Discussion
neuroinflammation-related symptoms, anxiety, inflammation, impaired cognition, cough, headache, chronic olfactory dysfunction, olfactory dysfunction
INFLAMMATION, CORTEX
The nascent literature on persistent COVID-19 olfactory dysfunction underscores the burden of chronic olfactory dysfunction and need for efficacious therapies [Although the primary endpoint of this analysis was olfactory recovery at 90 days, the outcomes at sub-intervals were also noted. Study participants receiving um-PEA–LUT + olfactory training regimen demonstrated olfactory recovery of ≥ 3 points by the first follow-up at nearly double the rate (21.4%), of other groups including olfactory training plus placebo (10.4%), um-PEA–LUT alone—twice daily (10%), our um-PEA–LUT alone—once daily (8.3%). Furthermore, at Combining um-PEA–LUT supplement with olfactory training was more effective than either olfactory training alone um-PEA–LUT alone. This result could represent either an additive or synergistic effect. The exact mechanisms by which olfactory training works are not fully understood, but olfactory training is thought to induce neuroplastic changes in the olfactory system. Repeatedly exposing the olfactory system to specific odors promotes adaptive changes and rewiring. These changes may involve synaptic strengthening, increased neural connectivity, and the formation of new connections between the olfactory receptor cells and the brain regions involved in olfaction, such as the olfactory bulb and olfactory cortex. Repeated exposure to odorants may help to reactivate and stimulate dormant or weakened olfactory receptors. In terms of odor identification, olfactory training engages individuals to actively focus attention on differentiating and categorizing odors to enhance identification. The active participation and practice inherent involved in olfactory training can also improve attention, concentration, and cognitive processing related to olfaction.Administering um-PEA–LUT appears to support the neuroplastic changes of olfactory training by fostering a more favorable regenerative milieu. The anti-neuroinflammatory effects of PEA–LUT reduce the inflammation in the olfactory bulbs and allow normal growth of immature neurons [Reduced inflammation in the peripheral neuroepithelium and olfactory bulbs is conducive to recovery of connections during olfactory training. Further work might explore whether um-PEA–LUT might alleviate other neuroinflammation-related symptoms, including headache, anxiety, cough, or impaired cognition [It is important to comment on patterns of attrition. We observed 24% of attrition both in the placebo + OT group and in the um-PEA–LUT + OT group. However, despite similar rates of attrition, the attrition seemed attributable to distinct reasons. In the case of the Placebo + OT group, the patients who did not present to all follow-up visits explained their missed appointment as not observing improvement (in several cases these patients presented at baseline and at the end of study). On the contrary, patients in the um-PEA–LUT reported that they did not present to all follow-ups (mostly arrived at the second only), because they recovered before the end of the study. In the um-PEA–LUT twice-daily group, some patients reported dropping out of the study, because they experienced a swift recovery of the olfaction after a single month of use, whereas um-PEA–LUT once a day group might have had more gradual recovery. These explanations of patients are anecdotal, however, and further studies are needed; the lower attrition in the once daily group receiving um-PEA–LUT may also reflect the relative ease of a once daily dosing regimen without olfactory training.