N-Palmitoylethanolamide (PEA), is an endogenously produced lipid1 found in the plasma membrane2 with concentrations increasing in response to tissue damage, inflammation, and nociceptive fibre stimulation.1 Dietary sources include egg yolks, soy lecithin, bovine and human milk, roasted coffee, apples, potatoes, lentils, black-eyed peas, tomatoes, corn, peanuts, common beans, garden peas, and soybeans.3
Initially positioned as a supplement for the prevention of influenza and the common cold,2 and treatment of rheumatic fever,2,4 today PEA is regarded for its anti-inflammatory, analgesic, immunomodulatory, antimicrobial, and neuroprotective effects with the ability to effect numerous pathways and sites within the body.5
The musculoskeletal system
From a lifestyle perspective, PEA supports exercise recovery and may reduce exercise withdrawal due to pain and loss of strength from inflammation. It also supports individuals looking to increase their strength, fitness, and overall health.5 In clinical trials, PEA reduced muscle damage, supported aerobic energy metabolism, and reduced lactate levels to encourage protein synthesis.6
PEA may reduce pain and inflammation in joints, with studies showing arthritis and rheumatoid arthritis joints had lower PEA levels in the synovial fluid.1 Meanwhile, PEA levels increased in chronic neck and shoulder pain subjects to reduce pain and inflammation, however, PEA levels did not increase in chronic widespread pain subjects suggesting a potential for PEA supplementation.7 Carpal tunnel syndrome patients demonstrated an objective improvement in sleep quality and associated pain intensity,1 while animal studies on fracture pain demonstrate PEA improved fracture repair.2
The nervous system
PEA reduces pain, stress, depression, and anxiety, as well as supporting post-traumatic stress disorder. It has shown to support γ-aminobutyric acid function and reduce animal seizure activity via allopregnanolone production.2 Concomitant use with analgesics and PEA has demonstrated pain reduction and decreased medication reliance.1 It is observed endogenous PEA levels rise in acute situations, with chronic demand potentially exhausting PEA levels, warranting exogenous supplementation.5
In animal models, PEA has shown to reduce mast cell- induced neuroinflammation, demyelination and neuropathic pain. Additionally, it functions to lower mast cell-mediated toxicity, brain oedema and ischaemia, delayed post glutamate excitotoxic neuronal death, depression, anhedonia, and amyloid γ-peptide-induced learning and memory impairment2 in neurodegenerative disorders.5 Parkinson’s disease patients prescribed ultra-micronised PEA (um-PEA) with levodopa demonstrated motor and nonmotor symptom improvement2 while multiple sclerosis clinical studies support a reduction in pain with increased plasma PEA levels.2,8
A clinical study using PEA in conjunction with risperidone demonstrated an improvement in irritability and hyperactivity in autistic patients2 while reduced dopamine rewarding effects of nicotine and cocaine were determined in animal studies,9 suggesting a potential therapeutic role for autism and addiction support. Observational studies on stroke patients identified improved cognitive function, spasticity, and ability following PEA administration,10 with circulation levels at the time of the stroke correlating with the degree of neurological impact.11
The immune system
Preclinical studies demonstrate PEA’s bacterial and viral resistance to infections through innate immune support by binding to macrophages and mast cells, supporting inflammatory cytokine modulation.5
Mast cell modulation by PEA inhibits histamine, prostaglandin D2, and tumour necrosis factor-a release, leading to the prevention of allergic rhinitis, dermatitis, asthma, and wheals that involve mast cell degranulation and inflammation.5 Topical application of PEA demonstrates a reduction of eczema.12
The gastrointestinal system
PEA is a ligand for cannabinoid-like-G-coupled receptors GPR55 and GPR119. The GPR55 receptor is expressed throughout the body although mainly in the gastrointestinal tract, frontal cortex, hippocampus, hypothalamus, cerebellum, and brainstem,2 whereas the GPR119 receptor is predominantly expressed in the gut and pancreas. Connections have been made between increased GPR119 expression and type 2 diabetes, obesity, and metabolic disorders.1 Mice with diabetic neuropathy demonstrated increased cutaneous PEA levels following irritation and inflammation.13
Gastrointestinal GPR55 expression modulates inflammation, gastric motility, secretion, cellular proliferation, and intestinal permeability.2 Gastrointestinal dysbiosis correction is enhanced with PEA increasing commensal bacteria including Akkermansia muciniphila, Eubacterium, and Enterobacteriaceae.5 Intestinal lipopolysaccharides promote inflammation and intestinal hyperpermeability, crossing the blood-brain-barrier where they promote neuroinflammation. PEA reduces the impact of lipopolysaccharides by preserving the gastrointestinal barrier integrity5 and stimulates the ligand-activated nuclear receptor Peroxisome proliferator-activated receptor-α (PPAR-α) subtype involved in the regulation of macronutrient metabolism.3
Clinical studies of ulcerative colitis demonstrated intestinal PEA levels 1.8 times greater than healthy controls,13 and two times greater for untreated coeliac disease patients, while pancreatitis, pancreatic cancer, cirrhosis, and colonic inertia also increase localised PEA.2 Studies on irritable bowel syndrome showed reduced symptoms14 while an increase in intestinal PEA reduced local and systemic inflammation in colitis-induced mice indicating therapeutic potential.2
The reproductive system
PEA reduced pelvic pain associated with painful bladder syndrome, dysmenorrhea, and endometriosis following PEA administration.15 PEA prevents mast cell recruitment, degranulation, and inflammation by downregulating COX-2, reducing pain associated with menstruation, hormonal fluctuation, and endometrial lesions.5 PEA combined with transpolydactin reduced dysmenorrhea, dyspareunia, and endometriosis symptoms, providing patients with a reduction in pain in a murine model.2
Toxicity and adverse events
An animal toxicity study found a no-observed-adverse-effect level of PEA for maternal toxicity, embryotoxicity, fetotoxicity, and teratotoxicity greater than 1,000 mg/kg body weight/day suggesting a human equivalent of 9.7 g/day.17
Patients with renal and hepatic impairment can safely use PEA as its metabolism is localised and cellular.18
Clinical and animal trials using PEA have not identified any adverse drug-drug interaction and adverse effects have been limited to occasional stomach upset or diarrhoea2 with PEA being well-tolerated.5
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References
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