Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsI read with interested the paper titled "Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?".
This is a very interesting paper of a very specific adverse event. The paper is well written and I have only minor comments to add on it.
1. Table 1 will be improved if references were added to each drug.
2. The specific objectives are written in a very artificial way. Lines 116-124 should be rewritten and information should be presented in a clear and smooth way.
3. Table 2 could be improved. Time is not necessary and query and search details are almost the same, so keep only one of them. When multiple combanations were made just refer as #1 + #2 and no need to present the whole query again. This will make the table easier to read.
4. Figure 1 - if identification from other sources doenst provide any results, those part could be supressed.
Author Response
Reviewer 1
Comment: I read with interested the paper titled "Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?". This is a very interesting paper of a very specific adverse event. The paper is well written and I have only minor comments to add on it.
Response: Thank you very much for taking the time to read our manuscript. We greatly appreciate your positive feedback and are happy to address the thoughtful comments you raised to improve the manuscript.
Comment 1. Table 1 will be improved if references were added to each drug.
Response: Thank you for the suggestion. A column has been added to the right-hand side of Table 1, including example references for the drugs mentioned. The revised part is marked yellow in the revised version of the manuscript.
Comment 2. The specific objectives are written in a very artificial way. Lines 116-124 should be rewritten and information should be presented in a clear and smooth way.
Response: Thank you for your valuable feedback. We agree that the phrasing of the specific objectives could be improved for clarity and flow. We have carefully revised Lines 116–124 to present the objectives in a clearer and more natural style while maintaining their original meaning and scope. The revised text now reads as follows:
This review synthesizes current evidence on drug-induced yawning (DIY), with a particular focus on its neurobiological mechanisms, clinical implications, and potential as a biomarker. Specifically, we aim to:
- Compare yawning patterns under both physiological and pharmacological conditions, examining differences in frequency and timing.
- Explore the neurochemical mechanisms involved in yawning, with particular attention to the roles of serotonin, dopamine, and oxytocin.
- Investigate the relationship between DIY and clinical outcomes, including therapeutic efficacy and adverse effects.
- Discuss and propose standardized methods for assessing yawning in clinical and research settings.
The revised part is marked yellow in the revised version of the manuscript.
Comment 3. Table 2 could be improved. Time is not necessary and query and search details are almost the same, so keep only one of them. When multiple combanations were made just refer as #1 + #2 and no need to present the whole query again. This will make the table easier to read.
Response: Thank you for your constructive suggestion regarding Table 2. We agree that simplifying the table will improve its clarity and readability. In response, we have revised Table 2 as follows:
The "Time" column has been removed, as it was not essential to the purpose of the table. Redundant information between the "Query" and "Search details" columns has been eliminated, keeping only the relevant content. Where multiple combinations were used, we now refer to them using simplified notations (e.g., "#1 + #2") rather than repeating the full search strings. These revisions have made the table more concise and reader-friendly, while preserving all essential information. The revised table and its caption are marked yellow in the revised version of the manuscript.
Comment 4. Figure 1 - if identification from other sources doenst provide any results, those part could be supressed.
Response: Thank you for the observation. We have updated Figure 1 accordingly. Since no records were identified through other sources, that section has been removed to streamline the flow diagram and avoid unnecessary elements. We inserted new Figure 1 and its legend, marked in yellow in the revised manuscript.
*Please note that to accommodate all inquiries, we have rewritten the entire introduction and discussion sections.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsJournal: Future Pharmacology (ISSN 2673-9879)
Manuscript ID: futurepharmacol-3560341
Type: Review
Title: Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?
The neurological processes and clinical relevance of drug-induced yawning (DIY) are highlighted in this scoping review, along with the possibility that it could serve as a biomarker for adverse effects and drug responsiveness. The review emphasizes the function of serotonin, dopamine, oxytocin, and opioid systems in yawning regulation by combining data on neurotransmitter interactions, pharmaceutical effects, and yawning patterns. Its clinical use is hindered by methodological irregularities, a lack of standardized evaluation instruments, and poor cross-study comparability. To confirm that yawning is a valid diagnostic and therapeutic tool, future research should concentrate on mechanistic studies, standardized techniques, and inclusion into CNS medication trials.
Author need to address the following minor comments to enhance the mechanistic details of the manuscript.
1: Sufficiently elaborate on how DIY specifically serves as a validated biomarker for these parameters?
2: General yawning theories take up too much of the introduction, which hinders from the DIY focus. Remove this part and emphasize earlier how DIY affects drug effects.
3: What are the main neural circuits that control yawning, such as the dopaminergic, serotonergic, oxytocinergic, cholinergic, etc. systems?
4: How does yawning sustain neurochemical balance if it is a compensatory reaction to changes in neurotransmitters?
5: Improve Mechanistic Explanations: Provide further information on receptor-specific mechanisms and neurotransmitter interactions.
6: Explain Clinical Implications: Could you provide further proof to support the claims that yawning is a biomarker?
7: Enhance Methodological Understanding: Provide more suggestions for standardizing studies on yawning?
Author Response
Reviewer 2
Comment: The neurological processes and clinical relevance of drug-induced yawning (DIY) are highlighted in this scoping review, along with the possibility that it could serve as a biomarker for adverse effects and drug responsiveness. The review emphasizes the function of serotonin, dopamine, oxytocin, and opioid systems in yawning regulation by combining data on neurotransmitter interactions, pharmaceutical effects, and yawning patterns. Its clinical use is hindered by methodological irregularities, a lack of standardized evaluation instruments, and poor cross-study comparability. To confirm that yawning is a valid diagnostic and therapeutic tool, future research should concentrate on mechanistic studies, standardized techniques, and inclusion into CNS medication trials.
Response: Thank you for your thoughtful summary and recognition of the key points presented in our review. We appreciate your acknowledgment of the relevance of drug-induced yawning (DIY) as a potential biomarker, as well as your emphasis on the need for further mechanistic studies and standardized approaches. We fully agree that advancing methodological consistency and integrating yawning measures into CNS drug trials will be essential steps for enhancing its clinical utility. These aspects have now been further emphasized in the revised conclusion of the manuscript.
The revised conclusion reads as follow and it is marked in yellow in the revised version of the manuscript:
This scoping review elucidates the neurobiological mechanisms and clinical implications of DIY, reinforcing its potential as a biomarker for drug responsiveness and adverse effects. By synthesizing evidence on yawning patterns, neurotransmitter interactions, and pharmacological influences, the review provides a foundation for future research and clinical application. The findings support the notion that yawning may serve as a non-invasive, real-time indicator of neurochemical activity, particularly relevant in contexts such as opioid withdrawal and serotonergic modulation.
However, the current body of evidence is limited by notable methodological inconsistencies, including a lack of standardized yawning definitions, variable assessment tools, and poor cross-study comparability. In response to these gaps, we emphasize the urgent need for methodological harmonization through standardized protocols and validated evaluation instruments.
Future research should prioritize controlled clinical trials, mechanistic studies targeting underexplored systems such as oxytocinergic and adrenergic pathways, and the systematic inclusion of yawning assessments in CNS drug development trials. Strengthening the methodological rigor and translational integration of DIY could advance its role as a diagnostic and therapeutic biomarker, ultimately contributing to more personalized and effective approaches in neuropsychopharmacology.
Comment: Author need to address the following minor comments to enhance the mechanistic details of the manuscript.
Response: Thank you for this helpful suggestion. We appreciate your attention to the mechanistic aspects and have carefully addressed this point in the revised manuscript. Relevant details have been incorporated in response to the specific comments outlined below. Changes in the revised version of the manuscript are highlighted in yellow.
Comment 1: Sufficiently elaborate on how DIY specifically serves as a validated biomarker for these parameters?
Response: Thank you for this insightful comment. In the revised manuscript, we have added a new paragraph in the Discussion section titled “DIY as a Pharmacodynamic Biomarker: Mechanistic Considerations”, which elaborates on the neurochemical mechanisms underlying drug-induced yawning (DIY) and discusses how consistent, receptor-specific yawning responses support its use as a potential biomarker for drug responsiveness and adverse effects.
Comment 2: General yawning theories take up too much of the introduction, which hinders from the DIY focus. Remove this part and emphasize earlier how DIY affects drug effects.
Response: Thank you for this valuable suggestion. In the revised manuscript, we have restructured the Introduction to place greater emphasis on drug-induced yawning (DIY) earlier in the section. The paragraph discussing the pharmacological basis and clinical relevance of DIY has been moved up immediately after the opening, to better align the introduction with the focus of the review. The revised version of the introduction is marked in yellow.
Comment 3: What are the main neural circuits that control yawning, such as the dopaminergic, serotonergic, oxytocinergic, cholinergic, etc. systems?
Response: Thank you for this excellent comment. While the roles of individual neurotransmitter systems were introduced in the manuscript, we have now expanded the Discussion section to more clearly summarize the key neural circuits involved in yawning. A new paragraph highlights the major pathways, including dopaminergic, serotonergic, oxytocinergic, cholinergic, and opioid systems, along with their functional relevance in regulating yawning behavior and their pharmacological modulation in drug-induced yawning (DIY). This part is marked in yellow in the revised version of the discussion.
Comment 4: How does yawning sustain neurochemical balance if it is a compensatory reaction to changes in neurotransmitters?
Response: Thank you for this insightful question. We have addressed this point by adding a brief explanation in the Discussion section that highlights yawning as a potential compensatory behavioral response to acute neurochemical shifts. Specifically, we describe how yawning may act through feedback mechanisms, such as receptor desensitization, modulation of arousal pathways, or activation of hypothalamic nuclei that serve to restore homeostasis following neurotransmitter fluctuations. This part is marked in yellow in the revised version of the discussion.
Comment 5: Improve Mechanistic Explanations: Provide further information on receptor-specific mechanisms and neurotransmitter interactions.
Response: Thank you for this helpful suggestion. We have expanded the Discussion section to include more detailed explanations of receptor-specific mechanisms involved in drug-induced yawning (DIY). This includes the roles of serotonin (5-HT1A and 5-HT2C), dopamine (D2 and D3), oxytocin, cholinergic, and opioid receptors in mediating yawning responses. We also describe how these systems interact within hypothalamic circuits, particularly the paraventricular nucleus (PVN), to regulate yawning behavior. These additions clarify the pharmacodynamic basis of DIY and strengthen the mechanistic framework of the review. We have 5-HT1A / 5-HT2C: We mentioned their role in yawning induction via SSRIs and buspirone. D2 / D3: We have covered this via apomorphine, pramipexole, and dopaminergic triggering. μ-opioid: Highlighted in terms of yawning suppression and withdrawal yawning. PVN involvement: We have explained this as the integrative hypothalamic hub. Interactions: The added neural circuit and compensatory mechanism paragraphs already enhance this as well. All changes and additions are marked in yellow.
Comment 6: Explain Clinical Implications: Could you provide further proof to support the claims that yawning is a biomarker?
Response: Thank you for this important comment. We have clarified and strengthened the discussion of yawning as a biomarker by incorporating examples from both experimental and clinical studies. Specifically, we now highlight that yawning frequency changes predictably in response to serotonergic and dopaminergic drugs, and that excessive yawning is a documented marker of opioid withdrawal. These consistent, reproducible patterns across drug classes and patient populations support the utility of drug-induced yawning (DIY) as a behavioral biomarker for neurochemical activity, therapeutic responsiveness, and adverse effects.
Comment 7: Enhance Methodological Understanding: Provide more suggestions for standardizing studies on yawning?
Response: Thank you for this valuable suggestion. In response, we have expanded the discussion to include specific recommendations for improving methodological consistency in yawning research. These include establishing clear operational definitions of yawning, using validated behavioral scoring protocols, reporting contextual variables (e.g., time of day, posture, environment), and incorporating objective measures such as electromyography or video-based detection. We believe these additions will help guide future research and enhance reproducibility across clinical and experimental studies. These points are marked in yellow.
*Please note that to accommodate all inquiries, we have rewritten the entire introduction and discussion sections.
Author Response File: Author Response.docx
