Unraveling the Effects of Melissa officinalis L. on Cognition and Sleep Quality: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. It would be beneficial to incorporate more visual details into the mechanisms to enhance readability for the audience;
2. The current “Conclusions” section offers broad suggestions for future research; specific directions could be proposed by addressing existing limitations in the literature;
3. Inconsistencies exist in the dosage descriptions within the clinical research section; standardization is recommended.

Author Response

RESPONSE TO REVIEWERS' COMMENTS

 

Manuscript number: ijms-3897699 ― International Journal of Molecular Sciences

"Unraveling the Effects of Melissa Officinalis L. on Cognition and Sleep Quality: A Narrative Review"

 

The authors of this document wish to express their deepest gratitude to the Editor-in-Chief and the Reviewer for their thorough and insightful evaluation of our manuscript. Their expert feedback has been invaluable in enhancing the quality of our work. We have carefully considered and diligently implemented each suggestion, which has significantly improved the manuscript. We have made substantial revisions to address the points raised. These noteworthy changes are marked mainly with YELLOW-highlighted text throughout the document for ease of reference. A note will be provided for the referee's attention, highlighting corrections in a different color. Additionally, we have prepared a detailed and comprehensive response to each comment and suggestion. This response is organized in a "point-by-point" format below, ensuring that every concern has been thoroughly addressed and explained. We sincerely appreciate the time and effort invested by the Editor-in-Chief and the Reviewer, and we believe their contributions have significantly strengthened the final version of our manuscript.

 

REVIEWER #1

General response

Dear Erudite Reviewer, thank you for taking the time to revise our manuscript and allowing us to improve based on your valuable comments and suggestions. After addressing all your comments and suggestions regarding our manuscript text, we are confident that a significantly enhanced manuscript version has emerged. We are excited to resubmit the modified version for your perusal and reevaluation. Thank you for your brilliant insights, essential contributions, and feedback. You do have an eye for improvement. As a gesture of our utmost respect for you, we would like to provide you with a detailed and comprehensive point-by-point response to your comments below. Thank you once again for your time and patience in revising our article.

 

Comment #1

It would be beneficial to incorporate more visual details into the mechanisms to enhance readability for the audience.

Response

Dear Erudite Reviewer, thank you for this comment and for your eye to improvement. We agree that our manuscript should include an additional figure summarizing the mechanistic effects of Melissa against sleep and cognitive disorders. Therefore, we included Figure 3 on Page 16, which visually summarizes the plant's mechanisms of action and clearly states its main benefits based on the included clinical studies. The figure’s first citation can be found in Lines 521-523 on Page 15, and its legend in Lines 525-529 on Page 16. Thank you for your attention to detail and eye for improvement. We look forward to having your opinion on our new figure.

 

Comment #2

The current “Conclusions” section offers broad suggestions for future research; specific directions could be proposed by addressing existing limitations in the literature.

Response

Dear Erudite Reviewer, thank you for your critical assessment of our conclusions. We agree with you that we must clarify more the limitations of the included studies and how future trials must minimize them. Therefore, we included Lines 499-517 on Page 15 to improve our conclusions based on your critical comment. To summarize, the current literature has significant limitations, including a lack of long-term studies that raise safety and efficacy concerns. Diverse study designs and dosing regimens complicate optimal dose identification and result comparison. The combination of M. officinalis with other herbs, like valerian, further obscures its specific effects. To address these issues, larger, well-designed randomized clinical trials are needed for better generalizability and confirmation of efficacy. More extended intervention periods should also be evaluated to assess sustained effects and safety. Standardizing M. officinalis preparations and quantifying key compounds, such as rosmarinic acid, are essential for establishing dose-response relationships. Future research should incorporate objective methods like neuroimaging and polysomnography to assess outcomes.

            Thank you for your attention to detail and eye for improvement. We look forward to your positive response regarding the revised version of our manuscript.

 

Comment #3

Inconsistencies exist in the dosage descriptions within the clinical research section; standardization is recommended.

Response

Thank you for your valuable feedback regarding the inconsistencies in the dosage descriptions within the clinical research section. To address this concern, we have taken steps to standardize how dosages are presented across the tables, ensuring greater clarity and consistency. We have unified the terminology used for dosages by standardizing the units of measurement (e.g., mg, grams) and clarifying the form of the intervention (e.g., extract, dried leaf, essential oil) wherever applicable. In cases where multiple dosages were used within a study, we have ensured they are listed in a consistent format and have made clear the specific form of the intervention, such as "encapsulated dried leaf extract" or "M. officinalis extract." Regarding side effects, we have streamlined the reporting process by consistently marking "NR" for trials where side effects were not mentioned. Where adverse effects were noted, I have ensured they are described clearly and uniformly across the tables. Additionally, we have standardized the descriptions of trial designs and durations, ensuring that details like trial phases, treatment periods, and extension phases are presented consistently.

We believe these revisions adequately address the inconsistencies and improve the overall clarity of the dosage information. You can find the revised Tables on Pages 9-10 and 12-13 of the revised manuscript document. The description of each included study is disposed in Lines 320-391 on Pages 10-12 and Lines 404-476 on Pages 13-14 of the revised manuscript document. Thank you again for your insightful suggestions.

 

I, the corresponding author of the manuscript "Unraveling the Effects of Melissa Officinalis L. on Cognition and Sleep Quality: A Narrative Review" under the assigned ID ijms-3897699, on behalf of my coauthors, once again extend my heartfelt gratitude to the knowledgeable Editor-in-Chief and reviewers for their time and expertise in revising our manuscript. After we addressed their constructive and refined feedback and suggestions, a significantly improved version of the manuscript emerged. Undoubtedly, their insightful suggestions and feedback have significantly enhanced the quality of our manuscript. We respectfully are at the disposal of the Editor-in-Chief and the Reviewer to address any additional suggestions regarding our publication. Suppose you are satisfied with our newly refined and significantly improved version. In that case, we look forward to the acceptance of our article for publication in the prestigious International Journal of Molecular Sciences. Thank you once again for your time and expertise.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a narrative review of the effects of Melissa officinalis (lemon balm) on cognition and sleep quality, with a focus on clinical trials. The topic is timely and relevant given the increasing interest in plant-based interventions for neurodegenerative diseases and sleep disturbances. Although the manuscript is generally well-structured and provides a comprehensive overview of clinical evidence, several limitations should be addressed to strengthen the scientific rigor and overall impact. Therefore, major revision of the manuscript is necessary prior to publication.

Detailed comments:

1. The conclusions should be rewritten. Please provide more insight for the future study in this field without overstatement.
2. Please cite more recent publications and remove some redundant and/or peripheral publications.
3. Please use same terminology.
4. The review relies heavily on a limited set of clinical trials, many of which are small, single-center studies. A clearer acknowledgment of this limitation, including the potential for publication bias, is necessary.
5. This review might overstate the therapeutic potential of “Melissa officinalis” by concluding on 'improvement in cognition and sleep quality' despite mixed evidence. A more cautious conclusion is warranted.
6. The authors often summarize results without critical comparison. For example, trials reporting null results are mentioned but not sufficiently contrasted with positive trials.
7. Mechanistic explanations are presented, but the link between preclinical findings and clinical evidence is weak.

Author Response

RESPONSE TO REVIEWERS' COMMENTS

 

Manuscript number: ijms-3897699 ― International Journal of Molecular Sciences

"Unraveling the Effects of Melissa Officinalis L. on Cognition and Sleep Quality: A Narrative Review"

 

The authors of this document wish to express their deepest gratitude to the Editor-in-Chief and the Reviewer for their thorough and insightful evaluation of our manuscript. Their expert feedback has been invaluable in enhancing the quality of our work. We have carefully considered and diligently implemented each suggestion, which has significantly improved the manuscript. We have made substantial revisions to address the points raised. These noteworthy changes are marked mainly with YELLOW-highlighted text throughout the document for ease of reference. A note will be provided for the referee's attention, highlighting corrections in a different color. Additionally, we have prepared a detailed and comprehensive response to each comment and suggestion. This response is organized in a "point-by-point" format below, ensuring that every concern has been thoroughly addressed and explained. We sincerely appreciate the time and effort invested by the Editor-in-Chief and the Reviewer, and we believe their contributions have significantly strengthened the final version of our manuscript.

 

REVIEWER #2

General comment

This manuscript provides a narrative review of the effects of Melissa officinalis (lemon balm) on cognition and sleep quality, with a focus on clinical trials. The topic is timely and relevant given the increasing interest in plant-based interventions for neurodegenerative diseases and sleep disturbances. Although the manuscript is generally well-structured and provides a comprehensive overview of clinical evidence, several limitations should be addressed to strengthen the scientific rigor and overall impact. Therefore, major revision of the manuscript is necessary prior to publication.

General response

Dear Erudite Reviewer, thank you for taking the time to revise our manuscript and allowing us to improve based on your valuable comments and suggestions. After addressing all your comments and suggestions regarding our manuscript text, we are confident that a significantly enhanced manuscript version has emerged. We are excited to resubmit the modified version for your perusal and reevaluation. Thank you for your brilliant insights, essential contributions, and feedback. You do have an eye for improvement. As a gesture of our utmost respect for you, we would like to provide you with a detailed and comprehensive point-by-point response to your comments below. Thank you once again for your time and patience in revising our article.

 

Comment #1

The conclusions should be rewritten. Please provide more insight for the future study in this field without overstatement.

Response

Dear Erudite Reviewer, thank you for your critical assessment of our conclusions. We agree with you that we must clarify more the limitations of the included studies and how future trials must minimize them. Therefore, we included Lines 499-517 on Page 15 to improve our conclusions based on your critical comment.

To summarize, the current literature has significant limitations, including a lack of long-term studies that raise safety and efficacy concerns. Diverse study designs and dosing regimens complicate optimal dose identification and result comparison. The combination of M. officinalis with other herbs, like valerian, further obscures its specific effects. To address these issues, larger, well-designed randomized clinical trials are needed for better generalizability and confirmation of efficacy. More extended intervention periods should also be evaluated to assess sustained effects and safety.

Standardizing M. officinalis preparations and quantifying key compounds, such as rosmarinic acid, are essential for establishing dose-response relationships. Future research should incorporate objective methods like neuroimaging and polysomnography to assess outcomes.

We also included a new figure in our manuscript summarizing the mechanistic effects of Melissa against sleep and cognitive disorders. We included Figure 3 on Page 16, which visually summarizes the plant's mechanisms of action and clearly states its main benefits based on the included clinical studies. The figure’s first citation can be found in Lines 521-523 on Page 15, and its legend in Lines 525-529 on Page 16.

            Thank you for your attention to detail and eye for improvement. We look forward to your positive response regarding the revised version of our manuscript.

 

Comment #2

Please cite more recent publications and remove some redundant and/or peripheral publications.

Response

Dear Erudite Reviewer, thank you for this precious comment and brilliant insight. We agree that adding more recent references to our manuscript would undoubtedly enhance its clarity and readability, as well as its novelty, considering recent advancements in the field of study. Therefore, we included 20 new references from 2025, six from 2024, one from 2023, and one from 2022. We believe our manuscript has been substantially updated. In addition, we removed unnecessary references from our bibliography to avoid redundancy as per your precious input. Thank you for your attention to detail and eye for improvement. We are confident that our manuscript has been significantly enhanced based on your comments and suggestions.

            To facilitate your review, we have provided the complete list of added references below. You will find the places where these references have been added by searching YELLOW reference brackets within the manuscript.

References from 2025 (n = 20)

1. Zhao et al., J Anim Sci — 2025
2. Uçar-Ekin et al., Cir Cir — 2025
3. Thapa et al., Pharmacological Research - Natural Products — 2025
4. Spaggiari et al., Advances in Sample Preparation — 2025
5. Rigillo et al., Children (Basel) — 2025
6. Murray et al., Neuron — 2025
7. Mabotja et al., Industrial Crops and Products — 2025
8. Li et al., Pharmaceuticals (Basel) — 2025
9. He et al., Int J Food Microbiol — 2025
10. Hazarika & Krishnatreyya, Acta Parasitol — 2025
11. Hassler et al., Int J Audiol — 2025
12. Günther & Bednarczyk-Cwynar, Antioxidants (Basel) — 2025
13. Gan et al., Mater Today Bio — 2025
14. Figueiredo Godoy et al., Biomedicines — 2025
15. Fajardo et al., ACS Omega — 2025
16. Dinh-Hung et al., Biology (Basel) — 2025
17. de Lima et al., Metabolites — 2025
18. Barbalho et al., Pharmaceuticals (Basel) — 2025
19. Awlqadr et al., Food Sci Nutr — 2025
20. Al-Hunaiti et al., Nanoscale Adv — 2025

References from 2024 (n = 6)

21. Yuan et al., Sci Rep — 2024
22. Valotto Neto et al., Antioxidants (Basel) — 2024
23. Sharifzadeh et al., BMC Microbiol — 2024
24. Mathews et al., Nutrients — 2024
25. Lobach et al., Food Chem Toxicol — 2024
26. Gavarić et al., South African Journal of Botany — 2024

References from 2023 (n = 1)

27. Gutiérrez-Pacheco et al., Antibiotics (Basel) — 2023

References from 2022 (n = 1)

28. Zam et al., Front Biosci (Schol Ed) — 2022

 

Comment #3

Please use same terminology.

Response

Dear Erudite Reviewer, thank you very much for your helpful comment regarding the importance of using consistent terminology throughout the manuscript. I fully agree that maintaining uniform language is essential for ensuring clarity, readability, and coherence, particularly in a narrative review such as this. In response to your observation, I have conducted a comprehensive review of the manuscript and carefully revised sections where inconsistent or ambiguous terminology was previously used.

All adjustments related to terminology consistency have been made with attention to both scientific accuracy and linguistic clarity. These modifications can be easily identified in the revised version of the manuscript, where they have been highlighted in PURPLE for your convenience. I hope these changes adequately address your concern and contribute to the overall quality of the manuscript

 

Comment #4

The review relies heavily on a limited set of clinical trials, many of which are small, single-center studies. A clearer acknowledgment of this limitation, including the potential for publication bias, is necessary.

Response

We thank the Erudite Reviewer for this valuable comment. We have now expanded the discussion to more clearly acknowledge the limitations related to the small number of available clinical trials, their typically single-center design, and the possible impact of publication bias on the overall interpretation of findings. The text was added in Lines 307-316 on Page 9.

            Again, thank you for your attention to detail and eye for improvement. We are confident that our manuscript has been significantly improved after we resolved all the issues you raised.

 

Comment #5

This review might overstate the therapeutic potential of “Melissa officinalis” by concluding on 'improvement in cognition and sleep quality' despite mixed evidence. A more cautious conclusion is warranted.

Response

We appreciate the Erudite Reviewer’s insightful observation. We have revised the conclusion to adopt a more cautious tone, emphasizing that the current evidence is mixed and that further well-designed studies are needed to confirm the potential effects of Melissa officinalis L. on cognition and sleep quality. You can find the revised text in Lines 478-482 on Page 14 of the revised manuscript document. Thank you for everything!

 

Comment #6

The authors often summarize results without critical comparison. For example, trials reporting null results are mentioned but not sufficiently contrasted with positive trials.

Response

Dear Erudite Editor, thank you for this insightful comment and brilliant suggestion. This is a very pertinent reviewer comment, and we are happy to resolve this issue based on your recommendations. Taken together, the inconsistent results across cognitive and sleep trials highlight the importance of considering methodological factors such as extract standardization, dosage, duration, and participant characteristics when interpreting the efficacy of M. officinalis. These endeavors have been tentatively summarized in our revised manuscript version. The tendency for small, positive trials to outweigh null findings underscores the need for larger, rigorously designed studies that directly address these sources of heterogeneity, which have also been summarized in our revised manuscript. Regarding the comparisons between positive and null results, we included two pieces of text: one on the cognition section and another on the sleep section, comparing positive to null trials and ensuring the comparability between them is adequately addressed. These can be found in Lines 377-391 on Pages 11-12 and Lines 444-457 on Page 14. Thank you for your attention to detail. I am confident that you will approve the corrections we’ve made based on your guidelines.

 

Comment #7

Mechanistic explanations are presented, but the link between preclinical findings and clinical evidence is weak.

Response

We appreciate the reviewer’s insightful observation. We have revised the manuscript to more clearly articulate the connection between the preclinical mechanisms of Melissa officinalis (M. officinalis) and the clinical outcomes observed in trials. While our preclinical data highlight the anti-inflammatory and antioxidant pathways (e.g., downregulation of NF-κB, TNF-α, COX-2; upregulation of Nrf2 and HO-1), we recognize that the translation of these mechanisms into clinical improvements remains preliminary. Most available clinical trials are limited by small sample sizes, lack of objective biomarkers, and variability in dosing and extract standardization.

To strengthen this connection, we have now:

• Clarified that the mechanistic hypotheses derived from in vitro and in vivo models provide a rationale for the observed (albeit modest and inconsistent) clinical benefits.
• Added critical analysis of the mismatch between mechanistic promise and human evidence, emphasizing the need for biomarkers in future clinical trials to confirm the engagement of these pathways.
• Highlighted in the discussion that while preclinical studies support neuroprotective and anxiolytic potential, current clinical data — though encouraging — are not yet sufficient to confirm efficacy in cognition and sleep disorders.

These revisions are reflected in Lines 458-476 on Page 14 of the revised manuscript document. Thank you for your attention to detail and eye for improvement.

 

I, the corresponding author of the manuscript "Unraveling the Effects of Melissa Officinalis L. on Cognition and Sleep Quality: A Narrative Review" under the assigned ID ijms-3897699, on behalf of my coauthors, once again extend my heartfelt gratitude to the knowledgeable Editor-in-Chief and reviewers for their time and expertise in revising our manuscript. After we addressed their constructive and refined feedback and suggestions, a significantly improved version of the manuscript emerged. Undoubtedly, their insightful suggestions and feedback have significantly enhanced the quality of our manuscript. We respectfully are at the disposal of the Editor-in-Chief and the Reviewer to address any additional suggestions regarding our publication. Suppose you are satisfied with our newly refined and significantly improved version. In that case, we look forward to the acceptance of our article for publication in the prestigious International Journal of Molecular Sciences. Thank you once again for your time and expertise.