Treatment of COVID-19 olfactory dysfunction with olfactory training, palmitoylethanolamide with luteolin, or combined therapy: a blinded controlled multicenter randomized trial

Purpose: Few evidence-based therapies are available for chronic olfactory dysfunction after COVID-19. This study investigated the relative efficacy of olfactory training alone, co-ultramicronized palmitoylethanolamide with luteolin (um-PEA–LUT, an anti-neuroinflammatory supplement) alone, or combined therapy for treating chronic olfactory dysfunction from COVID-19. Methods: This double-blinded controlled, placebo-controlled multicenter randomized clinical trial was conducted in 202 patients with persistent COVID-19 olfactory dysfunction of > 6 month duration. After a screening nasal endoscopy, patients were randomized to: (1) olfactory training and placebo; (2) once daily um-PEA–LUT alone; (3) twice daily um-PEA–LUT alone; or (4) combination of once daily um-PEA–LUT with olfactory training. Olfactory testing (Sniffin’ Sticks odor identification test) was performed at baseline and at 1, 2, and 3 months. The primary outcome was recovery of over three points on olfactory testing, with outcomes compared at T 0, T 1, T 2 and T 3 across groups. Statistical analyses included one-way ANOVA for numeric data and chi-square for nominal data. Results: All patients completed the study, and there were no adverse events. At 90 days, odor identification scores improved by > 3 points in 89.2% of patients receiving combined therapy vs. 36.8% receiving olfactory training with placebo, 40% receiving twice daily um-PEA–LUT alone, and 41.6% receiving once daily um-PEA–LUT alone (p < 0.00001). Patients receiving treatment with um-PEA–LUT alone demonstrated subclinical improvement (< 3 point odor identification improvement) more often than patients receiving olfactory training with placebo (p < 0.0001.) Conclusions: Olfactory training plus once daily um-PEA–LUT resulted in greater olfactory recovery than either therapy alone in patients with long-term olfactory function due to COVID-19. Trial registration: 20112020PGFN on clinicaltrials.gov. Level of evidence: 1b (Individual Randomized Clinical Trial).