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

Anders Helander; Matilda Bäckberg; Olof Beck

doi:10.1371/journal.pone.0232038

. 2020 Apr 23;15(4):e0232038. doi: 10.1371/journal.pone.0232038

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

Anders Helander ^1,^2,^*, Matilda Bäckberg ³, Olof Beck ^1,^2,⁴

Editor: Michelle Tye⁵

PMCID: PMC7179898 PMID: 32324788

Abstract

Background

In the past decade, hundreds of new psychoactive substances (NPS) have been introduced as unclassified alternatives to the illicit drugs. The NPS represent a growing health concern by causing adverse effects and deaths but are usually undetectable by conventional drug tests. This report summarizes results and experiences from analytically confirmed drug-related acute intoxications in emergency departments (ED) and intensive care units (ICU) enrolled in the Swedish STRIDA project on NPS in 2010–2016.

Methods and findings

ED/ICU intoxications suspected to involve NPS were enrolled in the project, after initial contact with the Poisons Information Centre (PIC). Serum/plasma and urine samples, and sometimes drug products, were subjected to a comprehensive toxicological investigation, and the PIC retrieved information on associated clinical symptoms and treatment. Between January 2010-February 2016, 2626 cases were enrolled. The patients were aged 8–71 (mean 27, median 24) years and 74% were men. Most biological samples (81%) tested positive for one, or more (70%), psychoactive drugs, including 159 NPS, other novel or uncommon substances, classical recreational and illicit drugs, and prescription medications. When first detected, most NPS or other novel substances (75%) were not banned in Sweden, but they usually disappeared upon classification, which however often took a year or longer. Some NPS were found to be especially harmful and even fatal.

Conclusions

The STRIDA project provided a good overview of the current drug situation in Sweden and demonstrated a widespread use and rapid turnover of many different psychoactive substances. The accomplishment of the project can be attributed to several key factors (close collaboration between the PIC and laboratory to identify suspected poisonings, free analysis, continuous updating of analytical methods, evaluation of adverse effects, and sharing information) that are useful for future activities addressing the NPS problem. The results also illustrated how drug regulations can drive the NPS market.

Introduction

New psychoactive substances (NPS) that are not covered by current drug legislation (previously commonly called “designer drugs”) have emerged since the 1960s. In the mid-2000s, herbal smoking mixtures sold under the brand name Spice and producing cannabis-like effects, although not containing Δ-9-tetrahydrocannabinol (THC), became available. After discussions on Internet drug chat forums in 2006 regarding which herbal ingredients were accountable for the psychoactive effects, it was demonstrated in 2008 that the products had in fact been laced with synthetic cannabinoid receptor agonists (SCRA) originally developed as therapeutic drug candidates and pharmacological tools to probe the endocannabinoid system [1–3]. The SCRA additives were banned in some countries but then soon replaced by other, uncontrolled structural variants [4].

This turned out to be a starting point for the ongoing global NPS era, whereby novel substances often bearing only small structural differences are continuously introduced through open trading on the surface web (hence also called “Internet drugs”) to replace those becoming controlled [5]. As a result, there has been a dramatic increase in the supply and availability of drugs intended for recreational use in the past decade [6]. The NPS initially comprised mainly SCRA and stimulants (e.g. cathinones), but later also hallucinogenic, sedative, analgesic and dissociative drugs appeared. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is currently monitoring more than 700 NPS that have been notified since 1997 to the European Union (EU) Early Warning System (EWS) operated by the EMCDDA and Europol [6].

The NPS represent a growing health concern, because there is usually no or only limited information available regarding their pharmacological and toxicological dose-response effects, thereby increasing the risk for adverse events and death. Indeed, emergency departments (ED) and intensive care units (ICU) are experiencing many severe poisonings involving NPS [7–9]. For example, analogues of fentanyl have required immediate medical support but also caused many fatalities due to the potentially life-threatening symptoms of opioid overdose [10–12], but unexpected acute and late toxic effects have also been reported for several other novel substances [13–15]. Furthermore, there are analytical problems to confirm NPS exposure, because the new substances are often undetectable by conventional toxicology tests, or may generate false-positive screening results for classical illicit drugs due to close structural similarities [16–18].

In Sweden, a nationwide project called STRIDA was started in 2010, to monitor the occurrence and health hazards of NPS appearing in the country, through evaluation of analytically confirmed serious adverse events among patients requiring emergency hospital care [7, 8]. The aim of this report was to summarize, evaluate and disseminate the results of the ~6-years STRIDA project on NPS, and consider how the generated experiences could be useful in future activities addressing the NPS problem.

Materials and methods

Selection of clinical cases and data acquisition

The STRIDA project (the name is an acronym of the Swedish project name, but the word also means “to fight”) was run in 2010–2016 as a collaboration between the Karolinska Institutet, the Karolinska University Laboratory, and the Swedish Poisons Information Centre (PIC) in Stockholm. The PIC is a nationwide 24/7 telephone consultation service concerning acute intoxications operated by pharmacists and medical doctors and is open for health care professionals and the public. All ED and ICU in the country were informed about the project by letter and whenever the PIC was consulted regarding suspected NPS- or unknown drug-related overdose cases. The ED/ICU also received a project laboratory request form that allowed free-of-charge comprehensive toxicological analysis in included cases.

During the planning of the STRIDA project, the PIC organized an internal NPS working group, as the number of consultations related to NPS or unknown drugs had shown a marked increase since 2007 while remaining constant for the classical illicit drugs [14]. Once a new drug was indicated to the project from PIC telephone inquiries, or notified from other sources of information (the project team had continuous communication and information sharing about the NPS situation with the Public Health Agency of Sweden, the Swedish National Forensic Centre, the National Board of Forensic Medicine, the Customs laboratory, the Medical Products Agency, as well as with the EMCDDA/EU EWS), the PIC documentation and treatment guidelines were updated and brief reports on case progress and recovery generated, which meant providing up-to-date toxicological information on new drugs. The Karolinska University Laboratory, who performed the toxicological analyses, was also informed, to allow for updating of analytical methods.

Patients admitted to ED/ICU after exposure to NPS or related products, or where poisoning by such substances was suspected after clinical investigation, met the inclusion criteria for participation in the STRIDA project. Participation required that the medical staff contacted the PIC to obtain a case code number to ensure patient anonymity and submitted biological samples for drug testing and a related laboratory request form containing clinical and treatment information and any other information relevant to the case. During the PIC consultation, case notes on the age, gender, symptoms, and treatment were recorded, and patient self-reports on the substance and/or branded name used, the dose, time of intake, and route of administration were collected, when available.

Urine and serum/plasma samples should be collected as soon as possible after arrival in the ED/ICU, according to standard routines for drug testing, and forwarded to the Karolinska University Laboratory, Department of Clinical Pharmacology in Huddinge, Stockholm. In the laboratory, an aliquot of the urine sample was immediately taken for analysis, as detailed below. The remaining urine volume and the serum/plasma samples were stored frozen until further used.

The clinical and treatment information from the ED/ICU and in de-identified hospital medical records shared with the PIC were paired with the analytical results through the code number. The severity of intoxication was graded retrospectively using the Poisoning Severity Score (PSS) [19], the level of consciousness according to the Reaction Level Scale (RLS) or Glasgow Coma Scale (GCS) [20], and based on the extent of treatment and length of hospital stay. Information on the time for classification of each substance as a narcotic or harmful substance was also collected.

The STRIDA project was conducted in accordance with the Helsinki Declaration and approved by the regional ethics review board (Regionala etikprövningsnämnden) in Stockholm (Nr. 2013/116–31/2).

NPS drug materials

Drug materials collected by the ambulance personnel or brought to hospital by the patient or accompanying persons were sometimes forwarded to the laboratory, along with the biological samples. The possibility to send drug materials was indicated on the laboratory request form. The materials were classified as powder, crystal, tablet, capsule, blotter, herbal material, liquid, or other, and stored frozen until subjected for analysis.

In addition, drug products with a claimed content of novel, uncontrolled NPS were sometimes purchased from online vendors, to be utilized as reference material. Following analytical confirmation of the content (see below), the materials were stored frozen.

Laboratory analysis of biological samples

The biological samples received in the STRIDA project were subjected to a comprehensive toxicological investigation, involving routine immunochemical assays targeting the classical illicit drugs, and multi-component liquid chromatographic–tandem mass spectrometric (LC–MS/MS) and LC–high-resolution single and tandem MS (LC–HRMS(/MS)) screening and confirmation methods targeting NPS, classical drugs, plant- and mushroom-derived substances, and prescription pharmaceuticals, as detailed elsewhere [8, 21–23]. The number of substances covered increased over time, as the LC–HRMS methods were continuously updated when new drugs appeared, and reference materials became available. To demonstrate the presence of newly appearing substances, retrospective evaluation of LC–HRMS data, or reanalysis of biological samples, was sometimes necessary. The lower quantification limit of the MS methods ranged from < 0.5 ng/mL for fentanyls and upwards.

When the analytical investigation of a biological sample was completed, the test result was reported to the ordering clinic.

Laboratory analysis of drug materials

The analysis of drug materials forwarded to the laboratory along with the biological samples, and of online purchased NPS products, was carried out using LC–HRMS/MS at the Karolinska University Laboratory, or by LC–quadrupole-time-of-flight–MS/MS and nuclear magnetic resonance spectroscopy at the Swedish Medical Products Agency in Uppsala [24, 25]. The investigation provided information on psychoactive substance identity but not on inactive components (e.g., binders in tablets and diluents or fillers in liquids, powders, and capsules), bacteria, viruses, minerals, or metals. Quantitative analysis was only performed for a few products intended for use as preliminary reference materials, until a certified material was available.

Results

The STRIDA cases

The recruitment of acute intoxication cases to the STRIDA project (i.e., demographic and clinical data as well as biological samples were obtained) started in January 2010. After only two cases were received in January–February, the number increased to range 5–12 cases per month resulting in a yearly total of 95. In the following years, the number of cases increased markedly to peak at 756 in 2014 (i.e. > 2 cases/day on average) after which it dropped to 659 in 2015 (Fig 1). In 2016, the STRIDA project had to be put on hold due to lack of funding to cover the cost for free toxicological analysis, but still > 100 cases arrived in January–February (Fig 1). During the ~6-years study period, a total of 2626 acute intoxication cases suspected to involve NPS or unknown psychoactive drugs presenting at ED/ICU were enrolled in the STRIDA project. The cases originated from all over Sweden, roughly in proportion to the regional distribution of inhabitants.

Fig 1 — Shown are yearly numbers of acute intoxication cases enrolled in the STRIDA project, telephone consultations on NPS with the Swedish Poisons Information Centre (PIC), and NPS reported to the European Union Early Warning System (EU EWS) operated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and Europol.

During the study period, the PIC experienced a marked increase in consultations related to suspected intoxications by NPS or unknown drugs. The number increased from a yearly starting level around 500 to peak at 1669 in 2014 (Fig 1). These data reveal that STRIDA samples were sent to the laboratory in slightly less than half of all PIC consultations suspected to involve NPS (the average for 2010–2015 was 40%). However, the relative proportion showed a steady increase with time and in 2015, the final full year of the project, biological samples were submitted in 57% of the invited cases.

Demographic data of the STRIDA patients

Overall, 74% of the patients enrolled in the STRIDA project were men but the sex distribution changed slightly over time. The proportion of women was 20% in 2010 but increased to range 24–29% (mean 26.4%) in the following years.

The age range of the STRIDA patients was 8–71 (mean 27.0, median 24) years and 57% were 25 years or younger (Fig 2A). The men were aged 11–72 (mean 27.9, median 25) years which was significantly higher (p < 0.0001; Mann-Whitney test) compared with the 8–60 (mean 24.5, median 21.5) years for women (Fig 2). The overall age of patients increased over time, from a mean (median) age of 22.2 (20) years in the first year to 26.9–28.8 (24–25) years in 2012–2015 (p < 0.0001) (Fig 2B).

Outside the STRIDA project, a newborn girl was tested because her mother was enrolled in the project after taking psychoactive drugs. A urine sample collected on the day after birth tested positive for the cathinone α-PVP (α-pyrrolidinovalerophenone), ritalinic acid (a metabolite of methylphenidate), and ketamine.

Psychoactive substances detected in the STRIDA cases

The vast majority (81%) of biological samples from ED/ICU submitted for toxicological investigation in the STRIDA project tested positive for psychoactive drugs, and often (70%) for more than one substance. Detected substances included novel drugs notified by the EU EWS (mainly NPS), classical common (e.g. amphetamine, cannabis and cocaine) and relatively uncommon (e.g. ketamine and psilocybin) illicit drugs in Sweden, approved recreational drugs (ethanol), and prescription medications that are often misused due to their psychoactive effects (e.g. benzodiazepines, buprenorphine and methadone).

From January 2010 until February 2016, a total of 159 novel or less common psychoactive substances were detected in the STRIDA project samples (Fig 3). Most of these (N = 140; 88%) were notified as NPS by the EU EWS in 2004–2016. When first detected, the novel substances were mostly (75%) not yet classified in Sweden (Fig 3).

New psychoactive substances (NPS)

In 2010, the first year of the STRIDA project, 28 NPS or uncommon drugs were detected in biological samples from the 95 cases (Fig 3), of which 25 substances (89%) were notified for the first time to the EU EWS in 2005–2010 [26]. Stimulants (mainly cathinones) and SCRA (JWH substances) each comprised ~20% of the NPS cases.

In 2011, another 21 novel or uncommon psychoactive substances (Fig 3) were detected in the 167 STRIDA cases (Fig 3), of which 16 (76%) were first notified to the EU EWS in 2005–2012. The NPS continued to be mainly cathinone and amphetamine derivatives.

In 2012, an additional 18 psychoactive substances were detected for the first time in the 406 STRIDA cases (Fig 3), and 14 (78%) of those were notified to the EU EWS in 2004–2015. Besides novel stimulants and SCRA, also designer benzodiazepines (etizolam and metizolam) and hallucinogens (25C- and 25I-NBOMe) started to appear. An especially harmful novel substance was 5-(2-aminopropyl)indole (5-IT) [15], that emerged in Sweden during the first half of 2012 and was involved in at least 15 deaths [27].

In 2013, 21 NPS or uncommon drugs emerged in the 470 cases (Fig 3), of which 19 (90%) were reported to the EU EWS in 2004–2013. Besides additional novel stimulants, cathinones, SCRA, benzodiazepines and hallucinogens, also NPS opioids (AH-7921 and MT-45) and dissociative drugs (3-MeO-PCP) started to appear. MT-45, a former analgesic drug candidate, induced not only typical opioid toxicity but also unexpected severe skin and hearing problems and even blindness requiring surgery [13, 28, 29].

In 2014, 39 novel or uncommon psychoactive substances were detected for the first time in the 756 cases (Fig 3), and 35 (90%) of those were reported to the EU EWS in 2008–2014. The NPS mainly comprised the same set of drug classes as in the previous years, but also butyrfentanyl, a fentanyl analogue without legitimate medical use [30], highly potent SCRA (MDMB-CHMICA) [31], and the phenmetrazine analogue 3-fluorophenmetrazine [32], all being linked to serious toxicity.

In 2015, 27 NPS or uncommon drugs were detected for the first time in the 659 STRIDA cases (Fig 3), and all but one (96%) were reported to the EU EWS in 2006–2016. Additional harmful designer fentanyls (4-fluorobutyrfentanyl, acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl) [30, 33] and benzodiazepines (e.g. clonazolam and nifoxipam) [34] appeared, and also novel hallucinogens (escaline and derivatives).

Finally, during the first months of 2016, after which the STRIDA project was put on hold, a few additional novel drugs appeared that were reported by the EU EWS in 2010–2016 (Fig 3).

In general, each NPS appeared for a relatively short period of time and commonly disappeared upon legal classification (Fig 3). In a retrospective comparison, however, there was a clear time delay between the first observation of a new substance in the STRIDA project to the legal response was implemented (median ~1.0 year, mean 1.6 years; range 2 months to ~8 years). Some novel stimulants and cathinones that appeared over several years were exceptions to this, notably MDPV (methylenedioxypyrovalerone) and α-PVP that became most popular after being classified as narcotics (MDPV was detected in 25% of the STRIDA cases in 2012, and in 16% in 2013; α-PVP was detected in ~10% of the cases in 2012–2015) (Figs 3 and 4A).

Fig 4 — The substances included are new psychoactive substances (NPS), other novel or uncommon illicit or unclassified drugs (in Sweden), an approved recreational drug (ethanol), as well as pharmaceuticals with misuse potential.

Uncommon psychoactive substances

Psychoactive substances detected in the STRIDA project that have been relatively uncommon as recreational drugs or drugs of abuse in Sweden comprised approved prescription medicines, unapproved medicines, substances controlled internationally under the United Nations Single Convention on Narcotic Drugs of 1961 or the Convention on Psychotropic Substances of 1971, and some other substances that were not banned in Sweden (Fig 4A). Substances of this category that were first detected in 2010 were pregabalin, tramadol and its metabolite O-desmethyltramadol (ODT), and the plant alkaloid mitragynine (kratom). In 2011, also 4-methoxy-amphetamine/-methamphetamine, methylphenidate, pethidine (meperidine), and fentanyl appeared. In the following years, additional uncommon 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).

Drugs of this category that were demonstrated to be relatively common throughout the years were pregabalin (mean 10.7%, yearly range 7.4–13.8%) and tramadol (mean 7.7%, range 6.0–11.6%) (Fig 4A).

Classical recreational and illicit drugs

Besides the many novel and uncommon psychoactive substances detected in the STRIDA cases, also classical recreational drugs (e.g. ethanol) and illicit drugs of abuse (e.g. cannabis and amphetamine) were common analytical findings (Fig 4B). Ethanol and/or its conjugated metabolites ethyl glucuronide (EtG) and ethyl sulfate (EtS) [35, 36], and cannabis (i.e. the metabolite THC-COOH), were found in on average 22.2% (yearly range 13.7–27.3%) and 21.3% (16.8–27.8%), respectively, of all cases (Fig 4B). Ethanol was also the most common single substance intoxication, making up 14% of the positive cases. Medicinal benzodiazepines with a potential of being misused (e.g. diazepam and metabolites) were also common (range for yearly mean 6.9–15.3%) (Fig 4B), but it should be noted that these may sometimes have been administered during the acute handling of patients in the ED/ICU (i.e. before sampling for the STRIDA project). Other common findings were amphetamine (mean 11.1%, yearly range 7.4–14.5%) and buprenorphine (mean 4.7%), whereas cocaine use (i.e. the metabolite benzoylecgonine) was relatively uncommon (mean 1.1%, range 0.3–2.4%) in the study population (Fig 4B).

Substance use versus age

When the STRIDA cases were sorted by detected primary substance class (i.e. cannabinoids, ethanol, opioids, stimulants, etc), there was a wide age distribution for patients of all substance categories (S1 Fig). However, patients categorized as cannabinoid or ethanol users had a median age of 20 and 21 years, respectively, which differed significantly (p < 0.0001; Mann-Whitney test) from those categorized as mainly opioid, stimulant, dissociative drug, or pregabalin users, who were generally older with median ages of 26–28 years.

Discussion

The number of acute intoxication cases enrolled in the STRIDA project on the occurrence and health hazards of NPS in Sweden increased markedly with time. Participation in the project was voluntary and submission of biological samples for toxicological investigation largely depended on ED/ICU staff interest and time. A parallel general increased demand for PIC consultations related to NPS, besides for inclusion in the project, indicated a lack of knowledge among hospital care givers about the many novel recreational drugs, which are often named only through combinations of letters and numbers, and how to deal with associated adverse effects. Furthermore, as the test results often were not reported until after discharge of the patients from the ED/ICU, it indicated an interest to contribute to a better awareness and understanding of NPS-related intoxications.

Later during the STRIDA project, the ED/ICU staff routinely contacted the PIC in relevant cases to obtain a project code number and free drug testing, regardless of whether consultation on treatment was needed. When the project could no longer offer free drug testing, due to lack of funding, the number of PIC contacts related to NPS or unknown drugs soon dropped and so did the number of biological samples that were submitted to the laboratory for NPS testing (i.e. routine testing outside the STRIDA project). This indicated that offering free analysis was an important incentive for participation in the project.

Most of the STRIDA patients were 25 years or younger, although the age range was large. The increased age of patients over time may be partly explained by the wider range of substance classes appearing for which the median age of users was higher. In terms of sex distribution, on average 75% were men, but a change was seen over time towards an increased proportion of women.

The analytical results demonstrated a widespread use of many different psychoactive drugs in Sweden in 2010–2016, and polysubstance use was indicated to be common in cases requiring acute hospital care. However, it should be noted that NPS products sometimes contained two or more psychoactive substances, indicating that all substances detected in the biological samples were not due to intentional intake [24]. In addition to the classical recreational and illicit drugs, with ethanol and cannabis being the most common, 159 novel (mainly NPS) or less commonly used (i.e. in Sweden) psychoactive substances were detected among the 2626 sets of biological samples from acute intoxication cases admitted to ED and/or ICU all over the country. In 2014, when the number of STRIDA cases peaked, it could be estimated that at least 4–5 patients per day on average needed acute hospital care in Sweden due to a suspected NPS-related intoxication, as less than half of all PIC contacts eventually became STRIDA cases. A contributing reason for the peak seen in 2014, when many serious poisonings caused by new potent SCRA appeared [31], may be a major interest in the media for the NPS problem.

For most classical illicit drugs, the relative frequency of positive findings was rather uniform over the years, while there were often highly variable annual figures for most NPS and some of the novel and uncommon substances. The NPS products marketed on Swedish websites and identified in the project also varied over time. Their disappearance often coincided with the date of classification as a narcotic or substance harmful to health which in Sweden is done individually [8]. Once a proposal of classification and the date for implementation was officially notified, the online drug retailers started selling out these substances and replaced them with other unclassified chemical variants [7, 37, 38]. This is evident from the fact that most novel substances (75%) were not classified when first detected in the project samples. Later, however, most of them (92%) became classified as a narcotic or harmful substance.

Exceptions to this were the cathinones MDPV and α-PVP which became most common after being classified [39–41]. However, because MDPV was reported to largely replace amphetamine as the main stimulant drug in some places [42], it is indicated that it was not primarily sold online but through street level dealers. The large number of MDPV and fentanyl analogues introduced over the years also highlights a risk with the individual drug classification system employed in Sweden. Once a new unclassified psychoactive substance has been detected in the country, it must be individually investigated and evaluated for classification as a narcotic or a substance harmful to health, even though it may already be evident from scientific publications to be dangerous [43, 44]. Furthermore, the classification process often takes long time. A retrospective investigation revealed that the median time from first detection of a novel substance in the STRIDA project until classification was one year but sometimes took several years and, meanwhile, these drugs continued to be sold openly. More proactive (generic or analogue) drug classification systems are in place in several other countries [45, 46].

There were sometimes variable annual figures also for the less common psychoactive substances in the STRIDA project. For example, intake of methylphenidate, a classified stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD), was not found in 2010 and only rarely in 2011, whereas 13.5% of the cases tested positive (i.e. parent drug and/or its metabolite ritalinic acid) in 2012 and close to 10% in 2013. In 2015, however, the frequency dropped to below 1%. Furthermore, in 2010, about 7% of the STRIDA cases tested positive for pregabalin, a medication used to treat epilepsy, neuropathic pain and generalized anxiety disorder, and that figure doubled to 14% in 2014 and remained high in the following years (pregabalin was classified in Sweden in 2018). Methoxetamine, a dissociative hallucinogenic drug, was detected in 5–6% of the cases in 2011–2012 but, after being classified in 2013, in only 1% or less in the other years.

When novel psychoactive substances started to appear, information on their pharmacological and toxicological effects was largely missing, and some later turned out to be more adverse, having very harmful and sometimes fatal effects. Toxicological case series from the STRIDA project highlighting a variety of especially harmful NPS have been published continuously, covering structural variants of phenethylamine and cathinone stimulants [15, 38–41], hallucinogenic and dissociative drugs [37, 47], fentanyl derivatives and other opioids [29, 30, 33, 48, 49], SCRA [31], and designer benzodiazepines [34]. There have also been several bioanalytical studies related to recommended strategies for drug testing of NPS [16, 17, 23, 50], and results from the investigation of drug products that were sometimes submitted together with the biological samples [24].

Conclusions

The STRIDA project was demonstrated to provide a good overview of the current drug situation in the country, covering both classical and novel substances. It also served as a warning system for especially harmful NPS, by sharing collected data on the incidence and distribution, identification of adverse effects, and treatment of analytically confirmed acute intoxications presenting in ED and ICU. As such, it represented an important complement to data and statistics on drug-related deaths. The results of the project also illustrated how drug regulations can drive the NPS market [51], as the novel substances usually disappeared upon classification and were replaced by other yet unclassified ones. The STRIDA project supported personnel at the national PIC, and thereby medical staff all over the country, in the knowledge and critical care of NPS intoxications, and contributed nationally and internationally through notifications to the EMCDDA, scientific presentations and publications.

The accomplishment of the STRIDA project can be attributed to several key factors that may be considered in future activities addressing the NPS problem:

A close collaboration between the PIC and the laboratory, to identify suspected cases of NPS intoxication from ED and ICU for enrollment in the project, and to follow up on associated adverse effects.
Use and continuous updating of sensitive, preferably HRMS-based, analytical methods to follow the changes in drug diversity, as poisonings caused by the latest set of NPS may otherwise be hidden.
Offering free-of-charge toxicological investigation to ensure a high inflow of relevant poisoning cases. Not receiving continued funding to cover the cost for drug testing was the reason why the project had to be finished.
Continuous collection of information on the rapid turnover of NPS, through monitoring of PIC inquiries, open web sites of drug dealers and drug chat forums, national collaboration with e.g. the police and customs, and notifications from the EU EWS.
Last, but not least, spreading updated information on the ever changing NPS landscape and results from the project through lectures and publications.

Supporting information

S1 Fig. Box-and-whisker plot showing age distribution of patients in relation to main substance class.

In 78% of the cases, a classification into either of the following main substance classes was possible: cannabis or synthetic cannabinoid receptor agonists (Cannabi), ethanol, hallucinogens (Hallucino), benzodiazepines (Benzodi), dissociative drugs (Dissocia), opioids, pregabalin (Pregaba), or stimulants (Stimula). N = number of cases; open point = outside value; filled point = far out value.

(PDF)

Click here for additional data file.^{(101.1KB, pdf)}

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by the Public Health Agency of Sweden (Folkhälsomyndigheten). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0232038.r001

Decision Letter 0

Michelle Tye

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

12 Feb 2020

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

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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

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PLoS One. 2020 Apr 23;15(4):e0232038. doi: 10.1371/journal.pone.0232038.r002

Author response to Decision Letter 0

26 Feb 2020

REBUTTAL LETTER – RESPONSE TO REVIEWERS

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

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'.

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• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Our response: Done.

Additional Editor Comments (if provided):

No additional comments.

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When submitting your revision, we need you to address these additional requirements:

Our response: The revised manuscript has been formatted following the style requirements of PLOS ONE.

2. Thank you for including your ethics statement:

"The STRIDA project was conducted in accordance with the Helsinki Declaration and approved by the regional ethical review board (Nr. 2013/116–31/2)."

Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

Our response: The full name of the regional ethics committee (in Swedish) is now given.

Our response: We have deleted this phrase and instead present the data in a supporting information file (cited as S1 Fig).

Our response: New copies of all figures have been generated (and approved) using the PACE system.

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: Yes

Reviewer #2: Yes

________________________________________

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

Reviewer #1: N/A

Reviewer #2: N/A

________________________________________

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

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

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

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

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.

Our response: Thank you for the constructive comments on our manuscript. In the revised version, we have better described the purpose of this report, as well as how different types of information about NPS were collected and the results of the STRIDA project shared. We hope that this is now clearer.

Our response: To be included in the STRIDA project, ED/ICU clinics treating suspected NPS poisoning cases first needed to contact the Swedish Poisons Information Centre (PIC; the Swedish PIC covers the entire country). When information on a new drug was indicated to the project through PIC telephone consultation or other sources of information (the project had continuous communication and information sharing about NPS with the Public Health Agency of Sweden, the Swedish National Forensic Centre, National Board of Forensic Medicine, Customs laboratory, Medical Products Agency, and the EU EWS), the PIC documentation and treatment guidelines were updated and brief reports on case progress and recovery generated. Accordingly, the PIC could provide up-to-date toxicological information to medical staff on the new drugs appearing in the country. This information is now given in the revised manuscript in the extended first section of the Materials and methods.

Our response: As detailed above (#1) and better explained in the revised manuscript, the PIC updated their toxicological consultation documentation on new drugs, when new information was available. As for the laboratory drug test results, these were reported to the ordering clinic as soon as the analysis was completed (also this information is now given), which could take from one or a few days up to several weeks depending on the substance(s) involved. Because this may not be considered as “real-time” and “early warning”, we have excluded these expressions in the revised manuscript. The typically long time from the first appearance of a new drug in the project to its classification as a narcotic or harmful substance (median about 1 year) was, however, never due to a long analysis time but to the legal process.

Our response: In the revised manuscript, we have better clarified the purposes of this report at the end of the Introduction. Main aims were to summarize, evaluate and share the results of the �6-year STRIDA project on NPS, and conisder how the experiences generated could be useful for improvement of future activities addressing the NPS problem. Please also see our responses above to issues #1 and #2.

Our response: As also stated above, we have decided not to use “real-time and early warning” in relation to the STRIDA project. However, the speed at which a new drug can be analytically confirmed, and the analytical and toxicological information shared with the medical and legal community, depends largely on the resources put into the activity, and “near real-time” reporting of analytical results is indeed possible. For example, in a case where nine young men ended up unconscious in the ED/ICU, we were able to identify the involved substance and return the test results to the hospital (and the police) within a few hours after the samples arrived in the laboratory. It turned out the young men had mistaken acrylfentanyl for amphetamine! Acrylfentanyl would not have been detected in any routine hospital laboratory in the country.

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.

Our response: It is now clarified that all analyses of biological samples in the STRIDA project were performed at the Karolinska University Laboratory. Once the appearance of a new drug was reported or indicated to the project (see also #1), the laboratory started to update the analytical methods and look for reference materials.

Our response: An important indication that NPS may be involved, in addition to self-reporting of patients or accompanying persons, was whether patients admitted to the ED/ICU exhibited unknown or unusual symptoms or side effects. Sometimes, NPS drug products were found or were forwarded to the ambulance or medical staff. Furthermore, as already explained in the text (Materials and methods), clinical and other details of the case was given on the project laboratory report form that was attached in each case, in addition to that forwarded during consultation with the PIC, and the possibility to also send drug materials was indicated.

Our response: This option was only used in a few cases when certified reference material was not available for purchase or to obtain from other sources (e.g. the National Forensic Centre). This is now better explained in the Materials and methods section under NPS drug materials.

Our response: We agree, and this was also an observation from the cited publication on NPS drug materials in the STRIDA project (Bäckberg M, et al. Investigation of drug products received for analysis in the Swedish STRIDA project on new psychoactive substances. Drug Test Anal. 2018;10(2):340-9.). The text has been revised accordingly. The results of a drug test cannot decide the origin of the substance

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:

Comments on the manuscript:

Our response: New copies of all figures have been generated (and approved) using the PACE system.

Our response: Although this case was not originally enrolled in the STRIDA project, but only indirectly via her intoxicated mother, we consider the information to be of general interest and suggest maintaining it in the text (side information) but not include it in the age range of STRIDA patients.

Our response: Ketamine is a relatively uncommon psychoactive substance in Sweden. We have revised the text so that this becomes more obvious to the readers.

Our response: These references were added in the revised manuscript.

Our 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.

Our response: We agree and will mention the financial sources to the STRIDA project (external: the Public Health Agency of Sweden; internal: Karolinska University Laboratory) when uploading the revised manuscript.

Our response: We have checked and revised these expressions and tried to improve the language also in other places. It should be noted that the term “designer drugs” was often used previously for the NPS phenomenon.

Our response: The abstract needed to be shortened considerably to comply with the maximum 300-word limit. Nevertheless, as suggested, we were able to give the key factors in the revised version.

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.

Our response: The revised manuscript has been checked for typos, spelling and grammar.

Our response: Please see our responses to similar comments given by the first reviewer (issues #2, #4). We do not use the term “early warning” for the STRIDA project in the revised manuscript.

________________________________________

PLoS One. doi: 10.1371/journal.pone.0232038.r003

Decision Letter 1

Michelle Tye

31 Mar 2020

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,

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

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.

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We look forward to receiving your revised manuscript.

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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)

**********

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

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?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

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.

**********

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.

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Reviewer #1: Yes: Jon E. Zibbell

Reviewer #2: Yes: Monica J. Barratt

PLoS One. 2020 Apr 23;15(4):e0232038. doi: 10.1371/journal.pone.0232038.r004

Author response to Decision Letter 1

2 Apr 2020

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

Our response: As recommended by the reviewer, we now state in the Methods section that the classification time for novel substances was collected, we have moved the data on median/mean/range time between the first analytical finding in the STRIDA project until the classification became effective from the Discussion to the Results section, and further cover this issue in the Discussion section.

PLoS One. doi: 10.1371/journal.pone.0232038.r005

Decision Letter 2

Michelle Tye

7 Apr 2020

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.

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Michelle Tye, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0232038.r006

Acceptance letter

Michelle Tye

10 Apr 2020

PONE-D-19-35565R2

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

Dear Dr. Helander:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Box-and-whisker plot showing age distribution of patients in relation to main substance class.

(PDF)

Click here for additional data file.^{(101.1KB, pdf)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

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

Anders Helander

Matilda Bäckberg

Olof Beck

Roles

Abstract

Background

Methods and findings

Conclusions

Introduction

Materials and methods

Selection of clinical cases and data acquisition

NPS drug materials

Laboratory analysis of biological samples

Laboratory analysis of drug materials

Results

The STRIDA cases

Fig 1. Statistics on new psychoactive substances (NPS) by year.

Demographic data of the STRIDA patients

Fig 2. Age distribution of patients enrolled in the STRIDA project on new psychoactive substances (NPS).

Psychoactive substances detected in the STRIDA cases

Fig 3. Novel psychoactive substances detected in the STRIDA project in 2010–2016.

New psychoactive substances (NPS)

Fig 4. Yearly frequency of STRIDA project samples testing positive for other common or uncommon psychoactive substances.

Uncommon psychoactive substances

Classical recreational and illicit drugs

Substance use versus age

Discussion

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Michelle Tye

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

Michelle Tye

Roles

Author response to Decision Letter 1

Decision Letter 2

Michelle Tye

Roles

Acceptance letter

Michelle Tye

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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