” analogy, we can view these lipid agonists as additional keys that, to various degrees, stimulate the same receptors as our endogenously produced cannabinoids do.
In fact, there is even data that these compounds affect other, non-cannabinoid receptor systems.
Thus, one can begin to see how complex and sophisticated the ECS truly is.
Given the wide range of EC receptor distribution, it follows that this system likely has modulatory effects on numerous biological functions.
Upon binding of endocannabinoids and related molecules to EC receptors, a chemical cascade of reactions takes place within the cell and has a variety of effects from appetite stimulation to analgesia and anxiolysis.
In fact, ECS factors have been shown to bind and stimulate a host of other aforementioned receptors including dopamine, serotonin and NMDA receptors 7.
This overlap of various other receptor systems and the ECS offers layers of complexity and dimensionality to the argument for “endocannabinoid tone” and the importance behind further research in understanding it.
“Endocannabinoid Tone”: A Complex & Intricate Balance
The link between brain disorders and clinical deficits in neurotransmitters was eventually applied to our own endogenously produced cannabinoids, called endocannabinoids (EC), and the endocannabinoid system (ECS) they act upon.
A 2016 study stated: “comparable deficiency in endocannabinoid levels might manifest similarly in certain disorders…” 7.
The phenomenon of Clinical Endocannabinoid Deficiency (CED) and it’s potential implications in disease pathology and treatments is worth further exploring here.
The optimal, homeostatic balance of this incredibly sophisticated and complex ECS and its constituents is called “endocannabinoid tone”.
Imbalance or deficiency in one’s endocannabinoid tone can result in an amalgamation of health concerns, including, but not limited to: Migraine, Fibromyalgia, IBS and other treatment-resistant disorders (to name a few) 7.
Recent studies have also shown clinical efficacy topical and transdermal cannabinoids in the treatment of Rheumatoid Arthritis.
It is clear that the impact of the ECS is widespread and affects many aspects of our health as well as a number of pathologies.
Further research is desperately needed to accommodate for the patients suffering from these disorders as, often times, they are stigmatized by the erroneous belief that their pain and discomfort is solely psychosomatic (“in their head”) 7.
The sociopolitical barriers to cannabinoid research (e.g. schedule I status of C. Sativa) have significantly hindered researchers to garner a better understanding of our own bodies and how they function.
This article aims to signify the importance of our “endocannabinoid tone” and how deficits in this complex and intricate system that is the ECS, may play a clinically significant role in various pathologies 5.
Endocannabinoid Tone in Chronic Illness
The identification of EC receptors across such a wide range of organ systems and cells gives credence to the versatility of cannabis as a medicinal herb, as it has the framework to modulate everything from sleep and appetite to pain tolerance and digestion.
Therefore, it is no longer surprising that maintaining healthy levels of EC’s is necessary for optimal health.
Just like the chemical imbalance that is said to underlie a disease such as depression, abnormality in “endocannabinoid tone” can have deleterious consequences to human health.
Subjective pain syndromes such as migraine, fibromyalgia and IBS have limited pharmacologic interventions that have any significant efficacy in relieving symptoms 7.
Let’s take a closer look at the evidence supporting this claim:
- Levels of anandamide in cerebrospinal fluid have been shown to have statistically significant differences in migraineurs, while advanced imaging studies “demonstrated ECS hypofunction in post-traumatic stress disorder (PTSD)” 7.
Irritable Bowel Syndrome (IBS)
- The field of gastrointestinal medicine is rapidly discovering the clinical significance of the gut-brain axis (also called the “enteric nervous system”) and how it relates to IBS (irritable bowel syndrome), an idiopathic illness with a dramatic prevalence of 10-15% in the Western world 7. In fact, studies show that GI propulsion, secretion and inflammation are all controlled and modulated by the ECS 7.
- It was observed that endocannabinoid hypofunction (reduced function; likely due to deficiency in EC’s) in the spinal cord was associated with increased pain sensitivity 7,3. This is why targeting the ECS can be so helpful for fibromyalgia patients.
Thus, all of these results make the ECS a “prime target” for therapeutic intervention and CED a “likely explanation” for these maladies.
Medical Cannabis Therapy: Compensating for CED
Whole plant cannabis formulations have shown noteworthy promise in the alleviation of even debilitating symptoms caused by these diseases 7.
Cannabis just happens to share an intrinsic complexity akin to our ECS in that it contains over 400 active cannabinoid and terpenoids compounds, over 60 of which are specifically cannabinoids (e.g. THC, CBD, CBG, CBN, etc.) 1.
The varying ratios of active cannabinoids and terpenoids (see “entourage effect” for benefits of whole-plant medicine over synthetic cannabinoids) in any given whole-plant cannabis formulation, creates and curates the physiological and psychological effects and thus, the potential clinical benefits it provides.
As discussed, the diverse symphony of cannabinoids and terpenoids contained within the Cannabis Sativa plant are strikingly similar in structure and function to our own endocannabinoids and related factors that act on our Endocannabinoid System (ECS) 2.
Symptomatic relief has been reported across the board for chronic illnesses that are idiopathic in nature when utilizing cannabinoid therapy 7.
From pain relief to reduced colonic spasticity to the alleviation and mitigation of migraine severity, there is clear evidence that cannabis plays a role in modulating various physiological pathways related to a number of pathologies.
To this effect, our own endocannabinoid system is implicated in these pathways as well and these findings do indeed suggest that medical cannabis therapy can make up for the shortages some of us have.
The role of cannabis in helping potentially uncover the mysteries of human physiology is diverse and versatile. The significance of the ECS in healthy biological functioning is present without a doubt.
However, determining specific exogenous cannabinoid therapies to treat EC imbalance and deficiency is a complex process that will require much more research.
The various pathologies potentially resulting from underlying disturbances to our innate “endocannabinoid tone” are uniquely diverse and require our attention so adequate treatments can be created.
Cannabinoid therapy in the treatment of CED, while indeed promising, will require further research to better elucidate its mechanisms of action as it relates to CED.
While clinical data from double-blind, placebo controlled trials may be limited; patients are widely reporting symptomatic relief from the use of cannabis for a wide range of illnesses.
Understanding concepts of “endocannabinoid tone” as it relates to ECS function is the key to understanding exactly how and why this happens.
- Atakan, Z. (2012). Cannabis, a complex plant: Different compounds and different effects on individuals. London, England: SAGE Publications.10.1177/2045125312457586
- Komorowski, J., & Stepie, H. (2007). [The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans]. Postepy Higieny I Medycyny Doswiadczalnej (Online), 61, 99-105.
- Kryspin, J., & Godfrey, C. M. (1976). Homeostasis and biofeedback. Canadian Family Physician, 22, 84-86.
- McPartland, J. M., Guy, G. W., & Di Marzo, V. (2014). Care and feeding of the endocannabinoid system: A systematic review of potential clinical interventions that upregulate the endocannabinoid system. PloS One, 9(3), e89566. 10.1371/journal.pone.0089566 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24622769/
- Pacher, P., & Kunos, G. (2013). Modulating the endocannabinoid system in human health and disease–successes and failures. The FEBS Journal, 280(9), 1918-1943. 10.1111/febs.12260 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23551849/
- Russo, E. B. (2004). Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinology Letters, 25(1-2), 31-39. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15159679/
- Russo, E. B. (2016). Clinical endocannabinoid deficiency reconsidered: Current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis and Cannabinoid Research, 1(1), 154-165. 10.1089/can.2016.0009 Retrieved from http://www.liebertonline.com/doi/abs/10.1089/can.2016.0009
- Vincenzo Di Marzo, & Luciano De Petrocellis. (2012). Why do cannabinoid receptors have more than one endogenous ligand? Philosophical Transactions: Biological Sciences, 367(1607), 3216-3228. 10.1098/rstb.2011.0382 Retrieved from https://www.jstor.org/stable/41740052