Safety of micronized palmitoylethanolamide (microPEA): lack of toxicity and genotoxic potential

Abstract

Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. MicroPEA of defined particle size (0.5–10 μm) was evaluated for mutagenicity in Salmonella typhimurium, for clastogenicity/aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP). PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation. PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90‐day rat oral toxicity study were based on results from the preliminary 14‐day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.

The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations

“…Preclinical and human studies indicate that PEA, especially when co‐micronized together with antioxidants, such as luteolin and polydatin, and in micronized or ultra‐micronized forms, is a therapeutic tool with high potential for the effective treatment of different pathologies characterized by neurodegeneration, (neuro)inflammation and pain. Likewise, PEA also shows high safety, as recently reported by Nestmann (). While it is intuitive why, for a particularly water insoluble compound such as PEA, any formulation aimed at enhancing its specific surface, such as m‐PEA and um‐PEA, is likely to increase tissue exposure to this compound following oral administration, or why co‐administration of PEA with anti‐oxidants should enhance its efficacy, it must be emphasized that full pharmacokinetic/pharmacodynamic comparisons between normal and m‐PEA or um‐PEA, or between PEA composites and the single components thereof, in the same study, have not been reported yet.…”

Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model

“…These findings are consistent with results of previous studies on the lack of PEAum cytotoxicity and its overall in vivo safety profile. 1,9,52 Our findings suggest that PEA-um effectively downmodulated compound 48/80-induced MC degranulation in the model used. However, some limitations should be considered when interpreting the data.…”

“…In the present ex vivo model, exposing skin organ cultures to PEA‐um for 96 h did not elicit any change in either the epidermal or dermal skin compartments, in terms of epidermal thickness or keratinocyte proliferation, the same pattern of keratinocyte differentiation markers, unchanged MC density and degranulation state, compared to vehicle‐treated samples. These findings are consistent with results of previous studies on the lack of PEA‐um cytotoxicity and its overall in vivo safety profile …”

Degenerative Joint Diseases and Neuroinflammation

“…Clinically, PEA reduces chronic and neuropathic pain associated with numerous pathological conditions and reduces pain and improves function in patients with temporomandibular disorders . Importantly, PEA possesses an optimum tolerability profile, conditions fundamental for chronic treatment of the elderly …”

“…115,116 Importantly, PEA possesses an optimum tolerability profile, conditions fundamental for chronic treatment of the elderly. 86,87,117,118 Both membrane and nuclear receptors appear to be important targets for controlling disease progression. Among membrane receptors, endocannabinoids may be of particular interest, as they play a key role in bone formation, resorption, and growth.…”