Recent scientific breakthrough:

Regulation of the body at the deepest level is now possible! Namely epigenetic, in other words, reversible heritable changes in gene function without altering the DNA in the cell nucleus. CBD and THC oil are not the long-term solution! THE ENDOCANNABINOÏDE SYSTEM (ECS)?= Endocannabinoids + cannabinoid receptors + enzymes. The endocannabinoid system is the "master regulator" in the body. "Endo" means "inside" and "cannabinoid" refers to any molecule that activates these receptors. All of our bodily systems are in a constant state of balance. Endocannabinoids help maintain this state when needed. The ECS plays a modulating role in the following systems:

  • Central and peripheral nervous system
  • Hormone System
  • Immune System
  • Metabolism
 
The six main features:
  1. Reducing cellular, oxidative, nitrosative, mitochondrial, chemical, mechanical, immunological, physiological, psychological and other forms of stress;
  2. Reducing chronic, inflammatory and acute pain;
  3. Ontstekingsremmend;
  4. Regulates the release and processing of traumatic experiences;
  5. Preventing and fighting cancer and neurodegenerative diseases;
  6. Social: promoting connection and reducing social anxiety and stress.
 

Pain and inflammation The endocannabinoid system (ECS) is central to fighting pain and inflammation. Most, if not all pain and inflammation inhibitors such as opioids, paracetamol, NSAIDs and aspirin, work through activating the ECS and the endorphin system. The ECS interacts with the endorphin system at a deeper level. So the endocannabinoid system consists of endocannabinoids, cannabinoid receptors and specific enzymes. A further explanation.

  • Endocannabinoids

These are molecules produced by the body itself that activate endo cannabinoid receptors and bind to them. The two main endocannabinoids in the body are anandamide and 2-AG.

  • Cannabinoid receptors

Receptors are a kind of antennae on cells on which molecules can hook up. Cannabinoid receptors play a fundamental role in the functioning of the ECS. They help pass messages of endocannabinoids between cells, as well as from outside the cell to the inside. The two main receptor types of the endocannabinoid system are called CB1 and CB2. These receptors are found on many cell types throughout the body. Various cannabinoids bind to, block or modulate the activity of these receptors. These include endocannabinoids, phytocannabinoids (found in plants) and synthetic cannabinoids (made in a lab such as medications). According to researchers, TRPV1 (transient receptor potential vanilloid one) is also part of the network. Namely, it serves as a receptor for CBD, THC and anandamide. CB1 regulates the release of dopamine via endorphin receptors (MOR) during rewards CB2 regulates the release of endorphins during inflammation and inflammatory pain

  • Enzymes are substances that catalyze chemical reactions. The ECS contains enzymes that both build up and break down endocannabinoids. Fatty acid enzyme amidohydrolase (FAAH) is one of primary enzymes in the system. This breaks down anandamide

 

Anandamide Anandamide is a substance released in response to all kinds of stress. E.g. pain, stress from endurance sports, hyperglutamate, cellular stress, injury and stress hormones. Anandamide activates reward via endorphins and dopamine. The reward effect of anandamide is more intense than dopamine. The nine main functions of Anandamide are:

  1. Antidepressant: along with BDNF, it is a strong feel-good substance;
  2. Activates anti-cancer genes;
  3. The strongest pain inhibitor (stronger than endorphins and enkephalins) via inhibiting the synaptic activity of glutamate and other pain mediators;
  4. Along with 2-AG the strongest glutamate inhibitor (very strong neurotransmitter that acts strongly on other nerve cells);
  5. Anandamide reduces anxiety and social stress;
  6. Has an anti-inflammatory effect;
  7. Restores Th1/Th2 balance (immune system); It reduces Th2 dominance = anti-allergic effect. It additionally acts as an antihistamine just like kaempferol, -an FAAH inhibitor- which inhibits the release of histamine from mast cells and has a beneficial effect in the treatment of lgE mediated conditions such as asthma, hay fever and other allergic respiratory diseases;
  8. Stimuleert de aanmaak van melanine. Melanine is tot 34 keer sterker dan EDTA om zware metalen te ontgiften. Cannabis (THC) vermindert (!) melanine met 75%;
  9. (not actually a function but an obvious relationship) Estrogen connection: estrogen stimulates the release of anandamide.A deficiency or malfunctioning endocannabinoid molecule anandamide in relation to disease:
 
Anandamide Pathology
  • Anandamide is decreased in ADD/ADHD, autism high sensitivity, depression, PTSD and most disorders and complaints with chronic hyperglutamate;
  • Anandamide dysfunctions cause anxiety, dejection, social stress and stress hypersensitivity;
  • Trauma causes impaired functioning of anandamide via epigenetic dysfunctions of the FAAH gene and the anandamide gene, making one hypersensitive to stimuli and stress. In a study of people with PTSD, FAAH inhibitors have a beneficial effect in reducing fear conditioning and anxiety;
  • SNPs (single-nucleotide polymorphism: variation in DNA) are a major cause of anandamide dysfunctions;
  • Dysfunctions of anandamide can lead to short- and long-term memory problems.
 
2-AG 2-AG is released in response to pain, injury, tissue and organ damage, infections, allergies and microbial invasions. 2-AG activates the immune system. In addition to a good status of anandamide and 2-AG, it is important that the receptors on the cells are sensitive enough to receive these molecules: CB1 RECEPTORS CB1 receptors are found mainly in the nervous system, but also elsewhere in the body. Functions and facts of the CB1 receptor The nine most important functions and facts:
 
  1. Connection to insulin; Overstimulation causes hyperinsulinemia (too much insulin production), insulin resistance, a chronic feeling of hunger, and inhibits GLUT4, an insulin-regulated glucose transporter that removes glucose from the bloodstream to the cell;
  2. Neural anti-inflammatory and neuroprotective function;
  3. Cardioprotective: prevents heart attacks, arrhythmias and lowers blood pressure;
  4. Prevents amyloid-P induced neurotoxicity.: e.g. Alzheimer's disease, Parkinson's disease;
  5. It is a tumor suppressor receptor;
  6. Stimulates processing of traumatic experiences;
  7. Anxiety-inhibiting, facilitates social interaction: being social is no longer a stressor but a rewarding factor;
  8. Reduces gastrointestinal complaints such as abnormal defecation pattern (diarrhea, constipation) unexplained abdominal discomfort, cramps, gas accumulation, etc., which occur in irritable bowel syndrome(PDS) or IBS, among others;
  9. Regulates the sensitivity and release of leptin. Leptin is a hormone that activates satiety when eating and is produced in white fat cells. CB1 suppresses the action of leptin in the hypothalamus. This is triggered by such things as a linoleic acid-rich diet, cannabis or antidepressants, causing one to experience a false sense of hunger and continue to eat.
 
Causes of a CB1 imbalance Overexpression, desensitization (reduced sensitivity) and downregulation are caused by overstimulation, SNPs and other factors. Causes of a CB1 imbalance:
 
  1. BDNF depletion: BDNF is the epigenetic protector of CB1;
  2. Glutathione depletion: glutathione regulates intracellular absorption of vitamin D!
  3. Linoleic acid-rich diet enhanced by combination with sugars, flavor enhancers and high-glycemic index agents such as beer, alcohol, corn, starches and exorphins (protein structures from gluten, cow's milk, soy and spinach), junk food and processed foods;
  4. Frequent use of alcohol;
  5. Hyper Cortisol: greatly reduced CB1 expression in the hippocampus;
  6. Acute, toxic and traumatic stress: PTSD, abuse, traumatic experiences, parental stress such as rejection and violence within the family, "social defeat" stress;
  7. Use of drugs: cannabis (THC), XTC, amphetamines;
  8. Use of pain medications: opioids, paracetamol, NSAIDs, aspirin (the latter enhances the effects of CB1 and CB2 receptors);
  9. Use of psychopharmaceuticals: antidepressants, benzodiazepines, antipsychotics.
 
CB2 RECEPTORS Less research has been done on CB2 receptors. They appear in smaller amounts in the body and exist mainly in the immune system. Nevertheless, they appear in lower concentrations in other parts of the body. Relationship CB1 and opioid receptors on the cell The ECS cooperates with the endorphin system. The endorphin system works through opioid receptors KOR, MOR and DOR. CB1 can efficiently "hook up" if enough opioid receptors are available. Relationship of MOR and CB1 receptors and Cholesterol The MOR and CB1 receptors are influenced by the concentration of cholesterol. Cholesterol is essential to activate the MOR receptors. Statins or red yeast rice (lower cholesterol) have a negative effect on MOR expression. In contrast, cholesterol (too low) stimulates CB1 receptors. Probably for the purpose of keeping blood vessels healthy. After all, cholesterol "repairs" the blood vessels in the absence of vitamin C. Relationship ECS with TCH and CBD After explaining endocannabinoids and their receptors, the relationship can be established with the use of popular "feel good" drugs THC (Cannabis) and CBD. Thus, these "drugs"-certainly with long-term use-affect the action of cannabinoid receptors. Medicines and drugs that make you feel heavenly take you to hell afterwards...THC Cannabis (THC) mainly affects the CB1 receptors. It is a strong FAAH inhibitor and a very strong anandamide reuptake inhibitor. This means that the fatty acid enzyme FAAH is inhibited, preventing anandamide from being properly broken down and reuptaken. In addition, THC is the strongest natural exogenous (outside the body) CB1 agonist causing CB1 downregulation in the cortex, reducing memory and motivation. THC is a weak CB2 agonist. THC causes oxytocin resistance, which promotes antisocial behavior. Long-term use of THC increases the risk of COPD, insulin resistance, obesity and cancer. CBD Cannabidiol (CBD) mainly only has a positive effect on CB2 receptors but specifically blocks the binding of anandamide to CB1 receptors and blocks its action. Technical story: CBD is according to the most current information in vivo studies (2019 & 2020) and corrections of misinterpretations of previous in vitro studies:
 
  • A weak partial CB2 agonist (agonist and antagonist), it increases the activity and density of CB2;
  • A NAM (negative allosteric modulator) of CB1, the latter means that CBD blocks the binding of anandamide to CB1 receptors. CBD is not a CB1 antagonist, it has no effect on CB1 density. CBD eliminates the action of anandamide. For this reason, CBD is to be avoided;
  • A FABP inhibitor, it inhibits the transport of anandamide to FAHH. It increases anandamide, but that effect is negated by NAM on CB1. CBD has no effect on CB1 expression and density.
How do I ensure that my Endocannabinoid System can function optimally?
  1. Take as little medication below as possible (in consultation with the doctor, of course):
 
  • Paracetamol: causes anandamide resistance (downregulation of the CB1 receptors), glutathione depletion, endorphin resistance, Th2 dominance (asthma and allergic reactions), leaky cell membranes, mitochondrial damage and strong increase in nitric oxide (NO), increasing nitrosative stress. Furthermore, it has been linked to autism.
  • Paroxetine: cause anandamide resistance via downregulation of CB1 receptors. These drugs cause BDNF depletion.
  • Fluoxitini: cause anandamide resistance via downregulation of CB1 receptors. These agents cause BDNF depletion.
 
  1. Limit Linoleic acid intake and ensure proper omega-6 / omega-3 balance by using appropriate fatty acids
 
Linoleic acid competes with gamma linolenic acid (GLA) and alpha linolenic acid (ALA), an essential omega-3 fatty acid that cannot be produced by the body. Linoleic acid also competes with other omega-3 fatty acids such as EPA and DHA. The energy supply from linoleic acid has increased from 1% to 8% over the last 50 years in America and non-Mediterranean countries. This increased 2-AG up to 300% resulting in widespread 2-AG resistance. As a result, most of the population has low-grade (chronic) inflammation. Linoleic acid: concentrations in vegetable oil:
 
  • Safflower oil and grape seed oil: 80%
  • Sunflower oil: 70%, a 15 g serving of mayonnaise contains 10 g of linoleic acid
  • Hemp oil: 50-70%
  • Walnut oil: 57%
  • Corn oil: 55%
  • Soybean oil: 50%
  • Rice oil: 40%
  • Peanut oil: 25%
  • Rapeseed oil: 20%
  • Avocado oil: 13% (50% oleic acid)
  • Olive oil: 8% (75% oleic acid)
  • Coconut oil: 2%
 
Avoid overconsumption of vegetable oils. Exceptions are coconut oil, avocado oil and olive oil. Make your own mayonnaise, such as with olive oil or avocado oil. Eat nuts, seeds and vegetable milk in moderation Nuts and seeds also contain relatively high amounts of linoleic acid. Excess linoleic acid promotes inflammation/inflammation (linoleic acid> arachidonic acid), and can unbalance the ECS. The good plant-based milk is organic coconut milk. All other milk substitutes are relatively high in linoleic acid. Walnuts, chia seeds and perilla nut are recommended. Flaxseed contains too many phytoestrogens (estrogen-like substances from plants with female "action"). Flaxseed oil contains no phytoestrogens. Omega-3 fatty acids and the ECS
 
  • DHA and EPA (omega-3) play an important role in the regulation of the expression and density of CB1 and CB2 receptors. DHA stimulates the production and expression of BDNF and thus is a central substance in the regulation of the ECS;
  • DHA (not EPA) reduces overexpression of CB1 receptors in a linoleic acid-rich diet;
  • DHA (not EPA) increases leptin sensitivity in the hypothalamus;
  • DHA and EPA provide flexibility to the cell membrane, improving cell metabolism and signaling of neurotransmitters and hormones.
 
Foods in omega-6 vs omega-3 ratio: Almonds 2000:1 Sunflower seeds 310:1 Cashew nut 125:1 Pumpkin seeds 114:1 Hazelnuts 90:1 Sesame seeds 57:1 Pistachios 52:1 Pecan 21:1 Walnuts 1:4 Chia seeds 3:1 Flax seed 4:1 Perilla nut: 5:1 Linoleic acid and obesity It is not the number of calories in fat that are critical to obesity but the fatty acid composition (omega-6 vs. omega-3) of the diet! Linoleic acid fattens (omega-6, white fat), gamma linolenic acid (GLA) slims (omega-3, brown fat). Omega-3 neutralizes (DHA-EPA) the fattening effect of linoleic acid, at an additional intake of omega-3 of about 10 to 15% of the energy supply from linoleic acid. White adipose tissue serves to store energy (fats). White adipose cells consist of one large fat droplet and have few mitochondria (energy factories). White adipose tissue produces leptin, the hormone that suppresses appetite.
 
  • At normal weight, 20 to 25% of body weight consists of white adipose tissue. Overweight people have too much white adipose tissue.
  • Linoleic acid stimulates the production of white adipose tissue.
 
CB1 receptors increase fat storage in white adipose tissue and promotes leptin resistance. CB2 receptors stimulate white fat cell breakdown and fat breakdown in white adipose tissue. CB2 activation helps to lose weight. Brown adipose tissue containing many mitochondria (energy factories), serves for heat production. It converts energy (fatty acids and glucose) into body heat. This dynamic becomes especially active in cold conditions. Slim people have more brown fat than obese people. Evening primrose oil, black currant oil and borage oil contain gamma linolenic acid that stimulates brown fat production. Supplement in moderation (because of the omega-6 vs. omega-3 ratio)!Alpha linolenic acid
 
  • Alpha-linolenic acid (ALA) is an omega-3 fatty acid. It is considered the "mother omega-3" because ALA is converted into EPA and DHA;
  • ALA increases the expression of CB2 receptors in humans when one supplements 2.5 grams of ALA from flaxseed oil for 10 weeks. The effect begins from the third week;
  • Linoleic acid is the competitor of alpha linolenic acid, gamma linolenic acid, EPA and DHA. The DHA and EPA deficiency occurs because of the typical Western diet rich in linoleic acid;
  • The highest concentration of ALA is found in flaxseed oil (75%), perilla oil (60%) and chia seeds (55%).
 
Gammalinolenic acid Gammalinolenic acid (GLA) is a non-essential fatty acid, a "good" omega- 6 that, among other things, stimulates the production of brown fat. GLA is a rare fatty acid and is found in the oils of evening primrose, blackcurrant and borage. Contrary to what one might expect, GLA has anti-inflammatory effects. Oleic acid
 
  • Oleic acid or olein is the main unsaturated fatty acid; it belongs to the omega-9 fatty acids. Unlike omega-3 and omega-6, it is not an essential fatty acid;
  • Oleic acid is the precursor of oleoylethanolamide, which increases upon FAAH inhibition. Oleoylethanolamide activates the PPAR-alpha receptors that inhibit nitric oxide (NO), thus contributing to lowering nitrosative stress. Presumably one of the reasons why a Mediterranean diet is healthy. Oleic acid inhibits neuropeptide Venghrelin, reducing appetite when CB1 is overstimulated by a high-fat diet;
  • Oleic acid increases the expression of the "anti-obesity" CB2 receptors in fat cells, thus helping to reduce the inflammatory effects of fat cells due to stress, obesity and excessive CB1 stimulation. Oleic acid stimulates the sense of satiety;
  • Olive oil contains the most oleic acid at 75%, followed by macadamia nut (60%),hazelnut (52%), pecan (43%), rice oil and sesame oil (42%), almond (35%) and cashew (28%).
 
Recommended oils Most nuts and vegetable oils contain too much linoleic acid, which quickly leads to more than 1% of the recommended intake of linoleic acid, or 2 grams of linoleic acid per day. The most suitable oils in the kitchen are:
 
  • Avocado oil: 50% oleic acid, 13% linoleic acid
  • Olive oil: 75% oleic acid, 8% linoleic acid
  • Coconut oil: 6% oleic acid, 2% linoleic acid, also suitable for frying
  • Ossewit: frying
 
Chia seeds and flaxseed oil are the best sources of alpha-linolenic acid. For gamma linolenic acid, borage oil is preferred in doses up to a maximum of 2.4 ml (= 2 grams), equivalent to 400 mg of GLA and 800 mg of linoleic acid. TREATMENT of ECS dysfunction:
 
  • Drastically reduce linoleic acid;
  • Bring ratio of omega 6:omega 3 to the ratio of 1:1;
  • Measurement in blood of Vitamin D and Glutathione. In case of measured deficiency supplementation;
  • Employ 2 specifically developed supplements to enhance CD1 and CD2 receptors.
 
The Endocannabinoid System underlies optimal cellular function. Many diseases can be prevented and/or cured by restoring this system. BeterKliniek is one of the first in the Netherlands to specialize in expert treatment of the ECS. 
 

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