PEA: Anti-Inflammatory Superstar

Think of your brain as an ocean, an ecosystem inhabited by numerous species of fish-like neurotransmitters and their receptors, with currents of electricity connecting and delicately balancing all the different components. Inflammation is like a bloom of red algae, harming everything around it and upsetting the homeostasis of the environment.

Enter our hero, Palmitoylethanolamide (PEA) – a lipid messenger kindred to the endocannabinoid system and a close cousin of anandamide (AEA), the famous endocannabinoid neurotransmitter. Sometimes referred to as “the endogenous version of CBD,” PEA is a powerhouse against inflammation and pain. Like CBD, PEA increases the levels of endocannabinoids and strengthens the endocannabinoid system. And, again like CBD, a constant theme in the scientific literature about PEA is its incredibly strong safety profile.

In our neural ocean metaphor, PEA weighs in as the “most venerable of the leviathans,” the grinning Right Whale, a stalwart fighter in our constant battle against inflammation and pain.

A Mystery

The PEA story begins with a mystery, which leads to another mystery — and ends with the next great wave of the cannabinoid revolution.

We begin during World War 2 – and indeed, geopolitics plays a significant role in our tale. Because of the war effort, we find it a prosperous time for the new-ish field known as “public health.” A healthy population of workers was essential to support the production of war materiel. Two NYC doctors named Coburn and Moore found that if they gave dried eggs to the poor children of the tenements, this helped to prevent rheumatic fever and other ills related to poor nutrition. They also discovered that egg yolks are an anti-inflammatory food.

Usually, when a plant or food is found to have unique health properties, scientists dig in to find the specific molecules responsible for the beneficial effect. And usually these are proteins because proteins are the workhorses of the cell. But in this case, as the researchers separated the various classes of molecules involved, they realized that it was the lipids – the fatty molecules — that caused the positive health effects.

Proteins may be the workhorses, but they’re more binary; usually they are either on or off. Lipids act in a more analog manner. Our cells are adept at sensing even minute changes in lipid levels and responding accordingly. While scientists used to think of lipids as just the foodstuff of cells, now we know them to be a finely tuned cellular system primed to find homeostasis and balance. But how do these fatty components of eggs work to maintain homeostasis?

Lipid Mechanisms

The first big breakthrough occurred in the 1950s when a team led by Dr. F.A. Kuehl identified the active anti-inflammatory ingredient in egg yolks to be palmitoylethanolamide. He also found the same molecule in soybeans and peanuts, two other anti-inflammatory foods.

But scientists struggled to understand the mechanisms that caused this intriguing lipid to influence inflammation. During the 1960s, some papers in animal models were published confirming the anti-inflammatory effects of PEA. And in an important turn of events, a team led by Dr. S. Udenfriend discovered that PEA naturally occurs in a number of mammalian organs, and at high levels. So scientists realized that PEA not only lessens inflammation — our own bodies and brains also produce it as an internal regulator of inflammation.

But it wasn’t until the 1970s that the first serious clinical trials emerged, and these happened in Czechoslovakia, a nation that no longer exists. The Czech pharmaceutical company SPOFA (United Pharmaceutical Works) developed a PEA drug called Impulsin. To test it, they turned to the gigantic Skoda factory, a manufacturer of cars, tanks, and industrial equipment, which employed a tremendous workforce. SPOFA ran several clinical trials with the factory workers as well as with the military and civilian populations. Altogether, 2,000 adults and 400 children entered these trials.

Administered in a double-blind manner (the gold-standard of modern medical trials), all of the results pointed in the same direction: PEA was safe and possessed a clear efficacy in treating respiratory infections. It reduced the incidence of fever, headache, and sore throat. And furthermore, according to the Czech researchers, “No side effects were registered after several years of clinical testing of Impulsin in military and civilian communities [emphasis added].”

PEA worked! This was proven in large trials. But then ensued what is known in endocannabinoid circles as the Silent Gap period.

Through the early 1980s, the work of SPOFA faded away, lost behind the so-called Iron Curtain. Interest also waned because scientists could not explain PEA’s mechanism of action. No one could figure out how it actually worked. PEA ended up being labeled an “unspecific immune enhancer” and the scientific community seemingly lost interest.

Rescuing PEA from Obscurity

That changed in 1993, when the human hero of our story, Dr. Rita Levi-Montalcini, entered the picture.

Here is where geopolitics get too real. Earlier in her life, as a Jewish scientist in Mussolini’s Italy, Dr. Levi-Montalcini lost her laboratory. Forced to flee to Florence, she set up a workstation in the basement of a house, and there she continued her work studying the early development of organisms — one of the most challenging problems in all of science. The work she performed in that basement led to her discovery of the brain’s nerve growth factors (NGFs), one of the most important neurochemical findings of the century — and resulted in her sharing the Nobel Prize in 1986.

Seven years later, while affiliated with the Institute of Neurobiology in Rome, Dr. Levi-Montalcini and her team published a famed paper in which they proposed that PEA works via its control of mast cells – an important type of white blood cell responsible for releasing histamine. Histamine, while most often associated with allergies, is a both a hormone and a neurotransmitter involved in the inflammatory response. Mast cells respond to the healing of wounds, the growth of new blood vessels, the defense against pathogens, and the rallying of the immune response.

They referred to PEA’s relationship to mast cells as “the ALIA hypothesis.”

A review of their work in the Journal of Pain and Relief summarizes, “Autocoid or autacoid is a rather old-fashioned term for a regulating molecule, locally produced and locally exerting its actions . . . . PEA is formed locally when inflammation or neurogenic pain occur, and increased PEA concentrations are based on the body-own mechanisms to cope with pain and inflammation. This is called: on-demand synthesis.”

“An ALIAmide is an autocoid synthesized in response to injury or inflammation, and acting locally to counteract such pathology. Thus, PEA is a classical example of an ALIAmide. The mast cell soon after the breakthrough paper of Levi-Montalcini was indeed shown to be an important target for the anti-inflammatory activity of PEA, and in the period 1993-2013 more than 30 papers were published on the impact of PEA on the mast cell.”

PEA for Pain

As often happens with important research, a partial solution to the problem of how PEA functions led to a rush of scientists following up on those clues to figure out exactly how PEA modulates mast cells. A key development in understanding PEA happened serendipitously in 1998, when a team in Naples was studying anandamide (AEA), the endogenous cannabinoid neurotransmitter that is structurally similar to PEA. (Both lipid compounds are “EAs” — N-acylethanolamines.) Specifically they were researching AEA’s ability to cause pain relief by blocking pain transmission in the spinal cord before it even reaches the brain.

For their experiments, they decided that they needed a control molecule to act as a placebo. As Dr. Daniele Piomelli relates, they wanted another endocannabinoid-like molecule that wouldn’t have the same effects. So they chose PEA, mostly because they knew that it didn’t bind to the CB1 or CB2 receptors thought to be causing the pain-relieving effects. But as their paper in Nature pointed out, they were quite surprised to find out that PEA had profound pain-relieving effects as well.

This result intrigued them. If PEA doesn’t bind to the classic cannabinoid receptors CB1 and CB2, then how does it do what it does?

The researchers reasoned that a sister lipid molecule known as oleamide (OEA) worked via the PPARα (alpha) receptors. What’s special about these PPARα receptors is that they’re nuclear receptors. They live, not on the surface of the cell, but on the surface of its nucleus – the cellular control center that contains the DNA. (In our neuronal ocean metaphor, the nucleus is City Hall and the PPAR receptors are the bureaucrats who send out the orders.) Activating these nuclear receptors alters the transcription of genes and hence the production of new proteins. Each of these new proteins would have its own host of downstream effects. If you view the cell like a city, altering genetic transcription is like hiring a whole bunch of specialized workers to fix your problems, each with their own toolkit.

Dr. Piomelli assigned his student Jesse LoVerme to study PEA’s mechanism of action. By 2005, they found that the PPARα receptor mediated the anti-inflammatory effects of PEA, and by 2007 they determined that this relationship also mediated PEA’s anti-pain effects. It was a huge breakthrough.

PEA & the Entourage Effect

With the mechanism unveiled and the positive clinical effects noted, PEA research poured forth like a spring. In 2008, UK-based scientists reported that the ability of anandamide to relax the arteries was strengthened by the presence of PEA — a phenomenon described as an “entourage effect.” Published in the British Journal of Pharmacology, the study noted this effect occurred via the role of vanilloid receptors, which are part of a large, ancient family of Transient Receptor Potential ion channels (also known as TRP or “trip” receptors) that regulate core body temperature, inflammatory pain, and other basic visceral sensations, such as the burning sensation of hot foods like capsaicin.

Anandamide binds to the TRPV1 vanilloid receptor as does CBD. The endocannabinoid system and the endovanilloid system are so intertwined that anandamide is often described as a vanilloid compound.

Also in 2008, a study on PEA and neuropathic pain found not only TRPV1 to be involved, but also the CB1 cannabinoid receptor and another nuclear receptor, PPARγ (gamma). And in a subsequent study of neuropathic pain, PEA helped by improving the release of amino acids as well as restoring the functioning of glutamate, the brain’s primary excitatory neurotransmitter (and the subject of a previous Project CBD article in this series). 

In mouse studies involving a wide range of disease models, PEA was found to lower inflammation, lessen cell death, and prevent tissue injury – often via multiple biochemical pathways. It even helped four jumping horses return to competition after their injuries didn’t respond to any other treatment.

Scientists now believe that PEA exists — at least at low levels — in every single mammalian cell.

Clinical Studies

Clinical experiments have also yielded impressive results. In patients with migraines, lower back pain, burning mouth syndrome, spinal cord injuries, or the neuropathy of shingles, PEA decreased pain and worked well as an add-on to the standard treatments. PEA also helped people with bladder problems, irritable bowels, glaucoma, osteoarthritis of the knee, and exercise recovery. (For an extensive list of conditions helped by PEA, see The PEA Health Files at the end of this article.)

In 20 patients undergoing chemo, PEA eased the pain and even showed “significant restoration of nerve function.” In a patient with ALS, PEA improved their clinical picture – probably via the mast cells as well as the microglia (the guardian immune cells of the brain). In multiple sclerosis patients, PEA combined well with the standard treatment to improve pain, lower inflammation, and raise the quality of life. Observational studies of 600 patients with treatment-resistant chronic pain found PEA to be effective and safe. In seven patients with chronic idiopathic axonal polyneuropathy (intense neuropathic pain from an unknown source), PEA significantly reduced pain with no side effects, and it did the same for 70 kids with migraines.

In 24 women with endometriosis and chronic pelvic pain, PEA combined with polydatin (a flavonoid often paired with PEA) helped with their cramps, their pain during sex, and with their overall quality of life; similar results were later reported for 30 more patients. And in 30 diabetic patients, PEA effectively reduced their neuropathic pain with no negative changes shown in their blood work or urine analysis. In two patients with autism, PEA caused “rapid improvements in cognitive, behaviors, and sociability.” In 58 patients with depression, 600 mg of PEA twice a day in addition to citalopram significantly and rapidly improved symptoms. And it even works topically for humans with eczema; when applied to the skin, PEA caused less itching and better sleep with many of the patients stopping the use of corticosteroids.

With respect to PEA, throughout all of these studies, there’s one assessment that comes up over and over again: “We also noted its safety due to the total absence of adverse effects.”

PEA as a Dietary Supplement

Decades of unravelling a series of scientific mysteries have led to exciting discoveries that transformed PEA from the stuff of egg yolk to the next great dietary supplement.

In the ocean of our brain, the PEA whale emerges to work its magic by orchestrating the lowering of inflammation and the reduction of pain across everywhere it roams. ClinicalTrials.gov lists 44 clinical trials for PEA that are currently recruiting patients, in process, or completed. FSD Pharma has PEA in Phase 2 trials for use against an inflammatory disease of mast cell activation.

PEA is already in widespread use around the world. In Italy and Spain, it’s an approved nutraceutical. Lesvi, a European pharmaceutical company, combines PEA with several plants as a nutraceutical for the brain. A Dutch firm produces a formulation called PeaPure. And the PEA formulation known as Levagen+ from Gencor Pacific is touted to improve joint health, mood, sleep, immune system health, exercise recovery, and quality of life.

Fortunately it’s relatively easy to access food-derived PEA as a legal health supplement in the US. A number of reputable vendors market PEA products, and one can order them online. Anecdotal accounts suggest that CBD and PEA amplify each other’s anti-inflammatory effects, and combining the two compounds could prove to be a powerful healing option.

See other articles in the Get to Know a Neurotransmitter series.

Lex Pelger writes articles about psychoactives and the endocannabinoid system. He publishes a weekly cannabinoid science newsletter Cannabinoids & the People and conducts 1-on-1 education sessions on using CBD, PEA, THC & CBDA for serious health conditions. © Copyright, Project CBD. May not be reprinted without permission.

The PEA Health Files & Review Papers

2013: A Kuhnian take on evolution of PEA knowledge
Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical 2022: A review on the potential of using PEA for antiseizure effects
Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence 2021: From Gencor (producers of the PEA product Levagen+, a paper reviewing the wonders of PEA
Palmitoylethanolamide: A Potential Alternative to Cannabidiol 2021: This review of female pelvic medicine and reconstructive surgery suggests PEA as a treatment
Cannabinoid Therapy in Female Pelvic Medicine and Reconstructive Surgery: Current Evidence and Future Directions 2021: This review looks at PEA for autism and suggests that it may help via several different mechanisms
Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence 2021: This review looks at the power of PEA to protect the astrocytes (essential support cells of the brain) and fight Alzheimer’s disease
Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes 2021: This review suggests using PEA for treating COVID patients
Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients 2021: This review looks at how PEA and oleoylethanolamide binds to GPR119 and GPR55 (receptors that may one day be known as CB3 and CB4)
GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide 2021: A special issue of the International Journal of Molecular Sciences is dedicated to PEA 2021: This mini-review examines why it makes sense to use PEA to treat COVID (includes one positive case study)
Micronized / ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation 2020: A review of how PEA moves through the body
The Basal Pharmacology of Palmitoylethanolamide 2020: A review of PEA for pets
Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing 2020: On using PEA for pain (nice charts)
ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain 2020: PEA + luteolin for neuroinflammation
An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events 2019: A good review of PEA’s mechanisms of action
Clinical Applications of Palmitoylethanolamide in Pain Management: Protocol for a Scoping Review 2019: A review on PEA for end of life care
The Potential Benefits of Palmitoylethanolamide in Palliation: A Qualitative Systematic Review 2019: A review on PEA for Alzheimer’s disease with a focus on neuroinflammation
Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer’s Disease 2019: On combining PEA with other antioxidant molecules found in your diet (nice diagrams)
Therapeutic Efficacy of Palmitoylethanolamide and Its New Formulations in Synergy With Different Antioxidant Molecules Present in Diets 2019: A review of PEA for asthma
Molecular Targets of Fatty Acid Ethanolamides in Asthma 2018: A review of PEA for depression
Role of Palmitoylethanolamide (PEA) in Depression: Translational Evidence: Special Section on “Translational and Neuroscience Studies in Affective Disorders” 2017: DiMarzo’s great review with history, pharmacology, and charts of where it’s found (breast milk!)
The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations 2017: A review of PEA and polydatin for endometriosis covers 4 studies
Micronized Palmitoylethanolamide/Trans-Polydatin Treatment of Endometriosis-Related Pain: A Meta-Analysis 2016: A review of pain covers 6 studies
Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy 2016: This review of 12 studies of patients with pain, PEA decreased pain with no serious adverse events
Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis 2015: A review of PEA for nerve compression problems like carpal tunnel and sciatic pain
Palmitoylethanolamide, a Neutraceutical, in Nerve Compression Syndromes: Efficacy and Safety in Sciatic Pain and Carpal Tunnel Syndrome 2015: PEA as a homeostasis mechanism for neuroinflammation in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease
N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution 2015: In humans, this review of studies finds PEA safe and effective for glaucoma and other retinopathies (nice chart of mechanisms of action)
Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy 2014: A review of PEA for inflammation
Harnessing the Anti-Inflammatory Potential of Palmitoylethanolamide 2013: A great review of the history of PEA and the clinical trials for the common cold
Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe Against Influenza and Common Cold 2013: A review of PEA for inflammation from trauma
Palmitoylethanolamide Is a New Possible Pharmacological Treatment for the Inflammation Associated With Trauma 2013: A review of PEA for cannabis dependence
Palmitoylethanolamide: From Endogenous Cannabimimetic Substance to Innovative Medicine for the Treatment of Cannabis Dependence 2013: A review of PEA and the mast cells
New Insights in Mast Cell Modulation by Palmitoylethanolamide: “In view of their strategic localization at sites directly interfacing with the external environment, mast cells act as surveillance antennae against different types of injury and can undergo activation, thereby regulating both innate and adaptive immune reactions through the release of several preformed and newly synthesized mediators. Mast cells are now viewed as key players in orchestrating several disorders including both acute and chronic inflammatory processes, and have a role in angiogenesis and hyperalgesia.” 2012: A review of PEA’s effect on mast cells, glia cells (brain support cells), and neuroinflammation
Mast Cell-Glia Axis in Neuroinflammation and Therapeutic Potential of the Anandamide Congener Palmitoylethanolamide 2012: Dr. Piomelli’s comments on lipids and PEA
A thickening network of lipids  2007: Dr. DiMarzo on use for companion animals
Palmitoylethanolamide, Endocannabinoids and Related Cannabimimetic Compounds in Protection Against Tissue Inflammation and Pain: Potential Use in Companion Animals 2005: Dr. Piomelli on history of discovery
The Search for the Palmitoylethanolamide Receptor

A Timeline of PEA Research

2022: Researchers look to create new molecules that help increase natural PEA levels
Discovery and SAR Evolution of Pyrazole Azabicyclo[3.2.1]octane Sulfonamides as a Novel Class of Non-Covalent N-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA) Inhibitors for Oral Administration 2022: A major carotenoid from brown seaweed called fucoxanthinol appears to help with inflammation via its modulation of the PEA pathway
Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway 2022: This survey shows that most women who used cannabis or the cannabinoids THC, CBD, or PEA for gynecologic conditions reported that it improved pain
Medical Cannabis for Gynecologic Pain Conditions: A Systematic Review 2022: In a mouse model of obesity, PEA restored the plasticity of their white and brown fat cells, leptin sensitivity, tissue hormone sensitivity and rewired the energy storing white into energy-consuming brown fat cells
Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α 2022: In a study of 90 patients with COVID-19, PEA reduced inflammatory states, oxidative states and alterations to blood biomarkers
Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case-Control Study 2022: In obese mice, PEA lessened neuroinflammation as well as anxious behavior
Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice 2021: In humans with induced migraines, the PEA levels in their spinal cords didn’t raise for those who regularly experienced episodic migraines
Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally-induced migraine attacks 2021: In an animal model of stroke, they already knew that PEA protects the blood-brain barrier and the brain itself. This study found that the effects weren’t only mediated by changes in genetic transcription (the PPARα receptor) but also by the regulation of the cell’s microfilaments
PEA prevented early BBB disruption after cerebral ischaemic/reperfusion (I/R) injury through regulation of ROCK/MLC signaling 2021: In humans, PEA as well as the flavonoid luteolin helped to recover the sense of smell after a COVID infection
Randomized clinical trial “olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin”: preliminary results 2021: In lung cells exposed to the spike protein of SARS-CoV-2, ultramicronized PEA reduced all inflammatory markers
Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages 2021: In Greek Navy SEALS undergoing strenuous exercise, their levels of anandamide, PEA and oleamide all increased, suggesting an adaptive ability of the ECS in helping with stress and heart-rate
Endocannabinoids and heart rate variability alterations after exposure to prolonged intensive physical exercise of the Hellenic Navy SEALs 2021: A case study of PEA for the neuropathic pain of shingles
Palmitoylethanolamide (PEA) in the treatment of neuropathic pain: a case study 2021: In rats with spinal cord injuries, PEA alleviated the injury, inhibited inflammation, mitigated oxidative stress, reduced cell death and promoted motor function recovery
PPARα agonist relieves spinal cord injury in rats by activating Nrf2/HO-1 via the Raf-1/MEK/ERK pathway 2021: In humans, CBD and PEA found safe for the skin
Tolerability Profile of Topical Cannabidiol and Palmitoylethanolamide: A Compilation of Single-Center Randomized Evaluator-Blinded Clinical and In Vitro Studies in Normal Skin 2021: In rabbits having eye surgery, PEA reduced postoperative inflammation and scarring via the nuclear PPARα receptors
Palmitoylethanolamide (PEA) reduces postoperative adhesions after experimental strabismus surgery in rabbits by suppressing canonical and non-canonical TGFβ signaling through PPARα 2021: In rats on an obesity diet, PEA as well as oleamide (OEA – another endocannabinoid) functioned as anti-obesity nutritional interventions
Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity 2021: In mice with inflamed colons, a combination of polydatin (a precursor of resveratrol) and ultra-micronized PEA decreased inflammation via several pathways
PEA/Polydatin: Anti-Inflammatory and Antioxidant Approach to Counteract DNBS-Induced Colitis 2021: In mice with their left carotid artery tied off, a combination of PEA and rutin (a helpful plant pigment) reduced inflammation, oxidative stress and vascular damage
Micro Composite Palmitoylethanolamide/Rutin Reduces Vascular Injury through Modulation of the Nrf2/HO-1 and NF-kB Pathways 2021: In a human lung tissue model of COVID-19 infection, a combination of PEA and α-lipoic acid (ALA) reduced oxidative stress and lowered the cytokine storm
A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19 2021: In a mouse model of traumatic brain injury (and a small clinical study), a combination of PEA and the flavonoid luteolin caused increased neurogenesis as well as improvements in memory recall
Co-Ultra PEALut Enhances Endogenous Repair Response Following Moderate Traumatic Brain Injury 2021: In human cells, PEA and polydatin lowered vascular inflammation
Palmitoylethanolamide associated to polydatin reduces inflammation in human endothelial vascular cells exposed to doxorubicin and trastuzumab through PPAR-a and NLRP3-related pathways 2021: In humans with Tourette’s, initial promise was seen with a combination of 10 mg of THC + 800 mg of PEA
A Phase-2 Pilot Study of a Therapeutic Combination of Δ 9-Tetrahydracannabinol and Palmitoylethanolamide for Adults With Tourette’s Syndrome
They found that “improvement in tic symptoms was statistically significant within 1 week of starting treatment compared with baseline” and that “treatment led to an average improvement in tic symptoms of more than 20%.” 2021: In the brain of a model organism, the injection of PEA or OEA mediated the brain levels of serotonin and acetylcholine
In vivo brain levels of acetylcholine and 5-hydroxytryptamine after oleoylethanolamide or palmitoylethanolamide administrations are mediated by PPARα engagement 2021: In rats with benign prostatic hyperplasia (the most common benign tumor in males), a combination of PEA and baicalein (an active ingredient in Baikal skullcap) lowered inflammation, reduced oxidative stress and helped to modulate apoptosis (programmed cellular suicide)
Palmitoylethanolamide/Baicalein Regulates the Androgen Receptor Signaling and NF-κB/Nrf2 Pathways in Benign Prostatic Hyperplasia 2021: In humans with nerve pain from rheumatic diseases, PEA combined well with acetyl-l-carnitine (ALC) to lower inflammation and to increase clinical scores
Efficacy of a fixed combination of Palmitoylethanolamide and acetyl-l-carnitine (PEA + ALC FC) in the treatment of Neuropathies secondary to Rheumatic Diseases 2021: In humans, this cohort analysis found that the diversity of your gut microbiome was related to your happiness and motivation via the endocannabinoid system, especially via PEA – which they call the endogenous version of CBD
Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort 2021: In microglial cells (the immune cells of the brain), PEA caused decreased inflammation and increased neuroprotection
Palmitoylethanolamide Modulation of Microglia Activation: Characterization of Mechanisms of Action and Implication for Its Neuroprotective Effects 2021: A clinical trial where PEA from Levagen+ improves many measures of sleep
Palmitoylethanolamide for Sleep Disturbance. A Double-blind, Randomised, Placebo-controlled Interventional Study 2021: Engineering bacteria to live in the guts and produce PEA on demand
Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice 2021: In mice with varicocele (a disorder of the veins taking blood away from the testicles, a major cause of human infertility), PEA helped via the PPAR-α receptors
The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele 2021: In mice with dermatitis, a topical containing CBD and PEA lessened inflammation
Anti-inflammatory Effect of Cannabidiol and Palmitoylethanolamide Containing Topical Formulation on Skin in a 12-O-Tetradecanoylphorbol-13-Acetate-Induced Dermatitis Model in Mice 2021: In a rat model of inflammatory pain, PEA combined well with acetyl-l-carnitine (LAC)
Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain 2021: In pregnant rats, even huge doses of PEA caused no measurable harms
Palmitoylethanolamide: Prenatal Developmental Toxicity Study in Rats 2021: In human with joint pain, PEA reduced pain and improved mood
The Effect of a Dispersible Palmitoylethanolamide (Levagen+) Compared to a Placebo for Reducing Joint Pain in an Adult Population – A Randomised, Double-Blind Study 2021: In rabbits having eye surgery, PEA reduced postoperative inflammation and scarring via the nuclear PPARα receptors
Palmitoylethanolamide (PEA) reduces postoperative adhesions after experimental strabismus surgery in rabbits by suppressing canonical and non-canonical TGFβ signaling through PPARα 2020: In a mouse model of Gulf War illness, exposure alters the response to PEA
Pyridostigmine bromide exposure creates chronic, underlying neuroimmune disruption in the gastrointestinal tract and brain that alters responses to palmitoylethanolamide in a mouse model of Gulf War Illness 2020: On using PEA for neurological disorders
Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases 2020: This hypothetical paper suggests that the ability of PEA to calm mast cells in the lungs may be a potential treatment for COVID
Sodium chromo-glycate and palmitoylethanolamide: A possible strategy to treat mast cell-induced lung inflammation in COVID-19 2020: In mice with mood disorders induced by high-fat diets, PEA limits mood disorders and cognitive dysfunction
Palmitoylethanolamide limits mood disorders and cognitive dysfunction induced by high fat diet in obese mice 2020: In 4 jumping horses with non-responsive lameness, ultramicronized PEA for four months allowed them to return to competition
Oral Supplementation with Ultramicronized Palmitoylethanolamide for Joint Disease and Lameness Management in Four Jumping Horses: A Case Report 2020: In cells, micronized PEA (FM-LipoMatrix®) combined with lipoic acid and vitamin D3 absorbed better and reduced neuroinflammation
A New Palmitoylethanolamide Form Combined with Antioxidant Molecules to Improve Its Effectivess on Neuronal Aging 2020: In a cellular model of Alzheimer’s, PEA protected the neurons and increased their survival
Astrocytic palmitoylethanolamide pre-exposure exerts neuroprotective effects in astrocyte-neuron co-cultures from a triple transgenic mouse model of Alzheimer’s disease 2020: In humans with glaucoma, PEA found helpful
Effect of palmitoylethanolamide on inner retinal function in glaucoma: a randomized, single blind, crossover, clinical trial by pattern-electroretinogram 2020: For patients with COVID-19, FSD Pharma received FDA approval to submit an Investigational New Drug Application for the use of PEA to increase endogenous levels of endocannabinoid 2020: In rats, PEA helpful for eye disorders via the PPARα nuclear receptors
PPARα-Dependent Effects of Palmitoylethanolamide Against Retinal Neovascularization and Fibrosis 2020: In rats, a look at how PEA causes vasodepression (the lowering of blood pressure) via the heart’s CB1, TRPV1 and probably GPR55 receptors, but not by CB2
Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats 2020: In a double-blind human study, CBD and PEA both helped reduce permeability in the colon and appear helpful for IBS
Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo-A Randomized, Placebo-controlled, Double-blind Controlled Trial 2020: In patients with lower back pain, the combination of therapy and ultramicronized PEA lowered pain past clinically relevant levels as well as increasing physical and mental quality of life
Combination of Rehabilitative Therapy With Ultramicronized Palmitoylethanolamide for Chronic Low Back Pain: An Observational Study 2020: In 70 pediatric patients with migraines, ultramicronized PEA decreased the number and severity of attacks with only one patient experiencing mild side effects (nausea and floating)
Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering From Migraine: A Pilot Study 2020: In a human study with 28 participants, Levagen+ helpful for exercise recovery by reducing myoglobin and lactate concentration
The Effect of Orally Dosed Levagen+ (Palmitoylethanolamide) on Exercise Recovery in Healthy Males-A Double-Blind, Randomized, Placebo-Controlled Study 2020: In mice with dry eye induced by sleep loss, they had lower levels of PEA in the lacrimal gland and its synthetic enzyme (N-acylated phosphatidylethanolamine-phospholipase D) – treatment with PEA restored lipid balance and protected the eye via PPARα
N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation-Induced Dry Eye Syndrome 2020: Mechanistic study of how the enzyme NAAA breaks down PEA
N-Acylethanolamine Acid Amidase (NAAA): Mechanism of Palmitoylethanolamide Hydrolysis Revealed by Mechanistic Simulations 2020: In a mouse model of Alzheimer’s, 3 months of oral ultramicronized PEA “rescued cognitive deficit, restrained neuroinflammation and oxidative stress, and reduced the increase in hippocampal glutamate levels”
Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in A Transgenic Murine Model of Alzheimer’s Disease 2020: In mice asphyxiated at birth, PEA attenuated the neuronal damage in corpus striatum, restored level of GFAP cells as well as preventing the decrease of pNF-H/M and MAP-2
Partial Reversal of Striatal Damage by Palmitoylethanolamide Administration Following Perinatal Asphyxia 2019: In 22 patients with pain, PEA was effective at reducing chronic neuropathic pain via “the ascending pain pathway that are likely driven by rhythmic astrocytic gliotransmission”
Effects of the Glial Modulator Palmitoylethanolamide on Chronic Pain Intensity and Brain Function 2019: A re-analysis of an old unpublished study on the efficacy of micronized PEA for lower back pain found it to be highly effective
Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients With Low Back Pain – Sciatica 2019: in human double-blind study, both CBD and PEA reduced inflammation and reducing permeability in the human colon
Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial 2019: In a human double-blind study of 111 participants with knee osteoarthritis, PEA found helpful for inflammation
A Double-Blind Randomized Placebo Controlled Study Assessing Safety, Tolerability and Efficacy of Palmitoylethanolamide for Symptoms of Knee Osteoarthritis 2019: In 23 patients with mastocytosis (accumulation of mast cells), they had increased PEA levels
Altered Metabolism of Phospholipases, Diacylglycerols, Endocannabinoids, and N-Acylethanolamines in Patients With Mastocytosis 2019: In 30 patients with endometriosis, both ultramicronized PEA and co-micronised palmitoylethanolamide/polydatin (PEA/PLD) showed significant improvements in all measures as well as quality of life
Effect of Ultramicronized-Palmitoylethanolamide and Co-Micronized Palmitoylethanolamide/Polydatin on Chronic Pelvic Pain and Quality of Life in Endometriosis Patients: An Open-Label Pilot Study 2019: In one patient with burning mouth syndrome, after gabapentin did little, adding PEA considerably improved the pain
Add-on Administration of Ultramicronized Palmitoylethanolamide in the Treatment of New-Onset Burning Mouth Syndrome 2019: In 32 patients with bladder problems, micronized PEA combined with polydatin reduced pain and urinary frequency
Micronized Palmitoylethanolamide-Polydatin Reduces the Painful Symptomatology in Patients With Interstitial Cystitis/Bladder Pain Syndrome 2019: In mice, great study on the broad lipid changes caused by PEA
Broad Lipidomic and Transcriptional Changes of Prophylactic PEA Administration in Adult Mice 2019: In cats with hypersensitive skin, ultramicronized PEA helped increase the efficacy window of a steroid course of methylprednisolone
Effect of Dietary Supplementation With Ultramicronized Palmitoylethanolamide in Maintaining Remission in Cats With Nonflea Hypersensitivity Dermatitis: A Double-Blind, Multicentre, Randomized, Placebo-Controlled Study 2019: In mice with injured spines, Noxiall (a combo of PEA, Beta-Caryophyllene, Carnosic Acid, and Myrrh) matched pregabalin and gabapentin  for lessening pain and reducing mechanical and thermal sensitivities
Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain: A Preclinical Study 2019: In rats with a heart attack, the combination of PEA and baicalein from Chinese medicine “decreases myocardial tissue injury, neutrophils infiltration, markers for mast cell activation expression as chymase and tryptase and pro-inflammatory cytokines production (TNF-α, IL-1β)” and “treatment reduces stress oxidative and modulates Nf-kB and apoptosis pathways”
Effects of a New Compound Containing Palmitoylethanolamide and Baicalein in Myocardial Ischaemia/Reperfusion Injury in Vivo 2019: In mice with a painful nerve injury, PEA restored cognitive behavior and neuronal functioning via two receptors in the glutamate system
Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated With Neuropathic Pain 2019: In mice with a painful nerve injury, ultramicronized PEA was able to “reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP” and restore “the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis” via PPARa
Ultra-micronized Palmitoylethanolamide Rescues the Cognitive Decline-Associated Loss of Neural Plasticity in the Neuropathic Mouse Entorhinal Cortex-Dentate Gyrus Pathway 2019: In a mouse with PTSD, PEA was used to activate PPARa and this helped with fear extinction, anxiety and increased allopregnanolone (ALLO – a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders)
Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior 2019: In a rat model of depression, PEA helped greatly via several different markers including stress hormones – probably via PPARα
N-Palmitoylethanolamide Exerts Antidepressant-Like Effects in Rats: Involvement of PPAR α Pathway in the Hippocampus 2019: In an animal model of dementia, PEA and oxazoline were protective
N-Palmitoylethanolamine-oxazoline (PEA-OXA): A New Therapeutic Strategy to Reduce Neuroinflammation, Oxidative Stress Associated to Vascular Dementia in an Experimental Model of Repeated Bilateral Common Carotid Arteries Occlusion 2019: In neurons, treatment with 2-AG or PEA affected microglial cells and caused protection but using them together blocked their positive effects and altered the distribution (but not the activation) of PPARa
Opposite Effects of Neuroprotective Cannabinoids, Palmitoylethanolamide, and 2-Arachidonoylglycerol on Function and Morphology of Microglia 2019: In a model of mast cells, they found “novel molecular mechanisms through which PEA controls mast cell degranulation and substance P (SP)-induced histamine release” with PEA increasing 2-AG via stimulation of DAGL-α and -β activity and the combination of PEA and 2-AG working together at low levels when they didn’t work on their own
Palmitoylethanolamide Counteracts Substance P-induced Mast Cell Activation in Vitro by Stimulating Diacylglycerol Lipase Activity 2018: In 155 patients with spinal damage and pain, ultramicronized PEA helped with mild and moderate pain, but not severe pain, with a special emphasis on its safety
N-Palmitoyl Ethanol Amide Pharmacological Treatment in Patients With Nonsurgical Lumbar Radiculopathy 2018: In 58 patients with depression, 600 mg of PEA twice a day + citalopram significantly improved symptoms and demonstrated a rapid-onset effect
Palmitoylethanolamide as Adjunctive Therapy in Major Depressive Disorder: A Double-Blind, Randomized and Placebo-Controlled Trial 2018: In 35 patients with burning mouth syndrome, 600 mg of ultramicronized PEA significantly reduced the pain after 60 days and caused no interference in the other pharmacological therapies
Efficacy of Ultramicronized Palmitoylethanolamide in Burning Mouth Syndrome-Affected Patients: A Preliminary Randomized Double-Blind Controlled Trial 2018: In 20 patients with migraines, ultramicronized PEA treatment relieved pain with no side effects
Effects of Add-On Ultramicronized N-Palmitol Ethanol Amide in Patients Suffering of Migraine With Aura: A Pilot Study 2018: In mice with pain, PEA potentiated morphine and lessened tolerance, suggesting it as an additive treatment
Ultramicronized N-Palmitoylethanolamine Supplementation for Long-Lasting, Low-Dosed Morphine Antinociception 2018: In mice with epilepsy, PEA injections lessened seizures, promoted neuroprotection and modulated ECS levels
Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy 2018: In a mouse model of Alzheimer’s, ultramicronized PEA improved learning and memory, lessened depression and anhedonia and helped with neuroinflammation via several methods
Ultramicronized Palmitoylethanolamide Rescues Learning and Memory Impairments in a Triple Transgenic Mouse Model of Alzheimer’s Disease by Exerting Anti-Inflammatory and Neuroprotective Effects 2018: In aged mice, pretreatment with PEA protected the brain from Parkinson’s disease-like damage via several mechanisms
N-palmitoylethanolamide Prevents Parkinsonian Phenotypes in Aged Mice 2018: In aged mice, PEA protected from a bacterial infection in the organs and brain
Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis 2018: In rats with induced pain, ultramicronized PEA reached the peripheral sites more readily and caused less inflammation and tissue damage via the downregulation of several “spinal inflammatory and oxidative pathways”
Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect 2018: In baby mice with simulated perinatal asphyxia (not able to breate), PEA treatment attenuated damage in the hippocampus and improved behavioral alterations
Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain 2018: In young rats deprived of oxygen, PEA treatment reduced neuroinflammation, astrogliosis (overabundance of astrocytes) and preserved cognitive function
Palmitoylethanolamide Prevents Neuroinflammation, Reduces Astrogliosis and Preserves Recognition and Spatial Memory Following Induction of Neonatal Anoxia-Ischemia 2018: In rats with joint inflammation, micronized PEA reduced the damage, pain and activation of macrophages
Micronized Palmitoylethanolamide Reduces Joint Pain and Glial Cell Activation 2018: In models of Alzheimer’s, PEA dampened the reactivity of the microglia and improved viability of the neurons as well as glial neurosupport
Palmitoylethanolamide Dampens Reactive Astrogliosis and Improves Neuronal Trophic Support in a Triple Transgenic Model of Alzheimer’s Disease: In Vitro and In Vivo Evidence 2018: In rats with induced liver fibrosis, PEA protected via several mechanisms
Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats 2018: In a mixture of astrocytes and neurons, PEA blunted the astrocyte activation caused by a challenge by Aβ42 (a plaque associated with Alzheimer’s disease)
Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures 2018: PEA nanoparticles for intraocular delivery
Innovative Nanoparticles Enhance N-Palmitoylethanolamide Intraocular Delivery 2017: In a mouse with traumatic brain injury, PEA protected the brain
Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury 2017: In 100 patients with spinal damage and pain, ultramicronized PEA combined well with paracetamol and codeine to relieve pain with no side effects
Nonsurgical Lumbar Radiculopathies Treated With Ultramicronized Palmitoylethanolamide (umPEA): A Series of 100 Cases
“We also noted its safety due to the total absence of adverse effects.” 2017: In 55 patients with lower back pain, ultramicronized PEA was an effective add-on to tapentadol for pain and improved quality of life
The Beneficial Use of Ultramicronized Palmitoylethanolamide as Add-On Therapy to Tapentadol in the Treatment of Low Back Pain: A Pilot Study Comparing Prospective and Retrospective Observational Arms 2017: In 10 patients with pain, ultramicronized PEA helped
N-of-1 Randomized Trials of Ultra-Micronized Palmitoylethanolamide in Older Patients With Chronic Pain 2017: In mice with a broken tibia, a product of micronized and ultramicronized PEA caused “an improved healing process, fracture recovery and fibrosis score” as well as “decreased mast cell density, nerve growth factor, matrix metalloproteinase 9 and cytokine expression” and apoptosis (cellular suicide) (correction)
Effect of a New Formulation of Micronized and Ultramicronized N-palmitoylethanolamine in a Tibia Fracture Mouse Model of Complex Regional Pain Syndrome 2017: In mice with brain and spine injuries, the combination of PEA and oxazoline protected the motor function and behavioral deficits
N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury 2017: In microglia and macrophage cells, PEA increased CB2 expression via PPAR-α
Palmitoylethanolamide Induces Microglia Changes Associated With Increased Migration and Phagocytic Activity: Involvement of the CB2 Receptor 2017: In mice with induced allergies, PEA helped to clear the bronchi and upregulated CB2 and GPR55, suggesting it use as a supplement against asthma
Palmitoylethanolamide Supplementation during Sensitization Prevents Airway Allergic Symptoms in the Mouse 2017: In colon cells, CBD and PEA are anti-inflammatory
Cannabidiol and Palmitoylethanolamide Are Anti-Inflammatory in the Acutely Inflamed Human Colon 2017: In intestinal cells, PEA lowered intestinal permeability via PPARα and in response to inflammatory mediators, the cells increased their PEA levels
Oleoylethanolamine and Palmitoylethanolamine Modulate Intestinal Permeability in Vitro via TRPV1 and PPARα 2017: In a canine skin model, PEA protected from the negative effects of mast cells
Ultramicronized Palmitoylethanolamide Counteracts the Effects of Compound 48/80 in a Canine Skin Organ Culture Model 2016: In a study of cells, animals and humans, PEA raised the level of 2-AG and potentiated its effects at TRPV1
The Anti-Inflammatory Mediator Palmitoylethanolamide Enhances the Levels of 2-arachidonoyl-glycerol and Potentiates Its Actions at TRPV1 Cation Channels 2016: In 27 patients with endometriosis, AEA and PEA levels increased along with condition severity
Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis 2016: In humans with multiple sclerosis, ultramicronized PEA added to the first line treatment (interferon IFN-β1a) caused an improvement in pain scores and quality of life
Oral Palmitoylethanolamide Treatment Is Associated With Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis 2016: In 72 patients with spinal cord injuries, ultramicronized PEA caused no positive effects at all for anything measured
Ultramicronized Palmitoylethanolamide in Spinal Cord Injury Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled Trial (followup comment: Ultramicronized Palmitoylethanolamide Treatment in Central Neuropathic Pain Following Longstanding Spinal Cord Injury: Try to Extinguish the Fire After Everything Was Burned) 2016: In a preclinical study in mice and a case study with a 10 year old, a combination of PEA and luteolin ameliorated symptomatology of autism
Beneficial Effects of Co-Ultramicronized Palmitoylethanolamide/Luteolin in a Mouse Model of Autism and in a Case Report of Autism 2016: In mice with heart attacks, ultramicronized PEA protected the heart via the PPARa receptors
Protective Effects of Ultramicronized Palmitoylethanolamide (PEA-um) in Myocardial Ischaemia and Reperfusion Injury in VIVO 2016: In rats with endometriosis, ultramicronized PEA worked via the mast cells to lower pain, as well as the levels of cysts and stones
Ultramicronized Palmitoylethanolamide Reduces Viscerovisceral Hyperalgesia in a Rat Model of Endometriosis Plus Ureteral Calculosis: Role of Mast Cells 2016: In this mouse model and patient study of colitis and Crohn’s disease, PEA “inhibits colitis-associated angiogenesis [blood vessel formation], decreasing VEGF release and new vessels formation” via the PPARa and helped to regulate the angiogenic process via the mTOR/Akt axis
Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α)-Dependent Manner 2016: In colon cancer cells, PEA caused a significant reduction in proliferation, angiogenesis, and VEGF secretion and expression via PPARa’s effect on the AkT/mTOR axis
Palmitoylethanolamide Exerts Antiproliferative Effect and Downregulates VEGF Signaling in Caco-2 Human Colon Carcinoma Cell Line Through a Selective PPAR-α-Dependent Inhibition of Akt/mTOR Pathway 2015: In two patients with autism, PEA caused “rapid improvements in cognitive, behaviors, and sociability”
Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases 2015: In 160 dogs with red itchy skin, ultramicronized PEA was “effective and safe in reducing pruritus and skin lesions” and improving quality of life
Efficacy of Ultra-Micronized Palmitoylethanolamide in Canine Atopic Dermatitis: An Open-Label Multi-Centre Study 2015: In rats with pain, PEA delayed the tolerance effects of morphine
Delay of Morphine Tolerance by Palmitoylethanolamide 2015: In rats with high blood pressure, PEA protected via several difference pathways
Palmitoylethanolamide Treatment Reduces Blood Pressure in Spontaneously Hypertensive Rats: Involvement of Cytochrome p450-derived Eicosanoids and Renin Angiotensin System 2015: In mice with damaged kidneys, PEA and silymarin combined to reduce “kidney dysfunction, histological damage, neutrophil infiltration and oxidative stress” and inhibited NF-κB and apoptosis (cellular suicide) pathways
Effects of Palmitoylethanolamide and Silymarin Combination Treatment in an Animal Model of Kidney Ischemia and Reperfusion 2015: In rats with inflamed eyes, PEA “decreased the inflammatory cell infiltration and improved histological damage of eye tissues” and reduced ocular inflammation
The Anti-Inflammatory Effects of Palmitoylethanolamide (PEA) on Endotoxin-Induced Uveitis in Rats 2015: In mice with induced colitis, PEA helps via the CB2, GPR55 and PPARa receptors as well as the TRPV1 channels
Palmitoylethanolamide, a Naturally Occurring Lipid, Is an Orally Effective Intestinal Anti-Inflammatory Agent 2015: In a mouse model of multiple sclerosis, treatment with PEA or CBD reduced disease severity with diminished inflammation, demyelination, axonal damage and inflammatory cytokine expression – but they did not work as well together
Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice 2015: In mice with painful nerve injuries, PEA restored their glutamate functioning and the changes in amino acid release (nice graphic)
Palmitoylethanolamide Reduces Pain-Related Behaviors and Restores Glutamatergic Synapses Homeostasis in the Medial Prefrontal Cortex of Neuropathic Mice 2015: In cells challenged by the Aβ amyloid plaques of Alzheimer’s disease, PEA “reduced expression of pro-inflammatory and pro-angiogenic markers” via PPARa
Palmitoylethanolamide Regulates Production of Pro-Angiogenic Mediators in a Model of β Amyloid-Induced Astrogliosis In Vitro 2015: In mice neurons challenged by the Aβ amyloid plaquess of Alzheimer’s, PEA rescued glutamate in non-transgenic mice but not the triple-transgenic murine model
Differential Effects of Palmitoylethanolamide Against Amyloid-β Induced Toxicity in Cortical Neuronal and Astrocytic Primary Cultures From Wild-Type and 3xTg-AD Mice 2014: In 30 diabetic patients, micronized PEA effectively reduced pain while blood work and urine analysis saw no significant alterations
Micronized Palmitoylethanolamide Reduces the Symptoms of Neuropathic Pain in Diabetic Patients 2014: In 60 patients with eczema, a PEA/AEA topical improved “passive and active skin functions simultaneously”
N-palmitoylethanolamine and N-acetylethanolamine Are Effective in Asteatotic Eczema: Results of a Randomized, Double-Blind, Controlled Study in 60 Patients 2014: In a patient with chronic vulvar and anal pain, a topical of PEA and baclofen decreased her pain by 50% and allowed for sex again
Vulvodynia and Proctodynia Treated With Topical Baclofen 5 % and Palmitoylethanolamide 2014: In dogs with red itchy skin, PEA probably helped via the downregulation of mast cells and levels of PEA increased as the disease progressed
Increased Levels of Palmitoylethanolamide and Other Bioactive Lipid Mediators and Enhanced Local Mast Cell Proliferation in Canine Atopic Dermatitis 2014: In a rat model of Alzheimer’s disease, PEA was able to restore the alterations via PPARa and to reverse the cognitive impairments
Palmitoylethanolamide Controls Reactive Gliosis and Exerts Neuroprotective Functions in a Rat Model of Alzheimer’s Disease 2014: In mice with an inflamed colon, PEA improved transit time in the GI tract and increased AEA levels via the CB1 receptors and TRPV1 channels
Palmitoylethanolamide Normalizes Intestinal Motility in a Model of Post-Inflammatory Accelerated Transit: Involvement of CB₁ Receptors and TRPV1 Channels 2014: In the intestines of rats undergoing chemotherapy, PEA protected via the mast cells for protection
Palmitoylethanolamide Regulates Development of Intestinal Radiation Injury in a Mast Cell-Dependent Manner 2014: In a rat model of inflammatory pain, micronized/ultramicronized PEA worked better orally than PEA
Micronized/ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model of Inflammatory Pain 2014: In mice, PEA treatment increased the ability of macrophages to phagocytose (engulf and digest) E. coli bacteria
Palmitoylethanolamide Stimulates Phagocytosis of Escherichia Coli K1 by Macrophages and Increases the Resistance of Mice Against Infections 2014: In colon cells, PEA improved all macroscopic signs of ulcerative colitis and decreased all the proinflammatory markers tested via PPARa
Palmitoylethanolamide Improves Colon Inflammation Through an Enteric Glia/Toll Like Receptor 4-dependent PPAR-α Activation 2013: In 24 women with endometriosis and chronic pelvic pain, micronized PEA and polydatin reduced pelvic pain, dysmenorrhea (cramps) and dyspareunia (pain during sex) but not dysuria (painful urination) and dischezia (strained stools) as well as improving overall quality of life
[Administration of Micronized Palmitoylethanolamide (PEA)-transpolydatin in the Treatment of Chronic Pelvic Pain in Women Affected by Endometriosis: Preliminary Results] 2013: In 7 patients with chronic idiopathic axonal polyneuropathy (intense pain), PEA reduced pain significantly with no side effects
Chronic Idiopathic Axonal Neuropathy and Pain, Treated With the Endogenous Lipid Mediator Palmitoylethanolamide: A Case Collection 2013: In a rat model of epilepsy, PEA reduced seizures via the PPAR-α receptors and indirectly by the CB1 receptors
Antiepileptic Action of N-palmitoylethanolamine Through CB1 and PPAR-α Receptor Activation in a Genetic Model of Absence Epilepsy 2013: In mice with spinal cord trauma, they found that PPAR-δ and PPAR-γ also contribute to PEA’s anti-inflammatory effects
Molecular Evidence for the Involvement of PPAR-δ and PPAR-γ in Anti-Inflammatory and Neuroprotective Activities of Palmitoylethanolamide After Spinal Cord Trauma 2013: In rats with high blood pressure, PEA reduced blood pressure and reduced damage to the kidneys
N-Palmitoylethanolamide Protects the Kidney From Hypertensive Injury in Spontaneously Hypertensive Rats via Inhibition of Oxidative Stress 2013: In mice with pain, PEA helped via recruitment and protection of mast cells, decrease of nerve growth factor, preservation of the nerves and the reduction of microglia activation in the spinal cord
Non-neuronal Cell Modulation Relieves Neuropathic Pain: Efficacy of the Endogenous Lipid Palmitoylethanolamide 2013: PEA targets both glial and mast cells for anti-inflammation and neuroprotective effects
Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator 2013: In mice injured by formalin, PEA activated microglia and glia cells, significantly reduced mechanical allodynia and thermal hyperalgesia, suggesting the use for spinal cord injuries
Palmitoylethanolamide Reduces Formalin-Induced Neuropathic-Like Behaviour Through Spinal Glial/Microglial Phenotypical Changes in Mice 2013: In rat neuronal cells challenged with the Aβ amyloid plaques of Alzheimer’s, “PEA is able to blunt Aβ-induced astrocyte activation and to exert a marked protective effect on neurons”
Neuroglial Roots of Neurodegenerative Diseases: Therapeutic Potential of Palmitoylethanolamide in Models of Alzheimer’s Disease 2013: In cells, PEA activated TRPV1, perhaps via PPARa
Activation and Desensitization of TRPV1 Channels in Sensory Neurons by the PPARα Agonist Palmitoylethanolamide 2012: In humans, a case series on PEA for pain
Therapeutic Utility of Palmitoylethanolamide in the Treatment of Neuropathic Pain Associated With Various Pathological Conditions: A Case Series 2012: In an observational study of 600+ patients, PEA helped all of them with their treatment-resistant chronic pain and caused no adverse effects
Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis 2012: In a patient with ALS, PEA improved the clinical picture, probably via the microglia and mast cells
Amyotrophic Lateral Sclerosis Treatment With Ultramicronized Palmitoylethanolamide: A Case Report 2012: In mice, PEA helped to protect from a Parkinson’s like insult, probably via the PPARa receptor
Neuroprotective Activities of Palmitoylethanolamide in an Animal Model of Parkinson’s Disease 2012: In rats, PEA protected the brain after injury by many pathways
Reduction of Ischemic Brain Injury by Administration of Palmitoylethanolamide After Transient Middle Cerebral Artery Occlusion in Rats 2012: In a mouse model of traumatic brain injury, PEA protected the brain via several pathways and improved neurobehavioral functions
Administration of Palmitoylethanolamide (PEA) Protects the Neurovascular Unit and Reduces Secondary Injury After Traumatic Brain Injury in Mice 2012: In a mouse model of Alzheimer’s disease, injected PEA significantly helped with learning and memory disfunction, probably via the PPARa pathway
Palmitoylethanolamide Protects Against the amyloid-β25-35-induced Learning and Memory Impairment in Mice, an Experimental Model of Alzheimer Disease 2012: In mice with intestinal injuries, pretreatment with PEA reduced inflammation and cell death, probably via the PPARa pathway
Effects of Palmitoylethanolamide on Intestinal Injury and Inflammation Caused by Ischemia-Reperfusion in Mice 2012: In mice with injured kidneys, PEA protected via several different pathways, probably via the PPARa pathway
Palmitoylethanolamide Reduces Early Renal Dysfunction and Injury Caused by Experimental Ischemia and Reperfusion in Mice 2012: In mice experiencing pain, PEA increased allopregnanolone (ALLO) levels via the PPARa receptor
Implication of Allopregnanolone in the Antinociceptive Effect of N-palmitoylethanolamide in Acute or Persistent Pain 2012: In neurons challenged by the β-amyloids of Alzheimer’s disease, PEA blunted activation and improved neuronal survival
Palmitoylethanolamide Exerts Neuroprotective Effects in Mixed Neuroglial Cultures and Organotypic Hippocampal Slices via Peroxisome Proliferator-Activated Receptor-α 2012: In microglial cells, PEA caused increased phagosytosis of E. coli and strep
Palmitoylethanolamide Stimulates Phagocytosis of Escherichia Coli K1 and Streptococcus Pneumoniae R6 by Microglial Cells 2011: In 20 patients undergoing chemo, PEA helped with the pain and showed positive effects on the myelinated fiber groups
Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients With Chemotherapy-Induced Painful Neuropathy 2011: In brain tissue, PEA appears to regulate neurosteroidogenesis (steroid production in the brain) and increase allopregnanolone (ALLO) via the PPARa receptor
Palmitoylethanolamide Stimulation Induces Allopregnanolone Synthesis in C6 Cells and Primary Astrocytes: Involvement of Peroxisome-Proliferator Activated Receptor-α 2011: In brain cells, PEA reduced the number of microglial cells and protected the neurons via the PPARa receptor
Palmitoylethanolamide Protects Dentate Gyrus Granule Cells via Peroxisome Proliferator-Activated Receptor-α 2011: In mice with spinal cord injuries, PEA “reduced the degree of the severity of spinal cord trauma through the reduction of mast cell infiltration and activation [and] reduced the activation of microglia and astrocytes expressing cannabinoid CB(2) receptor”
Effects of Palmitoylethanolamide on Release of Mast Cell Peptidases and Neurotrophic Factors After Spinal Cord Injury 2011: In brain cells, the β-amyloid plaques of Alzheimer’s increased PEA levels while treatment with PEA blunted their proinflammatory effects, probably via increased 2AG levels and the PPARa receptor
Palmitoylethanolamide Counteracts Reactive Astrogliosis Induced by β-Amyloid Peptide 2010: In mice, PEA modulated the hypnotic effect of phenobarbital via PPARa’s increase of allopregnanolone (ALLO) as well as a positive modulation of GABA
Palmitoylethanolamide Modulates Pentobarbital-Evoked Hypnotic Effect in Mice: Involvement of Allopregnanolone Biosynthesis 2010: In canine mast cells, PEA downregulated their activity via several factors, suggesting its use for inflammation and pain
Effects of Palmitoylethanolamide on Immunologically Induced Histamine, PGD2 and TNFalpha Release From Canine Skin Mast Cells 2009: In mice with pain, pretreatment with PEA lowered their pain levels via PPARa’s inhibition of signaling in the dorsal root ganglia and by the reduction of COX-2 and iNOS
Central Administration of Palmitoylethanolamide Reduces Hyperalgesia in Mice via Inhibition of NF-kappaB Nuclear Signalling in Dorsal Root Ganglia 2008: In this study of 2456 patients with eczema, PEA topical treatment caused less itching, more sleeping and half of them stopped using their corticosteroids
Adjuvant Treatment of Atopic Eczema: Assessment of an Emollient Containing N-palmitoylethanolamine (ATOPA Study) 2008: In a mouse model of multiple sclerosis, CB2, 2AG and PEA were upregulated and PEA applied topically reduced disability and lowered inflammation
Study of the Regulation of the Endocannabinoid System in a Virus Model of Multiple Sclerosis Reveals a Therapeutic Effect of Palmitoylethanolamide 2008: In mice with a spinal cord injury, PEA reduced “1) the degree of spinal cord inflammation and tissue injury, 2) neutrophil infiltration, 3) nitrotyrosine formation, 4) proinflammatory cytokine expression, 5) nuclear transcription factor activation-kappaB activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis” and it helped with recovery of motor function
Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury 2008: In mice, PEA helped with pain via CB1, TRPV1 and PPARγ
The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors 2008: In rat arteries, the ability of AEA to induce relaxation was potentiated by both PEA and OEA and the ability of PEA and OEA to cause relaxation may be via TRPV1
‘Entourage’ Effects of N-palmitoylethanolamide and N-oleoylethanolamide on Vasorelaxation to Anandamide Occur Through TRPV1 Receptors 2007: In mice with pain, preadministration of PEA reduced swelling and inflammation via the PPARa receptor
Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-Alpha Agonist, Modulates Carrageenan-Induced Paw Edema in Mice 2005: Dr. Piomelli identifies PPARa as PEA’s mechanism and in this mouse model, it reduced inflammation
The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-Alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide 2003: In mice, PEA potentiates the ability of AEA to induce microglia migration and this is not mediated by CB1 or CB2
Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility 2002: In a patient after stroke, levels of AEA, PEA and OEA all rise
Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study 2002: In cancer cells, PEA seems to potentiate the antiproliferative effects of AEA via the vanilloid system
Effect on Cancer Cell Proliferation of Palmitoylethanolamide, a Fatty Acid Amide Interacting With Both the Cannabinoid and Vanilloid Signalling Systems 2001: In breast cancer cells, PEA inhibited expression of FAAH and enhanced the anti-proliferative effects of AEA
Palmitoylethanolamide Inhibits the Expression of Fatty Acid Amide Hydrolase and Enhances the Anti-Proliferative Effect of Anandamide in Human Breast Cancer Cells 2001: In kidney cells, PEA enhanced AEA’s stimulation of vanilloid receptors
Palmitoylethanolamide Enhances Anandamide Stimulation of Human Vanilloid VR1 Receptors 1996: In neurons, PEA protected against glutamate toxicity and prevented neuron loss
The ALIAmide Palmitoylethanolamide and Cannabinoids, but Not Anandamide, Are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons 1995: In mast cells, PEA downmodulated mast cell activation via the CB2 receptor
Mast Cells Express a Peripheral Cannabinoid Receptor With Differential Sensitivity to Anandamide and Palmitoylethanolamide 1993: Levi-Montalcini’s big paper where she said PEA worked via mast cells and where she coined the acronym ALIA
A Proposed Autacoid Mechanism Controlling Mastocyte Behaviour 1980: Dr. Epps finds PEA accumulating in infarcted myocardium and becomes the first to suggest that fatty molecules may play a protective role during ischemia and that its presence “may signify a response of myocardial tissue to injury directed at minimizing damage and promoting survival”
Accumulation of N-acylethanolamine Glycerophospholipids in Infarcted Myocardium 1979: 3 large human trials shows PEA’s help for acute respiratory infections and with no negative effects on antibody production
Studies on prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory infections. Serologically controlled field trials 1975: The first supportive paper on the effects of PEA in cancer as a modulator of toxicity in chemotherapy
The Effect of Long-Term Administration of N-(2-hydroxyethyl)palmitamide on the Chemotherapy of RBA Rat Leukemia 1975: The first small pilot for rheumatic pain that supported PEA’s analgesic properties
Letter: Slow Encephalopathies, Inflammatory Responses, and Arachis Oil 1974: Two large scale double-blind trials shows PEA helping symptoms of respiratory tract infections, but not their timecourse
Prophylactic efficacy of N-2-hydroxyethyl palmitamide (impulsin) in acute respiratory tract infections 1972: In mice, PEA decreased mortality from a variety of immunological insults
Non-specific Resistance Induced by Palmitoylethanolamide 1965: Bachur’s work finds PEA consistently present in brain, liver and muscle of rats and guinea pigs
Fatty acid amides of ethanolamine in mammalian tissues 1957: Initial discovery paper
The identification of N-(2-hydroxyethyl)-palmitamide as a naturally occurring anti-inflammatory agent

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