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Randomized Controlled Trial
. 2022;20(10):2001-2012.
doi: 10.2174/1570159X20666220420113513.

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial

Arianna Di Stadio  1 , Luca D'Ascanio  2 , Luigi Angelo Vaira  3   4 , Elena Cantone  5 , Pietro De Luca  6 , Cristina Cingolani  2 , Gaetano Motta  5 , Giacomo De Riu  3 , Federica Vitelli  2 , Giuseppe Spriano  7   8 , Marco De Vincentiis  9 , Angelo Camaioni  10 , Ignazio La Mantia  1 , Fabio Ferreli  7   8 , Michael J Brenner  11
Affiliations
Randomized Controlled Trial

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial

Arianna Di Stadio et al. Curr Neuropharmacol. 2022.

Abstract

Background: Olfactory training is the only evidence-based treatment for post-viral olfactory dysfunction. Smell disorders after SARS-CoV-2 infection have been attributed to neuroinflammatory events within the olfactory bulb and the central nervous system. Therefore, targeting neuroinflammation is one potential strategy for promoting recovery from post-COVID-19 chronic olfactory dysfunction. Palmitoylethanolamide and luteolin (PEA-LUT) are candidate antiinflammatory/ neuroprotective agents.

Objective: To investigate recovery of olfactory function in patients treated with PEA-LUT oral supplements plus olfactory training versus olfactory training plus placebo.

Methods: Multicenter double-blinded randomized placebo-controlled clinical trial was held. Eligible subjects had prior COVID-19 and persistent olfactory impairment >6 months after follow-up SARS-CoV-2 negative testing, without prior history of olfactory dysfunction or other sinonasal disorders. Participants were randomized to daily oral supplementation with ultramicronized PEA-LUT 770 mg plus olfactory training (intervention group) or olfactory training with placebo (control). Sniffin' Sticks assessments were used to test the patients at baseline and 90 days.

Results: A total of 185 patients, including intervention (130) and control (55) were enrolled. The intervention group showed significantly greater improvement in olfactory threshold, discrimination, and identification scores compared to controls (p=0.0001). Overall, 92% of patients in the intervention group improved versus 42% of controls. Magnitude of recovery was significantly greater in the intervention group versus control (12.8 + 8.2 versus mean 3.2 + 3), with >10-fold higher prevalence of anosmia in control versus intervention groups at the 90-day endpoint.

Conclusion: Among individuals with olfactory dysfunction post-COVID-19, combining PEA-LUT with olfactory training resulted in greater recovery of smell than olfactory training alone.

Keywords: COVID-19; SARS-CoV-2; anosmia; anti-inflammatory; coronavirus; hyposmia; olfaction; olfactory dysfunction; olfactory training.

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Figures

Fig. (1)
Fig. (1)
Consort Diagram showing enrollment, intervention, and follow-up of patients who participated in the clinical trial. PEA: Palmitoylethanolamide; TDI: Threshold, Discrimination, and Identification.
Fig. (2)
Fig. (2)
Comparison among groups at the two different observational points. The y axis shows the composite olfactory Threshold, Discrimination, and Identification (TDI) scores of the patients. Standard deviation (SD) is reported. “**” indicates p <0.0001.
Fig. (3)
Fig. (3)
Distribution of the olfactory Threshold, Discrimination, and Identification (TDI) scores and recovery based on the results of the Sniffin’ Sticks test. The graph shows the distribution of the patients’ TDI scores in intervention and control groups. (A) Control group TDI scores at T0 vs. T3 (B) Intervention group TDI scores at T0 vs. T3. Patients in the intervention groups demonstrated improved recovery vs. control, as reflected by increase in TDI scores. “**” indicates p <0.0001. n.s: non statistically significant.
Fig. (4)
Fig. (4)
Recovery in Control group (CG) (T3 -T0) vs. Intervention group (IG) (T3 -T0). Patients in the intervention group demonstrated improved recovery vs. patients in the control group, as reflected by increase in Threshold Detection Identification (TDI) scores. “**” indicates p <0.0001. Patients in the intervention group had a larger recovery compared to patients in the control group, as shows by magnitude of recovery.
Fig. (5)
Fig. (5)
Variation of the Threshold Detection Identification (TDI) scores in the intervention group at T1, T2 and T3, at 30 days, 60 days, and 90 days respectively. “**” indicates p < 0.01.
Fig. (6)
Fig. (6)
Distribution of patients in the different categories of olfactory impairment as identified by Threshold/Detection/Identification (TDI) score after treatment in the two groups. In the intervention group, a higher percentage of patients recovered normal olfactory function (green) after three months of therapy; the percentage with recovery in the control group was lower. Considering also slight hyposmia/borderline normosmia (bright green) patients in the intervention groups recovered in over 50% of cases, whereas in the control group, fewer than 20% patients exhibited a similar recovery.
See this image and copyright information in PMC

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