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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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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.

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.

The number of new psychoactive substances (»NPS«) sold by online drug vendors (»Internet 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 (»Mees' 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.

The "STRIDA" project monitors the occurrence and trends of new psychoactive substances (NPS; "Internet drugs/designer drugs/legal highs") in Sweden, and collects information about their clinical symptoms, toxicity and associated health hazards. The initial results of the project documented a widespread use of many different NPS by mainly adolescents and young (age range 13-63 years, median 20), male (79%) adults, among cases of drug intoxications presenting at emergency departments and intensive care units across the country. The new substances were identified in samples of urine and blood by a multi-component LC-MS/MS method, and the severity of clinical symptoms were graded by the Poisoning Severity Score (PSS). Of the initial 189 samples submitted for laboratory investigation, 156 (83%) tested positive for at least one drug. Besides classical substances such as ethanol, cannabis and amphetamines, many NPS were detected comprising synthetic cannabinoid receptor agonists ("Spice"), piperazines, substituted phenethylamines, synthetic cathinones, hallucinogenic tryptamines, piperidines, opioid related substances, ketamine and related substances, and GABA analogues (in total more than 50 substances). About half of the cases were demonstrated to be multiple drug intoxications, sometimes making it hard to associate the clinical presentations with one specific substance. In conclusion, the STRIDA project has documented use of a broad variety of NPS among mainly young people all over Sweden., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

During the last years several synthetic opioids have been introduced on Internet sites selling new psychoactive substances (NPS). One of these, called MT-45, a piperazine derivative originally synthesized as a therapeutic drug candidate in the 1970s, has recently been detected in 21 deaths, according to unpublished data from the Swedish National Board of Forensic Medicine. We present clinical data from 12 analytically confirmed hospital cases of MT-45 poisoning. The cases demonstrate that MT-45, like other opioids, can induce potentially life threatening respiratory depression and loss of consciousness in users and that symptoms are usually reversed by standard doses of the opioid receptor antagonist naloxone. Significant auditory symptoms with transient tinnitus and hearing loss occurred in two cases and a pronounced sensorineural hearing loss still present at two weeks follow-up in one case. This indicates that MT-45 may be an ototoxic substance, illustrating the ubiquitous risk of unintended adverse effects NPSs pose to users.