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Antihistamine H1RAs for COVID-19
17 studies with >70,000 patients
Serious outcome risk
Antihistamine H1RAs
Control
Significantly lower risk for mortality, recovery, cases, and viral clearance.
10 studies from 8 independent teams in 6 countries show significant benefit.
COVID-19 Antihistamine H1RA studies · October 2026
Covid Analysis Antihistamine H1RAs reduce COVID-19 risk: real-time meta-analysis of 17 studies (Version 16)
Significantly lower risk is seen for mortality, recovery, cases, and viral clearance. 10 studies from 8 independent teams in 6 countries show significant benefit. Meta-analysis using the most serious outcome reported shows 37% [22..
Jan 10
2025
 Hamdan et al., Turkish Journal of Pharmaceutical Sciences, doi:10.4274/tjps.galenos.2024.49768 In silico Evaluation of H1-Antihistamine as Potential Inhibitors of SARS-CoV-2 RNA-dependent RNA Polymerase: Repurposing Study of COVID-19 Therapy
In silico study showing that H1RA antihistamines, including bilastine, fexofenadine, mizolastine, rupatadine, terfenadine, and the leukotriene receptor antagonists montelukast and zafirlukast, may inhibit SARS-CoV-2 RNA-dependent RNA poly..
Dec 13
2024
 Puigdellívol-Sánchez et al., Microorganisms, doi:10.3390/microorganisms12122589 COVID-19 in Relation to Chronic Antihistamine Prescription
Retrospective 140,681 patients in Spain showing lower COVID-19 infection, hospitalization, and mortality with chronic antihistamine treatment, with a greater protective effect for patients taking 2-7 chronic treatments. Results are provid..
Nov 26
2024
 Valerio-Pascua et al., BMC Infectious Diseases, doi:10.1186/s12879-024-10211-8 Mitigating the risks of post-acute sequelae of SARS-CoV-2 infection (PASC) with intranasal chlorpheniramine: perspectives from the ACCROS studies
90% lower long COVID (p=0.001). Prospective study of 259 COVID-19 outpatients from the ACROSS-I and ACROSS-III RCTs showing significantly lower long COVID with intranasal chlorpheniramine (iCPM) compared to placebo. 72% of placebo patients experienced at least one PASC ..
Oct 31
2024
 Meiser et al., Viruses, doi:10.3390/v16121914 (date from preprint) Azelastine Nasal Spray in Non-Hospitalized Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial
13% improved recovery (p=0.42) and 6% improved viral clearance (p<0.0001). RCT 294 low-risk subjects with mild COVID-19 showing significantly greater reduction in viral load with azelastine 0.1% nasal spray vs. placebo. There was no COVID-19 related hospitalization in either group. The reduction in viral load wa..
Jul 2
2024
 Yu et al., mBio, doi:10.1128/mbio.01088-24 The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2
In vitro and mouse study showing that antihistamine drugs targeting the histamine receptor H1 (HRH1) inhibit SARS-CoV-2 infection. Authors find that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the N-terminal..
Oct 29
2023
 Berkowitz et al., International Journal of Molecular Sciences, doi:10.3390/ijms242115718 Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics
Mouse study showing the combination of lactoferrin and diphenhydramine resulted in slower weight loss, improved survival, and faster weight recovery in SARS-CoV-2 infected animals compared to controls. The study authors propose the..
Aug 29
2023
 Elshaier et al., Cureus, doi:10.7759/cureus.92375 (date from preprint) Chlorpheniramine Maleate Displaying Multiple Modes of Antiviral Action Against SARS-CoV-2: An Initial Mechanistic Study
In vitro and in silico study showing that chlorpheniramine maleate (CPM) inhibits SARS-CoV-2 infection by affecting viral adsorption, replication, and having a direct virucidal effect in Vero E6 cells. Molecular docking analysis revealed ..
Aug 4
2023
 Hoertel et al., Pharmaceuticals, doi:10.3390/ph16081107 Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study
Retrospective 72,105 COVID+ hospitalized patients in France, showing no significant difference in mortality with antihistamine H1RAs desloratadine and hydroxyzine.
Jul 17
2023
 Salvucci et al., Frontiers in Cardiovascular Medicine, doi:10.3389/fcvm.2023.1202696 Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation
29% lower long COVID (p=0.1). Retrospective 14 patients with long-COVID symptoms attributed to mast cell activation treated with H1 and H2 antihistamines compared to 13 control patients, showing significant improvements in several symptoms in the treatment group compa..
Apr 26
2023
 Klussmann et al., Scientific Reports, doi:10.1038/s41598-023-32546-z Early intervention with azelastine nasal spray may reduce viral load in SARS-CoV-2 infected patients
14% improved viral clearance (p=0.22). RCT 90 outpatients showing potential benefit of azelastine nasal spray for reducing viral load. Patients were randomized to receive placebo, 0.02%, or 0.1% azelastine nasal spray for 11 days. The 0.1% azelastine group showed greater viral..
Dec 31
2022
 Sanchez-Gonzalez et al., Medical Research Archives, doi:10.18103/mra.v10i3.2752 Intranasal Chlorpheniramine Maleate for the treatment of COVID-19: Translational and Clinical Evidence
87% lower hospitalization (p=0.08). Small RCT showing significantly improved recovery with intranasal chlorpheniramine maleate. Authors also perform an in vitro study showing efficacy with a highly differentiated three-dimensional model of normal, human-derived tracheal/bro..
Dec 6
2022
 Morin-Dewaele et al., Scientific Reports, doi:10.1038/s41598-022-25399-5 Desloratadine, an FDA-approved cationic amphiphilic drug, inhibits SARS-CoV-2 infection in cell culture and primary human nasal epithelial cells by blocking viral entry
In vitro study showing that desloratadine inhibits SARS-CoV-2 infection in Vero E6 cells, Calu-3 cells, and primary human nasal epithelial cells (HNECs) by blocking viral entry through the endosomal pathway. Authors screened 8 FDA-approve..
Oct 18
2022
 Valerio-Pascua et al., Research Square, doi:10.21203/rs.3.rs-2167465/v1 Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials
54% faster recovery (p<0.0001). RCT and retrospective study of chlorpheniramine nasal spray for COVID-19. The retrospective study included 660 outpatients showing fewer days with general COVID-19 symptoms, cough, anosmia, and ageusia compared to standard of care alone. ..
Oct 18
2022
 Valerio-Pascua et al., Research Square, doi:10.21203/rs.3.rs-2167465/v1 Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials
61% improved recovery (p=0.0002) and 74% lower long COVID (p=0.001). RCT and retrospective study of chlorpheniramine nasal spray for COVID-19. The RCT included 101 outpatients showing significantly faster recovery with treatment. The retrospective study results are listed separately [Valerio-Pascua]. Long ..
Aug 16
2022
 Loucera et al., Virology Journal, doi:10.1186/s12985-023-02195-9 (date from preprint) Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments
40% lower mortality (p=0.003). Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with antihistamine H1RAs, without statistical significance. Since only hospitalized patients are included, results do not reflect different probabilitie..
Jun 29
2022
 Hunt et al., Journal of General Internal Medicine, doi:10.1007/s11606-022-07701-3 Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans
43% lower mortality (p<0.0001). Retrospective 26,508 consecutive COVID+ veterans in the USA, showing lower mortality with multiple treatments including antihistamines. Treatment was defined as drugs administered ≥50% of the time within 2 weeks post-COVID+, and may be a ..
Jan 8
2022
 Monserrat Villatoro et al., Pharmaceuticals, doi:10.3390/ph15010078 A Case-Control of Patients with COVID-19 to Explore the Association of Previous Hospitalisation Use of Medication on the Mortality of COVID-19 Disease: A Propensity Score Matching Analysis
80% lower mortality (p=0.05). PSM retrospective 3,712 hospitalized patients in Spain, showing lower mortality with existing use of loratadine.
Jan 6
2022
 Black, S., Cureus, doi:10.7759/cureus.20980 Molecular Modeling and Preliminary Clinical Data Suggesting Antiviral Activity for Chlorpheniramine (Chlorphenamine) Against COVID-19
In silico study suggesting that the over-the-counter antihistamine chlorpheniramine may have antiviral activity against SARS-CoV-2. Using structural database searches and molecular modeling, authors found that chlorpheniramine shares simi..
Dec 15
2021
 Sánchez-Rico et al., Journal of Clinical Medicine, doi:10.3390/jcm10245891 Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study
46% lower mortality (p=0.02). Retrospective 15,103 hospitalized COVID-19 patients in France showing lower mortality with hydroxyzine use.
Apr 30
2021
 Hou et al., Chemico-Biological Interactions, doi:10.1016/j.cbi.2021.109420 Testing of the inhibitory effects of loratadine and desloratadine on SARS-CoV-2 spike pseudotyped virus viropexis
In vitro study showing that histamine H1 antagonists loratadine (LOR) and desloratadine (DES) inhibit SARS-CoV-2 spike pseudovirus entry into ACE2-overexpressing HEK293T cells, with DES showing greater efficacy. Using cell membrane chroma..
Apr 30
2021
 Morán Blanco et al., Pulmonary Pharmacology & Therapeutics, doi:10.1016/j.pupt.2021.101989 Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients
Retrospective 84 elderly nursing home residents in Spain showing no mortality, hospitalization, or ICU admission with early treatment with antihistamines alone or in combination with azithromycin.
Mar 31
2021
 Mura et al., Signal Transduction and Targeted Therapy, doi:10.1038/s41392-021-00689-y (date from preprint) Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients
25% lower mortality (p=0.4). PSM retrospective TriNetX database analysis of 1,379 severe COVID-19 patients requiring respiratory support, showing lower mortality with H1RAs+H2RAs versus famotidine alone, without statistical significance.
Feb 22
2021
 McKeigue et al., BMC Medicine, doi:10.1186/s12916-021-01907-8 Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study
30% higher severe cases (p=0.0004). Retrospective 4,251 severe COVID-19 cases and 36,738 matched controls in Scotland showing increased risk of severe COVID-19 with PPI use and antihistamine H1RA use. Adjusted results are only provided for the patients not in care homes (2,..
Jan 31
2021
 Reznikov et al., Biochemical and Biophysical Research Communications, doi:10.1016/j.bbrc.2020.11.095 Identification of antiviral antihistamines for COVID-19 repurposing
34% fewer cases (p<0.0001). Retrospective 219,000 patients showing lower risk of COVID-19 with antihistamine H1RA use. In vitro study showing these drugs exhibit direct antiviral activity against SARS-CoV-2. Molecular docking suggests hydroxyzine and azelastine may ..
Jan 5
2021
 Rivas et al., bioRxiv, doi:10.1101/2021.01.04.424792 Hydroxyzine inhibits SARS-CoV-2 Spike protein binding to ACE2 in a qualitative in vitro assay
In vitro study showing that hydroxyzine inhibits the binding of SARS-CoV-2 Spike protein receptor-binding domain (RBD) to ACE2 in a qualitative assay. Hydroxyzine inhibited RBD binding to ACE2 in a dose-dependent manner, while labetalol, ..
Dec 10
2020
 Vila-Córcoles et al., BMJ Open, doi:10.1136/bmjopen-2020-041577 Influence of prior comorbidities and chronic medications use on the risk of COVID-19 in adults: a population-based cohort study in Tarragona, Spain
53% fewer cases (p=0.05). Retrospective 79,083 adults aged ≥50 years in Spain showing lower with of PCR-confirmed COVID-19 with antihistamine use, close to statistical significance.
Oct 27
2020
 Hoertel et al., medRxiv, doi:10.1101/2020.10.23.20154302 Association between Hydroxyzine Use and Reduced Mortality in Patients Hospitalized for Coronavirus Disease 2019: Results from a multicenter observational study
58% lower mortality (p=0.001). Retrospective 7,345 hospitalized COVID-19 patients in France showing lower mortality with hydroxyzine use, with a significant dose-response relationship. Hydroxyzine was also associated with a faster decrease in inflammatory markers.
Jul 25
2020
 Vila-Corcoles et al., The Journal of Clinical Hypertension, doi:10.1111/jch.13948 Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain
61% fewer cases (p=0.1). Retrospective 34,936 hypertensive outpatients in Spain showing no significant difference in COVID-19 cases with PPIs and antihistamine H1RAs.