Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols.

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The need for reliable and affordable supplements to current regimens is highlighted by the fast development of viral variations. A possible treatment choice for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is indicated by the broad-spectrum antiviral, anti-inflammatory, and immunomodulatory action of lignans from Linum usitatissimum and artemisinin from Artemisia annua. Methods 180 COVID-19-infected patients aged 20–70 years participated in a randomized controlled experiment conducted in Baghdad, Iraq, between September 2022 and August 2023. Patients were divided into mild, moderate and severe with comorbidities (n=60 each) and randomized to standard therapy alone or standard therapy and mixed artemisinin–lignan extract (10 g orally daily for 14 days). Recovery rate, time to symptom resolution, and viral RT-PCR clearance were the main outcomes. Secondary endpoints were length of hospitalization and safety. Results Adjuvant therapy significantly enhanced the prognosis of all the severity groups. The recovery rates (mild, moderate, and severe cases) were 95%, 85%, and 70% for patients, versus 80%, 65%, and 50% for the controls (p < 0.001). Symptoms resolved earlier (7 ± 2 vs 10 ± 3 days; p < 0.01) in 80% of treated patients, with viral clearance by day 10 in 80% of treated patients compared with 60% of controls (p < 0.01). Moderate-to-severe hospitalizations were shortened by 2.5 days’ average. The extract was well-tolerated with mild, transient headaches (10%) and nausea (8%) being the only adverse events. Conclusion Artemisinin–lignan extracts as adjunctive therapy can promote recovery, viral clearance, shorten hospital stay, and have no apparent severe toxicity. These results support larger multicenter studies to confirm efficacy and to determine its formalized integration into COVID-19 treatment strategy. 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F1000Research 2026, 15 :394 ( https://doi.org/10.12688/f1000research.173184.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] Zeyad Duraid Najmuldeen 1 , Mohammed Khalid Abbood https://orcid.org/0000-0002-0727-3576 2 , Ali Majeed Hantoush https://orcid.org/0000-0002-1408-3316 3 , Ali Khalaf Hasan https://orcid.org/0000-0001-9349-3913 4 , Nibras Jamal Tahseen 5 , Ruaa Aziz Jassim 6 Zeyad Duraid Najmuldeen 1 , Mohammed Khalid Abbood https://orcid.org/0000-0002-0727-3576 2 , [...] Ali Majeed Hantoush https://orcid.org/0000-0002-1408-3316 3 , Ali Khalaf Hasan https://orcid.org/0000-0001-9349-3913 4 , Nibras Jamal Tahseen 5 , Ruaa Aziz Jassim 6 PUBLISHED 12 Mar 2026 Author details Author details 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 2 Department of Clinical Pharmacy, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 3 Department of Pharmaceutical Chemistry, Alnukhba University College, Baghdad, Baghdad, 10013, Iraq 4 Department of Clinical Laboratory Science, College of Pharmacy, Tikrit University, Tikrit, Saladin Governorate, 34001, Iraq 5 Department of Pharmacology, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 6 Department of Pharmacognosy, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq Zeyad Duraid Najmuldeen Roles: Conceptualization, Funding Acquisition, Supervision Mohammed Khalid Abbood Roles: Methodology, Project Administration, Writing – Original Draft Preparation Ali Majeed Hantoush Roles: Resources, Writing – Review & Editing Ali Khalaf Hasan Roles: Formal Analysis, Investigation Nibras Jamal Tahseen Roles: Formal Analysis, Validation Ruaa Aziz Jassim Roles: Data Curation, Investigation OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Fallujah Multidisciplinary Science and Innovation gateway. Abstract Background Global health and economic consequences are still being attributed to coronavirus disease 2019 (COVID-19), despite developments in vaccine and antiviral therapy. The need for reliable and affordable supplements to current regimens is highlighted by the fast development of viral variations. A possible treatment choice for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is indicated by the broad-spectrum antiviral, anti-inflammatory, and immunomodulatory action of lignans from Linum usitatissimum and artemisinin from Artemisia annua. Methods 180 COVID-19-infected patients aged 20–70 years participated in a randomized controlled experiment conducted in Baghdad, Iraq, between September 2022 and August 2023. Patients were divided into mild, moderate and severe with comorbidities (n=60 each) and randomized to standard therapy alone or standard therapy and mixed artemisinin–lignan extract (10 g orally daily for 14 days). Recovery rate, time to symptom resolution, and viral RT-PCR clearance were the main outcomes. Secondary endpoints were length of hospitalization and safety. Results Adjuvant therapy significantly enhanced the prognosis of all the severity groups. The recovery rates (mild, moderate, and severe cases) were 95%, 85%, and 70% for patients, versus 80%, 65%, and 50% for the controls ( p < 0.001). Symptoms resolved earlier (7 ± 2 vs 10 ± 3 days; p < 0.01) in 80% of treated patients, with viral clearance by day 10 in 80% of treated patients compared with 60% of controls ( p < 0.01). Moderate-to-severe hospitalizations were shortened by 2.5 days’ average. The extract was well-tolerated with mild, transient headaches (10%) and nausea (8%) being the only adverse events. Conclusion Artemisinin–lignan extracts as adjunctive therapy can promote recovery, viral clearance, shorten hospital stay, and have no apparent severe toxicity. These results support larger multicenter studies to confirm efficacy and to determine its formalized integration into COVID-19 treatment strategy. READ ALL READ LESS Keywords Covid-organics, SARSCoV-2, Artemisia annu, Linum usitatissimum, Flaxseed, COVID-19. Corresponding Author(s) Mohammed Khalid Abbood ( [email protected] ) Close Corresponding author: Mohammed Khalid Abbood Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Najmuldeen ZD et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Najmuldeen ZD, Abbood MK, Hantoush AM et al. Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.12688/f1000research.173184.1 ) First published: 12 Mar 2026, 15 :394 ( https://doi.org/10.12688/f1000research.173184.1 ) Latest published: 12 Mar 2026, 15 :394 ( https://doi.org/10.12688/f1000research.173184.1 ) 1. Introduction On March 11, 2020, COVID-19 was classified and declared a pandemic. Following its first discovery in Wuhan, China, the novel coronavirus quickly spread throughout the world. The WHO named the new coronavirus disease COVID-19 on February 12, 2020, making it the fifth epidemic after the 1918 influenza outbreak. 1 – 3 In Iraq, treatment strategies in hospitals have relied primarily on antivirals (remdesivir, favipiravir), corticosteroids, anticoagulants, and supportive therapies such as oxygen supplementation. Despite these interventions, challenges remain in achieving rapid viral clearance and reducing hospitalization durations. Like severe acute respiratory syndrome coronavirus (SARS-CoV), COVID-19 was a virus-related illness that is brought on by SARS-CoV-2. 4 , 5 SARS-CoV-2 patients, in contrast to those infected with SARS-CoV, initially experience minimal symptoms and carry on with their daily activities, although they are contagious to others in the interim. 6 , 7 A cytokine storm known as cytokine release syndrome, which is characterized by immunosuppression and inflammation in the body, can cause certain patients' symptoms to abruptly and significantly worsen. 8 Acute Respiratory Distress Syndrome (ARDS) & multi-organ dysfunction can arise from respiratory failures caused by cytokine release syndrome in COVID-19 patients. 9 Worldwide efforts are focused on developing vaccinations that could prevent COVID-19 infection, but there is still a strong need for additional medications that can lessen the virus's severe symptoms. This is due in part to the possibility that new viral variations could evade vaccine detection. Since plants are a significant reservoir of chemo-diversity, it is possible that some safe and efficient plant molecules will be discovered that could help shield human life from the devastating effects of COVID-19. A medicinal plant Artemisia annua is widely recognized for its bioactive compound artemisinin, a sesquiterpene lactone with potent antiviral, anti-inflammatory, and antiparasitic properties. Due to its recognized pharmacological properties, artemisinin has been investigated for decades for its effects on viral infection, and this extensive research demonstrated that it blocks viral replication, modulates immune responses, and reduces cytokine storm—all of which are highly relevant for the management of COVID-19. 10 Lignans are plentiful in Linum usitatissimum (flaxseed); it is a polyphenolic material and possesses a variety of pharmacological features, such as immunomodulatory, antiviral, and antioxidant properties. Through reducing inflammatory cytokine production, inhibiting viral replication, & modulating host immune responses, lignans exert their antiviral activity. Xu et. al., had shown the potential of plant-derived lignans in disrupting viral entry mechanisms and inhibition of viral proteases, that are required for virus replication. 11 Moreover, the improvements of cell oxidative buffer situation using flaxseed lignans in such essential virus pathogenesis components had already been demonstrated by Vinardell & Mitjans. 12 Based on these properties, lignans may act as potential adjuvants in antiviral treatment, particularly in the case of COVID-19. The possible roles of them in reducing the symptoms of COVID-19 and improving immune resistance make it may be potentially developed in concert with other bioactive components such as artemisinin. The aim of this study is to investigate whether adjunctive therapy with artemisinin and lignans extracts improves recovery rates, viral clearance, and symptom resolution when compared with standard therapy alone in COVID-19 patients. 2. Methodology 2.1 Patients This Randomized Controlled Clinical Trial (RCT) consist of 180 patients diagnosed with COVID-19, both male & female, their age between 20-70 years old, were involved in this study from private clinics within the Al-Ilam, Al-Turath, and Al-Ma’alif areas, as well as near the Darweesh intersection, Al-Karkh district, Baghdad, Iraq, where the participating outpatient clinics are located. Pregnant women and patients with severe hepatic or renal impairment were excluded. Inclusion criteria included confirmed SARS-CoV-2 infection via RT-PCR, presence of mild-to-severe symptoms, and willingness to provide informed consent. Patient classification was based on the World Health Organization (WHO) clinical severity criteria for COVID-19, which categorize patients into mild, moderate, and severe cases according to clinical presentation, oxygen saturation levels, and comorbidity status. 13 Group 1 (Mild Symptoms): Consist of 60 patients showing mild symptoms, such as low-grade fever, a mild cough, and fatigue. Group 2 (Moderate Symptoms): Consist of 60 patients exhibiting more severe symptoms, including persistent fever, significant fatigue, and dyspnea without hypoxia. Group 3 (With Coexisting Diseases): Consist of 60 patients presenting with severe COVID-19 symptoms accompanied by underlying comorbidities such as diabetes mellitus, hypertension, or asthma. Each of the three main groups will be divided into two subgroups: • Intervention Group: Patients will receive a daily dose of 10 grams of the mixed extract (artemisinin and lignans) for 14 consecutive days, in addition to standard COVID-19 treatment protocols. • Control Group: Patients will receive only the standard COVID-19 treatment protocols as per the established guidelines without the mixed extract. Written informed consent will be requested from each participant, and the study will be authorized by the appropriate ethics committee in accordance with the Declaration of Helsinki's tenets. 2.2 Ethical approval The study was approved by the Institutional Review Board of [College of Pharmacy, Al-Bayan University], approval no. [ALCOP/IRB/2022/147], dated [10-Sep-2022]. All participants signed informed consent forms prior to enrolment. 2.3 Method of Artemisinin extraction Artemisia annua aerial parts and Linum usitatissimum (flaxseed) were purchased from certified local herbal suppliers in Baghdad. Dried aerial parts of Artemisia annua were harvested and air-dried under shaded conditions to preserve bioactive compounds. The dried plant material was finely powdered using an electric grinder. A total of 10 kilograms of the powder were extracted using ethanol (95%) in a Soxhlet apparatus for 6 hours. The ethanol extracts were then evaporated under reduced pressure at 40°C using a rotary evaporator to yield a concentrated artemisinin extract. The crude extract was purified by recrystallization using a hexane and ethyl acetate mixture (1:1, v/v) resulting in purified artemisinin extracts having a concentration of 1.5% w/w. using a sterile amber glass container to store the purified extracts at 4°C until further use. 14 , 15 2.4 Method of Lignans Extraction Mature Linum usitatissimum seeds were thoroughly cleaned and finely ground into powder. A total of 5 kilograms of the powdered seeds underwent extraction using 70% ethanol (v/v) at 60°C for 4 hours with continuous stirring. After passing through Whatman No. 1 filter paper, the resultant extract was concentrated at 50°C under reduced pressure using a rotary evaporator. Lignans were separated by liquid-liquid partitioning using hexane and ethyl acetate (1:1, v/v). A pure lignan extract with a three percent w/w lignans content was produced by purifying the ethyl acetate fraction using silica gel column chromatography. Finally, the extract was stored in a sterile, dark jar at 4°C to ensure stability. 16 2.5 Preparation of mixed extract The pure lignan and artemisinin extracts were combined in a 2:1 weight ratio. To achieve uniformity, 3.33 grams of the lignans extract (3% w/w lignans) and 6.67 grams of the artemisinin extract (1.5% w/w artemisinin) were carefully mixed for every ten grams of the final formulation using a vortex mixer. The resulting mixture was then stored in sterile, sealed containers at 4°C to preserve its stability until consumption. The final dosage form of the combined extract was a dry powder that was administered orally in hard gelatin capsules. 2.6 Intervention protocol All patients in the intervention groups received 10 g of the mixed extracts for 14 days through the oral route, together with COVID-19 standard therapy. Patients in the control groups received only the standard clinical therapy, that involve supportive therapy, steroids, & antiviral medication. 2.7 Parameters measured Primary outcomes: Recovery rate, symptom resolution time, viral clearance (RT-PCR). Secondary outcomes: Hospitalization duration, adverse effects. Clinical evaluations included vital signs, chest X-ray, renal function tests, and blood glucose monitoring. 2.8 Statistical analysis Data will be processed & analyzed utilizing SPSS version 22 for statistical significance. The following statistical methods will be applied; Chi-square test will be utilized to compare the recovery rates between the intervention and control groups across all severity levels. One-way Analysis of Variance (ANOVA) will be performed to assess differences in continuous variables, such as symptom duration and time to viral clearance, between the two groups. T-tests will be used to compare the mean recovery times between the intervention and control subgroups. Kaplan-Meier survival analysis will be conducted to evaluate the time to recovery and viral clearance for both groups. 3. Results 3.1 Recovery rates According to the results of this study, the intervention group showed significant improvements in recovery rates. The recovery rate was 95% in the intervention group compared to 80% in the control group for the first group (mild symptoms), 85% in the intervention group versus 65% in the control group for the second group (moderate symptoms), and 70% in the intervention group compared to 50% in control group for the third group (patients with coexisting diseases), as illustrated in Table 1 . This study was conducted over a 12-month period, including patient recruitment, intervention, & the follow-up phase. Table 1. Data summary (n = 180, duration = September 2022 – August 2023). Parameter Intervention group Control group Statistical test p -value Recovery Rate (%) Mild: 95% Mild: 80% Chi-Square Test p <0.001 Moderate: 85% Moderate: 65% Severe: 70% Severe: 50% Symptom Resolution Time (Days) Mild: 7 ± 2 Mild: 10 ± 3 One-way ANOVA p <0.01 Moderate: 7 ± 2 Moderate: 10 ± 3 Severe: 9 ± 3 Severe: 12 ± 3 Viral Clearance by Day 10 (%) Mild: 90% Mild: 70% Chi-Square Test p <0.01 Moderate: 80% Moderate: 60% Severe: 70% Severe: 50% Hospital Stay (Days) Severe Cases Only: Mean: 7.5 ± 1.5 days Mean: 10 ± 2 days Independent T-Test p <0.05 Median: 7 days (95% CI: 7–8 days) Median: 10 days (95% CI: 9–11 days) Time to Recovery (Days) Median: 8 days (95% CI: 7–9 days) Median: 11 days (95% CI: 10–12 days) Kaplan-Meier Survival Analysis p <0.01 Time to Viral Clearance (Days) Mean: 9 ± 1 days Mean: 12 ± 2 days Independent T-Test p <0.01 Adverse Effects (%) Headaches: 10% Headaches: 10% Descriptive Statistics Not significant Nausea: 8% (both mild and transient) Nausea: 8% (both mild and transient) 3.2 Symptom resolution time The mean time to complete symptom resolution is shorter in the intervention group, with an average of 7 ± 2 days compared to 10 ± 3 days in the control group. 3.3 Viral clearance Compared to 60% of patients in the control group, 80% of patients in the intervention group tested negative by RT-PCR within a period of ten days, indicating a quicker viral clearance in this group. 3.4 Hospitalization When compared to the control groups, the average hospital stays for patients who needed to be hospitalized in the intervention groups decreased by 2.5 days, suggesting a substantial benefit from the intervention. 3.5 Safety profile There were no serious side effects noted during this investigation. Headaches (10%) and nausea (8%) were among the mild side effects that were observed, but they went away on their own in 24 hours without the need for further treatment. 4. Discussion The results of this study demonstrate that the clinical outcomes of COVID-19 patients in various severity groups would be significantly improved by the use of combinations of artemisinin and lignan extract. Shorter times for symptoms to go away, higher rates of recovery, quicker virus clearance, and shorter hospital stay. These findings are consistent with previous research on the antiviral properties of artemisinin and similar substances. 4.1 Recovery rates and symptom resolution According to our research, group 1's recovery rate significantly improved (95% in the intervention group compared to 80% in the control), suggesting a substantial increase in disease resolution. This finding is consistent with the study of Nair et al., that reported the extracts of Artemisia annua decrease cytokine production & viral replication, thus improving the clinical outcomes. 17 Other study done by Nie et al., & Jassim RA, et al., demonstrate artemisinin adjunct treatment improve the viral clearance & decrease the severity of the symptoms in COVID-19 infected cells. 18 , 19 The efficacy of the combined extracts is further reinforced by shorting the mean symptoms resolution time (7 ± 2 days in the intervention group vs. 10 ± 3 days in the control). This finding aligns with the study done by Shi et al., that had proven use of artemisinin extract would reduce the duration of COVID-19 symptoms through its antiviral & immunomodulatory characteristics. 20 4.2 Viral clearance In this RCT, 80% of intervention patients were RT-PCR negative by day 10 days versus 60% in the control group with faster viral clearance. This result is in line with the findings of Cao et al. , who demonstrated the strong inhibitory effect of artemisinin and its derivatives against SARS-CoV-2 in vitro. 21 Additionally, Zhou et al., observed that artesunate had a strong blocking impact on viral entrance and reproduction, which resulted in the virus being cleared quickly. 22 4.3 Hospitalization duration The potential of artemisinin and lignans in treating severe COVID-19 cases is demonstrated by the average 2.5-day decrease in hospital stays among patients in the intervention group. This result is in line with the findings of Dolivo et al., who found that by lessening the severity of cytokine storms and lowering lung inflammation, artesunate treatment considerably reduced hospital stays and improved clinical outcomes. 23 4.4 Safety profile The combination extract therapy appears to be well tolerated based on the minor and temporary side effects (headaches in 10% of patients and nausea in 8%). This is in line with research by Farmanpour-Kalalagh K et al., who examined the safety profile of artemisinin-based therapies and discovered no serious side effects in COVID-19 patients. 24 4.5 Comparison with standard treatment protocols Antiviral medications, corticosteroids, and supportive care were the main COVID-19 treatment regimens employed in the control group. These therapies have limits, especially in severe cases, even if they have demonstrated efficacy in treating symptoms. Artemisinin and lignans seemed to enhance recovery outcomes due to their combination of antiviral and immunomodulatory qualities. Hunt et al., 's study, which demonstrated that extracts from Artemisia annua not only reduce viral loads but also modify immune responses to prevent excessive inflammation, is supported by this. 25 4.6 Limitations The fairly short monitoring time and the absence of people who were pregnant or had children are two of the limitations. The research study was conducted on a single site and had a moderate sample size, which would have limited the applicability of the findings. Statistical analysis of biochemical and immunological markers, such as cytokine profiles and inflammatory mediators, may have provided a deeper knowledge of the mechanisms of action. Additionally, the study did not evaluate the pharmacokinetic properties or extended bioavailability of the oral capsule formulation. Future multicenter studies with larger and more diverse populations are required to validate these findings and assess long-term safety and efficacy. 5. Conclusion This study provides compelling evidence that extracts of lignan, and artemisinin significantly increase recovery rates, speed up viral clearance, and shorten COVID-19 symptoms. These findings are in line with significant studies that have shown the immunomodulatory and antiviral qualities of artemisinin derivatives. The reported safety profile further supports its usage as adjuvant therapy. Larger-scale randomized controlled trials are necessary to establish standardized procedures for integrating these extracts into traditional COVID-19 treatment techniques. Future studies should look into the optimal dosages, long-term safety, and potential interactions with conventional medications. Informed consent Written informed consent was obtained from all participants prior to enrolment. Written consent was chosen to ensure proper documentation, ethical transparency, and full compliance with institutional and international ethical guidelines. Data availability Due to ethical and confidentiality constraints, the dataset supporting the study's conclusions cannot be publicly disclosed because it contains sensitive patient health information. The Institutional Review Board of Al-Bayan University's College of Pharmacy granted approval for the study (Approval No. ALCOP/IRB/2022/147). Therefore, it is unethical to make the raw datasets publicly accessible. Subject to ethics committee permission and patient privacy laws, data may be given to the related author upon reasonable request. This article does not contain any further underlying data. Acknowledgement We express our sincere gratitude to Al-Bayan University, Tikrit University, and Alnukhba University College for their invaluable assistance. References 1. Liu YC, Kuo RL, Shih SR: COVID-19: The first documented coronavirus pandemic in history. Biom. J. 2020; 43 (4): 328–333. 2. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020; 5 (4): 536–544. PubMed Abstract | Publisher Full Text 3. Chan JF, Yuan S, Kok KH, et al. : A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission. 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PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 12 Mar 2026 ADD YOUR COMMENT Comment Author details Author details 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 2 Department of Clinical Pharmacy, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 3 Department of Pharmaceutical Chemistry, Alnukhba University College, Baghdad, Baghdad, 10013, Iraq 4 Department of Clinical Laboratory Science, College of Pharmacy, Tikrit University, Tikrit, Saladin Governorate, 34001, Iraq 5 Department of Pharmacology, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq 6 Department of Pharmacognosy, College of Pharmacy, Al-Bayan University, Baghdad, Baghdad, 10013, Iraq Zeyad Duraid Najmuldeen Roles: Conceptualization, Funding Acquisition, Supervision Mohammed Khalid Abbood Roles: Methodology, Project Administration, Writing – Original Draft Preparation Ali Majeed Hantoush Roles: Resources, Writing – Review & Editing Ali Khalaf Hasan Roles: Formal Analysis, Investigation Nibras Jamal Tahseen Roles: Formal Analysis, Validation Ruaa Aziz Jassim Roles: Data Curation, Investigation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 12 Mar 2026, 15:394 https://doi.org/10.12688/f1000research.173184.1 Copyright © 2026 Najmuldeen ZD et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Najmuldeen ZD, Abbood MK, Hantoush AM et al. Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.12688/f1000research.173184.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 12 Mar 2026 Views 0 Cite How to cite this report: Hurrah IM. Reviewer Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r477488 ) The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-477488 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 May 2026 Ishfaq Majid Hurrah , CSIR-Indian Institute of Integrative Medicine, Srinagar, India Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.190975.r477488 The manuscript investigates the adjunctive use of artemisinin and lignan extracts in COVID-19 patients through a randomized clinical study involving 180 participants. The topic is relevant and potentially valuable because plant-derived antivirals and immunomodulators remain an active area of translational ... Continue reading READ ALL The manuscript investigates the adjunctive use of artemisinin and lignan extracts in COVID-19 patients through a randomized clinical study involving 180 participants. The topic is relevant and potentially valuable because plant-derived antivirals and immunomodulators remain an active area of translational research. However, despite the clinical relevance, the manuscript currently suffers from substantial methodological, statistical, pharmacological, and reporting deficiencies that limit scientific reliability and reproducibility. Several components also do not fully comply with F1000Research standards for transparent clinical research reporting. 1. Title and Overall Framing (Page 1) Highlighted text: “Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols.” Critical Review: The title clearly identifies the intervention and clinical context; however, the term “Innovative” is promotional and subjective. F1000Research generally prefers objective scientific wording. A more neutral title would improve professionalism and reduce bias. 2. Abstract Evaluation (Pages 1–2) Highlighted text: “Recovery rates (mild, moderate, and severe cases) were 95%, 85%, and 70%...” Critical Review: The abstract summarizes the findings adequately but lacks essential statistical details such as confidence intervals, adjusted odds ratios, and effect sizes. Reporting only p-values is insufficient for a clinical trial manuscript. Highlighted text: “The extract was well-tolerated with mild, transient headaches (10%) and nausea (8%).” Critical Review: The claim regarding safety is insufficiently supported because the manuscript does not report biochemical monitoring such as liver enzymes, renal function, ECG findings, or hematological parameters. Safety conclusions are therefore overstated. 3. Introduction and Literature Review (Page 3) Highlighted text: “A medicinal plant Artemisia annua is widely recognized for its bioactive compound artemisinin...” Critical Review: The introduction explains the antiviral and immunomodulatory importance of artemisinin and lignans individually; however, the manuscript does not provide a mechanistic explanation for combining both compounds into a single therapeutic formulation. Highlighted text: “The possible roles of them in reducing the symptoms of COVID-19...” Critical Review: The manuscript fails to explain whether the combination is expected to produce additive, synergistic, or complementary pharmacological effects. The rationale for selecting the specific 2:1 ratio is also absent. Critical Review: Most cited literature originates from 2020–2022, whereas the manuscript was published in 2026. The introduction requires updated literature including recent molecular docking studies, clinical trials, and variant-specific antiviral evidence. 4. Methodology and Clinical Design (Pages 3–5) Highlighted text: “This Randomized Controlled Clinical Trial (RCT) consist of 180 patients...” Critical Review: The study is described as randomized; however, the manuscript fails to describe the randomization process. There is no information regarding sequence generation, allocation concealment, block randomization, or stratification. Highlighted text: “Patients were divided into mild, moderate and severe with comorbidities...” Critical Review: Baseline demographic characteristics are missing. The manuscript does not report age distribution, sex ratio, comorbidity frequencies, vaccination status, or baseline oxygen saturation values. Without these data, comparability between groups cannot be assessed. Highlighted text: “10 g orally daily for 14 days” Critical Review: The dosage regimen is clinically questionable. A 10 g daily dry extract formulation would require approximately 15–20 capsules daily depending on capsule size. The manuscript does not describe capsule count, dosing frequency, excipients, or adherence monitoring. Highlighted text: “The final dosage form ... hard gelatin capsules.” Critical Review: No pharmaceutical formulation details are provided. There is no information regarding capsule uniformity, dissolution characteristics, stability validation, or manufacturing reproducibility. Critical Review: The manuscript also lacks clinical trial registration information, which is essential for human intervention studies and expected under international reporting standards. 5. Extraction and Phytochemical Standardization (Pages 4–5) Highlighted text: “1.5% w/w artemisinin” and “3% w/w lignans content.” Critical Review: The phytochemical characterization is inadequate. The manuscript does not provide HPLC, LC-MS, GC-MS, chromatographic fingerprints, purity analyses, or batch consistency validation. Critical Review: Extraction yields, recovery percentages, and analytical validation procedures are missing, making the methodology difficult to reproduce. 6. Statistical Analysis (Page 4) Highlighted text: “Chi-square test... One-way ANOVA... T-tests...” Critical Review: The statistical analysis is inadequate for a clinical trial involving heterogeneous COVID-19 patients. Only univariate statistical tests were used. Critical Review: The study requires multivariable logistic regression and Cox proportional hazards modelling to adjust for confounding variables such as age, comorbidities, and disease severity. Critical Review: No sample size calculation or statistical power analysis was reported. 7. Results Section (Pages 5–6) Highlighted text: “Recovery rate was 95% in the intervention group compared to 80%...” Critical Review: The results appear clinically promising; however, absolute patient numbers and confidence intervals are not reported. Only percentages are presented. Highlighted text: “Kaplan-Meier survival analysis...” Critical Review: Kaplan-Meier analysis is mentioned in the manuscript, but no survival curves, hazard ratios, or censoring information are presented. Critical Review: Table 1 lacks adjusted statistics and baseline demographic comparisons. This significantly reduces interpretability. 8. Discussion Section (Page 6) Highlighted text: “The results of this study demonstrate...” Critical Review: The discussion overinterprets the findings and assumes direct causality despite inadequate multivariate adjustment. Critical Review: The authors discuss artemisinin and lignans separately but fail to integrate mechanistic pharmacodynamic interactions between the two compounds. Critical Review: The discussion should compare the magnitude of the observed clinical effects with previously published monotherapy studies. 9. Limitations Section (Page 6) Highlighted text: “The fairly short monitoring time...” Critical Review: The limitations section is incomplete and omits several major weaknesses including unclear blinding status, lack of allocation concealment, absence of placebo control, lack of multivariate statistical adjustment, and absence of biochemical safety monitoring. 10. Data Availability and F1000Research Compliance (Page 7) Highlighted text: “dataset cannot be publicly disclosed...” Critical Review: F1000Research strongly encourages open data availability. The authors should provide de-identified datasets in repositories such as Zenodo, Figshare, or OSF. 11. Language and Grammar Issues Highlighted text: “This Randomized Controlled Clinical Trial (RCT) consist of 180 patients...” Critical Review: The manuscript contains numerous grammatical errors and awkward sentence constructions. Professional English editing is strongly recommended. Highlighted text: “The efficacy of the combined extracts is further reinforced by shorting the mean symptoms resolution time...” Critical Review: Several sentences contain grammatical inconsistencies, punctuation issues, and unclear phrasing. 12. Final Editorial Recommendation Recommendation: Major Revision Required Although the study explores an important therapeutic concept with potentially promising clinical implications, major revisions are required regarding methodology, statistical analysis, phytochemical standardization, trial transparency, safety validation, and reporting quality before the manuscript can be considered suitable for indexing Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Plant Molecular Biology and Biotechnology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Hurrah IM. Reviewer Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r477488 ) The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-477488 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Fawzi HA. Reviewer Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r469808 ) The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-469808 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 03 Apr 2026 Hayder Adnan Fawzi , Al-Mustafa university College, Baghdad, Iraq Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.190975.r469808 Novelty The true novelty of the manuscript lies in the specific combination of these two extracts within a clinical setting to treat COVID-19. While both compounds have been studied individually against various viral pathogens, ... Continue reading READ ALL Novelty The true novelty of the manuscript lies in the specific combination of these two extracts within a clinical setting to treat COVID-19. While both compounds have been studied individually against various viral pathogens, the synergistic application of a 2:1 artemisinin-to-lignan ratio as a clinical adjunct for SARS-CoV-2 infection represents an unexplored therapeutic frontier. However, the authors fail to adequately articulate the theoretical basis for this specific novelty within the manuscript. The introduction notes the individual benefits of each compound but does not provide a mechanistic hypothesis explaining why combining them is superior to utilizing either agent alone. For a combination therapy to be truly novel and scientifically compelling, the authors must hypothesize whether the interaction is additive, synergistic, or complementary (e.g., one compound targeting viral entry while the other suppresses host inflammatory responses). The lack of a defined pharmacological rationale for the 2:1 extraction ratio specifically diminishes the perceived novelty of the formulation. The authors must rigorously expand their rationale to explicitly detail the presumed synergistic mechanisms that justify this novel combination over monotherapy. Introduction Literature Review The literature review exhibits a profound temporal deficiency. The citations heavily rely on seminal papers published during the initial phases of the pandemic (2020–2021). By 2026, the scientific community's understanding of SARS-CoV-2 pathophysiology and the efficacy of phytochemical interventions will have advanced exponentially. The introduction omits references to recent, highly relevant in vitro and clinical evaluations of artemisinin derivatives and lignans against contemporary SARS-CoV-2 variants. For instance, numerous studies conducted between 2023 and 2026 have elucidated the precise molecular docking profiles of artemisinin with the SARS-CoV-2 spike protein and host cell receptors. Failing to integrate this current literature creates a false vacuum in the research landscape. Suggested references: (refer 1,2 ) gap of knowledge and objectives The "gap of knowledge" identified by the authors is weakly articulated. The manuscript implies a general need for new therapies but does not clearly define what remains unknown about artemisinin-lignan interactions in human subjects. The hypothesis is loosely implied rather than explicitly stated, and while the objective—to investigate whether the adjunctive therapy improves recovery rates and viral clearance—is clear, it lacks the specificity required of a high-tier clinical trial. The authors must revise the introduction to incorporate recent literature, clearly articulate the specific mechanistic gap this combination aims to address, and state a formal, testable hypothesis regarding the synergistic effects of the extract. Methods The clinical methodology is exceptionally opaque and lacks the precision required for reproducibility. The manuscript states that patients were "randomized" but fails to explain the mechanism of this randomization. In a study involving 180 patients divided into distinct severity cohorts (including patients with severe pre-existing comorbidities), simple randomization is highly susceptible to generating unequal groups. The authors must specify whether stratified or block randomization was employed to ensure that confounding variables were evenly distributed. Furthermore, there is no mention of allocation concealment (e.g., using sequentially numbered, opaque, sealed envelopes) or whether the trial was double-blind, single-blind, or open-label. The absence of these details makes it impossible to evaluate the risk of selection, performance, and detection biases. Clinical trial registration is a must. Please provide clinical trial registration information. A critical pharmacological ambiguity also exists within the dosing regimen. The authors state that the final formulation was a dry powder administered orally in hard gelatin capsules at a dosage of "10 g orally daily for 14 days". Ten grams of dry powder represents an enormous physical volume for capsular administration. Assuming the use of standard-size 00 capsules (which accommodate approximately 500-700 mg of powder), a single patient would need to ingest between 14 and 20 capsules per day. The logistical feasibility of this regimen, particularly for severe COVID-19 patients experiencing respiratory distress and potential dysphagia, is highly questionable. The manuscript provides no information on the daily dosing schedule (e.g., divided into twice- or thrice-daily doses), the excipients used in the capsules, or the metrics used to monitor patient adherence to this demanding pill burden. Reproducibility requires exact pharmacological and clinical administrative details, all of which are currently missing. Results The authors are strictly required to perform and report multivariate analyses. For binary and categorical outcomes, such as recovery rate and viral clearance by day 10, multivariable logistic regression must be used to estimate Adjusted Odds Ratios (aORs) with 95% Confidence Intervals, controlling for all relevant baseline covariates. For time-to-event outcomes, such as symptom duration and hospitalization length, the existing Kaplan-Meier analyses must be augmented with Cox proportional hazards regression models to yield Adjusted Hazard Ratios (aHRs). The absence of multivariate statistical adjustment in the current draft invalidates the authors' causal assertions and constitutes a critical barrier to publication. Discussion Because the discussion is predicated upon flawed, univariate statistical results, the interpretation is inherently compromised. The authors explain their findings under the assumption of direct, unconfounded causality, which has not been statistically proven. Furthermore, the discussion fails to address the underlying pharmacological mechanisms of the specific 2:1 combination. While the authors discuss artemisinin and lignans in isolation, they do not synthesize the data to explain how these compounds may have interacted synergistically within the human subjects to produce the observed outcomes. A robust discussion must delve into the pharmacodynamic interactions of the combination therapy, comparing the magnitude of the observed effects against historical data for either compound used as monotherapy. Limitations The true limitations of this research, which must be explicitly stated, include the lack of documented allocation concealment, the ambiguous blinding status of the trial, and the absence of multivariate statistical control for baseline confounders. If the trial was conducted as an open-label study, the authors must acknowledge the high risk of placebo effects and investigator bias, particularly when evaluating highly subjective secondary endpoints such as "symptom resolution." The failure to recognize these structural biases indicates a concerning lack of critical self-appraisal. The limitations section must be entirely rewritten to transparently address these profound methodological constraints (if not corrected as requested previously). Conclusion The assertion that the 10-gram dose has "no apparent severe toxicity" is particularly unsupported. The safety profile was evaluated based solely on patient-reported, subjective adverse events (headaches and nausea). There is absolutely no mention of systemic biochemical monitoring. Administering massive oral doses of crude botanical extracts poses known risks of hepatotoxicity and nephrotoxicity; historical data regarding Artemisia annua extracts have prompted regulatory warnings concerning potential drug-induced liver injury. Asserting a lack of severe toxicity without continuous laboratory monitoring of hepatic (ALT, AST, bilirubin) and renal (BUN, creatinine) function is scientifically negligent. The conclusions must be carefully softened to reflect the data's preliminary, unadjusted nature, and the authors must emphasize that rigorous biochemical safety validation is a strict prerequisite for any future integration into standardized care protocols. Formal F1000Research Peer Review Questionnaire Is the work clearly and accurately presented, and does it cite the current literature? The authors must update their literature review comprehensively, integrating clinical trial data and molecular docking studies published between 2023 and 2026. Additionally, the authors must meticulously review the manuscript for textual overlap, ensuring that all theoretical mechanisms, rationales, and conclusions are synthesized and articulated with complete originality. Is the study design appropriate, and is the work technically sound? The authors must provide the clinical trial registration number. If the trial was not registered prospectively, retrospective registration must be completed immediately, and the authors must provide a formal, transparent justification for this ethical oversight within the manuscript. Additionally, the methodology section must be expanded to explicitly detail the randomization technique (e.g., block size, stratification factors), the allocation concealment method (e.g., SNOSE), and the specific blinding protocols implemented. Are sufficient details of methods and analysis provided to allow replication by others ? The authors must detail the exact clinical administration protocol, including the number of capsules per dose, the dosing frequency, and the excipients used. They must also explicitly define the standardized clinical criteria or scoring systems used to measure "recovery" and "symptom resolution." If applicable, is the statistical analysis and its interpretation appropriate ? The authors must generate and insert a comprehensive "Table 1" detailing the baseline characteristics of both trial arms. Crucially, the authors must perform multivariate statistical analyses. Multivariable logistic regression is required for all categorical outcomes (yielding adjusted Odds Ratios), and Cox proportional hazards models must be applied to all time-to-event outcomes (yielding adjusted Hazard Ratios). The interpretations in the Results and Discussion sections must be revised to reflect these adjusted statistics. Are all the source data underlying the results available to ensure full reproducibility ? The authors must strictly adhere to the open data policy. The raw clinical dataset must be rigorously de-identified in accordance with the Safe Harbor criteria. Following de-identification, the dataset must be uploaded to an approved, openly accessible data repository (e.g., Open Science Framework, Zenodo, or Figshare) under a CC0 or CC-BY license. The Data Availability Statement in the manuscript must be rewritten to include the repository name, a description of the dataset, and a unique persistent identifier (DOI) linking directly to the data. If the institutional ethics committee imposes highly specific, legally binding constraints that prevent even the sharing of de-identified data, the dataset must be placed in a controlled-access repository (e.g., Zendo), and the exact legal conditions for access must be thoroughly detailed in the manuscript . Are the conclusions drawn adequately supported by the results? The conclusions must be substantially modulated. The authors must reframe their findings as preliminary evidence requiring further validation and as heavily contingent upon the results of the newly requested multivariate analyses. The claims regarding the safety profile must be heavily qualified, explicitly acknowledging the lack of continuous biochemical monitoring as a major limitation, and stating that rigorous systemic toxicological evaluations are necessary before clinical implementation. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Wang C, Li Y, Zhuo L, Xu S, et al.: Structural pharmacology of Chinese medicine: technological breakthroughs in decoding multi-target synergy and precision mechanisms. Advanced Biotechnology . 2026; 4 (1). Publisher Full Text 2. Shaer, N. A., Mohamed, A. A., & Schnug, E. (2025). Potential of Artemisia annua Bioactives as Antiviral Agents Against SARS-CoV-2 and Other Health Complications. Pharmaceuticals, 18(12), 1904. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Pharmacy, Pharmacology, infection I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Fawzi HA. Reviewer Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r469808 ) The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-469808 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 12 Mar 2026 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 12 Mar 26 read read Hayder Adnan Fawzi , Al-Mustafa university College, Baghdad, Iraq Ishfaq Majid Hurrah , CSIR-Indian Institute of Integrative Medicine, Srinagar, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Hurrah I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 May 2026 | for Version 1 Ishfaq Majid Hurrah , CSIR-Indian Institute of Integrative Medicine, Srinagar, India 0 Views copyright © 2026 Hurrah I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript investigates the adjunctive use of artemisinin and lignan extracts in COVID-19 patients through a randomized clinical study involving 180 participants. The topic is relevant and potentially valuable because plant-derived antivirals and immunomodulators remain an active area of translational research. However, despite the clinical relevance, the manuscript currently suffers from substantial methodological, statistical, pharmacological, and reporting deficiencies that limit scientific reliability and reproducibility. Several components also do not fully comply with F1000Research standards for transparent clinical research reporting. 1. Title and Overall Framing (Page 1) Highlighted text: “Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols.” Critical Review: The title clearly identifies the intervention and clinical context; however, the term “Innovative” is promotional and subjective. F1000Research generally prefers objective scientific wording. A more neutral title would improve professionalism and reduce bias. 2. Abstract Evaluation (Pages 1–2) Highlighted text: “Recovery rates (mild, moderate, and severe cases) were 95%, 85%, and 70%...” Critical Review: The abstract summarizes the findings adequately but lacks essential statistical details such as confidence intervals, adjusted odds ratios, and effect sizes. Reporting only p-values is insufficient for a clinical trial manuscript. Highlighted text: “The extract was well-tolerated with mild, transient headaches (10%) and nausea (8%).” Critical Review: The claim regarding safety is insufficiently supported because the manuscript does not report biochemical monitoring such as liver enzymes, renal function, ECG findings, or hematological parameters. Safety conclusions are therefore overstated. 3. Introduction and Literature Review (Page 3) Highlighted text: “A medicinal plant Artemisia annua is widely recognized for its bioactive compound artemisinin...” Critical Review: The introduction explains the antiviral and immunomodulatory importance of artemisinin and lignans individually; however, the manuscript does not provide a mechanistic explanation for combining both compounds into a single therapeutic formulation. Highlighted text: “The possible roles of them in reducing the symptoms of COVID-19...” Critical Review: The manuscript fails to explain whether the combination is expected to produce additive, synergistic, or complementary pharmacological effects. The rationale for selecting the specific 2:1 ratio is also absent. Critical Review: Most cited literature originates from 2020–2022, whereas the manuscript was published in 2026. The introduction requires updated literature including recent molecular docking studies, clinical trials, and variant-specific antiviral evidence. 4. Methodology and Clinical Design (Pages 3–5) Highlighted text: “This Randomized Controlled Clinical Trial (RCT) consist of 180 patients...” Critical Review: The study is described as randomized; however, the manuscript fails to describe the randomization process. There is no information regarding sequence generation, allocation concealment, block randomization, or stratification. Highlighted text: “Patients were divided into mild, moderate and severe with comorbidities...” Critical Review: Baseline demographic characteristics are missing. The manuscript does not report age distribution, sex ratio, comorbidity frequencies, vaccination status, or baseline oxygen saturation values. Without these data, comparability between groups cannot be assessed. Highlighted text: “10 g orally daily for 14 days” Critical Review: The dosage regimen is clinically questionable. A 10 g daily dry extract formulation would require approximately 15–20 capsules daily depending on capsule size. The manuscript does not describe capsule count, dosing frequency, excipients, or adherence monitoring. Highlighted text: “The final dosage form ... hard gelatin capsules.” Critical Review: No pharmaceutical formulation details are provided. There is no information regarding capsule uniformity, dissolution characteristics, stability validation, or manufacturing reproducibility. Critical Review: The manuscript also lacks clinical trial registration information, which is essential for human intervention studies and expected under international reporting standards. 5. Extraction and Phytochemical Standardization (Pages 4–5) Highlighted text: “1.5% w/w artemisinin” and “3% w/w lignans content.” Critical Review: The phytochemical characterization is inadequate. The manuscript does not provide HPLC, LC-MS, GC-MS, chromatographic fingerprints, purity analyses, or batch consistency validation. Critical Review: Extraction yields, recovery percentages, and analytical validation procedures are missing, making the methodology difficult to reproduce. 6. Statistical Analysis (Page 4) Highlighted text: “Chi-square test... One-way ANOVA... T-tests...” Critical Review: The statistical analysis is inadequate for a clinical trial involving heterogeneous COVID-19 patients. Only univariate statistical tests were used. Critical Review: The study requires multivariable logistic regression and Cox proportional hazards modelling to adjust for confounding variables such as age, comorbidities, and disease severity. Critical Review: No sample size calculation or statistical power analysis was reported. 7. Results Section (Pages 5–6) Highlighted text: “Recovery rate was 95% in the intervention group compared to 80%...” Critical Review: The results appear clinically promising; however, absolute patient numbers and confidence intervals are not reported. Only percentages are presented. Highlighted text: “Kaplan-Meier survival analysis...” Critical Review: Kaplan-Meier analysis is mentioned in the manuscript, but no survival curves, hazard ratios, or censoring information are presented. Critical Review: Table 1 lacks adjusted statistics and baseline demographic comparisons. This significantly reduces interpretability. 8. Discussion Section (Page 6) Highlighted text: “The results of this study demonstrate...” Critical Review: The discussion overinterprets the findings and assumes direct causality despite inadequate multivariate adjustment. Critical Review: The authors discuss artemisinin and lignans separately but fail to integrate mechanistic pharmacodynamic interactions between the two compounds. Critical Review: The discussion should compare the magnitude of the observed clinical effects with previously published monotherapy studies. 9. Limitations Section (Page 6) Highlighted text: “The fairly short monitoring time...” Critical Review: The limitations section is incomplete and omits several major weaknesses including unclear blinding status, lack of allocation concealment, absence of placebo control, lack of multivariate statistical adjustment, and absence of biochemical safety monitoring. 10. Data Availability and F1000Research Compliance (Page 7) Highlighted text: “dataset cannot be publicly disclosed...” Critical Review: F1000Research strongly encourages open data availability. The authors should provide de-identified datasets in repositories such as Zenodo, Figshare, or OSF. 11. Language and Grammar Issues Highlighted text: “This Randomized Controlled Clinical Trial (RCT) consist of 180 patients...” Critical Review: The manuscript contains numerous grammatical errors and awkward sentence constructions. Professional English editing is strongly recommended. Highlighted text: “The efficacy of the combined extracts is further reinforced by shorting the mean symptoms resolution time...” Critical Review: Several sentences contain grammatical inconsistencies, punctuation issues, and unclear phrasing. 12. Final Editorial Recommendation Recommendation: Major Revision Required Although the study explores an important therapeutic concept with potentially promising clinical implications, major revisions are required regarding methodology, statistical analysis, phytochemical standardization, trial transparency, safety validation, and reporting quality before the manuscript can be considered suitable for indexing Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Plant Molecular Biology and Biotechnology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Hurrah IM. Peer Review Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r477488) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-477488 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Fawzi H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 03 Apr 2026 | for Version 1 Hayder Adnan Fawzi , Al-Mustafa university College, Baghdad, Iraq 0 Views copyright © 2026 Fawzi H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Novelty The true novelty of the manuscript lies in the specific combination of these two extracts within a clinical setting to treat COVID-19. While both compounds have been studied individually against various viral pathogens, the synergistic application of a 2:1 artemisinin-to-lignan ratio as a clinical adjunct for SARS-CoV-2 infection represents an unexplored therapeutic frontier. However, the authors fail to adequately articulate the theoretical basis for this specific novelty within the manuscript. The introduction notes the individual benefits of each compound but does not provide a mechanistic hypothesis explaining why combining them is superior to utilizing either agent alone. For a combination therapy to be truly novel and scientifically compelling, the authors must hypothesize whether the interaction is additive, synergistic, or complementary (e.g., one compound targeting viral entry while the other suppresses host inflammatory responses). The lack of a defined pharmacological rationale for the 2:1 extraction ratio specifically diminishes the perceived novelty of the formulation. The authors must rigorously expand their rationale to explicitly detail the presumed synergistic mechanisms that justify this novel combination over monotherapy. Introduction Literature Review The literature review exhibits a profound temporal deficiency. The citations heavily rely on seminal papers published during the initial phases of the pandemic (2020–2021). By 2026, the scientific community's understanding of SARS-CoV-2 pathophysiology and the efficacy of phytochemical interventions will have advanced exponentially. The introduction omits references to recent, highly relevant in vitro and clinical evaluations of artemisinin derivatives and lignans against contemporary SARS-CoV-2 variants. For instance, numerous studies conducted between 2023 and 2026 have elucidated the precise molecular docking profiles of artemisinin with the SARS-CoV-2 spike protein and host cell receptors. Failing to integrate this current literature creates a false vacuum in the research landscape. Suggested references: (refer 1,2 ) gap of knowledge and objectives The "gap of knowledge" identified by the authors is weakly articulated. The manuscript implies a general need for new therapies but does not clearly define what remains unknown about artemisinin-lignan interactions in human subjects. The hypothesis is loosely implied rather than explicitly stated, and while the objective—to investigate whether the adjunctive therapy improves recovery rates and viral clearance—is clear, it lacks the specificity required of a high-tier clinical trial. The authors must revise the introduction to incorporate recent literature, clearly articulate the specific mechanistic gap this combination aims to address, and state a formal, testable hypothesis regarding the synergistic effects of the extract. Methods The clinical methodology is exceptionally opaque and lacks the precision required for reproducibility. The manuscript states that patients were "randomized" but fails to explain the mechanism of this randomization. In a study involving 180 patients divided into distinct severity cohorts (including patients with severe pre-existing comorbidities), simple randomization is highly susceptible to generating unequal groups. The authors must specify whether stratified or block randomization was employed to ensure that confounding variables were evenly distributed. Furthermore, there is no mention of allocation concealment (e.g., using sequentially numbered, opaque, sealed envelopes) or whether the trial was double-blind, single-blind, or open-label. The absence of these details makes it impossible to evaluate the risk of selection, performance, and detection biases. Clinical trial registration is a must. Please provide clinical trial registration information. A critical pharmacological ambiguity also exists within the dosing regimen. The authors state that the final formulation was a dry powder administered orally in hard gelatin capsules at a dosage of "10 g orally daily for 14 days". Ten grams of dry powder represents an enormous physical volume for capsular administration. Assuming the use of standard-size 00 capsules (which accommodate approximately 500-700 mg of powder), a single patient would need to ingest between 14 and 20 capsules per day. The logistical feasibility of this regimen, particularly for severe COVID-19 patients experiencing respiratory distress and potential dysphagia, is highly questionable. The manuscript provides no information on the daily dosing schedule (e.g., divided into twice- or thrice-daily doses), the excipients used in the capsules, or the metrics used to monitor patient adherence to this demanding pill burden. Reproducibility requires exact pharmacological and clinical administrative details, all of which are currently missing. Results The authors are strictly required to perform and report multivariate analyses. For binary and categorical outcomes, such as recovery rate and viral clearance by day 10, multivariable logistic regression must be used to estimate Adjusted Odds Ratios (aORs) with 95% Confidence Intervals, controlling for all relevant baseline covariates. For time-to-event outcomes, such as symptom duration and hospitalization length, the existing Kaplan-Meier analyses must be augmented with Cox proportional hazards regression models to yield Adjusted Hazard Ratios (aHRs). The absence of multivariate statistical adjustment in the current draft invalidates the authors' causal assertions and constitutes a critical barrier to publication. Discussion Because the discussion is predicated upon flawed, univariate statistical results, the interpretation is inherently compromised. The authors explain their findings under the assumption of direct, unconfounded causality, which has not been statistically proven. Furthermore, the discussion fails to address the underlying pharmacological mechanisms of the specific 2:1 combination. While the authors discuss artemisinin and lignans in isolation, they do not synthesize the data to explain how these compounds may have interacted synergistically within the human subjects to produce the observed outcomes. A robust discussion must delve into the pharmacodynamic interactions of the combination therapy, comparing the magnitude of the observed effects against historical data for either compound used as monotherapy. Limitations The true limitations of this research, which must be explicitly stated, include the lack of documented allocation concealment, the ambiguous blinding status of the trial, and the absence of multivariate statistical control for baseline confounders. If the trial was conducted as an open-label study, the authors must acknowledge the high risk of placebo effects and investigator bias, particularly when evaluating highly subjective secondary endpoints such as "symptom resolution." The failure to recognize these structural biases indicates a concerning lack of critical self-appraisal. The limitations section must be entirely rewritten to transparently address these profound methodological constraints (if not corrected as requested previously). Conclusion The assertion that the 10-gram dose has "no apparent severe toxicity" is particularly unsupported. The safety profile was evaluated based solely on patient-reported, subjective adverse events (headaches and nausea). There is absolutely no mention of systemic biochemical monitoring. Administering massive oral doses of crude botanical extracts poses known risks of hepatotoxicity and nephrotoxicity; historical data regarding Artemisia annua extracts have prompted regulatory warnings concerning potential drug-induced liver injury. Asserting a lack of severe toxicity without continuous laboratory monitoring of hepatic (ALT, AST, bilirubin) and renal (BUN, creatinine) function is scientifically negligent. The conclusions must be carefully softened to reflect the data's preliminary, unadjusted nature, and the authors must emphasize that rigorous biochemical safety validation is a strict prerequisite for any future integration into standardized care protocols. Formal F1000Research Peer Review Questionnaire Is the work clearly and accurately presented, and does it cite the current literature? The authors must update their literature review comprehensively, integrating clinical trial data and molecular docking studies published between 2023 and 2026. Additionally, the authors must meticulously review the manuscript for textual overlap, ensuring that all theoretical mechanisms, rationales, and conclusions are synthesized and articulated with complete originality. Is the study design appropriate, and is the work technically sound? The authors must provide the clinical trial registration number. If the trial was not registered prospectively, retrospective registration must be completed immediately, and the authors must provide a formal, transparent justification for this ethical oversight within the manuscript. Additionally, the methodology section must be expanded to explicitly detail the randomization technique (e.g., block size, stratification factors), the allocation concealment method (e.g., SNOSE), and the specific blinding protocols implemented. Are sufficient details of methods and analysis provided to allow replication by others ? The authors must detail the exact clinical administration protocol, including the number of capsules per dose, the dosing frequency, and the excipients used. They must also explicitly define the standardized clinical criteria or scoring systems used to measure "recovery" and "symptom resolution." If applicable, is the statistical analysis and its interpretation appropriate ? The authors must generate and insert a comprehensive "Table 1" detailing the baseline characteristics of both trial arms. Crucially, the authors must perform multivariate statistical analyses. Multivariable logistic regression is required for all categorical outcomes (yielding adjusted Odds Ratios), and Cox proportional hazards models must be applied to all time-to-event outcomes (yielding adjusted Hazard Ratios). The interpretations in the Results and Discussion sections must be revised to reflect these adjusted statistics. Are all the source data underlying the results available to ensure full reproducibility ? The authors must strictly adhere to the open data policy. The raw clinical dataset must be rigorously de-identified in accordance with the Safe Harbor criteria. Following de-identification, the dataset must be uploaded to an approved, openly accessible data repository (e.g., Open Science Framework, Zenodo, or Figshare) under a CC0 or CC-BY license. The Data Availability Statement in the manuscript must be rewritten to include the repository name, a description of the dataset, and a unique persistent identifier (DOI) linking directly to the data. If the institutional ethics committee imposes highly specific, legally binding constraints that prevent even the sharing of de-identified data, the dataset must be placed in a controlled-access repository (e.g., Zendo), and the exact legal conditions for access must be thoroughly detailed in the manuscript . Are the conclusions drawn adequately supported by the results? The conclusions must be substantially modulated. The authors must reframe their findings as preliminary evidence requiring further validation and as heavily contingent upon the results of the newly requested multivariate analyses. The claims regarding the safety profile must be heavily qualified, explicitly acknowledging the lack of continuous biochemical monitoring as a major limitation, and stating that rigorous systemic toxicological evaluations are necessary before clinical implementation. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Wang C, Li Y, Zhuo L, Xu S, et al.: Structural pharmacology of Chinese medicine: technological breakthroughs in decoding multi-target synergy and precision mechanisms. Advanced Biotechnology . 2026; 4 (1). Publisher Full Text 2. Shaer, N. A., Mohamed, A. A., & Schnug, E. (2025). Potential of Artemisia annua Bioactives as Antiviral Agents Against SARS-CoV-2 and Other Health Complications. Pharmaceuticals, 18(12), 1904. Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical Pharmacy, Pharmacology, infection I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Fawzi HA. Peer Review Report For: Artemisinin and Lignans Extracts: Innovative Adjuncts to Standard COVID-19 Treatment Protocols. [version 1; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2026, 15 :394 ( https://doi.org/10.5256/f1000research.190975.r469808) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-394/v1#referee-response-469808 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. 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