Palmitoylethanolamide (PEA)

    Palmitoylethanolamide (PEA) is a bioactive lipid mediator that belongs to the N-acetylanolamine class of phospholipids. It was initially discovered in egg yolk, soybean, and peanut oil. In animal cells, PEA is synthesised from palmitic acid, a fatty acid present in foods such as palm oil, meats, cheeses, butter, and other dairy products. PEA is widely distributed around the body, appearing in the adrenal glands, diaphragm, spleen, kidney, testis, lung, liver, heart, plasma, erythrocytes, and retina. It penetrates the blood-brain barrier, primarily accumulating in the hypothalamus, pituitary, brain stem, cerebellum, and brain córtex.

    During pathological states, PEA levels are often altered.  PEA is believed to be produced to help restore homeostasis  after cellular injury and is usually upregulated under disease  conditions.  In the brain, PEA is produced as required by neurons, microglia, and astrocytes, thus playing a pleiotropic and pro homeostatic role. When faced with pro-inflammatory external stressors, PEA exerts a local anti-injury role by down-regulating mast cell activation and protecting neurons from excitotoxicity. However, during chronic inflammation, tissue concentrations of endogenous PEA decrease due to reduced production and increased degradation. This makes endogenous PEA production inadequate to restore homeostasis. Therefore, supplementation with PEA presents a viable option to top up endogenous levels and restore bodily homeostasis.

    PEA has anti-inflammatory, analgesic, anticonvulsant, antimicrobial, antipyretic, antiepileptic, immunomodulatory and neuroprotective activities. It exerts its analgesic and anti-inflammatory effects primarily by activating the peroxisome proliferator-activated receptor alpha (PPAR)-α. Activation of the PPAR-α receptor initiates a range of actions that suppress pain and inflammatory signals, including inhibiting the release of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumour necrosis factor-α. PEA also down-regulates mast-cell degranulation and regulates microglial activity. Moreover, even though PEA has a low affinity for the cannabinoid receptors CB1 and CB2 and, therefore, cannot be considered a classic endocannabinoid, it is an endogenous endocannabinoid-like compound that targets similar pathways to cannabinoids.