Long-term neurological consequences following benzodiazepine exposure: A scoping review

Kyla N. Shade; Alexis D. Ritvo; Bernard Silvernail; A. J. Reid Finlayson; Jolene E. Bressi; D. E. Foster; Ian J. Martin; Christi Piper; Peter R. Martin

doi:10.1371/journal.pone.0330277

Peer Review History

Original SubmissionFebruary 6, 2025
5 Jun 2025 Decision Letter - Hira Rafi, Editor Dear Dr. Ritvo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 20 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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Thank you for stating the following in the Competing Interests section: [Alexis Ritvo is contracted as the medical director for the national non-profit the Alliance for Benzodiazepine Best Practices (501(c)(3)). Bernie Silvernail is the CEO of the Alliance for Benzodiazepine Best Practices.]. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 3. We note that your Data Availability Statement is currently as follows: [All relevant data are within the manuscript and its Supporting Information files.] Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition). For example, authors should submit the following data: - The values behind the means, standard deviations and other measures reported; - The values used to build graphs; - The points extracted from images for analysis. Authors do not need to submit their entire data set if only a portion of the data was used in the reported study. If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: By Kyla N. Shade, Alexis D. Ritvo, Bernard Silvernail, A. J. Reid Finlayson, Jolene E. Bressi,　D.E. Foster, Ian J. Martin, Christi Piper, and Peter R. Martin reported a research article entitled, “Long-Term Neurological Consequences Following Benzodiazepine Exposure: A Scoping Review” to PLOS ONE. The authors should clarify the rationale for defining a two- to four-week period as the threshold for benzodiazepine exposure risk. As various benzodiazepines were included, and the reviewed studies do not consistently examine the same agents, the authors are encouraged to discuss both the differences and any potential uniformities across these drugs. Furthermore, the duration of use, the ratio of duration to discontinuation, and the timing of discontinuation should be more clearly addressed in relation to the development of withdrawal symptoms. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0330277.r001
Revision 1
28 Jul 2025 Author Response Dear Editors: Thank you for the peer review comments which we have addressed below. This Response to Reviewers document contains all three responses to reviewers. Please also see the Response to Reviewers letter where these responses are delineated in a table. 1 Is the manuscript technically sound, and do the data support the conclusions? Comments: Partly Response: This is a scoping review and meets the standards for such. Without more specifics, it is difficult for us to address this. 2 Has the statistical analysis been performed appropriately and rigorously? Comments: Agreed Response: None 3 Have the authors made all data underlying the findings in their manuscript fully available? Comments: No Response: This comment confuses us. We have supplied a detailed search strategy (databases, flowchart, keyword lists) and inclusion/exclusion criteria. We feel that our research could be duplicated by any who followed the methodology we disclosed. We do not know what other underlying data are required 4. Is the manuscript presented in an intelligible fashion and written in standard English? Comment: Yes Response: Thank you 5A. Reviewer comments invited: The authors should clarify the rationale for defining a two- to four-week period as the threshold for benzodiazepine exposure risk. Response: We established the study criteria as patients ≥18 years who had taken BZD chronically, long terms, or consistently over a period of > 2 wk and who had discontinued them for >4 weeks. This is in line with the published literature and the literature review recently conducted for the ASAM BZD tapering guidelines. This guidance states that physical dependence may occur in as little as 2 wk and symptoms of protracted withdrawal may emerge as early as 4 wk post-discontinuation. We originally cited the FDA boxed warning for this (original reference #84). We substituted the ASAM guidelines (Brunner 2025), which makes the statements noted in the column to the left and also references the FDA boxed warning. We identified 8 additional references used to support this statement, and have included only the 5 with the highest quality evidence. If more references are desired, we will gladly add the other three: Maine BZD study group 2008, Pottie 2018, and Hood 2014. 5B. As various benzodiazepines were included, and the reviewed studies do not consistently examine the same agents, the authors are encouraged to discuss both the differences and any potential uniformities across these drugs. Response: This was a scoping review looking for evidence of protracted withdrawal within a class of medications. This is a common approach in this sort of research. A good example of this approach is NIH Project Number5R01AG060975 which treats benzodiazepines as a class. Since this is the first such study of its kind, the authors felt that it was wise to approach it in broad strokes. Fine-tuning it to specific agents exceeds our original goals. This would be a worthwhile topic for future research or a secondary analysis. However, as we started the project, it was unclear what, if anything, we would find. 5C. Furthermore, the duration of use, the ratio of duration to discontinuation, and the timing of discontinuation should be more clearly addressed in relation to the development of withdrawal symptoms. Response: The withdrawal symptoms in our study are not described by the studies in any in-depth way given the broad nature of studies accepted by our scoping review. We reported mainly on signals. The data as to duration of use, etc. to which we could reliably anchor these findings is spotty and inconsistent between the studies. None of the studies were looking for withdrawal symptoms but mentioned them as incidental findings. The interest in associating duration of use, etc. to our findings might introduce what could be potential bias to our scoping review. Our purpose was to look for the presence of withdrawal symptoms and not adjudicate their causes. By only looking for specific things (e.g., withdrawal related to duration of use), we defeat the purpose of the scoping review, which was just to look for evidence for withdrawal symptoms after benzodiazepine discontinuation. 6. PLOS authors have the option to publish the peer review history of their article. If published, this will include your full peer review and any attached files. Response: None In conclusion, we appreciate the comments offered to us, in particular suggestions that would be very worthwhile subjects for secondary analysis or future endeavors. Our scoping review is a first step in these efforts, and we hope not the last in our investigation into this subject. We acknowledge the previously noted competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Note that the "Combined Response to Reviewers" document filed under the Response to Reviewers category also contains our response to the PLoS One request for information to ensure the replicability of the study, which was emailed to Alexis Ritvo by Johnelle Ryan Razo on 6/22/2025. Attachments Attachment Submitted filename: Combined response to reviewers.docx https://doi.org/10.1371/journal.pone.0330277.r002
30 Jul 2025 Decision Letter - Hira Rafi, Editor Long-term neurological consequences following benzodiazepine exposure: A scoping review. PONE-D-25-04510R1 Dear Dr. Ritvo, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Hira Rafi Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0330277.r003
Formally Accepted
Acceptance Letter - Hira Rafi, Editor PONE-D-25-04510R1 PLOS ONE Dear Dr. Ritvo, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Hira Rafi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0330277.r004

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