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).

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.

•  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).

• 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).

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

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).

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).