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PONE-D-19-35565

Drug trends and harm related to new psychoactive substances (NPS) in Sweden from 2010 to 2016: Experiences from the STRIDA project

PLOS ONE

Dear Dr. Helander,

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.

Both reviewers found this paper of interest and were consistent in their views on the gaps that need to be addressed in this manuscript. Accordingly, we now invite you to provide point-by-point responses to all comments raised below. 

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PLOS ONE

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No additional comments.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Because of the current NPS epidemic afflicting the US and Europe—with the rapid and steady increase in illicitly-manufactured synthetic drugs, including cathinones, cannabinoids, and synthetic opioids—there is an urgent need for real or near-real time data system that tracks and monitors key indicators associated with drug-involved morbidity and mortality. Such a system would need to incorporate both state and federal government and private institutions so illegal drugs can be track and monitored as they emerge as an illicit product and make their way into illicit supply chains. This manuscript describes a country-wide attempt to do just that: the STRIDA project. Accordingly, the important part of this study, the main and most notable finding, and which is buried as the lead, is the strategy for incorporating government and non-governmental institutions into a communication web that allows for the identification of NPS in a time frame that is conducive for public health response and available as information to people working with drug users and their communities, such as ED docs or medical doctors in the ICU. Yet, as it currently stands, this descriptive information is relatively buried and hidden in the text and the findings isolated by the authors are associated with the identification of drugs using EMODC and PIC to make sense of the toxicological information provided by EDs and ICUs.

All that said, I have numerous comments and suggestions for making the manuscript more centered around STRIDA as a surveillance system that collects information on drugs and associated harms and then takes that information as actionable intelligence that can then be distributed through a centralized repository based on algorithms. I am also supportive of publishing this manuscript without stressing what I think is needed as described above. It’s just that doing so would not contribute all that much to the existing literature on NPS. The U.S. is currently trying to figure out how to get drug-specific information in (near)real time and working to speed up the time frame from when a new drug is discovered at an overdose scene, or seized during an arrest, or collected from people who use drugs by needle exchange. Reconfiguring the paper by stressing the ins and outs of the system (and the findings on drug types and demographics, of course) would make it a manuscript of great interest to public health systems in countries struggling with increasing supply and consumption of NPS, many of which are newly manufactured and making their way into country’s illicit supply chains.

1. The actionable surveillance ‘system’ that I am pointing to could be better described so readers from other countries could understand how STRIDA employed specific tactics for resource sharing and communication between participating institutions of medicine (medical staff), toxicology (Karolinsa/PIC) hospital systems (ED/ICU), poison centers (PIC), and cooperation of international and national organizations (EU EWS/EMD federal drug monitoring programs (STRIDA).

2. The surveillance system described therein is not collecting information and distributing it in what is referred to as real time. I believe the authors report that the timeline for the totality of the process—from the time a drug is collected to when it is identified via toxicology, its pharmacology described, and this information reported back to the parties who initially offered the sample—can take upwards of 8-10 months. So yes, in the context of the existing surveillance systems we have and use in the U.S., and that exist in Europe, may be considered closer to real time since most of the existing systems (NFLIS, NNDSS, SUDORS, TEDS, etc.) can take up to 2 years and sometimes longer to get data. Thus, I have a problem with the authors claiming that STRIDA represents an early warning system that can acquire, analyze, and disseminate information in real-time to be inaccurate. This is a large concern of mine since we’re in need of actionable intelligence related to drug information and associated health effects that can be generated and distributed timelier than 8-10 months. The Conclusion on page 3 describes the system this way and needs to be changed, or at the very least, STRIDA needs to be described in the context of other surveillance systems currently in use to demonstrate that 6-8 months is considered real time that can lead to an early warning.

3. The main research question or questions are unknown. There is no concrete reason for why the study was done. This ambiguity likely contributes to my concerns in #2 because there is nothing to compare the STRIDA system to. It is because most NPS are undetectable on traditional drug screening methods, or is it because of that, of course, but more important is the quality of intelligence gathering on NPS is relatively slow and clunky and the information loops that allow the medical system to acquire information on drugs that may be to blame for medical issues are non-existent or take too long to serve as actionable information. In other words, what is the capacity (sensitivity and specificity) of Sweden’s current drug surveillance systems, how long does it take to identify NPS and associated sequalae, how long does it take for the medical system to get this information, and what mechanisms is information distributed and to whom? These are some of the background information that would make for a productive introduction/lit review, since it would situate what is to demonstrate what could be by highlighting actually existing capacity and the limitation associated with these current systems. The last bullet point is the lead. The study, in my opinion, would be better suited as a description about the process and information algorithms that link the ED/ICU to the PIC and other toxicological generating information so that EDs and ICUs can submit samples with and chief complaints or acquire information on the latest NPS they are seeing in their particular jurisdiction/hospital.

4. We need a system that can do this in a month if we are planning to act on the information. As this study demonstrates, NPS making their way into Sweden’s illicit supply chains occur rapidly and their effects compound even quicker, so it is important that we do not trick ourselves into thinking that a system that takes more than 6 months to generate information useful to EDs and ICUs is a real-time, early warning system. Even SUDORS, CDC’s surveillance system takes several months for the process to complete. They call their timeframe NEAR-REAL TIME, which is perhaps a way to describe STRIDA.

5. How do laboratories fit into the system? On page 8, the authors tell us that the lab was also informed, but they do not say what for.

6. What is the eligible criteria for suspecting NPS are involved in a specific health outcome? The authors tell us on p.8 that much is based on self-report? Was there a form or a universal/standardized way for collecting this information?

7. Why was quantitative analysis only performed on a few product as reference materials (p.9)? Was there no concern for percentages of drugs in samples nor any interest in potency of the product found at a scene, for example? Since labs are used, it would seem useful to have quant findings for a variety of study needs for answering questions related to the correlation between drug and health outcome, much of which is contingent on potency and the percentage of other substance in the sample.

8. Polysubstance use is identified as occurring by urine (and blood?) toxicological analysis but urine only tells you what the decedent or patient ingested but not intent. Put differently, if sellers put myriad psychoactive drugs in a product being sold, could it be that people may be ingesting drugs that they are not taken intentionally? This was the type of situation in the US where fentanyl was being inserted into heroin but unbeknownst to consumers, many of whom did not even want it in their heroin. This is why the testing of drugs found at the scene of an overdose is critical for understanding intent of drugs ingested. Would the authors recommend a different strategy given the limitations associated with urine tox analysis?

Reviewer #2: This paper provide 6 years worth of data about the use of novel psychoactive substances in Sweden, collected through the STRIDA project. The information is based on patients who attend emergency departments and hospitals, where biological samples are analysed for the presences of psychoactive drugs. In some cases drug materials themselves are provided for chemical analysis, too. These data are used to show trends in NPS use over time in relation to when individual NPS were scheduled in Sweden.

Comment on criteria for PLOS ONE:

The study presents primary scientific research which has not been reported elsewhere (although the group have published many papers on individual drugs that have emerged through the project - this paper is the first 2010-2016 omnibus paper from what I can tell). Statistical analyses are descriptive (no inferential statistics are utilised). The data are presented as summary figures and tables and these accord with the claims made in the text and discussion. While described in sufficient detail, the figures need to be in higher resolution to fully assess. The article is intelligible albeit there are some issues with expression (see below). The research has ethics approvals which are satisfactory. Data availability statement is satisfactory.

Comments on the manuscript:

1. The figures are grainy - both in pdf form and in the original form (unless I'm having technical issues). So I found them difficult to properly assess. I recommend they be provided in higher resolution.

2. Demographic data of the STRIDA patients: The last paragraph in this section describes a newborn patient who tested positive, but this case was not included in the range of ages reported in the paragraph before, indicating that the age range was incomplete. The paper should be revised to ensure consistency between this information - either that case is ruled out, or included, and if included, the age range should include this case.

3. In the results: "In the following years, additional less common drugs detected were 2,5-dimethoxy-4-bromoamphetamine (DOB), hydrocodone, hydromorphone, and the tree alkaloid yohimbine in 2012, ketamine and oxycodone in 2013, and bromazepam, dihydrocodeine, meprobamate and pyrovalerone in 2014 (Fig. 3)." Ketamine is not considered a novel substance in Australia, UK, etc. although I am aware that ketamine is still on NPS lists in other places. Is it actually an uncommon or less common substance in Sweden? Perhaps it is worth some explanation for those reading this paper from parts of the world where ketamine is a common recreational substance, in the discussion?

4. In the discussion "More proactive (generic) drug classification systems are in place in several other countries." Please include some citations to articles describing these generic drug classification systems, e.g. van Amsterdam, J., Nutt, D., & van den Brink, W. (2013). Generic legislation of new psychoactive drugs. Journal of Psychopharmacology, 27, 317-324. , and/or Barratt, M. J., Seear, K., & Lancaster, K. (2017). A critical examination of the definition of ‘psychoactive effect’ in Australian drug legislation. International Journal of Drug Policy, 40, 16-25.

5. In the discussion "The median time from first detection of a novel drug in the STRIDA project to classification was ~1.0 year (mean 1.6 years; range 2 months to ~8 years)" - I can't locate this data report in the results section. It would be clearer to have a subsection in the results where the relationship between first detection and classification is described. Related to this, it may be useful for the reader to see more comprehensive aims stated immediately prior to the materials/methods section. This paper not only summarises the results but also charts the emergence of various NPS alongside local legislative actions. Readers interested in drug policy could be alerted to this content earlier, e.g. in the aims.

6. The authors note that this paper was not funded. But it is clear that the STRIDA project itself was awarded funding. Should the source of this funding not be mentioned, as without it, the manuscript would not be possible?

7. There are examples of expression in the manuscript that could be refined. E.g in the abstract 'hundreds of chemically designed new psychoactive substances'. Designed by whom? I'm not entirely sure what 'chemically designed' means. If it means that these NPS are all specifically designed as 'unclassified alternatives to illicit drugs', that may be true for some, but not all - some of these are failed medicines, for example. A further example in the introduction is "Designer drugs aimed at circumventing current drug legislation have occurred since the 1960s". I'm not sure designed drugs have 'occurred' since the 1960s - perhaps they have emerged? Or been designed? A further example: "novel recreational drugs, which are often named through anonymous combinations of letters and numbers". I don't think the authors mean 'anonymous' here?

8. Overall, the abstract is well written and well evidenced. It would improve the abstract if the final sentence 'The accomplishment of the STRIDA project can be attributed to several key factors that can serve as a model for future studies' also listed the 'key factors' other studies could learn from (hopefully just an additional few words).

9. There are some typographical errors in the manuscript, including but not limited to 'trough' in abstract should be 'through'. Please check the manuscript for spelling and grammar errors.

10. In the summary of value of the paper, the authors write "The project served as an effective Early Warning System for harmful NPS, by collecting data on the incidence and distribution, identification of adverse effects, and treatment of analytically confirmed acute intoxications." For the STRIDA project to serve as an effective EWS, it needs to not only collect this information, but also distribute it quickly enough to be useful for a network of stakeholders. Can this sentence be edited to reflect that STRIDA not only collected the information but also distributed it and thereby contributed to an EWS? (note, also applies to the same sentence in the conclusion)

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Reviewer #1: Yes: Jon E. Zibbell

Reviewer #2: Yes: Monica Barratt

[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 to be viewed.]

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PONE-D-19-35565R1

Drug trends and harm related to new psychoactive substances (NPS) in Sweden from 2010 to 2016: Experiences from the STRIDA project

PLOS ONE

Dear Dr. Helander,

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.

==============================

The reviewers both agree that the authors have addressed almost all their comments satisfactorily, there is a minor outstanding comment from Reviewer 2 that remains to be addressed before we can proceed.

==============================

We would appreciate receiving your revised manuscript by May 15 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Michelle Tye, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors have addressed my comments to my satisfaction in all but one point, which I comment on below:

Regarding my point 5, "5. In the discussion "The median time from first detection of a novel drug in the STRIDA project to classification was ~1.0 year (mean 1.6 years; range 2 months to ~8 years)" - I can't locate this data report in the results section. It would be clearer to have a subsection in the results where the relationship between first detection and classification is described. Related to this, it may be useful for the reader to see more comprehensive aims stated immediately prior to the materials/methods section. This paper not only summarises the results but also charts the emergence of various NPS alongside local legislative actions. Readers interested in drug policy could be alerted to this content earlier, e.g. in the aims."

Author response: The STRIDA project focused mainly on analytical and acute toxicological issues. After authorities are informed about the presence of a new substance in Sweden, the classification process is handled by the Public Health Agency or, sometimes, the Medical Products Agency. Because the STRIDA project had no impact on this part of the process, we do not consider it to be results of the project and therefore presented these data in the Discussion.

My response: If this is not considered core findings of the study, then the authors should also amend the abstract, because they include the statement in the methods and findings section regarding classification taking a year or longer, and that drugs typically disappeared upon classification. So it is inconsistent to say it is not part of the results of the study, while listing it in the findings section of the abstract. Indeed I think it is one of the most interesting findings of the paper - and therefore it would work best to include the time until classification as a variable in the methods, noting from what data the measure was derived. Then list it as a finding and discuss it as a result and in the discussion. The paper makes a big deal out of it through Figures 3a and 3b, through the colour change green to red, so I think this information is indeed part of the results/findings of the study, even if STRIDA was responsible for the decision to classify. Indeed the final sentence of the abstract "results also illustrated how drug regulations can drive the NPS market" relies in the classification time as part of the results of the paper. So I don't think it makes a lot of sense to relegate this aspect of the paper to a dot point in the discussion.

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7. PLOS authors have the option to publish the peer review history of their article (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: Yes: Jon E. Zibbell

Reviewer #2: Yes: Monica J. Barratt

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Drug trends and harm related to new psychoactive substances (NPS) in Sweden from 2010 to 2016: Experiences from the STRIDA project

PONE-D-19-35565R2

Dear Dr. Helander,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Michelle Tye, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: