3R-Refinement principles: elevating rodent well-being and research quality.

This review article delves into the details of the 3R-Refinement principles as a vital framework for ethically sound rodent research laboratory. It highlights the core objective of the refinement protocol, namely, to enhance the well-being of laboratory animals while simultaneously improving the scientific validity of research outcomes. Through an exploration of key components of the refinement principles, the article outlines how these ethics should be implemented at various stages of animal experiments. It emphasizes the significance of enriched housing environments that reduce stress and encourage natural behaviors, non-restraint methods in handling and training, refined dosing and sampling techniques that prioritize animal comfort, the critical role of optimal pain management and the importance of regular animal welfare assessment in maintaining the rodents well-being. Additionally, the advantages of collaboration with animal care and ethics committees are also mentioned. The other half of the article explains the extensive benefits of the 3R-Refinement protocol such as heightened animal welfare, enhanced research quality, reduced variability, and positive feedback from researchers and animal care staff. Furthermore, it addresses avenues for promoting the adoption of the protocol, such as disseminating best practices, conducting training programs, and engaging with regulatory bodies. Overall, this article highlights the significance of 3R-Refinement protocol in aligning scientific advancement with ethical considerations along with shaping a more compassionate and responsible future for animal research.

Using in vitro receptor activity studies of synthetic cannabinoids to support the risk assessment of new psychoactive substances - A Swedish strategy to protect public health from harm.

In the past 15 years, close to 1000 of new psychoactive substances (NPS) have been reported in Europe and globally. At the time of identification, data on safety, toxicity and carcinogenic potential of many NPS are not available or very limited. To work more efficiently, a strategy and collaboration between the Public Health Agency of Sweden (PHAS) and the National Board of Forensic Medicine was established involving in vitro receptor activity assays to demonstrate neurological activity of NPS. This report summarizes the first results on the synthetic cannabinoid receptor agonists (SCRAs), and subsequent actions taken by PHAS. A total of 18 potential SCRAs were selected by PHAS for in vitro pharmacological characterization. 17 compounds could be acquired and investigated for their activity on the human cannabinoid-1 (CB1) receptors expressed together with the AequoScreen system in CHO-K1 cells. Dose-response curves were established using eight different concentrations in triplicates at three occasions with JWH-018 as reference. For the MDMB-4en-PINACA, MMB-022, ACHMINACA, ADB-BUTINACA, 5F-CUMYL-PeGACLONE, 5C-AKB48, NM-2201, 5F-CUMYL-PINACA, JWH-022, 5Cl-AB-PINACA, MPhP-2201, 5F-AKB57 the half maximal effective concentration values ranged from 2.2 nM (5F-CUMYL-PINACA) to 171 nM (MMB-022). EG-018 and 3,5-AB-CHMFUPPYCA were none-active. The results contributed to 14 of these compounds being scheduled as narcotics in Sweden. In conclusion, many of the emerging SCRAs are potent activators of the CB1 receptor in vitro, although some lack activity or are partial agonists. The new strategy proved useful when data on psychoactive effects of the SCRAs under investigation were not available or limited.

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

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.

Occurrence and time course of NPS benzodiazepines in Sweden - results from intoxication cases in the STRIDA project.

CONTEXT: In recent years, many unclassified benzodiazepines (BZD) have appeared through online sale as new psychoactive substances (NPS). This study describes bioanalytical and clinical data related to intoxications involving NPS BZD ("designer BZD") in the Swedish STRIDA project. STUDY DESIGN: Case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals all over Sweden for emergency treatment in 2012-2016. PATIENTS AND METHOD: Urine samples collected in the STRIDA project were analyzed for 28 NPS BZD, using immunoassay and liquid chromatography-high-resolution mass spectrometry . Data of patient's age, gender, reported substance exposure, clinical signs, and treatment were obtained from medical and Poisons Information Center (PIC) records. RESULTS: A total of fifteen different NPS BZD were analytically confirmed in 217 of 1913 (11%) cases involving patients (81% men) aged 15-66 (mean 28) years. The frequency of positive samples increased from 4% in 2012 to 19% in 2015. Etizolam (20 cases) was the first detected NPS BZD (January 2012), and it was followed by metizolam (four cases), estazolam (two), pyrazolam (33), flubromazepam (33), nifoxipam (five), diclazepam (four), meclonazepam (26), bromazepam (one), flubromazolam (92), deschloroetizolam (one), clonazolam (16), 3-hydroxyphenazepam (eight), ketazolam (one), and phenazepam (one). Most cases (89%) also involved other drugs. Use of NPS BZD was rarely (15%) reported during PIC consultation. In 24 patients exposed only to NPS BZD, CNS depression was the most prominent clinical sign, seven were observed in the intensive care unit, and they responded positively to flumazenil treatment. CONCLUSIONS: An increasing use of NPS BZD in Sweden was detected in acute intoxication cases, sometimes leading to intensive care monitoring and support needs.

Epidemiology of NPS Based Confirmed Overdose Cases: The STRIDA Project.

The Swedish STRIDA project on new psychoactive substances (NPS) monitored the occurrence and health hazards of novel recreational drugs in Sweden through evaluation of analytically confirmed adverse events presenting in emergency departments and intensive care units. During a ~6-year period from 2010 to early 2016, about 2,600 cases of suspected NPS intoxications were included in the project. About 75% of patients were men and the total age range was 8-71 (median 24) years and 57% were 25 years or younger. A large number of NPS belonging to many different drug classes were identified in project samples of urine and blood (serum/plasma) submitted for free drug testing, including synthetic cannabinoid receptor agonists, stimulants, cathinones, hallucinogens, dissociative drugs, benzodiazepines, and opioids, and also in drug materials from the cases forwarded to the laboratory along with the biological samples. The STRIDA project has been shown to serve as an effective early warning system for NPS by collecting data on incidence, distribution, and adverse effects and has supported healthcare professionals in the knowledge and critical care of intoxications caused by a wide range of novel substances. The results of the STRIDA project have also illustrated how drug regulations can drive the NPS market.

Acute Intoxications Involving α-Pyrrolidinobutiophenone (α-PBP): Results from the Swedish STRIDA Project.

INTRODUCTION: Many new psychoactive substances (NPS) introduced as recreational drugs have been associated with severe intoxication and death. METHODS: Blood and/or urine samples were collected from intoxicated patients treated at Swedish hospitals that participated in the STRIDA project, a nationawide effort to address the growing problem of NPS. In patients undergoing evaluation for drug overdose, α-PBP was identified using liquid chromatography-mass spectrometry. Demographic and clinical data were collected during Poisons Information Centre consultations and retrieved from medical records. RESULTS: From April 2013 to November 2015, 43 patients tested positive for α-PBP. However, α-PBP was never specifically mentioned during consultation but only confirmed analytically. The α-PBP concentrations ranged 2.0-13,200 ng/mL in urine and 2.0-440 ng/mL in serum. The patients were aged 19-57 (mean 34) years, 81% were men, and 73% were known drug addicts. All cases except 1 also involved other NPS and/or classical drugs. MDPV, α-PVP, and other pyrovalerone analogues were the most common other NPS (31 cases; 72%). CNS depressants were detected in 28 cases (65%), with benzodiazepines (16 cases) being most frequent. Main clinical characteristics were agitation/anxiety (59%), tachycardia (54%), and hypertension (37%), and 14 patients (33%) required monitoring in the intensive care unit of which 8 were graded as severe intoxications. No fatalities were reported. CONCLUSION: Patients with intoxication from α-PBP resembled those by NPS cathinones MDPV and α-PVP. As patients never specifically declared α-PBP intake and poly-drug intoxication was common, they may have been unaware of the actual substance taken.

Intoxications in the STRIDA project involving a panorama of psychostimulant pyrovalerone derivatives, MDPV copycats.

CONTEXT: An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in intoxications involving 11 stimulant pyrovalerone NPS derivatives over a 5-year period. STUDY DESIGN: Case series of consecutive patients with admitted or suspected intake of NPS presenting to Swedish hospitals for emergency treatment from January 2011 to March 2016. PATIENTS AND METHOD: Blood and urine samples were collected from intoxicated patients presenting to hospitals all over Sweden. Analyses of NPS and other drugs of abuse were performed by immunochemical and liquid chromatography-mass spectrometry multi-component methods. Clinical data were collected during consultation with the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The study involved analytically confirmed cases with 11 pyrovalerone drugs. RESULTS: During the study period, 114 intoxications were detected that involved any of 11 new pyrovalerone drugs. In addition to these new pyrovalerone derivatives, 3,4-methylenedioxypyrovalerone (MDPV) was detected in 17 of the cases and α-pyrrolidinovalerophenone (α-PVP) in 45 cases. Identification was made according to forensic standards and comprised the following substances: 4F-α-PVP, α-PHP, PV8, 4Me-PPP, α-PBP, 4F-PV8, α-PPP, MDPHP, α-PVT, 4Cl-α-PVP, and 4F-α-PHP. The three most frequently detected drugs were α-PBP, MDPHP, and 4F-α-PVP. The age range of patients was 16-66 (median 30) years and 84% were males. The substance concentrations in urine and serum were highly variable, ranging from 1 ng/mL to 300 µg/mL. Poly-drug use was common with only 8 of 114 cases (7%) involving one pyrovalerone drug. The additional substances comprised other NPS and classical psychoactive drugs. The patients showed a variety of clinical signs; agitation, delirium, hallucinations, excessive motor activity, seizures, tachycardia, hypertension, and/or hyperthermia. CONCLUSIONS: In analytically confirmed NPS-related intoxications, 11 new pyrovalerone derivatives in addition to MDPV and α-PVP were found. The clinical features were consistent with a sympathomimetic toxidrome, but the urine and serum concentrations were highly variable. The results demonstrated that many novel pyrovalerone stimulants were introduced on the recreational NPS drugs market. Analytical investigations were necessary to obtain this information.

Investigation of drug products received for analysis in the Swedish STRIDA project on new psychoactive substances.

The web-based open sale of unregulated new psychoactive substances (NPS) has shown a steady increase in recent years. Analysis of drug products sold as NPS is useful to confirm the true chemical contents, for comparison with the substances detected in corresponding body fluids, but also to study drug trends. This work describes the examination of 251 drug products that were randomly submitted for analysis in 173 cases of suspected NPS-related intoxications in the Swedish STRIDA project in 2010-2015. Of the products, 39% were powders/crystals, 32% tablets/capsules, 16% herbal materials, 8% liquids, 1% blotters, and 4% others. The analysis involved tandem mass spectrometry and nuclear magnetic resonance spectroscopy. In 88 products (35%), classic psychoactive substances, prescription pharmaceuticals, dietary supplements, or doping agents were found; however, in none of these cases had an NPS-related intoxication been indicated from product markings or patient self-reports. Another 12 products tested negative for psychoactive substances. The remaining 151 products contained 86 different NPS (30% contained ≥2 substances). In 104 drug products, a specific NPS ingredient was indicated based on labelling (69%) or patient self-report; in 92 cases this was also analytically confirmed to be correct. Overall, the NPS products submitted for analysis in the STRIDA project showed a high degree of consistency between suspected and actual content (88%). The results of related urine and/or blood analysis further demonstrated that the patients commonly (89%) tested positive for the indicated NPS, but also revealed that polysubstance intoxication was common (83%), indicating use of additional drug products.

Intoxications involving acrylfentanyl and other novel designer fentanyls - results from the Swedish STRIDA project.

BACKGROUND: The number of new psychoactive substances (NPS) introduced through the online recreational drugs market increases continuously. This report from the Swedish STRIDA project describes analytically confirmed intoxications involving the novel fentanyl analogs acrylfentanyl, 4-chloroisobutyrfentanyl (4Cl-iBF), 4-fluoroisobutyrfentanyl (4F-iBF), and tetrahydrofuranfentanyl (THF-F), and cyclopentylfentanyl in a drug product. METHODS: Patients with suspected NPS exposure presenting in emergency departments (ED) or intensive care units (ICU) in Sweden and requiring hospital care are invited to the STRIDA project. NPS analysis of serum and urine samples was performed by multi-component liquid chromatography-mass spectrometry. Data on clinical features were retrieved from telephone consultations with the Swedish Poisons Information Centre and from medical records. RESULTS: Between April and October 2016, eleven intoxications involving acrylfentanyl (8 cases), acrylfentanyl together with 4Cl-iBF (1), 4F-iBF (1), and THF-F (1) were analytically confirmed. Patients were aged 19-51 (median 28) years and 91% were men. Six (55%) were monitored at the ED, and five admitted to the ICU. Typical clinical features were decreased consciousness, respiratory depression, and miosis. In 8 cases, the antidote naloxone was administered to counter the opioid effects. The 4F-iBF positive patient eventually died of brain edema. The serum acrylfentanyl concentration (n = 8) ranged 0.5-2.1 (median 0.9) ng/mL, and in urine (n = 9) 0.2-10.5 (mean 4.6, median 5.2) µg/mmol creatinine. For 4Cl-iBF, 4F-iBF, and THF-F (n = 1 each), higher serum (5-45 ng/mL) and urine (11-136 µg/mmol creatinine) concentrations were found. Other NPS (e.g., flunitrazolam) and/or classical drugs were detected in five cases. In early 2016, nasal sprays with a claimed content of acrylfentanyl brought to hospital by patients or obtained by test purchase were demonstrated to instead contain fentanyl. CONCLUSIONS: Potentially life-threatening opioid toxicity was seen in 11 acute intoxications involving the fentanyl analogs acrylfentanyl, 4Cl-iBF, 4F-iBF, and THF-F, which are available through open Internet trading. All patients were supported with acute and intensive hospital care, and naloxone was effective to reverse the opioid symptoms. One patient died of brain edema.

Analytically Confirmed Intoxications Involving MDMB-CHMICA from the STRIDA Project.

INTRODUCTION: About a decade ago, synthetic cannabinoids (SC) started to appear as recreational drugs on the new psychoactive substance (NPS) market. This report from the STRIDA project describes analytically confirmed intoxications involving MDMB-CHMICA (methyl-2-(1-(cyclohexylmethyl)-1H-indol-3-ylcarbonylamino)-3,3-dimethylbutanoate), a SC that was first detected in 2014. STUDY DESIGN: This is an observational case series of patients from Sweden with suspected NPS exposure presenting in emergency departments and intensive care units. The results of retrospective serum and urine toxicological analysis were compared with clinical signs reported during consultation with the Poisons Information Centre and retrieved from medical records. METHODS: Clinical and bioanalytical data in nine acute intoxications associated with MDMB-CHMICA during 2014-2015 are presented. The patients were aged 23-62 (median 34) years, and eight were men. MDMB-CHMICA (parent compound) was analytically confirmed in serum samples, using a liquid chromatography-high-resolution mass spectrometry multi-component method. RESULTS: Of the nine MDMB-CHMICA-positive patients, eight had a Poisoning Severity Score (PSS) of 2 or 3, and five were monitored in the intensive care unit and all patients survived. Development of seizures and deep unconsciousness were common features. All cases except one also tested positive for other NPS and/or classical psychoactive compounds, hampering the possibility to establish a causal relationship between drug and toxic symptoms. MDMB-CHMICA was also identified in seven drug materials donated by the patients. CONCLUSIONS: The association with severe adverse reactions in nine acute analytically confirmed intoxication cases involving MDMB-CHMICA is consistent with other reports of serious toxicity linked to this substance, suggesting that MDMB-CHMICA might be a particularly harmful SC.

Adverse events related to the new psychoactive substance 3-fluorophenmetrazine - results from the Swedish STRIDA project.

BACKGROUND: New psychoactive substances (NPS) are often poorly pharmacologically documented and the production is unregulated, implying high risks for toxic side effects. This report from the STRIDA project describes analytically confirmed non-fatal intoxications involving the phenmetrazine analogue 3-fluorophenmetrazine (3-FPM). STUDY DESIGN AND METHODS: Observational case series of patients with suspected acute NPS exposure requiring hospital care. Blood and urine samples were collected from patients presenting in emergency departments (ED) or intensive care units (ICU), after consultation with the Swedish Poisons Information Centre (PIC). Laboratory analysis was performed by multi-component liquid chromatography-mass spectrometry. Clinical data were collected during PIC consultations and retrieved from medical records. RESULTS: From November 2014 to October 2015, eight cases were registered as 3-FPM or "phenmetrazine" intoxications at the PIC after consultation. During the same period, analysis of STRIDA project samples confirmed 3-FPM use in a total of 19 patients (84% men) aged 22-54 (median 30) years. 3-FPM was detected in 15 out of 19 serum (2.7-1416 ng/mL) and in 14 out of 14 urine (1.0-6857 µg/mmol creatinine) samples. All patients were also tested positive for other psychoactive substances, with benzodiazepines being most common (57% of the cases). Ten patients were monitored in the ED for <4 h, while six needed ICU monitoring of which five were graded as severe intoxications (Poisoning Severity Score 3). Prominent clinical signs were tachycardia (47%), depressed consciousness (42%), agitation/anxiety (37%), delirium (37%), dilated pupils (26%), and seizures (16%). All patients survived. CONCLUSION: In 19 patients testing positive for 3-FPM, a high incidence of severe clinical features was demonstrated. However, as all patients had also used other psychoactive substances, it was difficult to identify a unique toxidrome for 3-FPM. The results further showed that many 3-FPM intoxications would have been missed, if relying solely on information from PIC consultations. These results emphasize the importance of performing bioanalytical investigation in cases of suspected NPS intoxication.

Toxicity evaluation of α-pyrrolidinovalerophenone (α-PVP): results from intoxication cases within the STRIDA project.

CONTEXT: An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in a series of intoxications involving the stimulant NPS α-pyrrolidinovalerophenone (α-PVP), a potent dopamine re-uptake inhibitor, over a 4-year period. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden from 2012 to 2015. PATIENTS AND METHODS: In the STRIDA project, blood and urine samples are collected from intoxicated patients with admitted or suspected intake of NPS or unknown drugs presenting to hospitals over the country. Analysis of NPS is performed by mass spectrometry multicomponent methods. Clinical data are collected when caregivers consult the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The severity of poisoning is graded retrospectively using the Poisoning Severity Score (PSS). The inclusion criteria for this study included absence of other stimulants than α-PVP. RESULTS: During the 4-year study period, 23 intoxications were originally coded as "α-PVP related" out of a total 3743 NPS-related inquiries (0.6%) at the PIC. The present study covered 42 analytically confirmed cases in which α-PVP was the only stimulant detected. The age range of patients was 20-58 (median 32) years, of which 79% were males. The α-PVP concentration in serum was 4.0-606 (median 64; n = 42) ng/mL and 2.0-41,294 (median 1782; n = 25) ng/mL in urine. There was no statistically significant association between the serum α-PVP concentration and urinary α-PVP/creatinine ratio in 25 cases, where both sets of data were available. In 14/42 (33%) cases, α-PVP was the only psychoactive substance identified. In the remaining cases, additional substances comprised opioids, benzodiazepines, and ethanol. The main clinical manifestations were tachycardia (80%), agitation (70%), hypertension (33%), hallucinations (20%), and delirium (18%). Classification of poisoning severity yielded 25 (60%) moderate (PSS 2), 7 (17%) severe (PSS 3), and 2 fatal cases (PSS 4). CONCLUSIONS: In analytically confirmed α-PVP intoxication cases involving no other stimulant drugs, the urine and serum concentrations showed high variability. The clinical features were consistent with a severe sympathomimetic toxidrome. The results further demonstrated that α-PVP prevailed as a drug of abuse after being classified as a narcotic substance, and despite a high incidence of severe poisonings and fatalities. However, the low prevalence of α-PVP cases registered at the PIC suggested that many were unaware of the actual substance they had taken.

Intoxications involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl: results from the Swedish STRIDA project.

BACKGROUND: Potent and potentially harmful new psychoactive substances (NPS) are continuously introduced on the recreational drugs market. This report from the Swedish STRIDA project describes analytically confirmed cases of intoxication involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl, and furanylfentanyl. METHODS: Patients with suspected NPS exposure presenting in emergency departments and intensive care units in Sweden and requiring hospital care are invited to the STRIDA project. Toxicological analysis of serum and urine samples was performed by multi-component liquid chromatographic-mass spectrometric methods. Data on clinical features were retrieved from telephone consultations with the Swedish Poisons Information Centre and from medical records. RESULTS: Between April and November 2015, 14 analytically confirmed intoxications involving acetylfentanyl (nine cases), 4-methoxybutyrfentanyl (3), furanylfentanyl (1), and 4-methoxybutyrfentanyl together with furanylfentanyl (1) were identified. The patients were aged 20-40 (mean 28.5) years and 86% were men. Twelve patients (86%) were admitted to intensive care, where two required intubation and mechanical ventilation. Typical clinical features were decreased consciousness, respiratory depression, and miosis. In eight cases, the antidote naloxone was administered to counter the effects. The serum acetylfentanyl concentration (N = 7) was 0.6-51.6 (mean 18.3 and median 14.8) ng/mL, and in urine (N = 8) 0.1-686 (mean 155 and median 66.6) ng/mmol creatinine. The serum 4-methoxybutyrfentanyl concentration (N = 2) was 1.3 and 3.1 ng/mL, and 5.1-51.3 ng/mmol creatinine in urine (N = 3). For furanylfentanyl, the serum concentrations were 4.4 and 148 ng/mL and in urine 9.2 and 85 ng/mmol creatinine, respectively. In 13 cases (93%), other NPS and/or classical drugs were also detected. Drug products brought to hospital by patients contained acetylfentanyl (nasal spray and pink tablet), 4-methoxybutyrfentanyl (green tablet), furanylfentanyl/traces of 4-methoxybutyrfentanyl (nasal spray), and 4-fluorobutyrfentanyl (purple tablet). CONCLUSION: Potentially life-threatening opioid toxicity was seen in acute intoxications involving acetylfentanyl, 4-methoxybutyrfentanyl, and furanylfentanyl. Intensive care treatment for one month was necessary in one acetylfentanyl case and one acetylfentanyl patient died from cerebral hemorrhage.

[Acute cutaneous symptom complex with subsequent cataract. The internet drug MT-45 may be the cause]. / Akut kutant symtomkomplex med efterföljande katarakt - Nätdrogen MT-45 kan vara orsaken.

The number of new psychoactive substances (¼NPS«) sold by online drug vendors (¼Internet drugs«) shows a steady increase. Over a short time period in 2013-2014, three Swedish men aged 23-34 years with suspected drug use experienced similar but unusual clinical symptoms including loss and depigmentation of hair, widespread folliculitis and dermatitis, painful intertriginous dermatitis, dryness of eyes, and elevated liver enzymes. Two also had lines of discoloration across the nails (¼Mees' lines«) of the fingers and toes. The symptoms gradually disappeared over time. However, two of them subsequently developed severe bilateral secondary cataracts requiring surgery. Blood tests for NPS performed within the Swedish STRIDA project demonstrated intake of the synthetic opioid MT-45, a piperazine derivative originally synthesized as a therapeutic drug candidate in the 1970s, in all three patients, suggesting this as a possible common causative agent. These clinical cases highlight the importance for physicians to consider the increasing number of untested recreational drugs as a potential cause of unusual clinical symptoms.

Intoxications involving MDPV in Sweden during 2010-2014: Results from the STRIDA project.

CONTEXT: In the recent years, there have been an increasing number of new psychoactive substances (NPS) available through marketing and sale on the Internet. The stimulant 3,4-methylenedioxypyrovalerone (MDPV) is a potent dopamine reuptake inhibitor, which can cause serious intoxications requiring intensive care and even fatality. This report from the STRIDA project presents the prevalence, laboratory results, and clinical features in a series of intoxications involving MDPV over a 5-year period. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presented at hospitals in Sweden from 2010 to 2014. PATIENTS AND METHODS: Blood and/or urine samples were collected from intoxicated patients with admitted or suspected intake of NPS presenting at hospitals over the country. Analysis of NPS was performed by a liquid chromatography-tandem mass spectrometry multicomponent method. Clinical data were collected when caregivers consulted the Swedish Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the poisoning severity score. RESULTS: During the 5-year study period, the number of MDPV-related inquiries to the Poisons Information Centre was 662 out of a total ∼4500 suspected NPS-related inquiries (∼15%), and 201 analytically confirmed MDPV intoxications were enrolled in the study. The study period covered the period when the use of MDPV in Sweden was at its peak and also the decline to an almost zero level. The age range of patients was 18-68 (mean 36, median 35) years, and 71% were males. The MDPV concentrations in serum ranged between 1.0 ng/mL and 1509 ng/mL (mean 63.6, median 20) and between 1.0 ng/mL and 81 000 ng/mL (mean 3880, median 1160) in urine. The urinary values were also creatinine corrected for variation in urine dilution, and the MDPV/creatinine ratio ranged between 0.10 ng/mmol and 2480 ng/mmol (mean 247, median 92.6). There was a statistically significant association between the serum MDPV concentration and the urinary MDPV/creatinine ratio, for 118 cases where both data were available (r = 0.764; p < 0.0001, Spearman's rank correlation). In 30 (15%) cases, MDPV was the single psychoactive substance identified in the serum or urine specimens. In the other 171 cases, other psychoactive substances were detected together with MDPV. The additional substances (n = 61) comprised of both conventional drugs of abuse, other NPS (n = 39), pharmaceuticals, and ethanol. The cathinone-derivative alpha-pyrrolidinovalerophenone (α-PVP) was the most frequent other NPS, and was detected in 58 (29%) cases, followed by methylone in 14 (7%) cases. The main clinical manifestations reported in patients testing positive for MDPV included agitation, tachycardia (≥100/min), and hypertension (systolic blood pressure ≥140 mmHg), which were observed in 130 (67%), 106 (56%), and 65 (34%) cases, respectively. Other symptoms included hallucinations (n = 31, 16%), delirium (n = 29, 15%), hyperthermia (>39°C/102.4°F; n = 18, 10%), and rhabdomyolysis (n = 16, 8%). In MDPV intoxications with serum levels >100 ng/mL, the cases were graded as more severe and hyperthermia was less common. CONCLUSIONS: In a large number of analytically confirmed MDPV intoxications from mostly polydrug users, the urine and serum MDPV concentrations showed a high variability. The clinical features were consistent with a severe sympathomimetic toxidrome. The results also demonstrated that MDPV prevailed as a drug of abuse for a long time, after its classification as a narcotic substance and despite a high incidence of severe poisonings.

Phencyclidine analog use in Sweden--intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project.

BACKGROUND: 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for the dissociative substance PCP ("Angel dust"), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP and/or 4-MeO-PCP within the STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with self-reported or suspected exposure to new psychoactive substances (NPS) and who require hospital care. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS analysis was performed by multicomponent liquid chromatographic-tandem mass spectrometric (LC-MS/MS) and LC-high-resolution MS (LC-HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. RESULTS: The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for 3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14-55 (median: 26) years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood pressure ≥ 140 mmHg; 7 cases), tachycardia (≥ 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation, dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1-2 days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy, 49% of the patients were treated with benzodiazepines and/or propofol. CONCLUSION: Laboratory analysis constitutes an important basis for the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4-MeO-PCP resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS, poly-substance use was found to be common.

Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project.

BACKGROUND: The supply of unregulated "new psychoactive substances" (NPS) has shown a steady increase over the past six years. This report from the Swedish STRIDA project describes analytically confirmed non-fatal intoxications involving butyrfentanyl (butyrylfentanyl) or 4-fluorobutyrfentanyl (para-fluorobutyrfentanyl), two fentanyl analogues recently introduced as NPS opioids. STUDY DESIGN: Observational case series of consecutive patients with suspected acute NPS exposure and requiring hospital care from all over Sweden. PATIENTS AND METHODS: From May 2014 to January 2015, blood and urine samples were obtained from four intoxication cases involving butyrfentanyl and one case involving 4-fluorobutyrfentanyl (men, 19-30 years) presenting in emergency departments (ED) or intensive care units (ICU). Laboratory analysis of serum and/or urine samples was performed by multi-component liquid chromatography-mass spectrometry methods. Data on clinical features were collected during consultations with the Poisons Information Centre and retrieved from medical records. CASE DETAILS: Of the five patients, two were discharged home from the ED and three were admitted to the ICU, of whom two required intubation and mechanical ventilation. Clinical features included typical opioid symptoms such as unconsciousness, respiratory depression, and apnea. In one case, naloxone successfully countered the effects. All patients were discharged the same or the following day. Butyrfentanyl was detected in two serum (0.6 and 0.9 ng/mL) and three urine (2.0-65.6 ng/mL) samples from three of four cases; three cases also contained fentanyl. In the 4-fluorobutyrfentanyl case, the substance was detected in serum (∼15 ng/mL) and urine (∼10 ng/mL). In four cases, other NPS and/or classical drugs were also detected. Analysis of two "butyrfentanyl" NPS products (nasal spray and powder) brought to hospital by patients showed that the 10-fold more potent fentanyl was the main active ingredient (∼7.5-10-fold higher amount) in both. CONCLUSION: Typical and potentially life-threatening opioid toxicity was seen in acute intoxications involving butyrfentanyl, 4F-butyrfentanyl, and fentanyl. The incorrect labelling of butyrfentanyl NPS products which instead mainly contained fentanyl is alarming, given the narrow range between a safe and a lethal dose for opioids.

Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine.

BACKGROUND: Diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) are substances with dissociative effects that were recently introduced for "recreational" purpose through the online-based sale of new psychoactive substances (NPS). A number of analytically confirmed non-fatal intoxications associated with diphenidine or MXP have occurred in Sweden and were included in the STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS and requiring intensive treatment in an emergency room and hospitalization in Sweden. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting at emergency departments all over the country. NPS analysis was performed by multi-component liquid chromatography-mass spectrometry methods. Data on clinical features were collected during telephone consultations with the Poisons Information Centre and retrieved from medical records. Information was also obtained from online drug discussion forums. CASE SERIES: Over a 12-month period from January to December 2014, 750 cases of suspected NPS intoxication originating from emergency departments were enrolled in the STRIDA project of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) tested positive for MXP. Co-exposure to several other NPS (e.g., 5-/6-(2-aminopropyl)benzofuran, 2-4-bromomethcathinone, butylone, 3,4-dichloromethylphenidate, 5-methoxy-N-isopropyltryptamine, methiopropamine, and α-pyrrolidinopentiothiophenone), also including other dissociative substances (3-/4-methoxyphencyclidine), and classical drugs of abuse (e.g., cannabis and ethanol) was documented in 87% of these cases. The 17 patients were aged 20-48 (median: 32) years, and 13 (76%) were men. They commonly presented with hypertension (76%), tachycardia (47%), anxiety (65%), and altered mental status (65%) including confusion, disorientation, dissociation, and/or hallucinations. Eight patients (47%) displayed severe intoxication (Poisoning Severity Score 3). The diphenidine- or MXP-positive patients required hospitalization for 1-3 (median: 2) days. In addition to standard supportive therapy, half of the cases were treated with benzodiazepines and/or propofol. CONCLUSION: The adverse effects noted in analytically confirmed cases of NPS intoxication involving diphenidine or MXP were similar to those reported for other dissociative substances such as ketamine and methoxetamine. However, the high proportion of polysubstance use might have played a role in the intoxication and clinical features in some cases.

Characteristics of analytically confirmed 3-MMC-related intoxications from the Swedish STRIDA project.

BACKGROUND: 3-Methylmethcathinone (3-MMC) is a synthetic cathinone stimulant structurally related to the new psychoactive substance (NPS) mephedrone (4-methylmethcathinone, 4-MMC). We describe a case series of analytically confirmed intoxications involving 3-MMC presented to emergency departments in Sweden and included in the STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with self-reported or suspected use of NPS presenting to hospitals in Sweden between August 2012 and March 2014. METHODS: NPS analysis was performed by a liquid chromatography-mass spectrometry (MS)/MS method that is updated with new substances as they appear. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. RESULTS: 3-MMC was detected in 50 (6.4%) of the 786 cases included in the STRIDA project during the 20-month study period, with the peak occurring in August 2013. The age range of patients testing positive for 3-MMC was 17-49 years (median 24) and 76% of them were men. The 3-MMC concentration in serum ranged between 0.002 and 1.49 µg/mL (median, 0.091) and between 0.007 and 290 µg/mL (median, 3.05) in urine. Co-exposure to other NPS and/or traditional drugs was very common, and 3-MMC mono-intoxication was found in only 4 (8%) cases. The most frequent clinical features were tachycardia (48% of cases) and agitation (42%). Other features included a reduced level of consciousness (32%), dilated pupils (24%), hallucinations (20%), diaphoresis (12%), seizures (8%), and hyperthermia (6%). Most patients (60%) needed hospital care for only 1 day but in 8% for 3 days or longer. CONCLUSION: The majority of patients with analytically confirmed 3-MMC exposure had sympathomimetic features similar to those associated with mephedrone intoxication. However, the high incidence of co-exposure to other drugs makes the clinical interpretation difficult. Nevertheless, 3-MMC was associated with a high admittance rate to intensive care (30%), and detected in two cases with a fatal outcome, suggesting that 3-MMC is a harmful drug.