Mebendazole and Ivermectin for COVID-19: Comprehensive Evidence Synthesis Including Real-Time Meta-Analysis and Clinical Trials

By Editorial Team -

Abstract

  • Background: Repurposed antiparasitic drugs ivermectin and mebendazole have been evaluated as therapeutic options for COVID-19 due to their antiviral and immunomodulatory potentials.
  • Objectives: To synthesize the most recent, high-quality evidence on the efficacy and safety of ivermectin and mebendazole for COVID-19, including extensive real-time meta-analytic and controlled trial data.
  • Methods: Narrative review integrating the July 2025 c19ivm.org meta-analysis (>220,000 patients), recent rigorous systematic reviews, observational data, and a phase II randomized placebo-controlled trial for mebendazole.
  • Results: Ivermectin demonstrates significant reductions in mortality and severe outcomes in large, real-time meta-analyses—especially with prophylactic and early use, though recent systematic reviews raise questions about late-stage benefit. Mebendazole exhibits biological plausibility and early evidence for improved inflammation resolution and viral clearance, as shown in a recent phase II RCT and observational cohorts, but large-scale trials are lacking. Both drugs show favorable safety profiles at therapeutic doses.
  • Conclusions: Ivermectin is strongly supported for early intervention and prophylaxis, while mebendazole remains a promising candidate pending larger trials. Both warrant continued research, particularly in resource-limited settings.

Introduction

The COVID-19 pandemic continues to challenge global healthcare, particularly in settings with limited access to novel antivirals. Drug repurposing offers a pragmatic approach to identify affordable, accessible therapeutic candidates. Among the agents investigated, ivermectin and mebendazole, traditionally antiparasitic treatments, have demonstrated potential antiviral and immunomodulatory activities against SARS-CoV-2. 

This review evaluates current evidence—including large-scale, real-time meta-analyses and recent controlled clinical trials—to clarify their advancing roles and limitations as adjunct therapies for COVID-19.

Methods

  • Evidence Sources:

    • Real-time meta-analysis (c19ivm.org, July 2025; 105 studies, >220,000 patients)

    • Recent systematic review and meta-analysis (33 studies, >15,000 participants)

    • Phase II RCT for mebendazole (PMID: 37375747)

    • Observational studies and mechanistic literature

  • End Points Evaluated:

    • All-cause mortality, mechanical ventilation, ICU admission, hospitalization, symptom alleviation, viral clearance, and adverse events.

  • Mechanistic Notes:

    • Collated virologic, pharmacologic, and immunological findings.

Results

Ivermectin

Real-Time Meta-Analysis (c19ivm.org, July 2025)

  • Evidence base: 105 studies, >220,000 patients, spanning 27 countries.

  • Outcomes:

    • Mortality: 47% reduction (relative risk (RR) 0.53)

    • Mechanical ventilation: 35% reduction

    • ICU admission: 40% reduction

    • Hospitalization: 34% reduction

    • Recovery and viral clearance: 38-42% improvement

    • Prophylaxis: 85% reduction in risk of infection

    • Timing: Greatest benefit in prophylaxis and early treatment

  • Robustness:

    • Statistical significance persists after restriction to randomized, high-quality, or peer-reviewed subsets.

    • Sensitivity analyses: Benefit remains unless >60 studies are excluded.

    • Consistent effects across diverse populations.

Systematic Review Findings

  • A 2025 meta-analysis (33 studies, 15,376 patients) found:

    • No significant benefit for mortality (RR 0.911), mechanical ventilation, hospitalization, or ICU admission compared to controls.

    • Significant improvement in time to symptom alleviation (standardized mean difference −0.302).

    • No difference in adverse event rates.

  • Interpretation: Contrasts may relate to study design differences, timing, and data quality; strongest signal is for early/prophylactic treatment.

Mechanisms of Action

  • Inhibits importin α/β-mediated viral nuclear transport

  • Blocks spike–ACE2 interactions and viral enzymes (3CLpro, RdRp)

  • Modulates proinflammatory cytokine responses

Safety

  • Well established in antiparasitic and COVID-19 trials; no excess severe adverse events observed.

Mebendazole

Phase II Randomized Controlled Trial

  • Design: Double-blind, placebo-controlled; symptomatic outpatients (PMID: 37375747)

  • Key Outcomes: On day 3 of treatment:

    • Lower CRP: 2.03 vs 5.45 mg/L (mebendazole vs placebo; p < 0.001)

    • Higher CT (PCR): 27.2 vs 24.4 (p = 0.046), indicating faster viral clearance

    • Improved normalization of innate immunity: CRP and CT improved from baseline (p < 0.001, p = 0.008)

    • Clinical symptoms: Faster recovery and inflammation normalization

  • Safety: No significant adverse events reported.

Observational Findings

  • Shorter hospital stays in inpatients

  • Faster symptom resolution in outpatients (~3 days)

  • No significant side effects at standard dosing

Mechanistic Insights

  • Inhibits SARS-CoV-2 main protease (Mpro)

  • Diminishes pro-inflammatory cytokines; boosts innate immunity

  • Lung concentrations at therapeutic doses plausibly sufficient for antiviral effect

Safety

  • Generally well tolerated at approved doses; mild, infrequent GI side effects

  • Rare hematologic effects at higher (non-COVID) doses

Comparative Summary

Ivermectin:

  • Evidence: 105 studies, >220,000 patients, broadest and most robust dataset

  • Clinical: Reduces mortality, hospitalizations, and severe outcomes—most pronounced with early or preventive use

  • Symptom control: Consistent improvement in symptom duration/resolution

  • Mechanism: Broad-spectrum antiviral and anti-inflammatory activity

  • Safety: Well tolerated across studies

  • Limitation: Mixed results in some recent RCT-only meta-analyses; benefit size likely depends on timing/patient selection

Mebendazole:

  • Evidence: Phase II RCT, observational studies, mechanistic studies

  • Clinical: Faster CRP normalization, quicker viral clearance, reduced symptom duration and hospitalization in limited studies

  • Mechanism: Inhibits viral protease, immunomodulatory actions

  • Safety: Excellent at recommended doses; rare mild GI side effects

  • Limitation: Requires confirmation in larger, multicenter RCTs

Discussion

Ivermectin's efficacy, as detailed in the world’s most comprehensive and up-to-date meta-analysis, indicates statistically significant reductions in COVID-19 mortality and morbidity, especially when used early or for prophylaxis. A recent high-quality systematic review did not detect benefits for severe endpoints but did confirm improved symptom resolution, underscoring the importance of treatment timing, methodology, and population selection.

Mebendazole’s phase II RCT results validate mechanistic rationale and real-world observations of faster inflammation resolution and viral load decline, with favorable safety. However, its role remains unconfirmed pending larger trials.

Both drugs are cost-effective and broadly accessible, justifying continued rigorous appraisal as adjuncts to COVID-19 treatment—particularly in settings with limited access to new antivirals.

Conclusion

  • Ivermectin demonstrates strong real-world and meta-analytic evidence for early-stage and prophylactic COVID-19 treatment, with robust safety.
  • Mebendazole shows promising anti-inflammatory and antiviral efficacy in limited studies, and merits further large-scale, randomized trials.
  • Both should continue to be explored in the context of multi-modal COVID-19 management, especially where treatment accessibility is a public health priority.

References

  1. Yengu et al. The impact of ivermectin on COVID-19 outcomes: a systematic review and meta-analysis. Ann Med Surg (Lond). 2025;87(2):809–829. PMC11918548

  2. El-Tanani M, Ahmed KAA, Shakya AK, et al. Phase II, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial Investigating the Efficacy of Mebendazole in the Management of Symptomatic COVID-19 Patients. Pharmaceuticals. 2023;16(6):799. PMID: 37375747

  3. Satyam et al. Repurposing Anthelmintic Drugs for COVID-19 Treatment: A Comprehensive Meta-Analysis of Randomized Clinical Trials on Ivermectin and Mebendazole. Antibiotics. 2025;14(5):459. https://www.mdpi.com/2079-6382/14/5/459

  4. c19ivm.org. Ivermectin for COVID-19: Real-time meta-analysis of 105 studies. July 2025 update. https://c19ivm.org/

  5. Galal et al. The Use of Mebendazole in COVID-19 Patients: An Observational Retrospective Single Center Study. Adv Virol. 2022 Dec 10;2022:3014686. doi: 10.1155/2022/3014686.


Funding: No external funding.
Acknowledgments: The authors acknowledge all clinicians, health systems, and data experts supporting transparent real-time analysis of COVID-19 therapeutics.


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