Palmitoylethanolamide (PEA): The Multiple Target Molecule · 2020. 1. 14. · Palmitoylethanolamide (PEA) is an 18-carbon long- chainfatty acid that is typically found in eggs, milk,

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The body has multiple systems that help regulate and maintain normal housekeeping – nervous, circulatory, immune, endocrine and gastrointestinal systems, to name a few. These systems not only modulate different tissues and organs to function properly, but also facilitate communications both within the system and with other systems.

As recent as the 1990s, another system was identified and termed the Endocannabinoid System. It also helps with communication, and it prepares the body against attack by a variety of harmful insults: stress, carcinogens, pain, inflammation, infections, UV damage, etc. Initially the definition was confined to what were referred to as the endocannabinoids (ECs), that being two molecules – arachidonoylethanolamide or anandamide (AEA) and 2-arachidonoylgycerol (2-AG) – produced by the body which act on the two cannabinoid receptors (CB1 and CB2) located throughout the body (mainly the central nervous system and immune system, respectively). The enzymes that help in the synthesis and breakdown of ECs were included as part of the system.

Further research has since identified more players thought to have critical roles in this system, including additional enzymes, other receptors (including some “orphan” receptors), as well as other molecules that the body produces including fatty acids palmitoylethanolamide (PEA), oleolylethanolamide (OEA), stearolyethanolamide (SEA), linoylethanolamide (LEA) etc. As a result, the definition of this vital system has been expanded within the scientific community to be more encompassing, and now is

Palmitoylethanolamide (PEA) is an 18-carbon long-chain fatty acid that is typically found in eggs, milk, cheese, meats and peanuts, and is especially abundant in soy lecithin (Appendix 1).

PEA is an intriguing health molecule that has been studied for over eighty years. What makes it unique is being a natural molecule made by the body whenever the demand arises; for example, during stress (psychological and physical), infections (viral and bacterial [e.g., colds and flu]), various forms of inflammation, trauma, allergies, pain, cardiac disease, kidney disease and obesity. It is responsible for maintaining overall cellular health or homeostasis.

In the body, PEA is synthesized from the phospholipids which make up all membranes. Since all cells are made up of membranes, it is no wonder PEA is found everywhere in the body and is available to all cells efficiently and quickly. PEA is significant not only as a cellular messenger, relaying information to and fro in the body, but also in acting as a quick fix or solution to cellular needs. In short, PEA is a go-to-molecule which maintains optimal cellular health throughout the body.

Synthesis of PEA takes place by the enzyme N-acylated phosphatidylethanolamine–phospholipase

referred to as the Endocannabinoidome. In common parlance, however, it is still referred to as the Endocannabinoid System, hence the title of this White Paper.

BAC KGRO UND: THE ENDOCANNABINOID SYSTEM

INTRODUCTION: PALMITOYLETH ANOL AMIDE (P EA)

Palmitoylethanolamide (PEA): The Multiple Target Molecule

By Dr. Traj Nibber, Founder and CEO of Advanced Orthomolecular Research

KEY PLAYER IN THE ENDOCANNABINOID SYSTEM

PEA: The Multiple Target Molecule



D (NAPE-PLD). Once PEA has performed its function, it is rapidly broken down by two enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amide hydrolase (NAAA) (Fig. 1).

ORIGIN

Alvin F. Coburn first studied PEA while researching the effects of egg yolk in preventing the recurrence of rheumatic fever in poor children living in New York in 1939. He found that the phospholipid fraction in egg yolk could effectively prevent streptococcal infection. Additional follow-up studies in New York as well as Chicago confirmed the effectiveness of the phospholipid fraction during outbreaks of infection. Later, soy phospholipids were found to be a more plentiful and cheaper source, and it was confirmed that PEA was indeed the active fraction. Since then, PEA has been extensively studied in numerous health conditions (Appendix 2).

MECH ANISM O F ACT IO N

It is important to know how a drug works, especially at the molecular level. Knowing a drug’s “mechanism of action” allows researchers to develop optimal formulations, dose and delivery systems to be tested in clinical trials. It took almost fifty years after PEA’s initial discovery before its mechanism of action was finally worked out. The credit for this goes to Italian

researcher Rita Levi-Montalcini and her work in the early 1990s. Italian scientists remain world leaders in the field of PEA research.

PEA has actions both in the central nervous system and the peripheral nervous system. However, PEA does not have a direct effect on CB1 or CB2 receptors, which differentiates it from the action of specific phytocannabinoids derived from marijuana or hemp (e.g., cannabidiol [CBD] or tetrahydrocannabinol [THC]). Instead, PEA works through a number of different mechanisms (Fig. 2). • Direct action by down-regulating the mast cells. Mast cells are present throughout the body and play a key role in immunity, inflammation, allergies and neural health. PEA has been shown to either prevent their recruitment to the site of damage and/or inhibit their degranulation or release of histamine and other key inflammatory mediators in many pathological conditions. Researchers have shown that when treated with PEA, mast cells switch from an “active” stage to a “resting” phenotype, meaning they become dormant. This suggests PEA could be a powerful molecule for immune health, inflammation, pain, neuro-protection and especially allergies.

• Direct action on orphan receptors like GPCR55 and GPR119 that produce results similar to the classical activation of the CB1 and CB2 receptors by phytocannabinoids like THC and CBD.

• Direct action on the perioxisome proliferator activated receptor alpha and delta and gamma (PPAR-alpha, delta and gamma). PPARs are transcription factors in the nucleus that can switch on and off genes that control pain and inflammation. PPARs also have other functions in obesity and glucose metabolism.

• Indirect action on other receptors like transient receptor potential vanilloid-type 1 (TRPV1, also known as capsaicin receptor), which opens or closes ion channels allowing a flow of sodium, magnesium and potassium ions into cells and is associated with transferring pain signals.

• Direct action by inhibiting enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL) that degrade the naturally produced endocannabinoids (ECs) AEA and 2-AG respectively, thus allowing for prolonged therapeutic action of these ECs on CB2 receptors.


Figure 1. Diagrammatic representation of the synthesis and breakdown of PEA.(Source: Skaper et al., 2018, p. 15)



UNIQUE EFFECTS OF PE A

Entourage EffectThe entourage effect is an indirect mechanism of action whereby the biological effects of ECs and phytocannabinoids are enhanced by related naturally produced molecules like PEA, which do not produce those effects by themselves. The enhanced effect may occur either by preventing the breakdown of ECs or phytocannabinoids through inhibiting the enzymes that degrade them, or by increasing the receptor binding affinity of ECs or phytocannabinoids. PEA has been shown to display the entourage effect in different health conditions. An elegant demonstration of this occurred in hypertensive rats, where it was observed that blood pressure was reduced with the addition of PEA to otherwise ineffective doses of AEA (Garcia et al., 2009).

Cannabinomimetic effectsA remarkable feature of PEA is that its chemical structure is very similar to the ECs (both AEA and 2-AG), even more so than the phytocannabinoids (derived from various sources, chiefly hemp and marijuana) (Fig. 3). In fact, the structural similarities allow PEA to produce effects similar to the ECs as well as enhancing the effects ofexogenous phytocannabinoids.

PEA Formulation and BioavailabilityPEA is a lipid molecule so it has poor solubility, absorption and overall bioavailability. In order to overcome these hurdles, novel delivery systems are required, including nano-emulsions, liposomes, solid lipid particles and other nano-delivery systems (Conte et al., 2017). Alternatively, bioavailability may also be improved through by-passing the first-pass effect of the liver, so that absorption occurs via the lymphatic system as opposed to the circulatory system (Zgair et al., 2017).

FIG URE 2. DIAGR AM M ATIC REP RESENTATION OF MECH ANISMS OF ACTION OF PEA.


A shows synthesis and breakdown. B depicts a direct effect of PEA on PPAR-alpha and GPR55 receptors. C depicts a direct effect of PEA by inhibiting FAAH enzyme, thereby elevating AEA and 2-AG levels which activate CB2 and TRPV1 receptors. D depicts an indirect effect on TRPV1 by having a direct effect on AEA and 2AG. E shows a direct effect of PEA on PPAR-alpha. (Source: Petrosino & Di Marzo, 2017, p. 1351)



FIG URE 3 . CHE M ICAL STRUCTU RES OF PEA, ENDOCANNABINOIDS AND PHYTOCANNABINOIDS.


(Source: Tsuboi et al., 2018, p. 2)

CLINICAL AP PL ICAT ION SAs stated previously, PEA is the body ’s go-to-molecule and is made on demand when required under disease conditions. Due to its ubiquitous nature and presence in all cells, PEA has wide-ranging therapeutic applications.

1. Analgesic EffectsPEA is produced by the body as a “compensatory factor” when confronted with pain. At least 6,000 patients with chronic pain and inflammation have been entered into clinical trials of PEA since the first studies in the 1970s. PEA has shown to be an important therapeutic molecule with an impressively positive risk/benefit ratio. Further, recent data support the hypothesis of deficient synthesis of PEA in pathologic states. For example, a study on fibromyalgia described deficient synthesis of PEA in the trapezius muscles in patients, and proposed that supplementation with PEA might be a useful therapeutic intervention in this chronic condition

(Ghaufori et al., 2013). This deficiency theory is not unlike the hypothesis of Ethan Russo, a long time researcher of cannabinoids, who first proposed in 2004 that a deficiency in the ECs may exist and be the causative factor in many pathological conditions (Russo, 2004). Several studies have shown that when PEA is used concurrently with opioid-type drugs (e.g., Tapentadol) for lower back pain, the dose of the opioid was significantly reduced, which alleviated some of the side-effects of the drug (Passavanti et al., 2017).

2. Chronic Pain One of the most important public health problems worldwide, chronic pain remains a major challenge in medicine and can have serious impact on quality of life. While acute pain is self-limiting and usually easily dealt with, chronic pain is more difficult to address and causes significant personal and social issues. Depending on its origin, chronic pain can be classified as inflammatory (e.g., osteoarthritis, rheumatoid arthritis) or neuropathic. Neuropathic pain can arise



from a disease or injury to the central or peripheral nervous systems; thermal and mechanical pain stimuli are amplified (hyperalgesia), while stimuli which were previously undetected are now perceived as aching (allodynia). PEA was found to exert pain relief in various animal models of inflammatory and neuropathic pain (Luongo et al., 2017). In all these models of pain, there was a significant decrease in plasma PEA levels. Increasing ECs and/or PEA levels lessened pain perception and also increased pain threshold levels. The analgesic effects of PEA were found to be due to either increasing AEA levels via inhibiting its breakdown by FAAH enzymes, or direct action on PPAR receptors and opening up TRPV1 channels, with the cumulative effect being reduction of pain signals.

3. Anti-Inflammatory Action Numerous animal models have documented the anti-inflammatory action of PEA, including rat paw edema, phorbol ester-induced ear edema, colitis, as well as topical application of various irritants. There is likely a two-pronged approach to this action. First, PEA prevents mast cell activation and release of numerous contents (degranulation), including histamine, inflammatory cytokines, chemokines, tryptases and proteases. Second, PEA stimulation of PPAR-alpha likely also mediates the anti-inflammatory action by preventing NF-kappaB translocation from the cytoplasm into the nucleus that would otherwise activate the inflammatory cascade.

4. Neuro-ProtectionInflammation can be especially perilous where the nervous system is involved, that is, neuro-inflammation. The microglia, mast cells and astrocytes play a critical role in the health of the nervous system. However, it can be a Jekyll and Hyde scenario – when acutely activated these cells help resolve the inflammation, but if the inflammation is chronic (e.g., diabetes, obesity or other conditions) then these cells create havoc in the brain and may be causative factors in various neurological disorders like Alzheimer ’s, Parkinson’s, multiple sclerosis, autism, amyotrophic lateral sclerosis, cerebral ischemia and traumatic brain injury. All three cells communicate with each other or cross-talk, with each apprising the other of any changes in the local environment (Appendix 3).

PEA levels are three times higher than EC levels in the central nervous system, suggesting PEA plays a major role in neuro-protection. PEA is locally produced and broken down in mast cells and microglia,

helping to modulate their behavior. In this regard, PEA acts as a local enforcer of the very cells that produce it. Deficiency of PEA may lead to cognitive issues like dementia, depression and other motor abnormalities. Animal studies have shown improved neuronal survival with PEA supplementation, as well as prevention of localized neuro-inflammation via multiple pathways.

5. PEA for Preventing Flu, Colds and Upper Respiratory Infections Between 1969 and 1975 six large human clinical studies to evaluate the effectiveness of PEA to reduce the number of days lost to colds and flu were conducted in the former Czechoslovakia. Five of these were in adults (groups of factory workers and soldiers) and one in children. In these double blind placebo controlled studies, patients were monitored for high temperature, headaches, sore throats, muscle pain, coughs and general malaise and fatigue.

The effectiveness of PEA in reducing all the symptoms and days lost to illness was very impressive (Appendix 4), and effects were evident usually within the second week of the treatment. In all six studies, PEA had clear treatment effect in reducing the incidence and frequency of respiratory infections and was found to be an effective influenza prophylaxis. No side-effects were observed. Health authorities observed the ease of application of PEA, and noted its potential in flu epidemics.

6. Antioxidant PEA has been shown to neutralize the damaging effects of free radicals by binding to them and preventing their destructive action. This is particularly important for the extra sensitive and highly prone neurons.

7. Allergies Due to its powerful mast cell stabilization properties, PEA should be useful in all forms of allergies, including airborne, food and contact allergic dermatitis. When activated, mast cells are key initiators of allergic responses through their release of inflammatory and allergic mediators like histamine, prostaglandins and other growth factors. Additionally, mast cells interact or cross-talk with other key players in the inflammatory process, including dendritic cells, macrophages, lymphocytes etc. Antihistamines work by preventing histamine release. PEA should be a powerful alternative with




its inhibiting action on mast cell degranulation, and without the side-effect of drowsiness caused by antihistamines.

8. MigraineTraditional phytocannabinoids like CBD and THC, and/or their combination, have been documented to produce anti-migraine effects. With migraines, EC levels decrease, and increasing ECs has been shown to reduce migraine episodes. Due to its structural similarity to ECs, it is conceivable that PEA may be helpful in migraine management.

9. DepressionOver 350 million people world-wide are affected by depression, with women at twice the risk as men. It is estimated one in twenty people in the Western world suffer from at least one depressive episode in a year. Despite the use of antidepressants, less than one-third achieve remission, and many still have residual depressive symptoms. Antidepressants work by increasing monoamines like serotonin and norepinephrine in the central nervous system. PEA has been shown to exert antidepressant and anxiolytic properties in animal models of depression (Crupi et al., 2013; Yu et al., 2011). It has also been shown to prevent the spreading of cortical depression wave following traumatic brain injury or cerebral ischemia. Notably, antidepressants have been found to increase levels of PEA in the brain, suggesting a protective role of PEA during depression. There is also a link between stress and low plasma PEA levels.

Animal studies have demonstrated that PEA can produce antidepressant effects similar to the drug fluvoxamine. Researchers in Iran studied the effect of PEA as an adjunct to the popular antidepressant drug citalopram in a double blind placebo controlled study. By week two, the citalopram plus PEA group experienced significantly greater antidepressant effect than the citalopram alone group (Ghazizadeh-Hashemi et al., 2018).

The antidepressant effect of PEA is likely to be multifactorial with TRPV1 receptor activation of TRPV1 and PPAR’s alpha, delta and gamma, but possibly other receptors like GPR55 as well. Finally, PEA’s inhibition of FAAH and NAAA enzymes that degrade AEA may also contribute to its antidepressant effect.

10. Digestive Disorders and a Key Role of PEA in Gut-Brain Axis The gastrointestinal tract has a dense concentration of cannabinoid receptors for AEA and 2-AG to maintain gut homeostasis and modulate gut motility and secretion of digestive enzymes. These play a key role in intestinal inflammatory diseases like inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, and inflammatory bowel syndrome (IBS). Recently, a double blind placebo controlled study has shown the efficacy of PEA in reducing pain severity in IBS patients (Barbara et al., 2014). This is consistent with PEA’s anti-inflammatory and analgesic effects. In previous animal models it has been shown that PEA is produced by the colon in response to inflammatory insults, and that PEA supplementation exerts anti-inflammatory effects in the gut; colon weight and length, which are considered a reliable and sensitive indicator of severity of inflammation, were markedly reduced by PEA (Borrelli et al., 2014). A more recent twelve-week study in IBS patients showed that PEA (dose of palmithoylethanolamide/polydatin 200 mg/20 mg twice a day) significantly reduced pain severity and improved quality of life (Cremon et al., 2017). Additional animal studies seem to suggest that PEA may also play a protective role in liver fibrosis and liver damage (Ohara et al., 2018).

The gut microbiome and the endocannabinoid system seem to be intertwined and cross-talk with each other on matters of energy utilization, thus impacting obesity and diabetes. Additional research suggests that PEA may also influence the gut microbiome in a positive manner, especially in affecting intestinal permeability (e.g., leaky gut syndrome). PEA seems to act as “gate keeper” and reduces permeability through the tight junctions of any pathogenic gut microbes, preventing their entry into circulation which could cause low grade inflammation affecting various organs like the liver.(Cani et al., 2016) (Appendices 5 and 6).

The gut-brain axis refers to the link between the gut and brain and the bidirectional communication and interactions that have physiological and psychological effects. Due to the strong interaction of the endocannabinoid system with both the gastrointestinal tract and the brain, PEA is an ideal molecule for addressing gut-brain axis issues.




11. Cardiovascular and Cerebrovascular Role Recently, plasma PEA has been shown to have strong association with, and may be predictive of, coronary dysfunction in morbidly obese individuals, and as such has been proposed as a novel bio-marker in heart disease. Moreover, due to its non-invasiveness, plasma PEA level testing may be more acceptable and cost effective compared to coronary angiography (Quercioli et al., 2017). However, more work needs to be done to establish whether the sensitivity and specificity of PEA could reach the standards for clinical application.

Numerous animal studies have shown that PEA plays a major role in neuro-protection. PEA acts on the glial cells which are the key immune cells in the brain that constantly survey the environment (immunosurveillance) in preparation for insult and injury, especially neuro-inflammation of the brain (e.g., cerebrovascular injury like stroke). Recently, a combination of PEA and the antioxidant flavonoid luteolin was evaluated in 250 stroke patients for neurological improvement in cognition, pain, degree of spasticity and quality of life. There was significant improvement in all the clinical indices, and evidence suggests a role for this formulation in stroke prevention and recovery (Caltagirone et al., 2016).

12. Cannabis DependencyPEA may be an innovative treatment for cannabis dependency since it has remarkable chemical structural similarities to the endogenous cannabinoids (AEA and 2-AG), even more structurally similar than phytocannabinoids derived from cannabis (THC or CBD). PEA may act as an antagonist and/or agonist to block various receptors and have a powerful entourage effect (Coppola and Mondola, 2013). This hypothesis needs to be confirmed. Some predicted effects of PEA include: 1) clinically significant reduction in withdrawal symptoms in cannabis dependent patients; 2) clinically significant reduction of craving in cannabis dependent patients; 3) clinically significant reduction of cannabis consumption; and 4) prevention of cannabis-induced neurotoxicity and neuro-psychiatric disorders. Whether PEA may play an important role in reducing dependency and help in the opioid crisis remains to be seen.

13. Autism Spectrum DisorderWhilst the exact mechanism for autism is not fully understood, glutamate excitotoxicity of the neurons and neuro-inflammation are thought to be

the key mechanisms involved. In addition, there is overactivity of mast cells. This excessive activation may be controlled by PEA since it helps modulate mast cells. A recent human clinical trial showed that PEA may augment the effects of risperidone, a prescription drug used to treat autism-related irritability and hyperactivity disorder, thus allowing reduction of the required dose. With PEA, the microglial cells were protected and there was evidence of improved synaptic plasticity and higher levels of dopamine. A reduced dose of risperidone meant fewer side-effects of the prescription drug (Khalaj et al., 2018). Other case reports have confirmed PEA having beneficial effects (Bertolino et al., 2017; Antonucci et al., 2015). Large scale studies need to be conducted.

C ONC LUSIONSThis fat-derived signalling compound has a long history, with PEA’s effects on pain being known for half a century. It is not a classic endocannabinoid, despite having some metabolic and structural similarities to other so-called ‘signalling’ molecules. It is now receiving more attention in the areas of chronic pain, inflammation and other diseases. Because it interacts with several receptors it has potential in numerous applications requiring ‘multiple target’ approaches.




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APPENDIX 1 . CO M M O N FOOD S OURC ES OF PALMITOYLET H A N OL AM ID E (PEA)

APPENDIX 2. PAL M ITOYL E T H ANOL AMIDE (PEA) EFFICACY IN CLINICAL STUD IE S A ND CL IN ICAL APPLICATIONS

Food Source

Pathology

References

References

Concentration of PEA (ng·g—1 fresh weight)

Bovine Milk

Elk Milk

Human Breast Milk

Human breast milk (110 ± 32.3 lactation days)

Common bean (Phaseoulus vulgaris)

Garden pea (Pisum sativum)

Southern or black-eyed peas (Vigna unguiculata)

Tomato

Medicago sativa

Corn

Soybean (Glycine max)

Soy lecithin

Peanut (Arachis hypogaea)

Amyotrophic lateral sclerosis

Autism

Benign prostatic hyperplasia (especially a combination of PEA with R+Lipoic acid)

Burning mouth syndrome

0.25

1.81

8.98 ± 3.35 nmol·L—1

23.4 ± 7.2 nmol·L—1

53.5

100

138

100

1150

200

6700

950 000

3730

Gouveia-Figueira & Nording, 2014

Gouveia-Figueira & Nording, 2014

Lam et al., 2010

Schuel et al., 2002

Venables et al., 2005

Venables et al., 2005; Kilaru et al., 2007


Kilaru et al., 2007


Kilaru et al., 2007


Kilaru et al., 2007


Amyotrophic lateral sclerosis

Antonucci et al., 2015; Bertolino et al., 2017

Cordaro et al., 2017

Barry et al., 2018




APPENDIX 3. D IAGR AM M AT IC R EPRESENTATION OF THE C ROSS-TALK BETWEE N M AST CE L L AND MIC ROGLIA, TWO KEY PL AYERS IN NEURO-INFL AM M AT IO N

Pathology References

Chronic pain (including neuropathic pain) of differing etiologies

Dermatological uses including pruritus, facial postherpetic neuralgia, atopic eczema, contact dermatitis and non-specified itch

Endometriosis

Fibromyalgia

Improving satiety and thus supporting weight loss

Non-surgical lumbar radiculopathies

Parkinson’s disease (adjuvant therapy)

Relapsing-remitting multiple sclerosis (add-on therapy for the treatment of interferon-β1a-related adverse effects)

Stroke (adjuvant therapy)

Skaper et al., 2014; Paladini et al., 2016

Visse et al., 2017; Phan et al., 2010; Eberlein et al., 2008; Mounessa et al., 2017

Iuvone et al., 2016; Indraccolo et al., 2017

Del Giorno et al., 2015

Bruun et al., 2018

Chirchiglia et al., 2018

Brotini et al., 2017

Orefice et al., 2016

Caltagirone et al., 2016

(Source: Skaper et al., 2018, p. 7)




APPENDIX 4. E FFE CT IVE NE S S OF PALMITOYLETH ANOL AMIDE (PEA) ON COL D S A ND FL U IN A SERIES OF C LINICAL STUDIES CONDUCTED IN CZE CHOS LOVAKIA

Study year % ProtectionPEA (n) Significance (p)Placebo (n) References

1972a

1972b

1973

1974

1975

19771

223

436

436

411

235

196

221

463

465

199

118

224

45%

32%

34%

52%

59%

16%




(Source: Cani et al., 2016, p.3)

APPENDIX 5. S HOW IN G CE RTAIN “ GATEKEEPERS” OF THE TIGHT JUNCT IO N S AL LOW E N TRY OF MIC ROBES INTO THE CIRCUL ATION CAUS IN G LOW GR ADE INFL AMMATION




(Source: Cani et al., 2016, p. 5)

APPENDIX 6. S HOW IN G PAL M ITOYLETH ANOL AMIDE (PEA) ACTS AS A “GATEKE E PE R” TO M AIN TAIN TH AT THE TIGHT J UNCTIONS REMAIN LOCKE D AND PRE VE N T ENTRY OF MIC ROBES INTO THE CIR CUL AT ION




APPENDIX 7. S H OW IN G T HE E F FECTS OF NATUR ALLY PRODUC ED MOLECULES L IK E PAL M ITOYL ETH ANOL AMIDE (PEA) ON VARIOUS DISE AS E S

Antioxidant

Antiapoptotic

Anticancer

Chemogenic Pain

Renal Injury

Obesity

Lipid Dysregulation

Diabetes

Brain Cancer

Inflammatory Bowel Disease

Endometriosis

Anti-Inflammatory

Alcohol Addiction

Depression

Anxiety

Neuropathic Pain

Alzheimer’s Disease

Cerebral Ischemia

Ulcerative Colitis

GlucoseHomeostasis

(Source: Sharma et al., 2015, p. 3)

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Palmitoylethanolamide (PEA): The Multiple Target Molecule · 2020. 1. 14. · Palmitoylethanolamide (PEA) is an 18-carbon long- chainfatty acid that is typically found in eggs, milk,