Could Palmitoylethanolamide Be an Effective Treatment for Long-COVID-19? Hypothesis and Insights in Potential Mechanisms of Action and Clinical Applications

COVID-19 is highly transmissive and contagious disease with a wide spectrum of clinicopathological issues, including respiratory, vasculo-coagulative, and immune disorders. In some cases of COVID-19, patients can be characterized by clinical sequelae with mild-to-moderate symptoms that persist long after the resolution of the acute infection, known as long-COVID, potentially affecting their quality of life. The main symptoms of long-COVID include persistent dyspnea, fatigue and weakness (that are typically out of proportion, to the degree of ongoing lung damage and gas exchange impairment), persistence of anosmia and dysgeusia, neuropsychiatric symptoms, and cognitive dysfunctions (such as brain fog or memory lapses). The appropriate management and prevention of potential long-COVID sequelae is still lacking. It is also believed that long-term symptoms of COVID-19 are related to an immunity over-response, namely a cytokine storm, involving the release of pro-inflammatory interleukins, monocyte chemoattractant proteins, and tissue necrosis factors. Palmitoylethanolamide (PEA) shows affinity for vanilloid receptor 1 and for cannabinoid-like G protein-coupled receptors, enhancing anandamide activity by means of an entourage effect. Due to its anti-inflammatory properties, PEA has been recently used as an early add-on therapy for respiratory problems in patients with COVID-19. It is believed that PEA mitigates the cytokine storm modulating cell-mediated immunity, as well as counteracts pain and oxidative stress. In this article, we theorize that PEA could be a potentially effective nutraceutical to treat long-COVID, with regard to fatigue and myalgia, where a mythocondrial dysfunction is hypothesizable.