{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:32:49Z","timestamp":1784734369023,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:00:00Z","timestamp":1701129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gencor Pacific (Hong King)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Allergic rhinitis (AR) is an inflammatory, symptomatic disorder stimulated by antigen-specific immunoglobulin E inflammation in response to allergens. Current treatments include the use of corticosteroids and antihistamines to reduce inflammation by preventing histamine release. Palmitoylethanolamide (PEA) is reported to be an alternative treatment, shown to downregulate mast cell activation and increase the synthesis of endocannabinoid 2-Arachidonoylglycerol to reduce histamine and the symptoms of AR. Method: A double-blind, randomised, placebo-controlled clinical trial in which 108 participants presenting with seasonal AR were supplemented with either 350 mg of PEA (Levagen+) or a placebo daily for two weeks. Symptom scores were recorded using the reflective total nasal symptom score (rTNSS) twice a day (morning and evening) for the two weeks, and blood was taken at baseline and week 2. Results: 101 participants completed the study with no baseline group differences. No significant difference was seen between groups for allergy symptoms scores (rTNSS) throughout the 14 days of treatment. A sub-group analysis of participants scoring over four (mild-to-moderate) on the total rTNSS at baseline showed that Levagen+ significantly reduced scores compared to the placebo group. Only 36 participants had full sets of blood taken due to COVID-19. The pathology results showed a significant difference in change from baseline between groups. The Levagen+ group had a significant decrease from baseline in histamine, IL-4, IL-8, IL-10, and TNF-\u03b1. The placebo group only had a reduction in IL-4. Conclusion: The results of this study show that Levagen+ can alleviate AR symptoms, resulting in a reduction in histamine and inflammatory markers.<\/jats:p>","DOI":"10.3390\/nu15234940","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T07:40:01Z","timestamp":1701157201000},"page":"4940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Effect of Levagen+ (Palmitoylethanolamide) Supplementation on Symptoms of Allergic Rhinitis\u2014A Double-Blind Placebo-Controlled Trial"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9867-6700","authenticated-orcid":false,"given":"David","family":"Briskey","sequence":"first","affiliation":[{"name":"RDC Clinical, Brisbane, QLD 4006, Australia"},{"name":"School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillippa","family":"Ebelt","sequence":"additional","affiliation":[{"name":"RDC Clinical, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0090-9217","authenticated-orcid":false,"given":"Amanda","family":"Rao","sequence":"additional","affiliation":[{"name":"RDC Clinical, Brisbane, QLD 4006, Australia"},{"name":"School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s12070-015-0828-5","article-title":"Allergic rhinitis: An overview","volume":"67","author":"Varshney","year":"2015","journal-title":"Indian J. Otolaryngol. Head Neck Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s11882-012-0331-y","article-title":"Comparative analysis of allergic rhinitis in children and adults","volume":"13","author":"Valero","year":"2013","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/S0030-6657(09)70135-0","article-title":"Prevalence of rhinitis in Polish population according to the ECAP (Epidemiology of Allergic Disorders in Poland) study","volume":"63","author":"Sybilski","year":"2009","journal-title":"Otolaryngol. Pol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"162","DOI":"10.14336\/AD.2016.0831","article-title":"Allergy and aging: An old\/new emerging health issue","volume":"8","author":"Sirufo","year":"2017","journal-title":"Aging Dis."},{"key":"ref_5","unstructured":"Akhouri, S., and House, S.A. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.jaci.2003.09.015","article-title":"Allergic rhinitis: Systemic inflammation and implications for management","volume":"112","author":"Borish","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1183\/09059180.00010401","article-title":"The rationale for treating allergic asthma with anti-IgE","volume":"16","author":"Hamelmann","year":"2007","journal-title":"Eur. Respir. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-4419-8056-4_4","article-title":"Histamine in allergic rhinitis","volume":"709","year":"2010","journal-title":"Histamine Inflamm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fphar.2019.00294","article-title":"Modulation of allergic inflammation in the nasal mucosa of allergic rhinitis sufferers with topical pharmaceutical agents","volume":"10","author":"Watts","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1007\/BF02484434","article-title":"Proinflammatory cytokines in allergic rhinitis","volume":"252","author":"Bachert","year":"1995","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1056\/NEJM200101043440106","article-title":"Allergy and allergic diseases","volume":"344","author":"Kay","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S0091-6749(05)80223-4","article-title":"The role of histamine in allergic diseases","volume":"86","author":"White","year":"1990","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39934","DOI":"10.1038\/srep39934","article-title":"Regulation of plasma histamine levels by the mast cell clock and its modulation by stress","volume":"7","author":"Nakamura","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000323763","article-title":"Clinical and laboratory parameters of mast cell activation as basis for the formulation of diagnostic criteria","volume":"156","author":"Valent","year":"2011","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1097\/MOO.0b013e3283533632","article-title":"Role of innate immunity in the pathogenesis of allergic rhinitis","volume":"20","author":"Melvin","year":"2012","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.5114\/ada.2022.113801","article-title":"Gold standard diagnostic algorithm for the differential diagnosis of local allergic rhinitis","volume":"39","author":"Wojas","year":"2022","journal-title":"Adv. Dermatol. Allergol.\/Post\u0229py Dermatol. I Alergol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1046\/j.1365-2222.1999.00013.x","article-title":"Beyond the histamine receptor: Effect of antihistamines on mast cells","volume":"29","author":"Cuss","year":"1999","journal-title":"Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.vetimm.2009.06.011","article-title":"Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNF\u03b1 release from canine skin mast cells","volume":"133","author":"Cerrato","year":"2010","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1186\/s12974-019-1671-5","article-title":"Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity","volume":"16","author":"Petrosino","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5836476","DOI":"10.1155\/2019\/5836476","article-title":"Altered metabolism of phospholipases, diacylglycerols, endocannabinoids, and N-Acylethanolamines in patients with mastocytosis","volume":"2019","author":"Ferrara","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hauer, D., Schelling, G., Gola, H., Campolongo, P., Morath, J., Roozendaal, B., Hamuni, G., Karabatsiakis, A., Atsak, P., and Vogeser, M. (2013). Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062741"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3389\/fphar.2019.00821","article-title":"Palmitoylethanolamide (PEA) as a potential therapeutic agent in Alzheimer\u2019s disease","volume":"10","author":"Beggiato","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_23","first-page":"10","article-title":"The effect of a dispersible palmitoylethanolamide (Levagen+) compared to a placebo for reducing joint pain in an adult population\u2014A randomised, double-blind study","volume":"10","author":"Briskey","year":"2021","journal-title":"Int. J. Nutr. Food Sci."},{"key":"ref_24","first-page":"325061","article-title":"Beneficial effects of palmitoylethanolamide on expressive language, cognition, and behaviors in autism: A report of two cases","volume":"2015","author":"Antonucci","year":"2015","journal-title":"Case Rep. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3389\/fphar.2017.00857","article-title":"Palmitoylethanolamide supplementation during sensitization prevents airway allergic symptoms in the mouse","volume":"8","author":"Roviezzo","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13643-018-0934-z","article-title":"Clinical applications of palmitoylethanolamide in pain management: Protocol for a scoping review","volume":"8","author":"Passavanti","year":"2019","journal-title":"Syst. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Clayton, P., Hill, M., Bogoda, N., Subah, S., and Venkatesh, R. (2021). Palmitoylethanolamide: A natural compound for health management. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105305"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2500\/aap.2012.33.3535","article-title":"Allergic rhinitis","volume":"Volume 33","author":"Uzzaman","year":"2012","journal-title":"Allergy and Asthma Proceedings"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1210\/en.2006-1522","article-title":"Endocannabinoids link rapid, membrane-mediated corticosteroid actions to behavior","volume":"148","author":"Denver","year":"2007","journal-title":"Endocrinology"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/23\/4940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:32:19Z","timestamp":1760131939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/23\/4940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,28]]},"references-count":29,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["nu15234940"],"URL":"https:\/\/doi.org\/10.3390\/nu15234940","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,28]]}}}