Despite the lack of clinical research, several scientific findings indicate that Palmitoylethanolamide (PEA) may be a natural molecule with potential applications in this field. PEA is a bioactive endogenous lipid mediator resembling endocannabinoids (eCB), belonging to the N-acyl-ethanolamine (NAE) fatty acid amide family. It is synthesized locally as needed within the lipid bilayer and can be detected in all tissues, including the brain [73]. The peroxisome proliferator-activated receptor (PPAR-α) is the primary target of PEA action, but it can also act on novel cannabinoid receptors, G protein-coupled receptors 55 (GPR55) and 119 (GPR119), or indirectly activate cannabinoid receptors 1 and 2 (CB1 and CB2) by preventing the breakdown of the endocannabinoid, anandamide (AEA), a process known as the “entourage effect”. PEA additionally exerts a strong anti-nociceptive impact via activating and desensitizing the transient receptor potential vanilloid receptor 1 (TRPV1) channels. It accomplishes this through several methods, including the entourage effect and PPAR-a activation and possibly functioning as a regulator of allosteric [73]. It is a pleiotropic molecule with anti-inflammatory, analgesic, anticonvulsant, antimicrobial, antipyretic, antiepileptic, immunomodulatory and neuroprotective activities [74,75,76]. For these reasons, PEA is already clinically helpful in a wide range of different disorders, such as depression, Parkinson’s disease, autism, or stroke [77,78,79]. All relevant data from randomized controlled trials (RCTs) assessing the effectiveness and tolerability of PEA supplementation across human ailments in patient populations have recently been gathered and thoroughly addressed by a systematic review and meta-analyses. RCTs examining the effects of PEA on pain management and overall wellbeing metrics have produced the strongest data, and they also show high tolerance when compared to controls. In addition to alleviating symptoms, PEA has been shown to modify biomarkers that are either early in the course of an illness or contribute to its progression, indicating the possibility of disease modification. PEA is also used in gynecological fields to suppress visceral disturbances across human conditions, such as endometriosis, chronic pelvic pain syndrome, and primary dysmenorrhea [80]. One intriguing finding from all these assessments was that PEA offers favorable safety for both short-term and long-term treatment, with a biological profile that closely resembles human physiology and possible disease-modifying effects. Recently, the hypothesis that PEA could also be used in the obstetric field has emerged. In a recent clinical trial, a total of 221 pregnant women, at ‘high-risk’ for PTB (previous PTB, a family history of PTB, history of 2 or more LLETZ procedures, cervical length < 25 mm on transvaginal ultrasound scan) were recruited between 24 and 34 gestational weeks [81]. The authors first measured AEA plasma levels, which are usually known to increase by the third trimester, and found that, also in the case of threatened PTB, their levels increased. Additionally, on a total of 51 patients, the authors also measured PEA plasma levels, using ultra-high performance liquid chromatography-tandem mass spectrometry. They evidenced that its concentrations were statistically higher (p = 0.042) in the women who delivered preterm (15.25 ± 5.38 nM) than in the women who delivered at term (12.01 ± 6.32 nM). The goal of the multivariate analysis was to consider both plasma AEA and PEA concentrations, a predictive marker for increased risk of PTB [81]. It could be explained by the fact that the increase in PEA levels is evidenced in many other inflammatory models and represents an anti-inflammatory response that the body initiates to establish homeostasis. Also in this case, with PTB being an “inflammation syndrome”, high levels of PEA could be either an anti-inflammatory response of the body to delay labor or maintain high levels of AEA itself, due to the entourage effect [81]. Unfortunately, endogenous PEA may be generally insufficient to counter chronic allostatic load as seen in chronic inflammatory disorders. Therefore, as suggested by the authors, making exogenous administration could be a viable therapeutic strategy to top-up endogenous levels and restore altered homeostasis [73].

Scientific studies highlighted how PEA acts on various factors that control premature uterine contractility. First, it significantly reduces, alone or in combination with other natural molecules, NF-kB levels, and increases those of its inhibitor, IkB [82,83]. PEA can downstream several inflammatory response-related genes, including cytokines (TNF-α, Il-1β, and IL-6) and inflammasome-dependent inflammatory pathways (NLRP3), whose activity is linked to preterm labor [84].

Moreover, PEA significantly downregulates signal mediators, such as COX2 [85], and downstream prostaglandin E2, whose increase is well known to lead to labor [86]. Moreover, the fact that PEA is an endogenous component of amniotic fluid and fetal membranes adds interest to the discussions about PEA, thus creating new scenarios and research opportunities in the field of obstetrics [87,88].

The further peculiar role of PEA in the context of preventing PTB could also depend on its action on the mast cell (MC). Mast cells are effectors of the immune system and are derived from bone marrow stem cells [89]. They are often associated with pathological disorders involving IgE (such as asthma), and they play a role in tissue remodeling, blood vessel formation, the resolution of viral and bacterial infections, and acute and chronic inflammatory diseases. Distributed throughout the body, mast cells are also normally present in the uterus, at the myometrial level, in close association with collagen fibers, fibroblasts, and smooth muscle cells [90]. Pregnancy problems such as asthma, psoriasis, mastocytosis, and urticaria can result from uncontrolled increases in MC quantity and/or activation, even though physiological amounts of MCs have been demonstrated to positively influence pregnancy outcomes, at least in mouse models [91]. Mast cells are under hormonal control throughout the gestational period. Endogenous progesterone (P4) keeps them in a quiescent state by inhibiting histamine release [92]. On the contrary, near childbirth, estrogens, oxytocin, and CRH trigger its degranulation. The released mediators thus activate uterine contractility and cervical ripening, promoting labor. Their premature activation and degranulation cause activation of several enzyme pathways, including arachidonic acid conversion by COX and lipoxygenase into prostaglandins, thus inducing an increased premature contractility in uterine tissues from pregnant humans [93]. The direct link between mast cells and uterine contractility has also been demonstrated in a study on human myometrial strips. The study highlighted that mast cell degranulation activates uterine contractility. Myometrial strips from women who delivered at term (>37 weeks) and women who delivered preterm (<37 weeks) were incubated with compound 48/80, which can activate mast cells. In both cases, treatment with this substance increased the contractility of the myometrial strips, while treatment with sodium cromoglicate (a mast cell stabilizer, an inhibitor of degranulation) reversed this increase in contractility. The use of a histamine receptor antagonist and a COX inhibitor also inhibited the induced contractility, both in the case of preterm labor and in the case of term labor, demonstrating that mast cell degranulation, and therefore their activation, activated uterine contractility [93]. PEA supplementation could be a valid preventive strategy to block premature activation of mast cells. In 1993, professor and Nobel prize winner in medicine, Rita Levi Montalcini, unveiled the mechanism of action of PEA, demonstrating that the molecule was able to restore the homeostasis of inflammatory processes because of its specific modulation and inhibition of mast cell degranulation [94]. Several scientific studies have demonstrated how PEA significantly reduces both the number of mast cells and the release of histamine, TNF-α, and prostaglandins [95,96,97]. Until now, no clinical research has examined the impact of PEA during pregnancy. Nonetheless, there is encouraging scientific data in this area, and we expect that more research will be performed soon. PEA is an endogenous component of amniotic fluid and fetal membranes; it may have an impact on all the inflammatory markers linked to premature labor, and moreover, it has no negative effects on the mother or the fetuses, as demonstrated by a recent in vivo study [98]. A micronized PEA formulation, the genetic and mammalian toxicology of which was evaluated through good laboratory practice (GLP) compliant toxicological investigations, which included the Ames test, in vitro mammalian cell micronucleus test, the acute oral up-and-down procedure, a 14-day toxicity study, and a 90-day toxicity study. The results revealed no evidence of mutagenicity, cytotoxicity, or genotoxicity. Additionally, results of the acute oral up-and-down procedure found the acute oral LD50 in rats to be >2000 mg/kg body weight. Furthermore, the 14-day (acute) and 90-day (subchronic) oral toxicity studies conducted on rats revealed no treatment-related adverse events and determined the no-observed adverse-effect level (NOAEL) of PEA, on rats, even at a high dose of 1000 mg/kg body weight/d (NOAEL), which translated to an HED, it corresponds to a dose of 9.7 g/d [98].

This prenatal developmental toxicity study contributes to opening new clinical applications for PEA. It indicates that PEA is well tolerated by and could be safe during pregnancy to prevent premature rats [98] (Table 4).

Despite the compelling biological profile of PEA, which exhibits anti-inflammatory, analgesic, neuroprotective, and mast cell-stabilizing effects through multiple molecular pathways, such as PPAR-α activation and the entourage effect with endocannabinoids, its clinical translation could be impeded by pharmacokinetic challenges [99]. PEA may have poor oral bioavailability, mostly caused by its high lipophilicity and low aqueous solubility. These properties could be an obstacle to converting the drug’s encouraging preclinical benefits into reliable clinical results. Otherwise, it could be easily bypassed through innovative formulations (such as micronizations, ultramicronizations) that could overcome solubility challenges. In any case, a dose of 200 mg should not have an absorption issue because it has the same absorption profile as micronized versions, as recently shown. Moreover, a strategy of double daily dosing could help maintain more stable therapeutic levels over time because of peak plasma concentrations [99].