I mentioned in my previous article some key benefits of the ECS (endocannabinoid system). Let’s get into more details today. This is a pretty long article, so feel free to pick and choose whatever interests you.
I. Quick Endocannabinoid System Review
II.Endocannabinoid System Review In Details. Endocannabinoid System Research
1.Endocannabinoid System & Brain Health
2.Endocannabinoid System & Immune System/Lymphatic Health, Inflammation
3.Endocannabinoid System & The Gut
4.Endocannabinoid System & The Heart
5.Endocannabinoid System & Obesity/Metabolic Syndrome
6.Endocannabinoid System & The Skin
7.Endocannabinoid System & The Reproductive System
8.Endocannabinoid System & The Eye
I. Quick endocannabinoid system review:
ECS= endocannabinoid system
ECS= endocannabinoid system. Also known as the endogenous cannabinoid system. Includes:
1.CB1 and CB2= cannabinoid receptors
2.AEA and 2-AG= endocannabinoids (act as neurotransmitters)
3.FAAH and MAGL= metabolic enzymes that break down AEA and 2-AG
II.Endocannabinoid System Research
ECS promotes health and homeostasis when in balance. The so-called “ECS tone” depends on levels of the endocannabinoids AEA and 2-AG, their production, metabolism, how abundant these cannabinoids (and the CB1, CB2 receptors) are.
However, like any other biological system, ECS can become imbalanced/dysfunctional.
Think of ECS deficiency the same way neurotransmitter deficiencies are linked with Alzheimer’s(acetylcholine), Parkinson’s (dopamine) or MS(norepinephrine) -a deficient ECS correlates with various conditions. There is also a genetic component that may increase the risk for impaired ECS- gene variants of FAAH or CB1 receptors [1],[2].
Common symptoms of endocannabinoid system deficiency include pain, mood problems(anxiety, depression), appetite and digestion issues and sleep disturbances.
These symptoms and ECS deficiency had been best described in IBS, fibromyalgia, and migraines. However, as you will see below, many diseases related to dysfunctional ECS. Most often, there is an ECS deficiency (low ECS tone) as you will see below, although in some cases ECS tone can be increased (overstimulated).
1.ECS In The Brain
ECS plays a key role in mood, pain perception, learning, memory, neuroplasticity
ECS offers neuroprotection
ECS has anti-anxiety, anti-depression, anti-seizure effects
Endocannabinoid system research: Improving ECS (with herbs/drugs)tone could help manage MS, Alzheimer’s, Parkinson’s disease, traumatic brain injuries, migraines, seizures, motion sickness, diabetic neuropathy, Huntington’s disease, PTSD, autism, and drug abuse. (most of these conditions are linked with ECS deficiency)
The neuroprotective effects of ECS were researched in cases of traumatic brain injury, MS, Parkinson’s, Alzheimer’s, depression, and in cases of drug abuse and dependence. ECS offers neuroprotection because cannabinoids have the ability to stimulate the formation of new neurons (both embryonic and adult neurogenesis), new synapses (thus promoting neuroplasticity) and overall maintaining the health of brain cells. Technical: In the CNS, eCBs play a key role in modulating synaptic activity as endocannabinoid release is triggered by excess neuron firing or “overactive neurons”. (act as retrograde messengers mediating feedback inhibition).[3],[4],[5].
ECS has anti-stress, anti-anxiety and anti-depression effects. ECS helps activate the hormonal hypothalamic-pituitary-adrenal (HPA) axis, thus modulating the stress response [6]. ECS is found in the hypothalamus, and hypothalamus connects the nervous system with the endocrine system and is involved in releasing hormones, regulating emotion response, appetite, sexual behavior, body temperature and more [7].CB1 receptors are abundant in brain areas associated with emotions (ie basal ganglia, substantia nigra, hippocampus). Cannabinoid receptors CB1 are involved in GABA, glutamate and dopamine neurotransmission, too. Although depression is classically associated with ECS deficiency, increased ECS tone can also cause depression[8].
ECS and cognition. While endocannabinoids promote learning and memory, the plant cannabinoid THC actually cause impairments in memory (especially short term memory); CBD helps protect against these effects of THC[9].
It is worth mentioning that cannabis was a mainstay of treatment of migraine in Europe and North America for a century (mid-1800s-mid 1900) for both treating and preventing migraines. However, most anti-migraine benefits come from surveys, not research papers[10].
ECS and astrocytes. I wrote about the role of astrocytes in the glymphatic system and brain health here. Research shows that astrocytes are involved in the ECS, and respond to cannabinoids (both endo and phytocannabinoids) through activation of the CR1 receptors. The communication between astrocytes and neurons is also mediated by ECS.
2.ECS In Inflammation, Immune System And Lymphatic System
ECS limits the inflammatory response
ECS has immunosuppressive properties
Endocannabinoid system research: Improving ECS could help manage inflammatory conditions, autoimmune diseases (MS, rheumatoid arthritis, IBD, psoriasis, eczema) and various cancers
There is a “good” or healthy inflammation triggered by microbes or an injury, and the role of this inflammation is to limit the tissue damage. The “bad” (unhealthy) inflammation is associated with abnormal activation of the immune system- it can persist for too long (chronic low-grade inflammations)-as seen in autoimmune conditions and cancers. Although ECS is activated during normal inflammation, this system is particularly helpful in those chronic, unhealthy types of inflammation. ECS works by suppressing or limiting this inflammatory response. ECS modulates the immune system, strengthening its connection with the nervous system. Cannabinoid receptors CB2s are the key players in modulating inflammation and the immune response, as they are abundant in the immune cells/ lymphatic system. [11].Technical: Through Cannabinoid receptors CB1 and CB2, cannabinoids modulate neurotransmitter and cytokine release. Cannabinoids possess immunosuppressive properties; they can inhibit proliferation of leukocytes, induce apoptosis of T cells and macrophages and reduce the secretion of pro-inflammatory cytokines [12].
Targeting ECS to improve autoimmunity had been researched in MS, rheumatoid arthritis, IBD, psoriasis, eczema and more. Using ECS as a therapeutic target works not only in cases of autoimmunity but also for cancers.
In vivo and in vitro studies show that ECS has various anti-cancer effects: promotes apoptosis (the death of cancerous cells) and autophagy (body’s detox mechanism), block the formation of new cells (by cutting off the blood flow to the tumor and the ability to spread to other organs). In addition, cannabinoids can help someone deal with the side effects of chemo drugs: loss of appetite, pain, nausea, and vomiting. Cannabis extracts appear to have the ability to inhibit cancer stem cell renewal. Cancer stem cells are one of the main reasons why cancer tumors are resistant or reoccur after treatment. One of the most powerful weapons against cancer is to kill cancer stem cells [13],[14]. ECS seems to act differently cancer cells vs normal cells, as endocannabinoid signaling is selective-” attacks “ the cancer cells, while promoting the health of the normal cells [15].
3.ECS In The Gut
ECS regulates the gastrointestinal function, gut peristalsis, acid secretion, food intake (especially fatty foods).
The ECS in gut interacts with the gut microbiota and regulates gut permeability.
ECS modulates the immune system and cellular regeneration.
ECS decreases inflammation and visceral pain (visceral pain is that diffuse ‘achy and dull’ sensation of the abdomen or pelvis).
Endocannabinoid system research: Improving ECS (with herbs/drugs)tone could help manage IBS, IBD, celiac disease, acid reflux, diverticulitis, obesity, liver fibrosis, fatty liver and digestive cancers (liver, colon cancers).
More details/ Technical: ECS works closely with the enteric system and its neurotransmitters.Cannabinoid receptors CB1 and CB2. The enteric nervous system is rich in CB1 receptors and appears to be the major site of action of cannabinoids in the GI tract.CB2 receptors are found in the immune cells of the gut (ie plasma cells, macrophages). 2-AG and AEA. Levels of 2-AG are 200 X higher than those of AEA in the gut [16].
Abnormal (higher) levels of AEA had been linked with colon cancer, diverticulitis, celiac.The ECS in the large intestine interacts with the gut microbiota and regulates gut permeability.ECB controls food intake (especially fatty foods) and energy balance, which are mediated through the vagus nerve. CB1 receptor agonists (ie THC) increase food intake, inhibit vomiting and gastric acid secretion They promote relaxation of the lower esophageal sphincter, gastric emptying, intestinal motility, and secretion. May have anti-cancer effects, too. Like CB2, CB1 receptors reduce visceral pain and decrease inflammation [17],[18]. THC-plant derived or synthetic help treat nausea and vomiting related to chemo drugs and appear to be more effective than common anti-emetic prescriptions. CB1 R agonists help reduce acid reflux. Cannabinoid CB1 and CB2 agonists may also reduce motility in the inflamed intestine, thus benefiting IBS-D and IBD. In the liver, ECS is involved in cellular regeneration, liver fibrosis, and lipid metabolism [19],[20].
4.ECS And The Cardiovascular System
ECS helps control heart rate and blood pressure in healthy people but also in people with heart diseases.
When CB1 and CB2 often seem to act in opposing ways (in heart diseases)
Endocannabinoid system research: Targeting ECS -specifically CB2 receptors- show potential to reduce the progression of atherosclerosis and acute ischemic events (angina, heart attacks)
Overstimulating ECS (as seen in chronic marijuana smokers) is detrimental, being linked with sudden cardiac death, vascular arrhythmias, and other heart diseases
CB1 receptors are found in the heart and are involved in fat and sugar metabolism. When activated, these receptors cause vasodilation, hypotension, and reduced heart rate. CB2 receptors are found in the heart and blood vessels and have anti-inflammatory effects. ECS helps protect the heart from both acute and chronic injuries and regulate the heart rhythm. Drugs targeting CB2 show the potential to reduce the progression of atherosclerosis, reduce acute ischemic events (angina, heart attacks), and overall reduce cardiovascular events. On the other hand, activating CB1 receptors seem to be overactivated, and high levels of AEA and 2-AG are found in unstable angina and myocardial infarction [21],[22]. On the other hand, overstimulating ECS, as seen in chronic marijuana smokers can have serious adverse reactions- from sudden cardiac death to coronary artery diseases and abnormal heart rhythms [23].
5.ECS and Obesity/Metabolic Syndrome
ECS adjusts your behavior and metabolism to food availability (if you limit food intake is beneficial; if you overeat, it can cause various conditions)
ECS plays a key role in fat metabolism
Endocannabinoid system research: Improving ECS could help treat obesity, insulin resistance (metabolic syndrome), fatty liver, abnormal cholesterol levels
ECS promotes increased food intake, inhibits thermogenesis (the generation of heat).ECS adjusts your behavior and metabolism to food availability. It is beneficial when food is limited (ie during fasting), but becomes harmful when food is abundant, by promoting obesity and metabolic disease. The endocannabinoid AEA is an important intermediate in fat metabolism [24]. Inhibiting ECS in metabolic syndrome helps reduce obesity, abnormal fat and sugar metabolism and fatty liver. CB1 receptor antagonist rimonabant was researched in randomized placebo-controlled studies- while promoted weight loss in obese individuals, there was also a significant increase (2 fold) in mood disorders (anxiety, depression, irritability, aggression). That’s because this drug blocked not only CB1 receptors in the brain (the appetite center) but all CB1 R throughout the body. This drug was withdrawn from the market in 2008 [25],[26].
ECS is beneficial when the food is limited or during fasting. However, ECS becomes impaired in obesity and metabolic syndrome/ diabetes In these cases ECS is overactivated in the brain areas that control appetite, in the gut and liver (promoting fatty liver, abnormal cholesterol levels, obesity, reducing insulin sensitivity) and promotes inflammation [27]. Technical: ECS effects. 1. In the brain & ANS: increases food intake, modulates gustatory and olfactory neurotransmission, reduces WAT lipolysis and BAT thermogenesis via SNS, reduces gut motility via vagus nerve.2.Nose: increases odor sensitivity and food seeking behavior.3.Mouth: increases neuronal response to sweet taste, may regulate taste sensitivity.4.GI: increases preference fat intake, increases secretion of ghrelin, increases nutrient absorption.5.Pancreas: increases insulin secretion, increases apoptosis and beta cell death.6.Liver: increases lipogenesis, reduces insulin clearance and insulin inducing signaling.7.Skeletal muscles: reduces insulin-dependent glucose uptake, may reduce oxidative metabolism.8.Adipose tissue: increases storage capacity (increased adipogenesis, increased glucose uptake, decreased fatty acid oxidation) and reduces mitochondrial biogenesis [28].
6.ECS In The Skin
ECS controls the ski cells growth, multiplication, renewal, and repair
ECS has anti-inflammatory and anti-allergy effects on the skin
Endocannabinoid system research: Impaired ECS is associated with eczema, psoriasis, skin allergies, acne, scleroderma, hair growth disorders, and skin cancer
The main physiological function of the skin ECS is to control the proper and well-balanced growth, multiplication and survival of the skin cells. It also plays a role in the immune function (as the skin contains immune cells) and fat metabolism (skin contains 50% of body fat) In summary, ECS helps maintain skin homeostasis. Impairments of the ECS has been associated with skin conditions such as atopic dermatitis, psoriasis, scleroderma, acne, hair growth disorders, and skin cancer. The skin is an emerging neuro-immuno-endocrine organ, as skin plays important roles in the health of the immune system, nervous system, and hormones. The skin contains both CB1 and CB2 receptors, and the endocannabinoids AEA and 2-AG are produced in the skin. Cancer skin cells also contain CB1 and CB2 receptors and synthetic CB1, CB2 analogs were found to inhibit the growth of cancerous cells (animal studies).
There is some scientific evidence that ECS can be modulated with cannabinoids (endo, synthetic or plant derived) and to treat skin allergies, itch, pain, and inflammation. Technical: ECS tone has to be suppressed (with CB1, CB2 antagonists) to treat certain hair growth (e.g. forms of alopecia, effluvium) and sebaceous gland disorders (e.g. acne, seborrhea). Most other skin conditions need augmentation of the ECS tone (with CB agonists). Boosting ECS tone could be beneficial for various benign and malignant skin tumors, psoriasis, hirsutism, various forms of dermatitis, dry skin conditions and sensory issues like pain and itch. More technical details here.[29],[30].
7.ECS and Reproductive Organs
ECS regulates fertility, reproduction and sex hormones
Impaired ECS is associated with adverse effects on female and male reproduction.
There is a cross-talk between the ECS and steroid hormones (related to hormone production and secretion) and the entire hypothalamic-pituitary-gonadal axis
Endocannabinoid system research: Impaired ECS is linked with PCOS and other conditions affecting the reproductive system, including hormone-dependent cancers (breast, ovarian, endometrial and prostate cancer)
Overstimulated ECS (ie chronic marijuana users) is associated with infertility, reduces levels of sex hormones and more
ECS has a strong impact on fertility, reproduction and sex hormones. ECS is located in the hypothalamus, particularly in those areas responsible for producing hormones (ie GnRH) that act through the hypothalamic-pituitary-ovarian (HPO) axis (which controls several aspects of reproduction). The entire ECS was discovered in ovaries, as well. While cannabinoids made in the body are regulated under tight control, plant and synthetic cannabinoids can be detrimental. Overstimulation of the ECS, as seen in chronic marijuana users is linked with abnormal menstrual cycles, reduces sperm count, and reduced levels of sex hormones in both genders.Impaired ECS is also found in PCOS (polycystic ovary syndrome), which is characterized by infertility, anovulation, obesity, insulin resistance and more.In women, various components of the ECS do vary with the menstrual cycle [31],[32]. Due to its close relation with sex hormones, ECS signaling could be used as a therapeutic target in hormone-dependent cancers such as breast, ovarian, endometrial and prostate cancer [33].
8.ECS in the eye
ECS seems to be important in visual processing, the control of intraocular pressure and modulating eye inflammation
It is possible that ECS’ role in eye health may be as important as ECS’s role in brain health.
Endocannabinoid system research: Altered ECS signaling was found in glaucoma, diabetic neuropathy, inflammatory (ie uveitis) and degenerative eye diseases (ie macular degeneration)
The retina is an extension of the brain, and they share similar qualities (ie contains layers of neurons, expresses similar cannabinoid receptors, but also neurotransmitters like dopa, serotonin, glutamate, and GABA). In addition, the retina is connected to the brain by the optic nerve and has its own (ocular) immune system. Therefore, it is possible that ECS’ role in eye health may be as important as ECS’s role in brain health. Although more research is needed, ECS seems to be important in visual processing, the control of intraocular pressure, modulating eye inflammation and preventing degeneration.
All components of the ECS system (receptors, enzymes, and endocannabinoids) are found in various tissues and components of the eye, and shows similar effects with the ECS in the brain (promotes neuroprotection, neuroplasticity in the neurons of the retina). Improving ECS could be used therapeutically to manage glaucoma and other eye conditions. For example, several recent studies show the potential of the ECS, and in particular CB2, as a therapeutic target to treat uveitis and other ocular inflammatory and degenerative diseases [34],[35],[36].
