Significant toxicity following an increase in poisonings with designer benzodiazepines in the Netherlands between 2010 and 2020

BACKGROUND: Designer benzodiazepines (DBs) are an emerging class of new psychoactive substances. While structurally derived from pharmaceutical benzodiazepines, their toxicological profile is less clear. We investigated time trends in the rate of DB poisonings and their clinical toxicity. METHODS: A retrospective observational study was performed on the incidence rate of DB poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010 to 2020. Time-trend analysis was performed using Poisson regression. A prospective cohort study was performed on toxicity of DBs, including the Poisoning Severity Score, from January 2016-June 2019. Data was collected through telephone interviews. RESULTS: Between 2010 and 2020, the DPIC was consulted on 142 DB exposures. The incidence rate of DB exposures increased from 0.1% to 4.3%, with a year effect estimate of 1.35 (95% CI [1.14;1.54]). Twenty different DBs were reported, mostly etizolam (33%), clonazolam (17%), and flunitrazolam (8%). During consultation (often shortly after exposure), poisoning was graded moderate-severe in 29% of cases (n = 146). In the prospective cohort sample with follow-up (n = 22), 86% of cases (n = 19) showed a moderate-severe poisoning. The severity of poisoning did not differ between mono- and mixed intoxications. Frequently reported symptoms in the prospective cohort sample included drowsiness (86%), confusion (59%), and agitation (55%). Coma was observed in seven cases (32%) and respiratory depression requiring mechanical ventilation in five cases (23%). CONCLUSION: The rate of DB poisonings reported to the DPIC strongly increased from 2010 to 2020, indicating increased (ab)use of DBs. Most DB exposures resulted in moderate-severe toxicity with neurological effects

High Incidence of Signs of Neuropathy and Self-Reported Substance Use Disorder for Nitrous Oxide in Patients Intoxicated with Nitrous Oxide

Introduction: The number of patients with excessive nitrous oxide (N2O) use and neurological disorders has been rising, indicating an addictive potential of N2O. We studied the incidence of self-reported substance use disorder (SUD)-related symptoms, signs of neuropathy, and the patterns of use in N2O-intoxicated patients. Methods: The Dutch Poisons Information Center (DPIC) provides information by telephone on the management of intoxications to healthcare professionals. Retrospective data on signs of neuropathy and patterns of use were collected for all N2O intoxications reported to the DPIC in 2021 and 2022. Frequent and heavy use were self-reported as "often/frequent/weekly use"and as "use of tanks or >50 balloons/session,"respectively. From this cohort, we included patients with excessive N2O use or signs of neuropathy in a prospective observational cohort study. Online surveys were sent 1 week, 1 month, and 3 months after DPIC consultation. The survey included the drug use disorder questionnaire (validated to measure self-reported substance abuse [SA] and substance dependence [SD] based on Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR criteria) and questions on patterns of use and signs of neuropathy. DSM-IV-TR criteria were translated to DSM-V criteria to score for mild, moderate, or severe SUD, with 2-3, 4-5, or ≥6 symptoms, respectively. Results: We included 101 N2O-intoxicated patients in the retrospective study. Of these, 41% showed signs of neuropathy (N = 41), 53% used N2O tanks to fill balloons (N = 53), 71% used them frequently (N = 72), and 76% used them heavily (N = 77). We included 75 patients in the prospective study and 10 (13%) completed the first survey. All 10 patients fulfilled the criteria for SA and SD (DSM-IV-TR, median number of questions answered "yes"= 10/12), all used N2O tanks to fill balloons, and 90% (N = 9) experienced signs of neuropathy. After 1 and 3 months, 6/7 and 1/1 patients, respectively, continued to fulfill SA and SD criteria. Translating to DSM-V criteria, 1/10 patients fulfilled the criteria for (self-reported) mild SUD, 1/10 patients for moderate SUD, and 8/10 patients for severe SUD, 1 week after consultation. Conclusion: The high proportion of N2O-intoxicated patients reporting frequent and heavy use of N2O indicates an addictive potential of N2O. Although follow-up rate was low, all patients fulfilled self-reported SA, SD (DSM-IV-TR), and SUD (DSM-V) criteria for N2O. Somatic healthcare professionals treating patients with N2O intoxications should be aware of possible addictive behavior in patients. The screening, brief intervention, and referral to treatment approach should be considered to treat patients with self-reported SUD symptoms

Monitoring new psychoactive substances (NPS) in The Netherlands: data from the drug market and the Poisons Information Centre

In recent years, the number of new psychoactive substances (NPS) appearing on the illicit drug market strongly increased. However, little is known about their toxic effects and risks. Therefore, we determined the most frequently occurring NPS in The Netherlands and combined this with data regarding drug-related intoxications. Data from the Drugs Information and Monitoring System (DIMS) and the Dutch Poisons Information Centre (DPIC) were combined and jointly analyzed. The number of drug samples submitted to DIMS for analysis containing NPS increased from 22 in 2007 to 431 samples in 2013. The most frequently submitted NPS in 2013 included 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA), methoxetamine (MXE) and 6-(2-aminopropyl)benzofuran (6-APB). From 2012 onwards, the number of NPS bought as drug of choice exceeded those appearing as adulterants in established drugs. The DPIC was consulted about 35 NPS exposures in 2013, most frequently involving 4-FA, mephedrone, MXE, 2C-B and 6-APB. Following NPS exposure, neurological and psychological symptoms were most frequently reported, like agitation and hallucinations. In addition, cardiovascular symptoms like hypertension and tachycardia often occurred. NPS are currently being purchased as drug of choice in The Netherlands and their availability and use is increasing. Although pharmacological and toxicological data are scarce, NPS can induce pronounced clinical effects. Therefore, the monitoring of trends in NPS prevalence needs to be continued, combined with reported clinical effects, and preferably supported by analytical confirmation of exposures in such patient

Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans

Background: Recently, the number of new psychoactive substances (NPS) appearing on the illicit drug market has shown a marked increase. Although many users perceive the risk of using NPS as medium or low, these substances can pose a serious health risk and several NPS have been implicated in drug-related deaths. In Europe, frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA) and benzofurans (5-(2-aminopropyl)benzofuran (5-APB) or 6-(2-aminopropyl)benzofuran (6-APB)). However, little is known about the health risks of these specific NPS. Methods: In this paper, existing literature on the pharmacokinetics and pharmacodynamics of 2C-B, 4-FA and benzofurans (5-APB/6-APB) was reviewed. Results: Our review showed that the clinical effects of 2C-B, 4-FA and benzofurans (5-APB/6-APB) are comparable with common illicit drugs like amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Therefore, NPS toxicity can be handled by existing treatment guidelines that are based on clinical effects instead of the specific drug involved. Even so, information on the health risks of these substances is limited to a number of case reports that are complicated by confounders such as analytical difficulties, mislabelling of drugs, concomitant exposures and interindividual differences. Conclusion: To aid in early legislation, data on clinical effects from poisons centres and user fora should be combined with (in vitro) screening methods and collaboration on an (inter)national level is essential. As a result, potentially hazardous NPS could be detected more quickly, thereby protecting public health. (C) 2015 Elsevier Ireland Ltd. All rights reserve

New psychoactive substances (NPS) in the Netherlands : occurrence in forensic drug samples, consumer drug samples and poisons center exposures between 2013 and 2017

Background and Aims Although European-wide data on the new psychoactive substances (NPS) drug market are available, country-specific data are limited. We studied recent NPS trend data relative to all recreational drugs on the Dutch drugmarket. Design National observational study. Setting The Netherlands. Data sources Three national indicators were used between 2013 and 2017: (1) forensic drug samples offered to the Netherlands Forensic Institute (NFI); (2) drug samples submitted by consumers to the Drugs Information and Monitoring System (DIMS); and (3) exposures in which the Dutch Poisons Information Center (DPIC) was consulted. Measurements Overall NPS incidence rate was the primary outcome. Numbers and specific categories of NPS were also studied. Changes in NPS incidence rates over time were analyzed using Poisson regression analyses [year effect expressed as incidence rate ratios (IRR)]. Findings From 2013 to 2017, NPS were involved in 1892 forensic samples, 6316 consumer samples and 481 poisons center exposures. In 2013, NPS incidence rates were 2.5, 7 and 4% versus 3, 11 and 11% in 2017, respectively, in the NFI, DIMS and DPIC samples/exposures. NPS incidence rates increased significantly in consumer samples between 2013 and 2016 [IRR=1.23; 95% confidence interval (CI) = 1.18, 1.29] and in poisons center exposures between 2013 and 2017 (IRR = 1.19; 95% CI = 1.06, 1.35), while the trend in forensic samples appeared more stable. Phenethylamines were the largest class and were detected in 58, 80 and 63% of NFI, DIMS and DPIC samples/exposures, respectively. Detected phenethylamines mainly involved 4-fluoroamphetamine and 2C-x derivatives. The second largest class were cathinones, which were detected in 21, 11 and 16% of NFI, DIMS and DPIC samples/exposures, respectively. Conclusions Analysis of forensic drug samples, consumer drug samples and exposures reported to poison centers from 2013 to 2017 shows the constant presence of new psychoactive substances on the Dutch drug market and its use by the Dutch population. The two largest classes present in the Netherlands were phenethylamines and cathinones

The Clinical Toxicology of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B): The Severity of Poisoning After Exposure to Low to Moderate and High Doses.

STUDY OBJECTIVE: We studied the severity of poisoning after exposure to low to moderate and high doses of 4-bromo-2,5-dimethoxyphenethylamine (2C-B). METHODS: Patients for whom the Dutch Poisons Information Centre was consulted for 2C-B exposure from 2016 to 2018 were included in a prospective cohort study. Data were collected through telephone interviews with the physician or patient. Patients were categorized according to the reported 2C-B dose: low to moderate (up to 20 mg), high (greater than 20 mg), or unknown. Presence of 2C-B was analyzed in leftover drug and biological samples with liquid/gas chromatography-mass spectrometry. The severity of poisoning was graded with the Poisoning Severity Score. RESULTS: We included 59 patients, of whom 32 could be followed up. Low to moderate 2C-B doses were reported by 9 patients (28%), high doses by 17 (53%), and unknown doses by 6 (19%). Poisoning was moderate in the majority of patients in both the low- to moderate-dose and high-dose groups. Frequently reported symptoms included mydriasis, agitation or aggression, hallucinations, confusion, anxiety, hypertension, and tachycardia. The presence of 2C-B was confirmed in 5 patients in urine (n=3) or drug samples (n=4). CONCLUSION: In this study, most 2C-B poisonings resulted in moderate toxicity even at high reported doses up to 192 mg. No severe cases were observed. The clinical course was usually short-lived (up to 24 hours) and typically involved hallucinations in addition to mild somatic effects

Intoxicatie met nieuwe psychoactieve stoffen

Abuse of new psychoactive substances (NPS) and the number of patients presenting to the ER with intoxication are increasing. Treatment may at first sight seem complicated because of limited knowledge of the substance involved, but should be based on a general supportive approach recognising the relatively predictable spectrum of symptoms caused by adrenergic, serotonergic and dopaminergic stimulation. In this article, we discuss the vital elements of this approach and possible complications of NPS intoxication. This is illustrated by two 20-year-old male patients with NPS intoxication who presented to our ER as participants in a group intoxication. Patient A suffered from mild symptoms and tested positive for 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (2C-I-NBOMe) only. Patient B presented with agitated delirium and tested positive for both 2C-I-NBOMe and cocaine. While patient A was treated with benzodiazepines and rehydration, patient B required sedation, intubation and short-term ventilation

New psychoactive substances (NPS) in the Netherlands: occurrence in forensic drug samples, consumer drug samples and poisons center exposures between 2013 and 2017

Background and Aims Although European-wide data on the new psychoactive substances (NPS) drug market are available, country-specific data are limited. We studied recent NPS trend data relative to all recreational drugs on the Dutch drugmarket. Design National observational study. Setting The Netherlands. Data sources Three national indicators were used between 2013 and 2017: (1) forensic drug samples offered to the Netherlands Forensic Institute (NFI); (2) drug samples submitted by consumers to the Drugs Information and Monitoring System (DIMS); and (3) exposures in which the Dutch Poisons Information Center (DPIC) was consulted. Measurements Overall NPS incidence rate was the primary outcome. Numbers and specific categories of NPS were also studied. Changes in NPS incidence rates over time were analyzed using Poisson regression analyses [year effect expressed as incidence rate ratios (IRR)]. Findings From 2013 to 2017, NPS were involved in 1892 forensic samples, 6316 consumer samples and 481 poisons center exposures. In 2013, NPS incidence rates were 2.5, 7 and 4% versus 3, 11 and 11% in 2017, respectively, in the NFI, DIMS and DPIC samples/exposures. NPS incidence rates increased significantly in consumer samples between 2013 and 2016 [IRR=1.23; 95% confidence interval (CI) = 1.18, 1.29] and in poisons center exposures between 2013 and 2017 (IRR = 1.19; 95% CI = 1.06, 1.35), while the trend in forensic samples appeared more stable. Phenethylamines were the largest class and were detected in 58, 80 and 63% of NFI, DIMS and DPIC samples/exposures, respectively. Detected phenethylamines mainly involved 4-fluoroamphetamine and 2C-x derivatives. The second largest class were cathinones, which were detected in 21, 11 and 16% of NFI, DIMS and DPIC samples/exposures, respectively. Conclusions Analysis of forensic drug samples, consumer drug samples and exposures reported to poison centers from 2013 to 2017 shows the constant presence of new psychoactive substances on the Dutch drug market and its use by the Dutch population. The two largest classes present in the Netherlands were phenethylamines and cathinones

Intoxicatie met nieuwe psychoactieve stoffen

Abuse of new psychoactive substances (NPS) and the number of patients presenting to the ER with intoxication are increasing. Treatment may at first sight seem complicated because of limited knowledge of the substance involved, but should be based on a general supportive approach recognising the relatively predictable spectrum of symptoms caused by adrenergic, serotonergic and dopaminergic stimulation. In this article, we discuss the vital elements of this approach and possible complications of NPS intoxication. This is illustrated by two 20-year-old male patients with NPS intoxication who presented to our ER as participants in a group intoxication. Patient A suffered from mild symptoms and tested positive for 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (2C-I-NBOMe) only. Patient B presented with agitated delirium and tested positive for both 2C-I-NBOMe and cocaine. While patient A was treated with benzodiazepines and rehydration, patient B required sedation, intubation and short-term ventilation

3-Methylmethcathinone (3-MMC) Poisonings: Acute Clinical Toxicity and Time Trend Between 2013 and 2021 in the Netherlands.

STUDY OBJECTIVE: The synthetic cathinone 3-methylmethcathinone (3-MMC, or metaphedrone) has recently gained popularity. We studied the numbers of 3-MMC poisonings over time and the clinical effects following poisonings with 3-MMC. METHODS: We performed a retrospective study on the numbers of self-reported 3-MMC poisonings to the Dutch Poisons Information Center (DPIC) from 2013 to June 2021. For poisonings reporting 3-MMC only, the symptoms were extracted and the Poisoning Severity Score (PSS) was determined. From 2016 to June 2019, a prospective cohort study on poisonings reporting only 3-MMC was performed, in which details on the clinical courses were collected through telephone interviews. RESULTS: From 2013 to June 2021, the DPIC was consulted on 184 3-MMC poisonings. The number of poisonings increased from 1 in 2013 to 70 in the first half of 2021. In 84 poisonings with only 3-MMC (46%), sympathomimetic symptoms were commonly reported, including tachycardia (n=29, 35%), hypertension (n=17, 20%), and agitation (n=16, 19%). The initial PSS was usually minor (n=37, 44%) to moderate (n=39, 46%). Five patients (6%) experienced severe effects, including 3 patients experienced severe hypertension (systolic blood pressure >180 mmHg; n=3) and nonfatal cardiac arrest (n=1). Sympathomimetic symptoms (n=8) were also reported in the prospective cohort study. The percentage of moderate poisonings increased (n=6, 75%), and 1 (13%) severe poisoning was observed. Analytical confirmation of 3-MMC exposure was performed in 2 cases. CONCLUSION: The number of 3-MMC poisonings reported to the DPIC has increased over time. Most poisonings with 3-MMC resulted in moderate toxicity and involved sympathomimetic effects, while severe effects were observed in 5 cases