Mast cells and neuroimmune interactions regulate the severity of intestinal radiation mucositis, a dose-limiting toxicity during radiation therapy of abdominal malignancies.


Because endocannabinoids (eCB) regulate intestinal inflammation, we investigated the effect of the cannabimimetic, palmitoylethanolamide (PEA), in a mast competent (+/+) and mast cell-deficient (Ws/Ws) rat model.


Rats underwent localized, fractionated intestinal irradiation, and received daily injections with vehicle or PEA from 1 day before until 2 weeks after radiation. Intestinal injury was assessed noninvasively by luminol bioluminescence, and, at 2 weeks, by histology, morphometry, and immunohistochemical analysis, gene expression analysis, and pathway analysis.


Compared with +/+ rats, Ws/Ws rats sustained more intestinal structural injury (p = 0.01), mucosal damage (p = 0.02), neutrophil infiltration (p = 0.0003), and collagen deposition (p = 0.004). PEA reduced structural radiation injury (p = 0.02), intestinal wall thickness (p = 0.03), collagen deposition (p = 0.03), and intestinal inflammation (p = 0.02) in Ws/Ws rats, but not in +/+ rats. PEA inhibited mast cell-derived cellular immune response and anti-inflammatory IL-6 and IL-10 signaling and activated the prothrombin pathway in +/+ rats. In contrast, while PEA suppressed nonmast cell-derived immune responses, it increased anti-inflammatory IL-10 and IL-6 signaling and decreased activation of the prothrombin pathway in Ws/Ws rats.


These data demonstrate that the absence of mast cells exacerbate radiation enteropathy by mechanisms that likely involve the coagulation system, anti-inflammatory cytokine signaling, and the innate immune system; and that these mechanisms are regulated by PEA in a mast cell-dependent manner. The eCB system should be explored as a target for mitigating intestinal radiation injury.

Palmitoylethanolamide is especially in Italy and the USA at the moment hot for the treatment of glaucoma. We prefer treatment either with the Italian PEA tablets, based on PEA-um or PEA-m, or by administrating the Dutch PEA capsules containing PEA-opt. Dutch capsules do not contain any chemical excipients and are 100% pure in vegetarian capsules.

For pain relief and for inhibiting inflammation, most patients choose:

  • PEA capsules produced in the Netherlands by Russell
  • PEA tablets produced in Italy by Epitech

Only for these the Dutch and the Italian formulations long-term safety and efficacy data gathered under the supervision of MDs are available. And only for these formulations (PEA-um, PEA-m and PEA-opt) there are currently data available proving that after intake PEA levels in the body significantly rise. Such data do not exist for me-too PEA formulations.


Palmitoylethanolamide regulates development of intestinal radiation injury in a mast cell-dependent manner.

Wang J, Zheng J, Kulkarni A, Wang W, Garg S, Prather PL, Hauer-Jensen M.

Dig Dis Sci. 2014 Nov;59(11):2693-703. doi: 10.1007/s10620-014-3212-5. Epub 2014 May 22.