Palmitoylethanolamide is a molecule that evolved hundreds of millions of years ago. It was first syn-thesized by coelenterates – invertebrate animals that live in the sea. Even single-celled organisms such as yeast cells produce palmitoylethanolamide. (35) The cell and tissue protective effects of pal-mitoylethanolamide were subsequently incorporated into the evolution of many animals and this also explains the absence of side effects lone and the very broad applicability. The preventive and therapeutic effects of palmitoylethanolamide are traced back mostly to its biological activity. Palmitoyl-ethanolamide normalizes some out-of-balance biological processes such as chronic inflammation or damage due to trauma or lack of oxygen. This is done, internally, through the influence of a specific nuclear receptor *, which is called the PPAR receptor *. (36,37) This nuclear receptor restores the bal-ance in cells that are brought out of balance, causing these cells to stop producing too many inflamma-tory substances, and pain-promoting substances (see figure 2). (38,39) The activation of this nuclear receptor also plays an important role in analgesia. (40) Palmitoylethanolamide can be formed in many cells, and can operate in case of chronic pain. (41,42 ) In fact, it is a part of a natural anti-pain system in our body. (43) Palmitoylethanolamide will find its place in any chronic pain syndrome, for example in cases where excessive activation of certain cells cause an inflammation, such as the mast cells and the glial cells *. It has been known for a few years that these non-neuronal cells maintain chronic pain. Therefore, it is of great importance to inhibit these activated inflammatory cells in their excessive activ-ity. That’s exactly what palmitoylethanolamide does. It puts these cells that cause chronic pain in the body, cheap jerseys to rest. (44,45) In addition to the calming effect on mast cells and glial cells, there are many oth-er action mechanisms that need yet to be identified. (46-48)

Palmitoylethanolamide has anti-inflammatory, cytoprotective and analgesic effect. It also has anti-carcinogenic, neuroprotective and neuroregenerative effects. It brings balance in disturbed body processes. (49.50) As a result, palmitoylethanolamide can be used during a large number of disease states. (51-53)There are a number of diseases in the respective six groups presented in Figure 3.

Operation of palmitylethanolamide

Figure 2: The effect of palmitoylethanolamide

FAAH: Fatty acid amide hydrolase * PPAR: Peroxisome proliferator-activated receptor *

NAPE N-acyl phosphatidylethanolamine * PEA: palmitoylethanolamide

 

Indications for palmitoylethanolamide

There is experimental evidence and / or evidence from clinical studies that palmitoylethanolamide van be used in a large number of disorders. (54)

Chronic pain

1.arthrosis and arthritis (56-58)
2.migraine
3.menstruation (59)
4.pelvic disorders (60,61)
5.prostate diseases
6.endometriosis (62.63)
7.chronic low back pain (64-66)
8.chronic unexplained abdominal symptoms (67,68)
9.neck pain and whiplash injuries
10.Fibromyalgia (69)
11.pain after tooth extractions (70)
12.visceral pain syndromes * (71.72)

Neuropathic pain

1.hernia (74-76)
2.carpal tunnel syndrome and other nerve entrapment syndromes (77,78)
3.shingles (79)
4.multiple sclerosis (80,81)
5.pains and spasm after a stroke (stroke) (82)
6.chronic idiopathic axonal neuropathy (CIAP *) (83)
7.diabetes type 1 and 2 (85)
8.chemotherapy (85)
9.radiation treatments for cancer
10.complex regional pain syndrome * (CRPS) or Sudeck pains (86)
11.neuralgic pains * (87)

Chronic inflammations

1.Chronic low-grade inflammation (88)
2.degenerative diseases, such as Alzheimer’s disease and Parkinson’s disease (89,90) (it can be noted that in degenerative diseases neuro-inflammation plays a major role, and there are no clinical studies about the effects of palmitoylethanolamide in these disorders)
3.MS and amyotrophic lateral sclerosis (91.92)
4.enteritis (Crohn’s disease, Inflammatory Bowel Disease)
5.metabolic syndrome in obesity (93)
6.atherosclerosis (94)
7.whooping cough (95)
8.vaginitis, * vulvodynia, vestibulitis * (96,97)
9.bladder pain syndrome *

Acute inflammation

1.influenza (98,99)
2.colds (100)
3.acute trauma (101)

Because palmitoylethanolamide activates a universal biological mechanism, this supplement is also of huge therapeutic value for pets that have chronic pain or inflammation. (102) Thus, in 2014, in United States, many dogs who had suffered  from chronic pain syndromes  were successfully treated.

 

Chronic pain

Many of the clinical studies on palmitoylethanolamide focus on chronic pain, including difficult to treat, neuropathic pain. The most extensive clinical placebo-controlled trial in chronic pain was conducted in Italy with 636 patients with severe pain from herniated disc. Here, a significant reduction of pain was noticed after few weeks (on a Visual Analogue Scale from 7 to 2) at a dose of 600 mg palmitoylethanolamide per day. (74) In addition to this, many other clinical studies in the field of chronic pain have been done to show the beneficial effects. (29)

A good measure of the effectiveness of an analgesic is the Number Needed to Treat (NNT). This indicates again the number of patients to be treated in order to get a patient who has benefited from the treatment. It’s very impressive that palmitoylethanolamide has an NNT of 1.5 for chronic pain. That’s a very good score compared with amitriptyline, a regular painkiller and antidepressant, which is often used in this indication. Amitriptyline has an NNT of only 4.6 and has much more side effects. Palmitoylethanolamide is effective and safe in chronic pain and should be considered more often as a treatment option. (178)

 

Indication for palmitylethanolamide

Figure 3: Indications for palmitoylethanolamide (some terms from this condition in the glossary in the back).

 

Protection of cells and tissues

Palmitoylethanolamide has wide biological activity. In many animal experiments involving cell or tissue damage, it has been found that palmitoylethanolamide can protect cells and tissues from damage. (103) This was first noticed in the eighties. (104.105) Palmitoylethanolamide had a protective effect on the heart muscle. (106) Recent news showed that palmitoylethanolamide also can protect the kidney, which is especially important for diabetics. (107)

 

Prevention and treatment of diabetes complications

Palmitoylethanolamide owns preventive and therapeutic values which help in cell and tissue damage related to diabetes type 1 and 2. Various experiments  as well as clinical meanwhile studies (108) indicate that the three major effects of palmitoylethanolamide are the following:

Inhibits cell damage as a result of oxidative and inflammatory processes

Promotes repair mechanisms

Encourages regeneration

These mechanisms can be of great significance to the tissue and organ damage that may develop long term in people with diabetes.

 

Diabetic polyneuropathy

Half of all diabetic patients are affected by peripheral neuropathy caused by oxidative damage of the peripheral nervous system. This is the part of the nervous system that transmits impulses between the central nervous system (spinal cord and brains), and the muscles, glands and sensory organs of the body. The symptoms that arise, usually manifest by numbness in limbs, pain, motor problems and loss of function. But also the nerve conduction to vital organs such as heart, liver and kidneys can be disturbed.

In Italy palmitoylethanolamide is given as prescription in diabetic painful neuropathy, retinopathy and eye disease *. (109.110) Clinical studies show the value of palmitoylethanolamide in neuropathic pain caused by diabetes. (111) A placebo-controlled study has shown that palmitoylethanolamide (1200 mg / day), improved the disrupted nerve conduction and reduced the pain. (112) It has been discovered that palmitoylethanolamide can have nerve-protective properties, which is particularly of interest in a disorder such as diabetes. (113)

 

Cataract and diabetic retinopathy

Diabetes increases the risk of retinopathy and other eye disorders. Palmitoylethanolamide is going to inhibit the development of cataracts against the inflammatory and oxidative processes. (114) It is formed in the nerve cells of the eye, presumably to protect the cells against “the attacks of sugars.” (115) Research on rats with palmitoylethanolamide shows that the development of diabetic damage to the eyes can be slow, in addition, can lower the blood pressure (which is also beneficial to the eyes), and it could also have a protective effect on the vessel wall. (116.117)

 

Diabetic nephropathy

It is now clear that the renal damage that occurs in diabetes is the result of a chronic inflammation. (118.119) Diabetes mellitus is the most important cause of chronic renal failure. Palmitoylethanolamide activates the nuclear receptor (PPAR receptor) with which the kidney is protected. (120) In an animal model for diabetes mellitus, palmitoylethanolamide (30 mg / kg / day) was used to oxidative the stress in the body stress during the disease process. (121) The compound can be taken into consideration during kidney transplants and it also appears to limit palmitoylethanolamide kidney damage due to lack of oxygen.(122)

 

Protection of the nervous system

Palmitoylethanolamide readily crosses the blood-brain barrier and protects the nerve tissue against oxidative stress, lack of oxygen and neuroinflammation. (123,124) Especially in the brain (which has a high energy requirement) many free radicals are formed, and this substance may play an important protective role. (125) It is palmitoylethanolamide that can protect the nervous tissue against ischemia-reperfusion injury * (after a stroke), and acute damage to the central nervous system. Palmitoylethanolamide protects both the nervous tissue and the blood vessels in an animal model of brain tissue injury (126) In this model, it turns out that palmitoylethanolamide has many important biological effects:. It inhibits the infiltration of inflammatory cells in the damaged brain tissue, it restores the homeostasis level of some important markers such as nitrotyrosine and iNOS * *. Finally, palmitoylethanolamide restores the disturbed behavior of the animals with brain damage. All this leads to clear neuroprotective effects. (127) In the neurodegenerative disorders, a beneficial effect is also observed, including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. (128-131) Palmitoylethanolamide inhibits the inflammation-related and age-related cognitive decline in Alzheimer’s models and improves the long-term memory in aged animals. (132) Therefore, on the basis of these studies, palmitoylethanolamide is seen as a neuroprotective agent. (133.134)

 

Kidneys and bladder protection

Recent studies have shown that palmitoylethanolamide (30 mg / kg / day) can protect the kidneys against oxidative damage. (135) In addition, it can protect the kidneys against damage caused by a too high blood pressure, too. (121) In experimental cystitis palmitoyl-ethanolamide decreases the pain-related aspects such as the brakes inflammation.(136.137) The chronic pain reflexes that can occur in the chronic urinary tract infections could be slowed down by palmitoylethanolamide. (138)

 

Protection of heart and blood vessels

Dysfunction of vascular endothelium (caused by decrease in formation of nitric oxide in the vascular wall) leads to a decreased vasodilation, increase in blood pressure, increase in atherosclerosis and an increased risk of thrombosis. Palmitoylethanolamide has a favorable influence on the pathologic process. (139.140) A recent study has demonstrated that palmitoylethanolamide protects the heart against damage by ischemia-reperfusion (in angina pectoris, myocardial infarction) via anti-oxidative, anti-apoptotic and anti-inflammatory mechanisms.

 

Support for cancer

Indications that palmitoylethanolamide has anti-cancer characteristics date back to the last century. (141) It may protect against cancer (progression) by several mechanisms, including inhibition of pro-inflammatory cytokines such as TNF-α: a well-known mechanism of action of this substance. But there are additional reasons that may explain the anti-cancer effect of palmitoylethanolamide. (142.143) Palmitoylethanolamide and similar natural molecules, appear to promote apoptosis (cell death) in cancer cells. (144) A model of melanoma cancer showed that palmitoylethanolamide growth is able to inhibit the malignant cells. (145) Strikingly surprising, supplementation with palmitoylethanolamide in animal models was able to prolong significantly the survival in certain types of cancer. (146) Similarly, in breast cancer, palmitoylethanolamide and related natural molecules can have a relevant effect. (147.148) Palmitoylethanolamide also appears to be able to inhibit the excessively active metabolism of cancerous cells. (149)

 

Protection of intestines

In an animal model, damage in the intestines was caused by a blockage of the blood supply. Palmitoylethanolamide appeared to limit this damage. (151) In a recent in vitro study, it was observed that palmitoylethanolamide had an inhibitory effect on various proinflammatory markers, and that the macroscopic aspects associated with inflammatory bowel disease such as ulcerative colitis were able to improve. (176)

 

Flu and colds

In six clinical double-blind and placebo-controlled trials with more than 3,000 people, it was found that palmitoyl ethanolamide is effective and safe in the treatment and prevention of flu and colds. The dosages which were used here, ranged between 1200 and 1800 mg per day. In these studies it was shown that palmitoylethanolamide is safe and without side effects, even in young children over 4 years. For children, the dose was maintained from about 20 mg / kg body weight. Overall, the ones that received palmitoylethanolamide had 30-60% less chance of getting the flu. If the flu was already present, supplementation with palmitoylethanolamide was definitely reducing the severity of the symptoms and the sick feeling. In addition, significantly fewer flu cases lasted longer than those who were not supplemented at all. Palmitoylethanolamide appears to be an important new prophylactic and therapeutic treatment of flu. The operation has the potential to be used as a natural and safe alternative to flu vaccinations and flu remedies. (177)

 

Other possible applications of palmitoylethanolamide

Various (pre-clinical) studies and clinical cases indicate other possible applications of palmitoylethanolamide:

Burning mouth/tongue burning (burning mouth syndrome): this condition is likely to be the result of a small fiber peripheral neuropathy. Palmitoylethanolamide (1200 mg / day) helps in this case, especially when it is used together with R-alpha lipoic acid.

Osteoarthritis, rheumatoid arthritis and other rheumatic conditions: in vitro studies and animal studies suggest that palmitoylethanolamide helps relieve the joint inflammation and the associated chronic pain.

Migraine: A pilot study suggests that palmitoylethanolamide (1200 mg / day) reduces the frequency, duration and reduces severity of migraine attacks.

Glaucoma substances, such as palmitoylethanolamide, play a role in protecting the eye in glaucoma. (152-154) Supplementation with palmitoylethanolamide (1200 mg / day) resulted with improvement in intraocular pressure in two different clinical trials (155.156) as the single use of palmitoylethanolamide in glaucoma gave moderate effects. However, the treatment regimen of glaucoma and the effectiveness of the other agents needs to be improved. •

Itching: palmitoylethanolamide relieves pain but also appears to reduce itching (157).

Kounis angina: this specific form of angina is characterized by many excessively activated wholesale mlb jerseys mast cells in the heart (158.159); palmitoylethanolamide can stop the mast cell activation. (160)

Atopic eczema and psoriasis: Palmitoylethanolamide also can help these two inflammatory conditions.

Various chronic diseases in which mast cells play a pathological role, including irritable bowel syndrome. (165-167)

 

Metabolism

Palmitoylethanolamide can be produced in virtually every cell of the body. Its synthesis is a so-called on-demand synthesis. This means that the palmitoylethanolamide is produced by the cells, if it is necessary. This is necessary in situations in which tissue and cells are damaged. These situations range from inflammation, such as influenza or whooping cough, up to infarcts and situations with injuries of nerves that lead to chronic pain. However, in certain situations, the body’s own palmitoylethanolamide formed in the cell is accelerated by intracellular enzymes, such as the FAAH enzyme *. In cancer cells, for example, that enzyme is active as a part of the whipped cancer cell metabolism. The cancer cell-inflammatory and pain-relieving palmitoylethanolamide is therefore present in the cell in a low concentration. The same is true for other chronic diseases. In these situations, the cell attempts to synthesize additional palmitoylethanolamide, but this is not always enough. In those pathological situations with too little production and/or too much degradation, it is useful for an extra palmitoylethanolamide to be prescribed as a dietary supplement.

The metabolism of palmitoylethanolamide in each cell is in simple. The cell can produce palmitoylethanolamide from fatty substances that are already present in the cell membrane (via the precursor NAPE *). The degradation is simple, each cell in which palmitoylethanolamide can be made is available on the FAAH enzyme. This enzyme can produce palmitoylethanolamide again by breaking down into its building blocks which are then again to be included in the membrane. A good example of recycling within the body.

 

Safety

The studies of palmitoylethanolamide show that no negative side effects have emerged, not even when used by elderly people and children. (29,30) In clinical studies, doses up to 100 mg / kg of body weight per day are without adverse effects (apart from tiny side effects that occur as placebo effect). (168)

Questions about whether palmitoylethanolamide is safe to be used during pregnancy is still insufficiently studied. Presumably, it is just as safe as peanuts and eggs. Since the breakdown of palmitoylethanolamide is so simple and occurs at the cellular level, dosage adjustment in renal impairment is probably not necessary. This also applies to liver failure. Nevertheless, it is recommended to be more cautious in renal and hepatic conditions, starting with 400 mg once per day and increasing the dose slowly (within one week) to the normal dose of 1200 mg / day.

To our knowledge, there are no negative interactions between palmitoylethanolamide and regular medicines.

 

Synergy

Together with analgesics: palmitoylethanolamide increases the effectiveness of analgesics such as opiates, amitriptyline and pregabalin. Also, it can be used to reduce the dosage of these substances, or to be replaced after some time. (169-171)

Along with cytostatics: palmitoylethanolamide protects against the toxic effects of many resources that are given as part of chemotherapy. It is recommended that, where possible and in consultation with the oncologist, to start the chemotherapy with palmitoylethanolamide (1200 mg / day) and stop a few months after chemotherapy. Furthermore, palmitoylethanolamide has a significant anti-tumor activity, making the administration of chemotherapy along with palmitoylethanolamide have a dual therapeutic effect: a better functioning of the chemotherapy and better protection of the body cells from the side effects of chemotherapy.

In diabetes: Palmitoylethanolamide and R-alpha lipoic acid have synergistic effects on oxidative stress in a diabetes condition, palmitoylethanolamide R-alpha lipoic acid should be considered at least three times per day/100 mg. The combination of palmitoylethanolamide and alpha lipoic acid has an analgesic and cytoprotective effect.

Other: palmitoylethanolamide can also be prescribed together with supplements such as acetyl-L-carnitine in symptoms of neuropathic nature. The combination with vitamin D3 supplement may also be very useful in chronic pain.

 

Palmitoylethanolamide: choose a pure form

For the most optimal operation of palmitoylethanolamide, it is important to choose the purest product, without the addition of any unnecessary excipients or other ingredients such as herbs for which the efficacy in combination with palmitoylethanolamide has not been studied. (31) In addition, the dosage is also important. Not all products found on the market contain a high enough dose per capsule or tablet.

 

Dosage and Use

The standard recommended daily dose of palmitoylethanolamide for therapeutic purposes is 1,200 mg, preferably divided over the day (eg 400 mg in the morning, afternoon and evening or 800 mg in the morning and 400 mg in the evening).

Palmitoylethanolamide has a number of different mechanisms, including rapid (172.173) and slower mechanisms. (174.175) It may also be that the analgesic effect start slowly. Therefore, use it at least for two months. Only after two months of consistent use, the operation of palmitoylethanolamide can be properly assessed. If, after one month of use, the effects can’t be noted, the dose can be doubled. However, where rapid analgesia is required, it has been found in practice that intake of palmitoylethanolamide can be useful if sprinkled under the tongue. This may provide rapid absorption into the blood through the blood vessels of the oral mucosa. If, after two months, the desired effect is achieved, the dosage can be reduced in many cases up to 800 mg per day.

After four months, a dose of 400 mg per day can be sufficient or it may be even needed to terminate the intake fully. If the result decreases after lowering of the dosage, it is recommended to increase the dosage again to 800-1200 mg.

Maintenance dosage for people without serious health issues can be maintained at around 400 mg per day. A prophylactic dose at a time of flu epidemics can be 400 mg twice daily. At the outbreak of influenza the recommended dose is 1200-1600 mg per day.

The inclusion of palmitoylethanolamide as a supplement is probably better if the supplement is taken after meals, but there is no clear research that has been done.

 

Glossary

Mast cells: cells which are located in the lining of the respiratory tract, nose and intestine, but also in the skin and other tissues. Among other substances, these cells produce histamine which is stored in granules. Mast cells can become activated by, for example, damage or contact with an allergen. The content of the beads is then released and causes an inflammatory response.

Nuclear Receptor: A receptor which is located in the cell nucleus and can bind with certain substances such as hormones. Through the binding of these substances, the DNA is influenced which then causes certain genes to be more or less expressed (an example of this is when palmitoylethanolamide binds to the nuclear receptor and this influences the DNA in a way which reduces the production of inflammatory factors).

Receptor PPAR: peroxisome proliferator-activated receptor; a specific nuclear receptor that occurs in different types of tissues. Originally, it was thought that these receptors were able to grow in the cell. Later, it was found that PPAR receptors have many more features and that they play an essential role in cell differentiation, growth and metabolism of higher organisms.

Glial cells: (Greek: glia = adhesive) non-neuronal cells that occur in the nervous system and protect and take care of the neurons. The ratio of glial cells / nerve cells is about 10: 1. In contrast to the glial cells, the neurons are unable to divide.

CIAP: chronic idiopathic axonal neuropathy; a condition of the nerves which has an unknown cause and leads to a reduction or change of feeling and an insufficient muscle function.

Sciatica: full ischiasneuralgie; a form of nerve pain (neuralgia) in the back. The pain is caused by pressure on the roots of the sciatic nerve, where they come out from the spine. Sciatica is often caused by a spinal hernia.

Perineal nerve pain: nerve pain in the area between the genitals and the anus.

Vulvodynia: burning sensation, tingling and pain in the vulva.

Interstitial cystitis: also known as painful bladder syndrome or bladder pain syndrome; this is a recurrent disorder that causes discomfort and pain in the bladder and the surrounding pelvic area, and which is not caused by a bladder infection or a kidney stones.

Slow inflammation: chronic low-grade inflammation.

Visceral pain syndromes: pain in one or more organs (viscera).

Complex regional pain syndrome (CRPS or Sudeck pains): a syndrome with continuous pain in a limb, often with a burning feeling, usually after an injury or surgery and inactivity. These changes occur in the senses, the muscle functions and blood flow.

Neuralgic pains: neuralgia.

Vestibulitis: a condition that gives a lean, painful and burning sensation at the entrance of the vagina.

Retinopathy (retina = retina; -pathie = disease) the impairment of the retina, the light sensitive membrane behind the eye. This is often a result of damage to small stroke veins and capillaries of the eye, which include poorly controlled diabetes mellitus.

Ischemia-reperfusion Your injury: injury that occurs in the tissue as a result of the recovery of the blood flow in tissues that have oxygen deficiency, for example, by an infarct. Instead of restoration of the original functions, it provides a restoration of the blood circulation in the first instance, an increase in oxidative stress and inflammation.

Nitrotyrosine – a substance that can show up in the body due to oxidative damage. It is used as a marker for cell damage and inflammation and is increased in certain conditions such as rheumatoid arthritis.

iNOS: nitric oxide synthesis; enzymes that catalyze the synthesis of nitric oxide (NO) catalyst. NO is a very important messenger substance in the body. iNOS (inducible NOS) is important for the production of NO at defense reactions and is increased in inflammatory processes.

FAAH enzyme: fatty acid amide hydrolase; an enzyme that allows the degradation of palmitoylethanolamide and related molecules in the cell.

NAPE N-acyl phosphatidylethanolamine- the precursor of palmitoylethanolamide in the cell. NAPE is formed from phospholipids that are present in the cell membrane and then react with the aid of certain enzymes in, among other things, palmitoylethanolamide.

 

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