The Endocannabinoid System
Our Primary Neurophysiological Regulatory and Harm-Reduction System
- Engaging and Supporting the ECS
The endocannabinoid system (endo= internal/within) is our primary harm-reduction and neurophysiological regulatory system. We naturally produce compounds that parallel the function of the better-known phytocannabinoids (from the cannabis plant) THC and CBD. These and related chemicals, receptors, enzymes, and proteins work together to regulate and modulate all other physiological systems and functions (digestion, metabolism, cardiovascular, nervous system, immune function, healing/repair/restoration, sleep, etc.). Among countless other functions and benefits, cannabinoids are neuroprotective by preventing cell-death by excitotoxicity: neural cells firing too fast for too long. In addition, the ECS is our body's primary way to "tune" our systems: it up-regulates and/or down-regulates various systems and functions to maintain the homeodynamic coherence of all our systems necessary for health and wellbeing.
Overview of the ECS
What is the Endocannabinoid System? (hereafter "the ECS")
The ECS is truly pervasive and extensive throughout the body. For example, there are more cannabinoid receptors in the brain than there are receptors for all the neurotransmitters combined. Likewise, cannabinoid receptors are found everywhere, in every system, including the skin, skeleton, gut, muscles and even at the subcellular level (i.e. within cells; e.g. on mitochondria and nuclei).
History and Discovery
- The endocannabinoid system emerged in evolutionary development around 600 million years ago
- fun facts: the dorsal branch of the parasympathetic nervous system and the Cambrian explosion both occurred around 600 million years ago
- all animals except insects have an ECS
- Endo (Greek: endon, ἔνδον) means within, inside, inner, absorbing, containing
- this means that our bodies naturally produce cannabinoids much like the phytocannabinoids ("phyto" from Greek phuein "come into being/bring forth," and Greek phuton "plant") from the cannabis sativa plant popularly -- and pejoratively, not to mention botanically and biologically incorrectly -- known as "weed"
- the cannabis sativa plant emerged in evolution as early as 60 million years ago
- historical evidence shows that human cultivation of cannabis stretches back at least 12,000 years
- hops (the stuff in beer) are a close botanical relative to cannabis, and the plants share some terpenoid content such as high concentrations of β-caryophyllene, which binds to CB2 receptors (common in the immune system, nervous system, and many other tissues throughout the body and brain). β-caryophyllene has been shown to be anti-inflammatory, and thus can help with pain and the prevention of neurodegenerative diseases like Alzheimer's. It may also prevent inflammatory colon disorders, and many other inflammation-based harms to the body.
- The discovery of the ECS emerged diachronically through the late 1980s and early 1990s
- 1964: Raphael Mechoulam, Ph.D. isolates and discovers THC
- 1988: Cannabinoid receptors discovered in the brain by Allyn Howlett and William Devane at the St. Louis University School of Medicine
- 1992: Lumír Hanuš (Czech chemist) and William Devane (American pharmacologist) discover N-arachidonoyl ethanolamine -- i.e., anandamide (the endogenous version/correlate of THC)
- 1993: cannabinoid receptors discovered in immune system
- 1990s-present: following these pioneering discoveries, thousands of researchers and clinicians around the world have published extensively on the ECS and cannabinoid medicine. Today, there exist over 24,000 peer-reviewed scientific and medical journal articles (and many books) discussing phytocannabinoid and endocannabinoid medicine. So, the bogus claim of anti-cannabis folk that "We just don't know enough yet to legalize and/or embrace and promote cannabis as a legitimate medicine" is just that: totally bogus.
***Even before the discovery of the fact that our internally-produced cannabinoids are fundamental and essential to our health and wellbeing, the safety of cannabinoid medicine had been officially recognized by the Drug Enforcement Agency in the 1980s. After a two year rescheduling hearing (1986-1988), the DEA's Chief Administrative Law Judge concluded that cannabis is "one of the safest therapeutic constituents known to man." ***
Slowing Down: Excitotoxicity and the Dis-ease of Speed
- Key players in the ECS: The primary compounds
- There are two primary endocannabinoids, which parallel the function of the better-known phytocannabinoids, THC and CBD. These are:
- Arachidonylethanolamine (AEA); or anandamide (from Sanskrit term meaning "bliss, joy"); like THC
(2-AG); like CBD
- The two primary phytocannabinoids (or exogenous [external] cannabinoids) are:
- THC (tetrahydrocannabinol)
- Crucially, however, the remarkably medicinal and therapeutic potential of the cannabis plant entails much more than THC and CBD. Terpenoids and flavonoids play an essential role in the medicinal function of cannabis. This involves the "entourage effect," and this is very important for understanding how cannabis works and how we can best support our ECS and our overall health. More on this below.
How does the ECS work?
As the ECS affects virtually every aspect of our being, I couldn't possibly detail, comprehensively, how the ECS works. Here, I will describe just one essential and very important function of the ECS. For further information, see the resources in the bibliography below.
- Excitotoxicity and slowing down
- The ECS is characteristically neuroprotective, a phenomenon achieved by encouraging our nervous systems to slow down when hyperactive (but also to up-regulate when hypoactive [i.e., too little stimulation; e.g. "depression"], see below).
- Excitotoxicity is a phenomenon in which neural cells die and neural networks break down as a result of excessive stimulation, or hyperactivity. In other words, working too hard, for too long, is quite literally toxic to cells. This constitutes a "functional" toxin, but this is just as toxic as chemical toxins such as alcohol, which of course is well-known to destroy brain cells and generally wreck havoc on many aspects of our systems, such as tissue, blood, and immune health.
- Research has shown that cannabinoids (both exogenous [external, from the plant] and endogenous [internal, from within us]) function to prevent such hyperactivity, and thus quell the phenomenon of excitotoxicity.
- Cannabinoids block the action of glutamate, for instance, which is one of the primary stimulatory neurotransmitters. Too much glutamate release from a pre-synaptic neuron to a post-synaptic neuron will over-stimulate the receiving brain cell and, left unchecked, will eventually destroy it. Cannabinoids can help prevent this form of cell death, which is central in neurodegenerative diseases such as Alzheimer's and dementia.
The Master Homeodynamic Regulator
- The ECS doesn't simply function to slow us down, however. The ECS can be up-regulating, as well. Simply put, the overall job of the ECS is to restore holistic balance to our systems, whether by limiting excessive activity or stimulating deficient activity.
- Note that I write "homeodynamic" rather than the more commonly used "homeostatic" to refer to a neurophysiological condition of health and balanced regulation. This is because there is, quite literally, nothing in our existence that is truly static (not even our bones). Everything in our mind-bodies is in continual, dynamic flux. See the excellent article "Why Homeodynamics, not Homeostasis?" for more details. I also discuss this further on the "Embodied Cognition" page.
- As just one example of how cannabinoids can be activating as well as relaxing/sedating, it is a myth that CBD is straightforwardly and always relaxing/calming/sedating. As the pioneering neurologist and endocannabinologist Ethan Russo, MD, explains, CBD in small to moderate doses is actually "distinctly alerting." See his excellent article on myths and misconceptions about CBD (https://pubmed.ncbi.nlm.nih.gov/28089139/). Here is an excerpt from the article:
"Misconception: CBD Is Sedating"
"Some early anecdotal literature cited a low incidence of sedation after CBD administration, and contemporaneously, this side effect is frequently attributed to CBD. However, low to moderate doses are distinctly alerting, as proven in its ability to counteract sedative effects of THC, delay sleep time as documented via electroencephalography, and reduce THC-associated 'hangover'. Numerous modern studies, even those with single doses of 600 mg of oral CBD, in normal subjects have been free of sedative effects. By contrast, CBD as Epidiolex (an investigational cannabis extract with traces of THC, other cannabinoids, and terpenoids) employed in very high doses of 25 mg/kg/day or more to treat intractable epilepsy has produced sedation under conditions of polypharmacy, especially linked to elevated levels of N-desmethylclobazam when co-administered with clobazam, which resolves well after reduction of the dose of the latter.
"Whereas pure CBD is not sedating, many CBD-containing drug and hemp chemovars do display this liability. This is not attributable to CBD concentration per se, but rather to the predominance of myrcene in high titer in many commercial varieties. Myrcene, a monoterpenoid, displays a prominent narcotic-like profile that is seemingly responsible for the 'couch-lock' phenomenon frequently associated with modern cannabis phenomenology." (From Ethan Russo, 2017. "Cannabidiol Claims and Misconceptions." Trends in Pharmacological Sciences 38 (5): 198-201. https://doi.org/10.1016/j.tips.2016.12.004)"
Engaging and Supporting the ECS
History and contemporary research has shown -- and is increasingly showing -- that cannabinoid medicine is one of the most powerful, safest, and versatile medicines available to humans. As the pioneering cannabinologist and medical chemist Raphael Mechoulam, Ph.D., says, cannabis is a "pharmacological treasure trove." Likewise, the brilliant neurologist and cannapharmacologist Ethan Russo, MD reminds us that cannabis is a "pharmacy in a plant."
- For me, one of the most exciting aspects of knowing about the ECS is the fact that this means we quite literally produce medicine from within! We are not just figuratively self-healing; we can literally self-medicate (in the good way, not in the pejorative sense of "self-medicating" associated with actual drug abuse). So, even if someone has no interest in consuming a medicine from the cannabis plant, they can access the healing power of cannabinoids in their endogenous form (produced/arising from within).
- Indeed, regardless of whether a person is aware of their engagement with their ECS and its essential function and extensive roles in healing and health, we are all supported by the ECS in everything we do, on a daily basis!
- The ECS can be supported and enhanced through a wide range of common and simple activities. For an excellent introduction to foods and activities that support ECS function and efficacy, see Dr. Dustin Sulak's webpage "Endocannabinoid Diet and Activities."
- Here is a very basic overview of activities that can support and enhance ECS function:
- Any one of a variety of types of focused/intentional/mindful movement, such as yoga, dance, martial arts, sports/athletics, gymnastics, parkour...even simply walking at a slow, rhythmic pace, etc.
- Meditative practices such as sitting meditation, walking meditation, simply hiking through a forest or park, breathing exercises, etc.
- The arts! Playing/listening to music; cooking and eating whole, nutrient rich, organic food; singing; gardening; writing/reading poetry and story; visual arts; etc.
- For more info on the ECS and how to engage it through simple, daily practices, see Rachel Knox, MD's excellent TED Talk, The Endocannabinoid System and the Revolution of One.
A Case Study in Cannabis Medicine: Food as Medicine or Drug
Cannabis medicine encourages a framework of seeking a proper ratio of quality to quantity. In modern culture, excessive emphasis has been placed on mere quantity -- quantity of food/nutrients; work productivity and speed; life experiences; etc. For example, many people in modern culture experience a huge amount (quantity) of activities meant to be fun, entertaining, and enjoyable, and yet remain dissatisfied with life at the end of the day.
We live in a "fast food culture" -- just as industrially-produced, chemically-modified, homogenized food at fast food restaurants such as Taco Bell and McDonalds is cheap and pretends to be satisfying by creating a shock of flavor sensation with chemical additives and high amounts of unhealthy ingredients but is not actually nourishing or satiating, many of our sociocultural, relational, cognitive, aesthetic/artistic and spiritual experiences are similarly mass-produced, cheap, superficial and low in quality but high in quantity. Social media is one of countless examples. Today, billions of people are addicted to mindlessly scrolling through massive amounts of high-quantity, low-quality content on a variety of social media platforms. Our senses are, initially, acutely stimulated by such content (like with fast food or junk food) but we have to keep going back for more because the quality of such content is so shallow. Likewise, much artistic and literary content in our culture has high shock value, is stimulating through excessive intensity (speed, volume, extremity of sensation generally [e.g. the explicit and detailed graphic violence as depicted in TV and film]), but is not truly satisfying, satiating, and nourishing to our aesthetic appetites. This is how companies get people hooked, endlessly buying more and more consumer goods manufactured expressly to exploit people's addictive-compulsive tendencies while leaving them substantively unsatisfied and thus going back for more in a vicious cycle that has contributed to a global pandemic of chronic depression-anxiety.
Snack Foods and Sonic Sensitivity: Acute Acoustic Appeal
Such consumer exploitation is pervasive and disturbing. For example, the U.S. savory snack food industry rakes in $33 billion in revenue annually. Some studies suggest that up to 94% of Americans snack at least once a day, and 62% of people report snacking in order to satisfy a craving. There are multiple components to the appeal of snacking, of course, but here I want to highlight one aspect that is mostly unknown.
Research has shown that all sensory modalities can contribute to the flavor of a food or drink. But as we continue to eat the same food, the intensity of sensation diminishes over time -- with the exception of the sound of eating.
So, for instance, let's say you're hungry and relatively malnourished such that your body starts sending signals that say "Eat something now!" Given our culture of convenience, impatience, and speed, many people are likely to reach for a bag of crunchy snacks such as corn or potato chips. That first bite will provide a rush of taste sensation: the salt, sugar, spices, fats, starches, and synthetic chemical flavor enhancers will flood your sensory capacities and you'll likely get a surge of dopamine, making you feel really good (note that this is very similar to how addictive drugs work, too). But as you continue to eat the chips, the tactile sensations (mouth feel), the flavor, and the aroma of the food will begin to diminish. Your body will not respond as intensely to these sensory stimulations, as it will adjust to having consumed the physical substance of food.
However, this does not happen with sound. That sharp, crisp CRUNCH of biting into a chip remains just as stimulating no matter how much you eat. And isn't that an appetizing sound? So even while our bodies may become physically full (high quantity of food) but not truly nourished (low quality of nutrient content), we often keep eating those crunchy snacks because the sound keeps us going back.
This is such a powerful sensation that large snack companies employ mechanical engineers to help create the most addictive recipes possible. So, many snacks are quite literally engineered to require a certain amount of jaw force to bite through them to produce the most addicting crunch sound possible. All while they also employ chemists, psychologists, and other scientific experts to leverage our knowledge of human psychology and neurophysiology to create chemical ingredients and recipes that will keep us as hooked as possible. In a society (U.S.) that, in the aggregate, works more hours and is simultaneously in more debt than any other society on Earth, the fact that Americans spend $33 billion annually on savory snack foods attests to how addicted many people are.
So, What about "The Munchies?"
It is a well-known phenomenon that consuming phytocannabinoids often gives people "the munchies" (i.e. makes them acutely hungry). (But, some chemovars of the cannabis plant actually function to suppress appetite. This is another example of how cannabinoids and the ECS can be either up-regulating/stimulating or down-regulating/relaxing. Cannabis is a very dynamic and adaptable medicinal phenomenon.)
In the context of a snack-obsessed culture, it's understandable how the munchies phenomenon has become associated with gorging oneself on snack foods or fast food takeout. But when cannabis gives us the munchies, this is our body telling us we are actually malnourished in some way!! (Or, at least, that you'll be benefited by supplementing your diet with something nutritious and/or supportive of gut bacterial diversity, which is essential for health.) To truly satisfy our munchies, we must eat wholesome, nutrient-dense, organic foods. The next time you consume cannabis and get the munchies, try slowly savoring a freshly-made, nutrient-dense meal of whole organic foods. The experience can be divine.
The ECS interacts extensively with our metabolic systems and functions, in fact. For example, THC and CBD binds to receptors in the gut (which is a brain in itself with over 500 million neurons), and among other functions they work to support the growth of healthy gut bacteria and limit the growth of harmful gut bacteria. The quantity and quality (diversity) of our gut's microbiome is crucial for health, "physically" and "mentally" -- holistic health. This is another widespread, chronic issue among Americans especially and citizens of industrial societies generally: people living within and eating industrialized, synthetic food cultures display markedly lower gut bacterial diversity than people who eat diets rich in whole foods containing natural levels of pre- and pro-biotics (such as fermented foods; other natural chemicals in food, such as capsaicin in peppers, also interact directly with the ECS -- food quite literally is medicine!). This is a major problem for many reasons. E.g., as Ethan Russo, MD explains, "Severity of Irritable Bowel Syndrome symptoms is inversely related to gut bacterial diversity." So, the more homogenized and qualitatively shallow our diet, the more dis-ease we will experience.
Resources on the Endocannabinoid System, Phytocannabinoids, and Cannabinoid Medicine Generally
Online Resources (videos, podcasts, websites)
- "The Endocannabinoid System and the Revolution of One" - TEDxPortland - Rachel Knox, MD
- The Doctors Knox and PIVITAL | EDU
- Dr. Miyabe Shields (biochemist) and Dr. Riley Kirk's (pharmaceutical scientist/chemist) website and podcast provide excellent and accessible resources for understanding cannabinoid medicine and the ECS
- Here is their YouTube Channel, which includes basic educational videos as well as podcast recordings with in-depth discussion.
- And here is a link to an annotated bibliography of open-access peer-reviewed articles. Thank you Miyabe and Riley for curating this!
- Dr. Rachel Knox -- pioneering endocannabinologist, physician, holistic healer
- Interview with Project CBD - "Endocannabinology"
- Interview with The Cannabis Conversation - The Endocannabinoid System
- 6 Myths about Cannabis
- Dr. Ethan Russo, neurologist, pioneering endocannabinologist, cannabis researcher
- Phytecs Interactive Tour of the ECS
- Interview with Project CBD on CBD and Endocannabinoid Deficiency
- The ECS in Health and Disease, part 1
- The ECS in Health and Disease, part 2
- The Pharmacology of Cannabinoids and Terpenes
- The ECS and Migraine, Fibromyalgia, and IBS
- The Grand Unified Theory (G.U.T.) - the ECS, Cannabis and the Microbiome
- Interview with Project CBD - CBD, the Entourage Effect, and the Microbiome
- Interview with Shango Los - Foods that boost the ECS
- Interview with Agrify - The Science of Cannabis
- Dr. Raphael Mechoulam, pioneering endocannabinologist and researcher
- The ECS: A Fifty Year Trip - Medicinal Genomics
- Cannabinoid Research, Past and Future - Medicinal Genomics
- Jeffrey Block, MD: "Cannabinoids and Adaptive Immuno-Modulation - Nurturing Nature"
- "CannaKeys." https://cannakeys.com/.
- "Steep Hill Labs | Science of Cannabis."
Books and Articles on the ECS and Cannabinoid Medicine
- Bearman, David, and Maria Pettinato. 2019. Cannabis Medicine: A Guide to the Practice of Cannabinoid Medicine. Independently published.
- Di Marzo, Vincenzo, and Jenny Wang, eds. 2014. The Endocannabinoidome: The World of Endocannabinoids and Related Mediators. Amsterdam: Academic Press.
- Murillo-Rodríguez, Eric, ed. 2017. The Endocannabinoid System: Genetics, Biochemistry, Brain Disorders and Therapy. San Diego, CA: Academic Press. https://www.elsevier.com/books/the-endocannabinoid-system/murillo-rodriguez/978-0-12-809666-6.
- Novack, Victor. 2018. "Medical Cannabis: What Physicians Need to Know?" European Journal of Internal Medicine, Special Issue: Cannabis in Medicine, 49:1. https://doi.org/10.1016/j.ejim.2018.02.008.
- Onaivi, Emmanuel, Vincenzo Di Marzo, and Takayuki Sugiura, eds. 2005. Endocannabinoids: The Brain and Body's Marijuana and Beyond. CRC Press. https://doi.org/10.1201/9781420023640.
- Pacher, Pal, and George Kunos. 2013. "Modulating the Endocannabinoid System in Human Health and Disease - Successes and Failures." The FEBS Journal 280: 1918-43.
- Panche, A. N., A. D. Diwan, and S. R. Chandra. 2016. "Flavonoids: An Overview." Journal of Nutritional Science 5 (December). https://doi.org/10.1017/jns.2016.41.
- Parker, Linda A. 2018. Cannabinoids and the Brain. Reprint. Cambridge, MA: The MIT Press.
- Pearlson, Godfrey. 2020. Weed Science: Cannabis Controversies and Challenges. San Diego: Academic Press.
- Premoli, Marika, Francesca Aria, Sara Anna Bonini, Giuseppina Maccarinelli, Alessandra Gianoncelli, Silvia Della Pina, Simone Tambaro, Maurizio Memo, and Andrea Mastinu. 2019. "Cannabidiol: Recent Advances and New Insights for Neuropsychiatric Disorders Treatment." Life Sciences 224 (May): 120-27. https://doi.org/10.1016/j.lfs.2019.03.053.
- Roman, Matthew. 2020. The Clinician's Guide to Medical Cannabis. Independently published.
- Russo, Ethan B. 2004. Cannabis: From Pariah to Prescription. Binghamton, NY: Routledge.
- _____ . 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): 154-65.
- _____. 2016. "Beyond cannabis: plants and the endocannabinoid system." Trends in Pharmacological Sciences 37 (7): 594-605.
- _____. 2017. "Cannabidiol Claims and Misconceptions." Trends in Pharmacological Sciences 38 (5): 198-201.
- _____. 2018. "Cannabis Therapeutics and the Future of Neurology." Frontiers in Integrative Neuroscience 12.
- Russo, Ethan, and Franjo Grotenhermen, eds. 2006. Handbook of Cannabis Therapeutics: From Bench to Bedside. Haworth Series in Integrative Healing. New York: Haworth Press.
- Sulak, Dustin. 2021. Handbook of Cannabis for Clinicians: Principles and Practice. New York: W. W. Norton & Company.