Patient handout for Palmitoylethanolamide (PEA)
Palmitoylethanolamide (PEA)
Palmitoylethanolamide (PEA)
SCIENTIFIC NAME
N-(2-Hydroxyethyl) hexadecanamide
FAMILY

+ Other Common Names

  • Hydroxyethylpalmitamide, Impulsin, N-(2-Hydroxyethyl)palmitamide, Palmidrol, Palmitamide MEA, Palmitic Acid Monoethanolamide, Palmitoylethanolamine, PEA.

Overview

Palmitoylethanolamide (PEA) is a fatty acid amide. In the diet it is found in egg yolk and plant fats, such as soy lecithin and ground peanuts (93320,93322,93333,93371). PEA is also made naturally by the body in response to stress and pain. In Europe, PEA is available for use under medical supervision as a micronized or ultramicronized product and classified by the European Commission as 'Food for Special Medical Purposes' (93314).

Safety

POSSIBLY SAFE ...when used orally and appropriately, short-term. PEA has been used with apparent safety in doses of up to 1400 mg daily for up to 3 months (93314,93326,93327,93333,93335,93338,93339,93369,93373,101333)(101335,106269,106274). ...when used topically and appropriately, short-term. An emollient containing PEA 0.3% and N-acetylethanolamine 0.21% (Stiefel Laboratories Ltd) had been used with apparent safety twice daily for up to 28 days (106271).

There is insufficient reliable information available about the safety of PEA when applied topically or when used orally, long-term.

CHILDREN: ...when used orally and appropriately, short-term. PEA 300-600 mg twice daily for 10-12 weeks has been used with apparent safety in children 4-17 years old (101338,106266).

PREGNANCY AND LACTATION: Insufficient reliable information available; avoid using.

+ Adverse Effects

General: Orally and topically, PEA seems to be generally well tolerated.

Most Common Adverse Effects:

Orally: Nausea.
  • + Cardiovascular

    Orally, PEA has been reported to cause palpitations in one patient (93322).
  • + Dermatologic

    Topically, applying a lotion containing PEA twice daily worsened pruritus and caused stinging, scaling, or reddening in 13% of patients with dry skin. However, these adverse effects did not occur more frequently than in patients applying the vehicle alone (106272).
  • + Gastrointestinal

    Orally, PEA has been rarely reported to cause mild and transient gastrointestinal symptoms, such as nausea (93325,93327,106266).
  • + Genitourinary

    Orally, PEA has been rarely reported to cause spotting when used in combination with polydatin. However, it is unclear whether this adverse effect is due to PEA, polydatin, or the combination (93325).
  • + Neurologic/CNS

    Orally, PEA has been reported to cause drowsiness or a sensation of floating in one patient each (93322,106266).

+ Effectiveness

POSSIBLY EFFECTIVE
Osteoarthritis. Oral PEA seems to reduce pain and improve function in patients with osteoarthritis.
+ Details:  Clinical research in patients with osteoarthritis shows that taking PEA (Levagen, Gencor Pacific) 300 mg or 600 mg daily in two divided doses for 8 weeks modestly improves function and reduces pain, stiffness, and the need for rescue analgesics when compared with placebo. The worst reported pain from the day prior was reduced by 40% to 50% in patients taking PEA, compared with no improvement in those taking placebo. Also, the number of patients reporting no pain in the previous 24 hours was more than doubled in those taking PEA when compared with placebo (106274).
Pain (chronic). Oral PEA seems to reduce pain in patients with chronic pain due to various causes.
+ Details:  A meta-analysis of the available clinical research, as well as one observational study, shows that taking micronized or ultramicronized PEA (Normast, Epitech Group) 300-1200 mg daily for up to 60 days reduces pain in people with chronic pain due to various causes, regardless of the use of other analgesics. The meta-analysis estimated a five-fold reduction in pain every two weeks in patients using PEA when compared to control. Estimates also suggest that pain reduction to a score of less than or equal to 3 is approximately twice as likely to occur in patients using PEA when compared to control (93314,93320). A more recent meta-analysis of small clinical studies in patients with pain of various etiologies taking PEA 300-1200 mg for 10-180 days did not find any further pain reduction with the use of higher doses or longer durations. There was also no difference in pain reduction when compared with either a placebo control or a non-placebo control (101327). The validity of these findings is limited by the variability of the studies in the analysis and the lack of differentiation between patients with neuropathic and non-neuropathic pain.
POSSIBLY INEFFECTIVE
Spinal cord injury. Oral PEA does not seem to reduce pain or spasticity associated with spinal cord injury.
+ Details:  Clinical research shows that taking ultramicronized PEA (Normast, Epitech Group SpA) 600 mg sublingually twice daily for 12 weeks as add-on pain therapy does not reduce neuropathic pain, spasticity, or insomnia in patients with pain and spasticity associated with spinal cord injury when compared with using conventional pain treatments (93370).
+ Details:  Preliminary clinical research in adults with ALS shows that taking ultramicronized PEA 600 mg twice daily for 6 months, in addition to riluzole 50 mg, slows the decline of pulmonary function when compared with a control group taking riluzole alone. Taking PEA also attenuates the reduction in forced vital capacity, with a 4% decrease in the treatment group compared to a 15% decrease in the control group (93369).
Atopic dermatitis (eczema). Topical PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  Clinical research in patients with atopic dermatitis shows that using an emollient containing PEA 0.3% and N-acetylethanolamine 0.21% (Stiefel Laboratories Ltd) twice daily for 28 days modestly improves skin hydration, scaling, dryness, and itching when compared with a control emollient. There was no effect on skin redness or integrity (106271).
Autism spectrum disorder. It is unclear if oral PEA is beneficial for autism.
+ Details:  A small clinical study in children aged 4-12 years with autism and moderate to severe irritability shows that taking PEA 600 mg twice daily for 10 weeks as an adjunct to treatment with risperidone improves irritability and hyperactivity, but does not seem to affect lethargy/social withdrawal, inappropriate speech, or stereotypic behavior, when compared with placebo and risperidone (101338).
Cannabis use disorder. Although there is interest in using oral PEA for cannabis withdrawal, there is insufficient reliable information about the clinical effects of PEA for this condition.

Carpal tunnel syndrome. It is unclear if oral PEA is beneficial for carpal tunnel syndrome.
+ Details:  Preliminary clinical research in patients with moderate severity carpal tunnel syndrome shows that taking PEA 600 or 1200 mg daily in divided doses for 30 days reduces or delays discomfort when compared to no treatment (93377). The validity of these findings is limited by the lack of an adequate comparator group. Another small preliminary clinical trial in patients with moderate to severe carpal tunnel syndrome shows that taking ultra-micronized PEA (Normast, Epitech Group S.p.A) 1200 mg daily prior to carpal tunnel surgery improves sleep disturbance and pain when compared with control. Two 600 mg sachets of the product were used daily for 10 days, followed by two 600 mg tablets daily for 50 days. The treatment regimen was then continued for another 90 days, but there was no difference between groups with regard to sleep and pain outcomes during this period (101333).

PEA might not work as well in patients with milder carpal tunnel syndrome. A clinical study in patients with low to moderate severity carpal tunnel syndrome shows that taking PEA 300 mg twice daily for 60 days does not improve symptoms when compared with placebo (101334).
Chronic kidney disease (CKD). Although there is interest in using oral PEA for CKD, there is insufficient reliable information about the clinical effects of PEA for this condition.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  A small preliminary clinical study in patients with CP/CPPS shows that taking a specific combination product containing PEA 300 mg with alpha-lipoic acid 300 mg (Peanase) daily for 12 weeks improves lower urinary tract symptoms, pain, and quality of life, but does not improve erectile function, when compared with taking saw palmetto 320 mg (101336). It is not clear if these effects are due to PEA, other ingredients, or the combination.
Circadian rhythm sleep disorders. It is unclear if oral PEA is beneficial in patients with disturbed sleep patterns.
+ Details:  A clinical study in healthy adults with disturbed sleep patterns shows that taking a specific formulation of oral PEA (Levagen+) 350 mg nightly, one hour prior to sleep, for 8 weeks does not improve the quality of sleep when compared with placebo. However, treatment with PEA shortens the time needed to fall asleep at weeks 4 and 8 when compared with placebo (107807). This study may have been inadequately powered to detect a difference between groups.
Cognitive impairment. Although there is interest in using oral PEA for cognitive impairment, there is insufficient reliable information about the clinical effects of PEA for this condition.

Complex regional pain syndrome. Although there is interest in using topical PEA for complex regional pain syndrome, there is insufficient reliable information about the clinical effects of PEA for this condition.

Coronavirus disease 2019 (COVID-19). It is unclear if oral PEA is beneficial for recovery of smell following COVID-19 infection.
+ Details:  COVID-19 infection has been associated with persistent smell or taste disorder. In patients with olfactory impairment lasting at least 90 days after a confirmed negative COVID-19 test, a small preliminary clinical trial shows that taking PEA 700 mg plus luteolin 70 mg (Glialia, Epitech pharmaceutical) daily for 30 days in combination with olfactory rehabilitation modestly improves olfactory recovery, based on threshold, discrimination, and identification, when compared with olfactory rehabilitation alone. However, patients randomized to PEA plus luteolin had worse olfactory status at baseline and had experienced olfactory impairment for about twice the duration as those in the control group. These baseline differences may have confounded any findings (106270).
Depression. It is unclear if oral PEA is beneficial for depression when used in combination with citalopram.
+ Details:  A small clinical trial in patients with major depressive disorder shows that, in addition to citalopram, taking ultra-micronized PEA 600 mg twice daily for 6 weeks results in at least a 50% improvement on the Hamilton Depression Rating Scale (HAM-D) in all patients, compared to about 75% of patients in the group receiving placebo and citalopram. However, there was no between-group difference in complete remission rates (101335).
Diabetic neuropathy. It is unclear if oral PEA is beneficial for diabetic neuropathy.
+ Details:  Preliminary clinical research in adults with diabetic neuropathy shows that taking a specific type of micronized PEA (Normast, Epitech Group srl) 300 mg twice daily for 60 days reduces neuropathic pain when compared with baseline (93335). The validity of this finding is limited by the lack of a comparator group.
Dry eye. It is unclear if eye drops containing PEA are beneficial for dry eye.
+ Details:  Observational research in patients with glaucoma and dry eye has found that applying specific PEA eye drops (Defluxaa), one drop in each eye twice daily for 30 days, is linked to improved tear stability and tear production (101332).
Dry skin. It is unclear if topical PEA is beneficial for dry skin.
+ Details:  Preliminary clinical research in patients with pruritus related to dry skin shows that applying a lotion containing PEA (Physiogel Calming Relief) twice daily for 14 days does not reduce itchiness, roughness, or scaling when compared with applying the vehicle alone (106272).
Dysmenorrhea. Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  Clinical research in adolescents and young adults with primary dysmenorrhea shows that taking a combination of PEA 400 mg plus trans-polydatin 40 mg daily for 10 days, starting on the 24th day of the cycle, modestly reduces pelvic pain when compared with placebo. Also, approximately 98% of patients taking PEA had some pain reduction, compared with 56% of those taking placebo (106273).
Endometriosis. Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  A meta-analysis of clinical and observational research in patients with endometriosis-related pain shows that taking micronized PEA 400 mg and trans-polydatin 40 mg twice daily for 3 months moderately improves pelvic pain and dysmenorrhea and modestly improves pain with intercourse when compared with placebo (101337). However, taking the same specific combination of PEA 400 mg plus polydatin 40 mg (Pelvilen, Epitech Group Srl) daily for 3 months was not as effective as taking celecoxib 200 mg twice daily for 7 days. Satisfaction with treatment is comparable between PEA and celecoxib (101407).

Limited research has also assessed PEA in combination with alpha-lipoic acid. Preliminary clinical research shows that taking a combination of PEA 300 mg and alpha-lipoic acid 300 mg twice daily for 6-9 months reduces endometriosis-associated pelvic pain and improves quality of life and sexual function when compared to baseline (93379). The validity of this finding is limited by the lack of a comparator group.
Exercise-induced muscle damage. It is unclear if oral PEA is beneficial for the prevention or treatment of exercise-induced muscle damage.
+ Details:  A small clinical study in young males shows that taking a drink containing PEA 150 mg (as Levagen+) plus maltodextrin 832.5 mg before, immediately after, and 3 hours, 24 hours, and 48 hours after an exercise session designed to cause muscle damage modestly reduces myoglobin levels, a marker of muscle damage, in the 3-hour post-exercise period when compared with taking maltodextrin 1 gram. However, there were no effects on levels of creatine kinase or inflammatory cytokines over 72 hours (106267).
Exercise-induced muscle soreness. It is unclear if oral PEA is beneficial for the prevention or treatment of exercise-induced muscle soreness.
+ Details:  A small clinical study in young males shows that taking a drink containing PEA 150 mg (as Levagen+) plus maltodextrin 832.5 mg before, immediately after, and 3 hours, 24 hours, and 48 hours after an exercise session designed to cause muscle soreness does not reduce muscle soreness in the 72-hour post-exercise period when compared with taking maltodextrin 1 gram (106267).
Fibromyalgia. It is unclear if oral PEA is beneficial for fibromyalgia.
+ Details:  Retrospective and prospective observational research in patients with fibromyalgia who are taking duloxetine and pregabalin shows that taking micronized or ultramicronized PEA (PEA-m or PEA-um, Epitech Group) 600-1200 mg daily for 3 months reduces pain and tender points when compared with duloxetine and pregabalin alone (93338). The validity of these findings is limited by poor study design and the lack of a placebo control.
Glaucoma. Taking oral PEA seems to have a small beneficial effect on intraocular pressure. However, it is unclear if oral PEA is beneficial for glaucoma.
+ Details:  In patients with normal-tension glaucoma, preliminary clinical research shows that taking ultramicronized PEA 600 mg in divided doses for 6 months reduces intraocular pressure by 3.3 mmHg and improves visual field indices without impacting visual acuity when compared to baseline (93378). Other preliminary clinical research in patients with stable open-angle or normal tension glaucoma already using standard topical therapy shows that taking PEA (Visimast) 600 mg daily for 4 months modestly improves the function of retinal ganglion cells, intraocular pressure, and quality of life when compared with not taking PEA. However, in this study there was no effect on the visual field (106268).

PEA has also been evaluated for the general reduction of intraocular pressure. In patients undergoing bilateral laser iridotomy for the prevention of primary closed-angle glaucoma, a small clinical study shows that taking a specific PEA product (Visimast, Epitech Group Srl) 300 mg twice daily for 15 days prior to surgery prevents a rise in intraocular pressure within 2 hours of surgery when compared with placebo (93323). In patients with ocular hypertension but without other symptoms of glaucoma, preliminary clinical research shows that taking PEA 300 mg twice daily for 90 days reduces levels of intraocular pressure by approximately 3% when compared to baseline (93326). The validity of these findings is limited by the lack of a comparator group.
Inflammatory bowel disease (IBD). Although there is interest in using oral PEA for IBD, including Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of PEA for these conditions.

Interstitial cystitis. Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  Preliminary clinical research in males and females with interstitial cystitis and chronic bladder pain shows that taking a product containing micronized PEA 400 mg plus polydatin 40 mg (Pelvilen Forte, Epitech Group SpA) twice daily for 3 months, and then once daily for an additional 3 months, modestly reduces pain intensity, urgency, and frequency when compared with baseline. The pain reduction was maintained for at least an additional 2 months (106269). The validity of these findings is limited by the lack of a comparator group.
Irritable bowel syndrome (IBS). Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  A small clinical study in patients with IBS shows that taking PEA 200 mg and polydatin 20 mg (EP1844784, Epitech group Srl) twice daily for 12 weeks reduces abdominal pain severity but does not affect other gastrointestinal symptoms when compared with placebo (101331). It is not clear if these effects are due to PEA, other ingredients, or the combination.
Migraine headache. It is unclear if oral PEA is beneficial for reducing the frequency and severity of migraines in children.
+ Details:  Preliminary clinical research in children and adolescents aged 5-17 years with migraine without aura shows that taking ultra-micronized PEA 300 mg twice daily for 3 months reduces the frequency of migraine attacks by at least 50% in about 64% of patients when compared with baseline. The intensity of migraine attacks was reduced by approximately 30%, with an 80% reduction in the number of patients experiencing a severe migraine attack (106266). The validity of these findings is limited by the lack of a comparator group.
Multiple sclerosis (MS). It is unclear if oral PEA is beneficial for MS.
+ Details:  Anecdotal evidence from case reports has suggested that PEA can reduce MS-related pain (93319,93321). Preliminary clinical research in patients with relapsing-remitting MS being treated with subcutaneous interferon-beta1a shows that taking ultra-micronized PEA (Normast, Epitech Group SpA) 600 mg daily for 12 months improves some, but not all, symptoms of MS, as well as adverse effects from interferon treatment. However, taking PEA does not seem to improve physical or emotional well-being or overall quality of life (93368).
Neuropathic pain. It is unclear if oral PEA is beneficial for improving neuropathic pain.
+ Details:  Small, low-quality clinical studies and case series suggest that taking PEA 600-1200 mg daily in divided doses reduces neuropathic pain from various causes, including chemotherapy and trauma. Pain reduction has been reported to occur even if patients are using other treatments or receiving acupuncture (93333,93336,93376). The validity of these findings is limited by small study size, poor study design, and the lack of a comparator group.
Obesity. Although there is interest in using oral PEA for weight loss, there is insufficient reliable information about the clinical effects of PEA for this use.

Parkinson disease. It is unclear if oral PEA is beneficial for patients with Parkinson disease using levodopa.
+ Details:  Observational research in patients with Parkinson disease using levodopa found that taking a specific ultra-micronized PEA product (Normast, Epitech Group SpA) 600 mg twice daily for 3 months, followed by 600 mg once daily for up to one year, is associated with improved symptoms when compared to baseline, such as mood, sleep disturbances, and tremor, and improved activities such as getting out of bed and walking (101328). The validity of these findings is limited by the observational nature of the study and the lack of a comparator group.
Postoperative pain. It is unclear if oral PEA is beneficial for reducing postoperative pain.
+ Details:  Preliminary clinical research in adults undergoing impacted third molar extraction shows that taking a specific type of micronized PEA (Normast, Epitech Group SpA) 300 mg twice daily for 15 days reduces postoperative pain when compared with a control group. PEA reduces pain by 36% and 33% at 3 and 7 days, respectively, when compared with control (93322).
Prurigo nodularis. Topical PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  Preliminary clinical research in elderly individuals with chronic pruritus or prurigo nodularis shows that topical application with a cream containing 10% omental lipids and 'anti-itching' agents, including PEA, twice daily for 4 weeks reduces itching severity by 86% when compared with baseline. Skin barrier function was also improved. Other 'anti-itching agents' included polidocanol and stimutex made up of spent grain wax, shea extract, and Argania spinosa kernel oil (106275). The validity of these findings is limited by the lack of a comparator group.
Respiratory tract infections. It is unclear if oral PEA is beneficial for preventing respiratory tract infections.
+ Details:  Some low-quality, clinical studies in adults and children shows that taking a specific type of PEA (Impulsin) up to 1800 mg daily in divided doses for at least 12 days reduces the risk of developing an acute respiratory infection by 32% to 59% (93372,101412). Retrospective, observational research in children with recurrent respiratory infections shows taking a specific product (Sinerga) containing PEA, bovine colostrum, and phenylethylamine, as one sachet daily for 10-20 consecutive days each month for 4 months, reduces the need for antibiotics. The combination product reduced the need for antibiotic treatment to only 52% of children, compared to 95% of the children taking a probiotic extract (93337). It is not clear if these effects are due to PEA, other ingredients, or the combination.
Sciatica. Small clinical studies suggest that oral PEA may be beneficial for reducing pain associated with sciatica.
+ Details:  Some small clinical studies in patients with sciatica shows that taking PEA 300 mg twice daily for 30 days in conjunction with standard treatment reduces pain and physical aspects of quality of life when compared with standard treatment alone (93374,93375). Some higher quality clinical research in adults with sciatica and low back pain also shows that taking a specific type of PEA (Normast, Epitech Group srl) 300 mg or 600 mg daily for 21 days reduces pain by 45% to 70% in patients with lumbosciatica, compared to a 30% reduction with placebo (101408,101409).
Shigellosis. Although there is interest in using oral PEA for shigellosis, there is insufficient reliable information about the clinical effects of PEA for this use.

Stroke. Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  Preliminary clinical research in stabilized, conventionally-treated adults undergoing rehabilitative treatment for a recent stroke shows that taking a specific product (Glialia, Epitech Group SpA) containing ultra-micronized PEA 700 mg and luteolin 70 mg twice daily sublingually for 60 days improves spasticity, pain, and activities of daily living when compared to baseline (93339). The validity of these findings is limited by the lack of a comparator group.
Temporomandibular disorders (TMD). It is unclear if oral PEA is beneficial for TMD.
+ Details:  Preliminary clinical research shows that taking PEA 600-900 mg in divided doses for 14 days improves pain associated with temporomandibular arthritis by 89%, compared to only 46% in patients taking ibuprofen 600 mg three times daily for 14 days. PEA also increased mouth opening by 11.5%, compared to an increase of 5.5% with ibuprofen (93373).
Tourette syndrome. Although there is interest in using oral PEA for Tourette syndrome, there is insufficient reliable information about the clinical effects of PEA for this use.

Vulvar pain. Oral PEA has only been evaluated in combination with other ingredients; its effect when used alone is unclear.
+ Details:  A small clinical study in patients with vestibulodynia shows that taking PEA 400 mg plus polydatin 40 mg daily, in conjunction with intravaginal transcutaneous electrical nerve stimulation (TENS) therapy, does not reduce pain more than the use of TENS therapy and placebo (93327).
More evidence is needed to rate PEA for these uses.

Dosing & Administration

  • Adult

    Oral:

    PEA has most often been used in doses of 300-1200 mg daily in one or two divided doses for 2-12 weeks. See Effectiveness section for condition-specific information.

    Topical:

    PEA is used in creams and lotions. See Effectiveness section for condition-specific information.

    Ophthalmic:

    PEA is used in eye drops. See Effectiveness section for condition-specific information.

  • Children

    Oral:

    PEA has most often been used in doses of 300-600 mg once or twice daily for up to 3 months. See Effectiveness section for condition-specific information.

  • Standardization & Formulation

    PEA is available in micronized formulations. Unmodified PEA is approximately 100-700 micron. Micronized PEA is approximately 2-10 micron and ultra-micronized PEA is approximately 0.8-6 micron. These smaller compounds are intended to provide enhanced dissolution and increased absorption (93333,93335,93338).

    Ultra-micronized and micronized PEA are available commercially in sachets or in tablets or capsules (93333,93336). The capsule may be swallowed whole or the contents can be emptied under the tongue. The contents of the sachets are often poured under the tongue (93332,93333).

Interactions with Drugs

None known.

Interactions with Supplements

None known.

Interactions with Conditions

None known.

Interactions with Lab Tests

None known.

Overdose

There is insufficient reliable information available about the presentation or treatment of overdose with PEA.

Commercial Products Containing: Palmitoylethanolamide (PEA)


Pharmacokinetics

Absorption: In human research, taking ultra-micronized PEA by mouth increases plasma levels of PEA (93368). Plasma levels increase within 2 hours and return to baseline levels after approximately 4 hours (101406,101410).

Distribution: Animal research shows that PEA is distributed throughout the brain soon after oral intake, with the majority in the hypothalamus. Intraperitoneal administration resulted in PEA distribution throughout the body, including the adrenals, diaphragm, spleen, kidney, testes, lung, liver, heart, brain, and blood (101406,101410).

Mechanism of Action

General: PEA is a fatty acid amide made endogenously in the body by glial and other cells. It also occurs naturally in various foods, including milk and breast milk, egg yolk, beans, and nuts (101410). PEA is made from the fatty acid palmitic acid and ethanolamine. Its production is typically stimulated by stress, inflammation, or injury (93314). PEA is related to anandamide, an endocannabinoid made from arachidonic acid. As a group, the lipid mediators anandamide and PEA belong to a family of acylethanolamides (93319,93320,93323,101402,101404,101405,101410).

Analgesic effects: There is interest in using PEA for pain. Its analgesic effects are likely related to its local anti-inflammatory effects at the site of nerve injury (93320,93368,93371,101402,101404). However, PEA might also prolong the action of endocannabinoids by inhibiting the enzyme fatty acid amide hydrolase (FAAH) (93370,101410). In humans with multiple sclerosis, there is evidence that PEA might reduce the expression of the FAAH gene. Also, levels of the related compounds anandamide and oleoylethanolamide are increased in patients with multiple sclerosis, which possibly relates to the decrease in inflammatory cytokines (93368). It has also been suggested that PEA might desensitize the transient receptor potential cation channel subfamily V member 1 (TRPV1) channels on sensory neurons (93319,101404).

Topical application of PEA also appears to reduce pain. In patients with vulvar pain, it is thought that it targets free nerve endings of the vaginal epithelium, as well as epithelial cells and immunocompetent cells. It is possible that PEA might decrease the production of nerve growth factor and other mediators by more than one type of cell to stop the feedback loop of pain and inflammation (101403).

Anti-inflammatory effects: Laboratory and animal research suggests that PEA has anti-inflammatory effects in various cell types and animal models. PEA is thought to have direct effects on various peroxisome proliferator-activated receptors (PPAR). However, it also likely has other effects. These may involve endocannabinoid-mediated mechanisms of action, such as the activation of cannabinoid receptors or TRPV1 channels. This broad mechanism of action might explain the effects of PEA in cells such as mast cells, glial cells, astrocytes, and keratinocytes (92311,101404,101410). In general, PEA is thought to inhibit the release of inflammatory compounds from mast cells, activated at the site of nerve injury. This results in an inhibition of further mast cell recruitment, as well as an inhibition of microglial activation and neuropathic pain and edema. The mast cells and glial cells shift from a phase of immune activation to a resting phase. Both administration of PEA, and increasing its levels by blocking endogenous breakdown, result in these effects (93314,93320,93368,93371,101402,101404,101410). In animal and human research, PEA reduces levels of various inflammatory cytokines, such as interferon (IFN)-gamma, interleukin (IL)-17, and tumor necrosis factor (TNF)-alpha (93368,101401,101411). This is possibly related to inhibition of cyclooxygenase and nitric oxide synthases (101404).

In animal research, micronization of PEA appears to increase its anti-inflammatory effects following oral use (101415).

Endometrial effects: In human research, taking a combination of PEA and polydatin reduces pelvic pain due to endometriosis (93325). In animal research, this combination reduces the development of endometrial lesions, likely by decreasing inflammatory pathways and angiogenesis (101414).

Gastrointestinal effects: PEA is of interest for inflammatory bowel disorders such as Crohn disease or ulcerative colitis, which are associated with increased gut permeability and inflammation. In animal and in vitro research, PEA decreases intestinal permeability and inflammation. The mechanism of action appears to involve the TRPV1, CB2, GPR55, and PPAR-alpha receptors (101416,100879). Research in humans shows that PEA attenuates increased absorption of lactulose and mannitol, which was experimentally induced by aspirin intake (100879).

Musculoskeletal effects: There is interest in using PEA in the management of amyotrophic lateral sclerosis (ALS). Clinical research in adults with ALS shows that taking PEA reduces laboratory measures of skeletal muscle defects. In these patients, PEA appears to reduce the rundown of acetylcholine receptor currents, possibly resulting in improved muscle function (93369).

Neurologic effects: There is interest in using PEA for various neurological conditions, including Alzheimer disease and autism spectrum disorder. In an animal model of Alzheimer disease, PEA reduces certain pro-apoptotic pathways, including increased lipid peroxidation and protein nitration. In vitro, PEA protected the neurons and astrocytes that were cultured with amyloid. The PPAR receptors -alpha, -gamma, and -delta all appear to play a role in this neuroprotection (101405). In an animal model of autism, PEA improves behavior. Behavior improvements are associated with reduced levels of inflammatory cytokines in the brain and improved neurogenesis and synaptic plasticity (101401).

There is also interest in using PEA for neuronal protection following stroke. In animal research, PEA reduces the neurological damage following an ischemic stroke, possibly by protecting against neuronal and astrocyte cell death by maintaining levels of brain derived- and glial cell derived-neurotrophic factors and reducing infiltration of mast cells (93339).

Ocular effects: PEA is found naturally in ocular tissue. It is thought that the anti-inflammatory effects of PEA play a role in the protection of ocular tissue, such as the retina. This might be helpful in diabetic retinopathy, glaucoma, and other diseases. The anti-inflammatory effects of PEA likely protect the retina against oxidative stress and inflammatory cytokines. In animal models with high levels of glucose, PEA might protect against toxicity associated with advanced glycation end products, thereby reducing the activation of the retinal glial cells and others (101405). In human research, possible benefits of PEA might be related to improved peripheral endothelial function as measured by flow mediated dilation (93326).


References

See Monograph References


Monographs are reviewed on a regular schedule. See our Editorial Principles and Process for details. The literature evaluated in this monograph is current through 3/30/2023. This monograph was last modified on 4/10/2022. If you have comments or suggestions, please tell the editors.