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; Luca      D’Ascanio; Luigi   Angelo   Vaira; Elena      Cantone; Pietro      De Luca; Cristina      Cingolani; Gaetano      Motta; Giacomo      De Riu; Federica      Vitelli; Giuseppe      Spriano; Marco      De Vincentiis; Angelo      Camaioni; Ignazio      La Mantia; Fabio      Ferreli; Michael   J.   Brenner

doi:10.2174/1570159X20666220420113513

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, coronavirus, anosmia, hyposmia, olfactory dysfunction, olfactory training, olfaction, anti-inflammatory.

« Previous

Graphical Abstract

[1] 
Tong, J.Y.; Wong, A.; Zhu, D.; Fastenberg, J.H.; Tham, T. The Prevalence of olfactory and gustatory dysfunction in COVID-19 patients: A systematic review and meta-analysis. Otolaryngol. Head Neck Surg.,  2020, 163(1), 3-11.
[http://dx.doi.org/10.1177/0194599820926473] [PMID:  32369429] 
[2] 
Gerkin, R.C.; Ohla, K.; Veldhuizen, M.G.; Joseph, P.V.; Kelly, C.E.; Bakke, A.J.; Steele, K.E.; Farruggia, M.C.; Pellegrino, R.; Pepino, M.Y.; Bouysset, C.; Soler, G.M.; Pereda-Loth, V.; Dibattista, M.; Cooper, K.W.; Croijmans, I.; Di Pizio, A.; Ozdener, M.H.; Fjaeldstad, A.W.; Lin, C.; Sandell, M.A.; Singh, P.B.; Brindha, V.E.; Olsson, S.B.; Saraiva, L.R.; Ahuja, G.; Alwashahi, M.K.; Bhutani, S.; D’errico, A.; Fornazieri, M.A.; Golebiowski, J.; Dar, H.L.; Öztürk, L.; Roura, E.; Spinelli, S.; Whitcroft, K.l.; Faraji, F.; Fischmeister, F.P.S.; Heinbockel, T.; Hsieh, J.W.; Huart, C.; Konstantinidis, I.; Menini, A.; Morini, G.; Olofsson, J.K.; Philpott, C.M.; Pierron, D.; Shields, V.D.C.; Voznessenskaya, V.V.; Albayay, J.; Altundag, A.; Bensafi, M.; Bock, M.A.; Calcinoni, O.; Fredborg, W.; Laudamiel, C.; Lim, J.; Lundström, J.N.; Macchi, A.; Meyer, P.; Moein, S.T.; Santamaría, E.; Sengupta, D.; Rohlfs, D.P.; Yanik, H.; Hummel, T.; Hayes, J.E.; Reed, D.R.; Niv, M.Y.; Munger, S.D.; Parma, V. Gccr Group Author. Recent smell loss is
the best predictor of Covid-19 Among Individuals With Recent
Respiratory Symptoms. Chem. Senses,  2021, 46, Bjaa081.
[3] 
D’Ascanio, L.; Pandolfini, M.; Cingolani, C.; Latini, G.; Gradoni, P.; Capalbo, M.; Frausini, G.; Maranzano, M.; Brenner, M.J.; Di Stadio, A. Olfactory Dysfunction in COVID-19 Patients: Prevalence and Prognosis for Recovering Sense of Smell. Otolaryngol. Head Neck Surg.,  2021, 164(1), 82-86.
[http://dx.doi.org/10.1177/0194599820943530] [PMID:  32662745] 
[4] 
Mercante, G.; Ferreli, F.; De Virgilio, A.; Gaino, F.; Di Bari, M.; Colombo, G.; Russo, E.; Costantino, A.; Pirola, F.; Cugini, G.; Malvezzi, L.; Morenghi, E.; Azzolini, E.; Lagioia, M.; Spriano, G. Prevalence of taste and smell dysfunction in coronavirus disease 2019. JAMA Otolaryngol. Head Neck Surg.,  2020, 146(8), 723-728.
[http://dx.doi.org/10.1001/jamaoto.2020.1155] [PMID:  32556070] 
[5] 
Khan, A.; Kallogjeri, D.; Piccirillo, J. Growing public health concern
of Covid-19 chronic olfactory dysfunction. JAMA Otolaryngol. Head Neck Surg., 2021.
[PMID:  34792577] 
[6] 
Sampaio Rocha-Filho, P.A.; Voss, L. Persistent headache and persistent anosmia associated with COVID-19. Headache,  2020, 60(8), 1797-1799.
[http://dx.doi.org/10.1111/head.13941] [PMID:  32790179] 
[7] 
Vaira, L.A.; Hopkins, C.; Petrocelli, M.; Lechien, J.R.; Cutrupi, S.; Salzano, G.; Chiesa-Estomba, C.M.; Saussez, S.; De Riu, G. Efficacy
of corticosteroid therapy in the treatment of long- lasting olfactory
disorders in COVID-19 patients. Rhinology,  2021, 59(1), 21-25.
[PMID:  33290446] 
[8] 
Burges Watson, D.L.; Campbell, M.; Hopkins, C.; Smith, B.; Kelly, C.; Deary, V. Altered smell and taste: Anosmia, parosmia and the impact of long Covid-19. PLoS One,  2021, 16(9), E0256998.
[http://dx.doi.org/10.1371/journal.pone.0256998] 
[9] 
Phillips, S.; Williams, M.A. Confronting our next national health disaster - long-haul Covid. N. Engl. J. Med.,  2021, 385(7), 577-579.
[http://dx.doi.org/10.1056/NEJMp2109285] [PMID:  34192429] 
[10] 
Whitcroft, K.L.; Hummel, T. Olfactory dysfunction in COVID-19: Diagnosis and management. JAMA,  2020, 323(24), 2512-2514.
[http://dx.doi.org/10.1001/jama.2020.8391] [PMID:  32432682] 
[11] 
Levy, J.M. Treatment recommendations for persistent smell and taste dysfunction following COVID-19-the coming deluge. JAMA Otolaryngol. Head Neck Surg.,  2020, 146(8), 733.
[http://dx.doi.org/10.1001/jamaoto.2020.1378] [PMID:  32614399] 
[12] 
Sorokowska, A.; Drechsler, E.; Karwowski, M.; Hummel, T. Effects of olfactory training: A meta-analysis. Rhinology,  2017, 55(1), 17-26.
[http://dx.doi.org/10.4193/Rhino16.195] [PMID:  28040824] 
[13] 
Cecchetto, C.; Di Pizio, A.; Genovese, F.; Calcinoni, O.; Macchi, A.; Dunkel, A.; Ohla, K.; Spinelli, S.; Farruggia, M.C.; Joseph, P.V.; Menini, A.; Cantone, E.; Dinnella, C.; Cecchini, M.P.; D’Errico, A.; Mucignat-Caretta, C.; Parma, V.; Dibattista, M. Assessing the extent and timing of chemosensory impairments during COVID-19 pandemic. Sci. Rep.,  2021, 11(1), 17504.
[http://dx.doi.org/10.1038/s41598-021-96987-0] [PMID:  34471196] 
[14] 
Laurendon, T.; Radulesco, T.; Mugnier, J.; Gérault, M.; Chagnaud, C.; El Ahmadi, A.A.; Varoquaux, A. Bilateral transient olfactory bulb edema during COVID-19-related anosmia. Neurology,  2020, 95(5), 224-225.
[http://dx.doi.org/10.1212/WNL.0000000000009850] [PMID:  32444492] 
[15] 
Stoyanov, G.S.; Petkova, L.; Dzhenkov, D.L.; Sapundzhiev, N.R.; Todorov, I. Gross and Histopathology of COVID-19 With First Histology Report of Olfactory Bulb Changes. Cureus,  2020, 12(12), e11912.
[http://dx.doi.org/10.7759/cureus.11912] [PMID:  33415060] 
[16] 
Lee, M.H.; Perl, D.P.; Nair, G.; Li, W.; Maric, D.; Murray, H.; Dodd, S.J.; Koretsky, A.P.; Watts, J.A.; Cheung, V.; Masliah, E.; Horkayne-Szakaly, I.; Jones, R.; Stram, M.N.; Moncur, J.; Hefti, M.; Folkerth, R.D.; Nath, A. Microvascular injury in the brains of patients with Covid-19. N. Engl. J. Med.,  2021, 384(5), 481-483.
[http://dx.doi.org/10.1056/NEJMc2033369] [PMID:  33378608] 
[17] 
Khani, E.; Khiali, S.; Beheshtirouy, S.; Entezari-Maleki, T. Potential pharmacologic treatments for COVID-19 smell and taste loss: A comprehensive review. Eur. J. Pharmacol.,  2021, 5912, 174582.
[http://dx.doi.org/10.1016/j.ejphar.2021.174582] 
[18] 
Skaper, S.D.; Facci, L.; Giusti, P. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol. Neurobiol.,  2013, 48(2), 340-352.
[http://dx.doi.org/10.1007/s12035-013-8487-6] [PMID:  23813098] 
[19] 
D’Ascanio, L.; Vitelli, F.; Cingolani, C.; Maranzano, M.; Brenner, M.J.; Di Stadio, A. Randomized clinical trial “olfactory dysfunction after COVID-19: Olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin”: Preliminary results. Eur. Rev. Med. Pharmacol. Sci.,  2021, 25(11), 4156-4162.
[PMID:  34156697] 
[20] 
Balvers, M.G.; Brouwer-Brolsma, E.M.; Endenburg, S.; de Groot, L.C.; Kok, F.J.; Gunnewiek, J.K. Recommended intakes of vitamin D to optimise health, associated circulating 25-hydroxyvitamin D concentrations, and dosing regimens to treat deficiency: Workshop report and overview of current literature. J. Nutr. Sci.,  2015, 4, e23.
[http://dx.doi.org/10.1017/jns.2015.10] [PMID:  26090099] 
[21] 
Salehi, B.; Berkay Yılmaz, Y.; Antika, G.; Boyunegmez Tumer, T.; Fawzi Mahomoodally, M.; Lobine, D.; Akram, M.; Riaz, M.; Capanoglu, E.; Sharopov, F.; Martins, N.; Cho, W.C.; Sharifi-Rad, J. Insights on the use of α-lipoic acid for therapeutic purposes. Biomolecules,  2019, 9(8), 356.
[http://dx.doi.org/10.3390/biom9080356] [PMID:  31405030] 
[22] 
D’Ascanio, L.; Vitelli, F.; Cingolani, C.; Maranzano, M.; Brenner, M.J.; Di Stadio, A. Randomized clinical trial “olfactory dysfunction
after COVID-19: Olfactory rehabilitation therapy vs. intervention
treatment with Palmitoylethanolamide and Luteolin”: Preliminary
results. Eur. Rev. Med. Pharmacol. Sci.,  2021, 25(11), 4156-4162.
[PMID:  34156697] 
[23] 
Kuznetsova, O.M.; Tymofyeyev, Y. Preserving the allocation ratio at every allocation with biased coin randomization and minimization in studies with unequal allocation. Stat. Med.,  2012, 31(8), 701-723.
[http://dx.doi.org/10.1002/sim.4447] [PMID:  22161821] 
[24] 
Palmer, C.R.; Rosenberger, W.F. Ethics and practice: Alternative designs for phase III randomized clinical trials. Control. Clin. Trials,  1999, 20(2), 172-186.
[http://dx.doi.org/10.1016/S0197-2456(98)00056-7] [PMID:  10227416] 
[25] 
Dumville, J.C.; Hahn, S.; Miles, J.N.; Torgerson, D.J. The use of unequal randomisation ratios in clinical trials: A review. Contemp. Clin. Trials,  2006, 27(1), 1-12.
[http://dx.doi.org/10.1016/j.cct.2005.08.003] [PMID:  16236557] 
[26] 
Torgerson, D.; Campbell, M. Unequal randomisation can improve the economic efficiency of clinical trials. J. Health Serv. Res. Policy,  1997, 2(2), 81-85.
[http://dx.doi.org/10.1177/135581969700200205] [PMID:  10180369] 
[27] 
Peckham, E.; Brabyn, S.; Cook, L.; Devlin, T.; Dumville, J.; Torgerson, D.J. The use of unequal randomisation in clinical trials-An
update. Contemp. Clin. Trials,  2015, 45(Pt A), 113-122.
[http://dx.doi.org/10.1016/j.cct.2015.05.017] [PMID: 26027788] 
[28] 
Dibao-Dina, C.; Caille, A.; Sautenet, B.; Chazelle, E.; Giraudeau, B. Rationale for unequal randomization in clinical trials is rarely reported: A systematic review. J. Clin. Epidemiol.,  2014, 67(10), 1070-1075.
[http://dx.doi.org/10.1016/j.jclinepi.2014.05.015] [PMID:  25201357] 
[29] 
Cantone, E.; Ricciardiello, F.; Cuofano, R.; Castagna, G.; Oliva, F.; Sequino, G.; Abate, T.; Villani, R.; Iengo, M. The human sense of
smell. Transl. Med. Reports,  2017, 1, 2.
[30] 
Shay, K.P.; Moreau, R.F.; Smith, E.J.; Smith, A.R.; Hagen, T.M. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta,  2009, 1790(10), 1149-1160.
[http://dx.doi.org/10.1016/j.bbagen.2009.07.026] [PMID:  19664690] 
[31] 
Alpers, D.H. Vitamins as drugs: The importance of pharmacokinetics in oral dosing. Curr. Opin. Gastroenterol.,  2011, 27(2), 146-151.
[http://dx.doi.org/10.1097/MOG.0b013e32834172c0] [PMID:  21157328] 
[32] 
Boyce, J.M.; Shone, G.R. Effects of ageing on smell and taste. Postgrad. Med. J.,  2006, 82(966), 239-241.
[http://dx.doi.org/10.1136/pgmj.2005.039453] [PMID:  16597809] 
[33] 
Hess, J.R.; Brenner, M.J.; Myckatyn, T.M.; Hunter, D.A.; Mackinnon, S.E. Influence of aging on regeneration in end-to-side neurorrhaphy. Ann. Plast. Surg.,  2006, 57(2), 217-222.
[http://dx.doi.org/10.1097/01.sap.0000215258.57614.89] [PMID:  16862007] 
[34] 
Xie, Y.; Schneider, K.J.; Ali, S.A.; Hogikyan, N.D.; Feldman, E.L.; Brenner, M.J. Current landscape in motoneuron regeneration and reconstruction for motor cranial nerve injuries. Neural Regen. Res.,  2020, 15(9), 1639-1649.
[http://dx.doi.org/10.4103/1673-5374.276325] [PMID:  32209763] 
[35] 
Barresi, M.; Ciurleo, R.; Giacoppo, S.; Foti Cuzzola, V.; Celi, D.; Bramanti, P.; Marino, S. Evaluation of olfactory dysfunction in neurodegenerative diseases. J. Neurol. Sci.,  2012, 323(1-2), 16-24.
[http://dx.doi.org/10.1016/j.jns.2012.08.028] [PMID:  23010543] 
[36] 
Doty, R.L. Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol.,  2012, 8(6), 329-339.
[http://dx.doi.org/10.1038/nrneurol.2012.80] [PMID:  22584158] 
[37] 
Doty, R.L. The mechanisms of smell loss after SARS-CoV-2 infection. Lancet Neurol.,  2021, 20(9), 693-695.
[http://dx.doi.org/10.1016/S1474-4422(21)00202-7] [PMID:  34339627] 
[38] 
Xydakis, M.S.; Albers, M.W.; Holbrook, E.H.; Lyon, D.M.; Shih, R.Y.; Frasnelli, J.A.; Pagenstecher, A.; Kupke, A.; Enquist, L.W.; Perlman, S. Post-viral effects of COVID-19 in the olfactory system and their implications. Lancet Neurol.,  2021, 20(9), 753-761.
[http://dx.doi.org/10.1016/S1474-4422(21)00182-4] [PMID:  34339626] 
[39] 
Sjögren, M.; Folkesson, S.; Blennow, K.; Tarkowski, E. Increased intrathecal inflammatory activity in frontotemporal dementia: Pathophysiological implications. J. Neurol. Neurosurg. Psychiatry,  2004, 75(8), 1107-1111.
[http://dx.doi.org/10.1136/jnnp.2003.019422] [PMID:  15258209] 
[40] 
Paterniti, I.; Cordaro, M.; Campolo, M.; Siracusa, R.; Cornelius, C.; Navarra, M.; Cuzzocrea, S.; Esposito, E. Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer’s disease models: The control of neuroinflammation. CNS Neurol. Disord. Drug Targets,  2014, 13(9), 1530-1541.
[http://dx.doi.org/10.2174/1871527313666140806124322] [PMID:  25106636] 
[41] 
Caltagirone, C.; Cisari, C.; Schievano, C.; Di Paola, R.; Cordaro, M.; Bruschetta, G.; Esposito, E.; Cuzzocrea, S. Co-ultramicronized palmitoylethanolamide/luteolin in the treatment of cerebral ischemia: From rodent to man. Transl. Stroke Res.,  2016, 7(1), 54-69.
[http://dx.doi.org/10.1007/s12975-015-0440-8] [PMID:  26706245] 
[42] 
Assogna, M.; Casula, E.P.; Borghi, I.; Bonnì, S.; Samà, D.; Motta, C.; Di Lorenzo, F.; D’Acunto, A.; Porrazzini, F.; Minei, M.; Caltagirone, C.; Martorana, A.; Koch, G. Effects of palmitoylethanolamide combined with luteoline on frontal lobe functions, high frequency oscillations, and GABAergic transmission in patients with frontotemporal dementia. J. Alzheimers Dis.,  2020, 76(4), 1297-1308.
[http://dx.doi.org/10.3233/JAD-200426] [PMID:  32623398] 
[43] 
Kempuraj, D.; Thangavel, R.; Kempuraj, D.D.; Ahmed, M.E.; Selvakumar, G.P.; Raikwar, S.P.; Zaheer, S.A.; Iyer, S.S.; Govindarajan, R.; Chandrasekaran, P.N.; Zaheer, A. Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma. Biofactors,  2021, 47(2), 190-197.
[http://dx.doi.org/10.1002/biof.1687] [PMID:  33098588] 
[44] 
Cordaro, M.; Cuzzocrea, S.; Crupi, R. An update of palmitoylethanolamide and luteolin effects in preclinical and clinicalstudies of neuroinflammatory events. Antioxidants,  2020, 9(3), 216.
[http://dx.doi.org/10.3390/antiox9030216] 
[45] 
Meinhardt, J.; Radke, J.; Dittmayer, C.; Franz, J.; Thomas, C.; Mothes, R.; Laue, M.; Schneider, J.; Brünink, S.; Greuel, S.; Lehmann, M.; Hassan, O.; Aschman, T.; Schumann, E.; Chua, R.; Conrad, C.; Eils, R.; Stenzel, W.; Windgassen, M.; Rößler, L.; Goebel, H.H.; Gelderblom, H.R.; Martin, H.; Nitsche, A.; Schulz-Schaeffer, W.J.; Hakroush, S.; Winkler, M.S.; Tampe, B.; Scheibe, F.; Körtvélyessy, P.; Reinhold, D.; Siegmund, B.; Kühl, A.A.; Elezkurtaj, S.; Horst, D.; Oesterhelweg, L.; Tsokos, M.; Ingold-Heppner, B.; Stadelmann, C.; Drosten, C.; Corman, V.M.; Radbruch, H.; Heppner, Fl. Olfactory transmucosal Sars-Cov-2 invasion as a port of central nervous system entry in individuals with Covid-19. Nat. Neurosci.,  2021, 24, 168-175.
[http://dx.doi.org/10.1038/s41593-020-00758-5] [PMID:  33257876] 
[46] 
De Melo, Gd.; Lazarini, F.; Levallois, S.; Hautefort, C.; Michel, V.; Larrous, F.; Verillaud, B.; Aparicio, C.; Wagner, S.; Gheusi, G.; Kergoat, L.; Kornobis, E.; Donati, F.; Cokelaer, T.; Hervochon, R.; Madec, Y.; Roze, E.; Salmon, D.; Bourhy, H.; Lecuit, M.; Lledo, Pm. Covid-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Sci. Transl. Med.,  2021, 13(596), Eabf8396.
[http://dx.doi.org/10.1126/scitranslmed.abf8396] 
[47] 
La, V.; Hopkins, C.; Petrocelli, M. Lechien, Jr.; Chiesa-Estomba, Cm.; Salzano, G.; Cucurullo, M.; Salzano, Fa; Saussez, S.; Boscolo-Rizzo, P.; Biglioli, F.; De Riu, G. Smell and taste recovery in coronavirus disease 2019 patients: A 60-day objective and prospective study. J. Laryngol. Otol.,  2020, 134(8), 703-709.
[http://dx.doi.org/10.1017/S0022215120001826] 
[48] 
Cocco, A.; Amami, P.; Desai, A.; Voza, A.; Ferreli, F.; Albanese, A. Neurological features in SARS-CoV-2-infected patients with smell and taste disorder. J. Neurol.,  2021, 268(5), 1570-1572.
[http://dx.doi.org/10.1007/s00415-020-10135-8] [PMID:  32767117] 
[49] 
Paterson, R.W.; Brown, R.L.; Benjamin, L.; Nortley, R.; Wiethoff, S.; Bharucha, T.; Jayaseelan, D.L.; Kumar, G.; Raftopoulos, R.E.; Zambreanu, L.; Vivekanandam, V.; Khoo, A.; Geraldes, R.; Chinthapalli, K.; Boyd, E.; Tuzlali, H.; Price, G.; Christofi, G.; Morrow, J.; McNamara, P.; McLoughlin, B.; Lim, S.T.; Mehta, P.R.; Levee, V.; Keddie, S.; Yong, W.; Trip, S.A.; Foulkes, A.J.M.; Hotton, G.; Miller, T.D.; Everitt, A.D.; Carswell, C.; Davies, N.W.S.; Yoong, M.; Attwell, D.; Sreedharan, J.; Silber, E.; Schott, J.M.; Chandratheva, A.; Perry, R.J.; Simister, R.; Checkley, A.; Longley, N.; Farmer, S.F.; Carletti, F.; Houlihan, C.; Thom, M.; Lunn, M.P.; Spillane, J.; Howard, R.; Vincent, A.; Werring, D.J.; Hoskote, C.; Jäger, H.R.; Manji, H.; Zandi, M.S. The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain,  2020, 143(10), 3104-3120.
[http://dx.doi.org/10.1093/brain/awaa240] [PMID:  32637987] 
[50] 
Kanberg, N.; Ashton, N.J.; Andersson, L.M.; Yilmaz, A.; Lindh, M.; Nilsson, S.; Price, R.W.; Blennow, K.; Zetterberg, H.; Gisslén, M. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology,  2020, 95(12), e1754-e1759.
[http://dx.doi.org/10.1212/WNL.0000000000010111] [PMID:  32546655] 
[51] 
Dossantos, M.F.; Devalle, S.; Aran, V.; Capra, D.; Roque, N.R.; Coelho-Aguiar, J.M.; Spohr, T.; Subilhaga, J.G.; Pereira, C.M.; D’andrea Meira, I.; Niemeyer, S.F.P.; Moura-Neto, V. Neuromechanisms
Of Sars-Cov-2: A Review. Front. Neuroanat.,  2020, 16, 37.
[52] 
Kandemirli, S.G.; Altundag, A.; Yildirim, D.; Tekcan Sanli, D.E.; Saatci, O. Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia. Acad. Radiol.,  2021, 28(1), 28-35.
[http://dx.doi.org/10.1016/j.acra.2020.10.006] [PMID:  33132007] 
[53] 
Aragão, M.F.V.V.; Leal, M.C.; Cartaxo Filho, O.Q.; Fonseca, T.M.; Valença, M.M. Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI. AJNR Am. J. Neuroradiol.,  2020, 41(9), 1703-1706.
[http://dx.doi.org/10.3174/ajnr.A6675] [PMID:  32586960] 
[54] 
Morbini, P.; Benazzo, M.; Verga, L.; Pagella, F.G.; Mojoli, F.; Bruno, R.; Marena, C. Ultrastructural evidence of direct viral damage to the olfactory complex in patients testing positive for SARS-CoV-2. JAMA Otolaryngol. Head Neck Surg.,  2020, 146(10), 972-973.
[http://dx.doi.org/10.1001/jamaoto.2020.2366] [PMID:  32790835] 
[55] 
De Luca, P.; Scarpa, A.; Ralli, M.; Tassone, D.; Simone, M.; De Campora, L.; Cassandro, C.; Di Stadio, A. Auditory disturbances
and Sars-Cov-2 infection: Brain inflammation or cochlear affection? Systematic Review and Discussion Of Potential Pathogenesis.
Front Neurol,  2021, 12, 707207.
[56] 
Guida, F.; Luongo, L.; Boccella, S.; Giordano, M.E.; Romano, R.; Bellini, G.; Manzo, I.; Furiano, A.; Rizzo, A.; Imperatore, R.; Iannotti, F.A.; D’Aniello, E.; Piscitelli, F.; Sca, R.F.; Cristino, L.; Di Marzo, V.; de Novellis, V.; Maione, S. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: Involvement of the CB2 receptor. Sci. Rep.,  2017, 7(1), 375.
[http://dx.doi.org/10.1038/s41598-017-00342-1] [PMID:  28336953] 
[57] 
Liu, D.T.; Sabha, M.; Damm, M.; Philpott, C.; Oleszkiewicz, A.; Hähner, A.; Hummel, T. Parosmia is associated with relevant olfactory recovery after olfactory training. Laryngoscope,  2021, 131(3), 618-623.
[http://dx.doi.org/10.1002/lary.29277] [PMID:  33210732] 
[58] 
Damm, M.; Pikart, L.K.; Reimann, H.; Burkert, S.; Göktas, Ö.; Haxel, B.; Frey, S.; Charalampakis, I.; Beule, A.; Renner, B.; Hummel, T.; Hüttenbrink, K.B. Olfactory training is helpful in postinfectious olfactory loss: A randomized, controlled, multicenter study. Laryngoscope,  2014, 124(4), 826-831.
[http://dx.doi.org/10.1002/lary.24340] [PMID:  23929687] 
[59] 
Abdelalim, A.A.; Mohamady, A.A.; Elsayed, R.A.; Elawady, M.A.; Ghallab, A.F. Corticosteroid nasal spray for recovery of smell sensation in COVID-19 patients: A randomized controlled trial. Am. J. Otolaryngol.,  2021, 42(2), 102884.
[http://dx.doi.org/10.1016/j.amjoto.2020.102884] [PMID:  33429174] 
[60] 
Kasiri, H.; Rouhani, N.; Salehifar, E.; Ghazaeian, M.; Fallah, S. Mometasone furoate nasal spray in the treatment of patients with COVID-19 olfactory dysfunction: A randomized, double blind clinical trial. Int. Immunopharmacol.,  2021, 98, 107871.
[http://dx.doi.org/10.1016/j.intimp.2021.107871] [PMID:  34147912] 

Rights & Permissions Print Cite

Article Metrics

16

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570159X20666220420113513	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190

Current Neuropharmacology

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

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract