Palmitoylethanolamide (PEA) is produced in the body to combat pain and inflammation. Some scientists believe this fatty acid may boost natural cannabinoids and protect the nerves. Its purported health benefits are intriguing–but does solid evidence back them up? Read on to find out.
What is Palmitoylethanolamide (PEA)?
Overview
Palmitoylethanolamide, or PEA, is produced in the body naturally to combat pain and inflammation. Many animals and plants also produce PEA. The highest amounts can be found in soy lecithin, soybeans, egg yolk, peanuts, and alfalfa [1].
PEA is classified as a dietary supplement and has not been approved by the FDA for medical use. In general, dietary supplements lack solid clinical research. Regulations set manufacturing standards for supplements but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.
As a supplement, PEA is available in tablet, capsule, and powder form. In Italy and Spain, PEA is marketed as a food for special medical purposes [2].
However, most PEA supplements available to consumers are of synthetic origin. Hence, they do not fall under the category of “natural supplements.” Instead, the FDA considers them unapproved drugs.
Since its discovery in the 1950s, researchers have been curious about PEA. It shows promise as a painkiller and anti-inflammatory, though large-scale safety and efficacy data are still lacking. Nonetheless, many consumers hope PEA will ease their chronic and neuropathic pain [3].
The clinical studies published to-date explored the effects of PEA on complex pain. Despite their efforts, a number of these studies had major drawbacks (such poor design, low quality, or small sample size). Larger, multi-center studies are needed to confirm the effects of PEA on different types of pain [3].
Scientists are also investigating the effects of PEA on activating the cannabinoid receptors. Limited research suggests PEA might support brain, heart health, and immune health. But much more research remains to be carried out [1, 4].
PEA is a fatty acid amid like anandamide, the main cannabinoid bliss molecule your body makes. Unlike regular fats, amide-containing fatty acids like PEA and our cannabinoids are directly involved in nerve communication. These intriguing and recently-discovered molecules are called “neuroactive lipids” [5].
Mechanism of Action
PEA activates the energy-boosting, fat-burning, and anti-inflammatory PPAR alpha. By activating this key protein, PEA stops the activity of pro-inflammatory genes and the production of many inflammatory substances [2].
PEA reduces the activity of the bliss gene FAAH that breaks down natural cannabinoid anandamide. This increases the levels of calming anandamide in your body, helping to combat pain and increase relaxation. It may also activate cannabinoid receptors (CB2 and CB1) [2].
PEA contains palmitic acid in its structure. The starting point for making PEA in the body is precisely this saturated fatty acid [4].
However, some scientists say that simply increasing your intake of palmitic acid or other dietary fats will not affect PEA production in the body. This is because your body will use PEA only when it needs to compensate for inflammation or pain, and its levels will also normally vary throughout the day [4]
Researchers hypothesize that the best way to get the benefits of PEA are standardized supplements, or alternatively, PEA-rich foods. Their hypothesis remains unproven, though [4].
Purported Health Benefits of Palmitoylethanolamide (PEA)
Possibly Effective for:
1) Pain Relief
A decent amount of evidence backs up PEA’s ability to reduce complex pain. It has been investigated in over 30 clinical trials and a total of ~6k people since the 1970s [3].
While most of the research speaks to PEA’s ability to reduce pain in general, studies often fail to make a distinction between neuropathic and non-neuropathic pain.
The benefits of PEA for neuropathic pain are less clear due to insuffucient reliable evidence to date.
Another limitation was that most of these studies lakced a placebo control. More high-quality research is needed to determine how effective PEA is at relieving different types of pain.
In an analysis of 12 human studies, PEA supplements reduced chronic and neuropathic pain intensity without any serious adverse effects. At least 2 weeks need to pass to achieve pain relief. PEA was typically given over 3 – 8 weeks at dosages between 300 and 1,200 mg/day. Taking it over a longer period of time strengthens its effects without causing tolerance [1].
In a pivotal trial of over 600 people, PEA (300 or 600 mg/day) strongly reduced sciatic pain, higher dose having a more beneficial effect. PEA reduced pain intensity by over 50% in just 3 weeks, which is rarely seen with most painkillers [6].
PEA reduced lower back pain in a trial of over 100 people (600 mg PEA/day). It was so effective that half of the included participants stopped taking any additional painkillers by the end of the trial [6].
PEA seemed to relieve pain caused by diverse health conditions. To outline some of these studies, PEA was investigated in:
- Women with pelvic pain caused by endometriosis, an overgrowth of the uterus lining. In a trial of 56 women, PEA (300 mg/day) relieved pain and improved sexual function over 6 months [7]
- Pain caused by fibromyalgia. In 80 people, PEA reduced the intensity of pain and tenderness when added to the standard treatment (pregabalin) [8]
- People with sciatica who don’t respond to painkillers like Oxycodone [9]
- Diabetics with pain from carpal tunnel syndrome caused by nerve compression (at a higher dose of 1,200 mg PEA/day) [9]
- Pain after failed back surgery [9]
- Cancer pain [9]
- Arthritis pain [9]
Importantly, PEA didn’t cause side effects or drug interactions in any of the above studies. Nonetheless, proper safety studies are still lacking. Also, there is still insuffucient evidence to rate the effectiveness of PEA in people with these types of pain.
However, animal studies add to its pain-relieving potential. In experimental animals (mice and rats), PEA:
- Reduced nerve pain from a chemotherapy drug (paclitaxel) [10]
- PEA’s derivative adelmidrol reduced acute and chronic pain and inflammation [11]
- Reduced inflammation and lung damage [12]
- Improved inflammation and pain in arthritis [13]
- Lowered inflammation from spinal cord injuries [14]
Scientists hope to explore the effects of PEA on diverse types of pain and inflammation in humans in the future.
Insufficient Evidence for:
The following purported benefits are only supported by limited, low-quality clinical studies.
There is insufficient evidence to support the use of PEA for any of the below-listed reasons.
Remember to speak with a doctor before taking PEA supplements. PEA should never be used as a replacement for approved medical therapies.
2) Brain Health and Regeneration
PEA may be beneficial for neurodegenerative diseases and stroke because it seems to help brain cells survive and lower inflammation. Further clinical studies are needed to verify this.
In a study of 250 stroke sufferers, a formulation of PEA with luteolin (Glialia) improved recovery. It had a beneficial effect on cognitive skills, overall brain health, pain, and daily functioning. The effects were noticeable after 30 days and further improved over another month of supplementation [15].
Both with luteolin and alone, PEA prevented Parkinson’s disease in mice, reducing damage in the brain and protecting dopamine neurons. Since the destruction of dopamine neurons is what causes Parkinson’s disease, PEA may be able to prevent this disease or its worsening. Clinical studies are needed to confirm these findings [16, 17].
In another study, PEA with luteolin enhanced the healing of nerves in mice with spinal cord injuries. It increased neurotrophic factors (BDNF, NGF), small but powerful proteins that help create new brain cells needed to regenerate tissues after traumatic damage of the spinal cord or brain [16, 18].
But aside from its direct effects on brain cells, PEA is important for brain health due to its action on our endocannabinoid system. In the brain, our natural cannabinoids play diverse roles in behavior, cognition, mood, and seizure risk, among others.
Impaired natural cannabinoids may also play a role in epilepsy. PEA could relieve seizures and shorten their duration in rats by increasing cannabinoid activity in the brain. Its effects on seizures have yet to be investigated in humans [19].
3) Supporting Eye Health
PEA’s effects on protecting nerve cells might not be restricted just to the brain. Healthy nerves in the eyes are crucial for maintaining proper vision.
Retinopathy is an eye disease that can result in vision loss. It’s triggered by inflammatory damage to the nerves in the eye, most commonly caused by glaucoma and diabetes. PEA reduced eye nerve damage in over 9 clinical trials used in doses up to 1.8 g/day [20].
In 32 people with glaucoma, PEA reduced high eye pressure and improved vision over 6 months. PEA supplementation was safe and didn’t cause any side effects [21].
People with glaucoma can choose to undergo laser surgery but risk experiencing high eye pressure shortly after that can cause damage. PEA prevented increases in eye pressure given shortly after laser eye surgery in 15 people [22].
Animal studies revealed how PEA may achieve these benefits. In diabetic rats, it reduced eye key inflammatory substances that break down the blood-retinal barrier. Like the blood-brain barrier protects the brain, this eye barrier is crucial for eye health. It nourishes the eye but prevents harmful substances from entering [23, 24].
4) Symptoms of Depression
In a recent study of 58 people with depression, PEA (1.2 g/day) given over 6 weeks greatly and rapidly improved mood and overall symptoms. PEA was added to antidepressant treatment (citalopram) and lowered symptoms by an impressive 50% [25].
This clinical study was a follow-up on numerous studies in which PEA improved symptoms of depression in animals.
Further clinical trials are needed before we can draw any reliable conclusions.
5) Symptoms of Multiple Sclerosis
The analgesic and anti-inflammatory benefits of PEA make it an ideal candidate for Multiple Sclerosis (MS), which has a strong autoimmune and inflammatory nature. The first-line therapy (interferon IFN-β1a), on the other hand, often causes serious adverse effects. PEA may increase the effects of this immunotherapy while lowering the negative effects.
As an add-on to standard therapy, PEA reduced adverse effects and pain, improving the quality of life and cognition in a trial of 29 people with rapidly-advancing MS. The supplement also increased blood levels of PEA and anandamide [26].
The effects of PEA alone on MS has not been investigated yet.
6) Fighting the Common Cold
As scientists became excited about PEA’s ability to relieve pain and nerve damage, its effects on the immune system were almost forgotten. In many early studies of over 4k people, PEA could fight the influenza virus that causes the common cold [4].
Despite achieving good results, the main problem with the initial studies was that egg yolk or other supplements that contained only small amounts of PEA were used. These were not standardized and it’s impossible to know how much PEA they contained. Fast-forward to the late 1970s, studies started using higher-quality PEA supplements [4].
PEA (1,200 mg/day) reduced the duration of the cold and symptoms such as fever, headaches, and sore throat in a study of about 900 young soldiers. In four additional studies, PEA lowered the chances of catching a cold and the severity of symptoms. Additional studies should explore its effects as a standalone supplement and as an add-on to standard therapy [4].
Possibly Ineffective for:
Spasticity from Spinal Cord Injury
In one study, a special PEA formulation (ultramicronized PEA) was given as an add-on to conventional therapy for 12 weeks in 73 people with pain and spasticity associated with spinal cord injury. Compared to conventional therapy alone, PEA did not reduce neuropathic pain, spasticity, or insomnia [27].
Lacking Evidence (Animal Research):
The below-described studies were conducted only in animals and cells; clinical evidence is lacking.
Future studies in humans have yet to determine the effects of PEA on the heart, gut, and histamine release. The studies listed below should not be interpreted as supportive of any health benefit.
Effects on the Heart
Heart attacks result from a total blockage of blood vessels leading to the heart. For the damaged heart tissue to recover, proper blood flow needs to be recovered. In mice, PEA improved the recovery from heart attacks, reduced heart tissue injury, and lowered inflammatory cytokine levels [28].
PEA also reduces high blood pressure in rats and prevents kidney damage by lowering inflammatory substances. It also has specific effects similar to drugs commonly used to lower high blood pressure (ACEI). PEA blocked enzymes and receptors that increase blood pressure by narrowing the blood vessels (angiotensin receptor 1 and angiotensin-converting enzyme) [29].
Gut Inflammation
PEA was successfully used to relieve symptoms of inflammatory bowel disease (IBS) in animals. Mice with chronic gut inflammation have low PEA levels, while PEA supplements normalized bowel movement and prevented damage to the gut lining [2, 30].
In tissues taken by biopsy from people with ulcerative colitis, PEA lowered inflammatory cytokines and the buildup of neutrophils, immune cells that worsen symptoms and contribute to gut damage [2].
The gut damage caused by ulcerative colitis increases the risk of cancer. In mice, PEA prevented normal gut tissue from developing cancerous overgrowth [2].
Adelmidrol is an anti-inflammatory substance made by modifying PEA that can also improved IBS symptoms such as diarrhea and weight loss in mice [31].
Histamine Release
Some scientists think PEA might be a histamine-release blocker. In animal and cell-based studies, PEA improved eczema and skin allergies by lowering mast cell activation and blocking the release of histamine [2].
In dogs with eczema, PEA helped soothe symptoms by reducing skin inflammation and itching. PEA reduced inflammatory substances (TNF-alpha) and increased endocannabinoids in the skin (2-AG), which altogether strongly diminishes the allergic response [2].
PEA Dosage & Safety
Supplements
Talk to your doctor before supplementing with PEA. As a dietary supplement, PEA has not been approved by the FDA for medical use.
More clinical studies would be beneficial, but limited data suggests that PEA is safe. Long-term PEA supplementation has not been linked to adverse effects in small-scale studies. PEA was used in doses of 300 mg to 1.8 g/day in clinical studies.
- At least 600 mg/day may be needed to relieve nerve pain, while doses of 1.2 g/day were used for diabetic nerve pain
- PEA up to 1.8 g/day was used for reducing damage to eye nerves in people with glaucoma or diabetes
- For fighting the common cold, 1.2 g/day was the standard dosage
Certain manufacturers suggest splitting up the total dose into two during the day. People report starting out with the standard dosage of 1.2 g/day divided into 600 mg in the morning and 600 mg in the afternoon. Some people gradually increase their dosage after 1 month if needed.
Micronized PEA supplements were used in most studies, some scientists considering them superior to other forms. Micronized PEA is a fine powder that may be better absorbed. PEA combined with luteolin was also used in clinical trials.
Food Sources
Soy lecithin, soy products, and alfalfa are good food sources of PEA. However, these will not be a suitable option for people with food sensitivities. Egg yolk is another great food source for people who don’t react to eggs. If you’re on a meat-heavy diet or are prone to food sensitivities, PEA supplements are a safer and more effective choice.
Even though PEA is made from saturated fatty acids, including more saturated fats in your diet will not increase your body’s PEA production. On the contrary, a diet high in saturated fatty acid will probably only increase your risk for various chronic and inflammatory health problems.
Pregnancy and Children
A couple of studies have used PEA in children without any risks. Larger studies would need to confirm the safety of PEA in children.
PEA did not have toxic effects in pregnant animals. It didn’t have any potential to damage cells, cause mutation, or cancer. Long-term PEA given at the highest achievable doses to animals (1 g/kg of body weight) wasn’t toxic. We advise caution in pregnant and breastfeeding women due to a lack of clinical data [32].
Genetics and the Bliss Enzyme (FAAH)
General Overview
As a fatty acid amine, PEA is broken down by the same enzyme as our natural cannabinoids are. This enzyme is called Fatty Acid Amide Hydrolase or simply FAAH. Since less FAAH activity will increase anandamide, FAAH is also called the bliss enzyme (ananda = bliss) [2].
If you are genetically predisposed to higher FAAH activity, you will likely benefit from PEA.
Having lower FAAH enzyme activity can offer plenty of benefits.
Mice completely lacking FAAH experience less pain and seizures. It was thought that these benefits result from increased anandamide. But scientists are now realizing how important a role PEA plays – it offers some unique benefits, while others overlap with or support our natural cannabinoids [33].
For one, a lower FAAH will boost PEA levels as less of it will be broken down. PEA blocks the expression of the FAAH gene, further boosting the activity of your natural cannabinoids [34].
FAAH not only breaks down cannabinoids, PEA, and similar substances but also degrades cannabinoid receptors (CB1 and CB2). By blocking FAAH, PEA boosts the number of these receptors and the body’s sensitivity to cannabinoids [34].
PEA can also activate other receptors that boost cannabinoid activity (TRPV1).
FAAH and CNR1 SNPs
If you really want to dig deeper, your genetic data can offer you a lot of powerful insight. For example, if you know that you are predisposed to low endocannabinoid levels (high FAAH and/or low CNR1 gene activity), you’re more likely to benefit from PEA. You’ll ideally be able to balance your cannabinoids before they cause any problems.
Matching your supplements to your unique genetic makeup is a powerful approach called nutrigenomics. PEA and the endocannabinoid system is a great example of this concept in action.
SelfDecode is a software tool we created to help you analyze your genetic data.
Look at the following FAAH SNPs:
- rs324420 (A = lower FAAH)
- rs2295633 (G = likely higher FAAH activity)
- rs3766246 (G = possibly higher FAAH)
To get a complete picture of your endocannabinoid genetics, you should also take a look at your cannabinoid receptor genes, CNR1, and the following SNPs in this gene:
Note: Make sure you buy Palmitoylethanolamide and NOT Phenylethylamine (a completely different supplement that’s also sometimes referred to as PEA).
Takeaway
Palmitoylethanolamide, or PEA, is produced in the body naturally to combat pain and inflammation.
The highest amounts can be found in soy lecithin, soybeans, egg yolk, peanuts, and alfalfa. PEA is also available as a supplement, though large-scale studies are still lacking to support its use as a natural painkiller.
Solid evidence shows that PEA may reduce complex pain, but its impact on neuropathic pain is less clear.
Scientists believe that PEA may act on cannabinoid pathways to reduce pain and inflammation. For this reason, certain genetic variations in cannabinoid-related genes are thought to affect the activity of PEA in the body.
However, more research is needed to determine PEA’s exact mechanism and long-term safety.
