The Basal Pharmacology of Palmitoylethanolamide

Abstract

Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide) is an endogenous compound belonging to the family of N-acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.

Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients

“…um-PEA would seem to have numerous healthy effects on different organs and systems, thanks to its various mechanisms acting on inflammation, pain and improving a wide variety of signs and symptoms of both chronic and acute pathological conditions, among them COVID-19 [ 53 ]. In this perspective, as um-PEA is safe, endogenous, and nontoxic, its supplementation, aiming at the modulation of the immune system, could represent an add-on therapy to traditional pharmacological drugs for COVID-19 patients [ 20 , 22 ].…”

“…In addition, um-PEA is able to decrease hyperalgesia as it can reduce COX-2 and iNOS gene transcription and restore the action of PPARα at the dorsal root ganglia level. In fact, um-PEA seems to inhibit the degradation of IkB-α and the nuclear translocation of p65 NF-κB, acting as a transcription modulator for the attenuation of peripheral hyperalgesia, with inhibition of the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and some interleukins (ILs) [ 25 , 46 , 53 ]. Further action of um-PEA can be related to direct activation at low doses of the orphan GPR55 receptor, largely expressed in many brain areas and in the gastrointestinal system [ 17 , 54 , 55 ].…”

Palmitoylethanolamide Reduces Colon Cancer Cell Proliferation and Migration, Influences Tumor Cell Cycle and Exerts In Vivo Chemopreventive Effects

“…Because the antiproliferative effect, at least for the 30 µM concentration, was maximal after 24 h of treatment, we selected this timepoint for further evaluations. The gradual disappearance of um-PEA's effect after 24 h incubation could be due to its enzymatic catabolism [22], since NAAA (i.e., the main PEA hydrolytic enzyme) is expressed in HCT116 cells. Also, the possibility that HCT116 cells could activate biological pathways able to overcome um-PEA's antiproliferative activity cannot be ruled out.…”

Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence

“…Other ethanolamines of various long-chain fatty acids also naturally occur, and along with anandamide they are collectively referred to as N-acylethanolamines. However, they are more abundant than anandamide in the body and do not bind to cannabinoid receptors, while exerting most of their biological effects by activating the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, and PPAR-α-independent pathways involving other receptors such as Transient Receptor Potential Vanilloid 1 (TRPV1) and GPR55 [ 17 , 18 ]. Research evidence suggests that such specific mechanisms of action would account for their anti-inflammatory, analgesic, anticonvulsant, and neuroprotective properties [ 17 , 18 ].…”

“…However, they are more abundant than anandamide in the body and do not bind to cannabinoid receptors, while exerting most of their biological effects by activating the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, and PPAR-α-independent pathways involving other receptors such as Transient Receptor Potential Vanilloid 1 (TRPV1) and GPR55 [ 17 , 18 ]. Research evidence suggests that such specific mechanisms of action would account for their anti-inflammatory, analgesic, anticonvulsant, and neuroprotective properties [ 17 , 18 ]. Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide), in particular, is a saturated N-acylethanolamine which has been suggested to be effective in the control of inflammatory responses [ 19 , 20 ], depressive symptoms [ 21 ], epilepsy [ 22 ], and pain [ 23 ], possibly through a neuroprotective role against glutamate toxicity [ 17 ].…”