Fatalities, Cerebral Hemorrhage, and Severe Cardiovascular Toxicity After Exposure to the New Psychoactive Substance 4-Fluoroamphetamine: A Prospective Cohort Study.

STUDY OBJECTIVE: We study adverse health effects after use of the new psychoactive substance 4-fluoroamphetamine. METHODS: All patients who reported 4-fluoroamphetamine exposure and for whom the Dutch Poisons Information Center was consulted by their physician in 2016 were included in a prospective cohort study. The clinical course was investigated through telephone interviews with the physician and/or patient, using standardized questionnaires. 4-Fluoroamphetamine was analyzed in remaining drug material and biological samples with liquid and gas chromatography-mass spectrometry techniques. RESULTS: We included 45 patients, and follow-up with the physician and/or patient was performed in 33 cases. All patients experienced adverse effects after 4-fluoroamphetamine use. Severe toxicity was reported in 8 patients. In 5 of these patients, 4-fluoroamphetamine exposure was confirmed in biological specimens. Severe toxicity that was reported included 2 fatalities, 4 patients with cerebral hemorrhage (1 fatal), 2 patients with inverted Takotsubo's cardiomyopathy, 1 patient with myocardial infarction, 1 patient with acute heart failure, and an overall high prevalence of pronounced hypertension and tachycardia. CONCLUSION: Since the introduction of 4-fluoroamphetamine to the Dutch drug market in 2007, its use continues to increase, possibly because users perceive it as "ecstasy light" and thus relatively safe. However, the proportion of patients with severe toxicity after 4-fluoroamphetamine use is relatively large in our study population. Therefore, users should be warned about the risks of 4-fluoroamphetamine.

Prevalence of medicinal drugs in suspected impaired drivers and a comparison with the use in the general Dutch population.

The aim of this study was to investigate the prevalence of psychotropic medicines in drivers suspected of driving under the influence of medicinal and illicit drugs in The Netherlands and to compare the prevalence of selected impairing medicines with the use of these medicines in the general Dutch population. In total, 3038 blood samples of suspected impaired drivers in The Netherlands have been analyzed for the presence of medicinal and illicit drugs between January 2009 and December 2012. In 94% (2842/3038) of the cases medicinal and/or illicit drugs were detected. Medicinal drugs were found in 33% of the blood samples, with the highest prevalence for anxiolytics. In 86% of the cases illicit drug-positive results were obtained, with the highest prevalence for cannabis. At least in 56% of the blood samples poly-drug use was determined, including medicinal and/or illicit drugs. The highest prevalence of poly-medicine use was found for combinations including anxiolytic and hypnotic drugs. In general, the prevalence of driving impairing medicines in suspected impaired drivers is higher than the use of these medicines in the general Dutch population, due to a positive selection bias in the first population. Differences between both populations may be explained by the used methodological approach (e.g., classification criteria of analytical findings, sample selection bias) and abuse of certain medicinal drugs (e.g., diazepam). Negative effects of medicinal drugs on driving performance determine largely the prevalence in the population of suspected impaired drivers. The degree of impairment depends on different factors, including pharmacokinetic properties of the drug and pharmacodynamic aspects. More research is needed to study the prevalence of all prescribed driving impairing medicines and to investigate if providing additional information to medicinal drug users on driving impairing medicines would lower the prevalence of medicinal drug positive drivers.

Repeatability of oral fluid collection methods for THC measurement.

STUDY OBJECTIVES: To determine the influence of sample collection for two different collection methods on THC concentrations and to compare THC concentrations collected by both methods. METHODS: A total of 136 pairs of oral fluid samples from subjects who had recently smoked Cannabis were obtained by the non-acidic Statsure oral fluid collection device and by ordinary spit tubes. Oral fluid was analyzed for THC by LC-MS/MS. Bland-Altman plots were used for the quantitative analysis of repeatability, whereas Cohen's kappa was used for qualitative analysis to determine the consistency of the results with regard to the Belgian legal limit. RESULTS: Repeatability of both sampling methods was very low. The Statsure device had a better rate of agreement when compared with the Belgian legal limit than the spitting method. THC concentrations of samples collected by spit tubes were on average a factor 5.9 higher than the corresponding concentrations in samples collected by the Statsure device. CONCLUSIONS: The repeatability of both the Statsure collection method and the ordinary spit tubes was low when applied to subjects who had consumed Cannabis very recently. Furthermore, THC concentrations were higher in samples obtained by spitting than samples collected with Statsure. These results may have implications for confirmation analysis in oral fluid, when applied for legal purposes.

An analytical evaluation of eight on-site oral fluid drug screening devices using laboratory confirmation results from oral fluid.

The performance of eight on-site oral fluid drug screening devices was studied in Belgium, Finland and the Netherlands as a part of the EU-project DRUID. The main objective of the study was to evaluate the reliability of the devices for testing drivers suspected of driving under the influence of drugs (DUID). The performance of the devices was assessed by their ability to detect substances using cut-offs which were set at sufficiently low levels to allow optimal detection of positive DUID cases. The devices were evaluated for the detection of amphetamine(s), cannabis, cocaine, opiates and benzodiazepines when the relevant test was incorporated. Methamphetamine, MDMA and PCP tests that were included in some devices were not evaluated since there were too few positive samples. The device results were compared with confirmation analysis results in oral fluid. The opiates tests appeared to perform relatively well with sensitivity results between 69 and 90%. Amphetamines and benzodiazepines tests had lower sensitivity, although the DrugWipe test evaluated was promising for amphetamine. In particular, it is evident that the cannabis and cocaine tests of the devices still lack sensitivity, although further testing of the cocaine tests is desirable due to the low prevalence and low concentrations encountered in this study.

The relationship between benzodiazepine use and traffic accidents: A systematic literature review.

In many countries, benzodiazepines are the most commonly used and misused psychoactive medicinal drugs. Results of epidemiological studies investigating the association between benzodiazepine use and traffic accidents seem to be inconclusive or inconsistent at first sight. However, the outcome of epidemiological studies may be influenced by several methodological factors like study design, study population, exposure measurement, outcome definitions and possible confounders. Our objective was to conduct a systematic literature review of epidemiological studies that investigated the association between benzodiazepine use and traffic accidents, including related outcomes like culpability and injury or accident severity. We searched EMBASE, PubMed and Forensic Science Abstracts 3/0 (FORS) for references included in these databases at 1 June 2009 using the term 'benzodiazepines' in combination with 'driving performance' or 'accident risk' or 'traffic accident'. For inclusion in this review, the study design had to be comparative, include road users involved in accidents and provide specific data about benzodiazepines. Sixty-six studies were included in the review. The study populations varied from the general (driving) population, accident-involved road users with or without injury and persons admitted to a hospital to fatally injured accident-involved drivers. Exposure assessment was performed by using toxicological results, prescription data or questionnaires. The divergent study populations and comparison groups and the variety of methods used to express the outcome of interest hampered comparison between results. Evidence is growing that exposure to benzodiazepines is related to increased accident risk. The literature indicates that the greatest accident risk is associated with the use of long half-life benzodiazepines, increasing dosage and the first few weeks of use of benzodiazepines. Clear evidence of increased culpability associated with benzodiazepine use is scarce. More research has to be done to elucidate the relationship between benzodiazepine use and injury severity.

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam.

AIMS: To measure and compare the concentration-time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing. METHODS: Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration-time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model. RESULTS: For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04-0.07) and 0.004 (range 0.002-0.006), respectively. The concentration-time profiles in oral fluid paralleled those in blood. CONCLUSION: After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

Post-mortem cases involving amphetamine-based drugs in The Netherlands. Comparison with driving under the influence cases.

In this study we reviewed the post-mortem cases in the years 1999-2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death. In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41-84 mg/L with a median concentration of 3.7 mg/L (n=30). MDMA blood concentrations in the MDMA related deaths (n=20) and in the DUI cases (n=360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n=7). The median concentrations of amphetamine in the amphetamine related deaths (n=13) and the DUI cases (n=208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.

Cognitive, psychomotor and actual driving performance in healthy volunteers after immediate and extended release formulations of alprazolam 1 mg.

RATIONALE: Alprazolam extended-release (XR) is approved for the treatment of panic disorder. This sustained formulation is absorbed in a delayed manner and is therefore expected to produce fewer and less severe side effects than its immediate release equivalent (alprazolam IR). The effect of alprazolam XR on potentially dangerous daily activities, such as driving a car, is expected to be less as compared to alprazolam IR. OBJECTIVES: The present study was designed to compare the effects of alprazolam XR (1 mg) and alprazolam IR (1 mg) on actual driving ability and cognitive function. METHOD: Eighteen healthy volunteers (aged 20-45 years) participated in a double-blind, placebo-controlled, three-way crossover study. At 4 h post-dose, subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed 1, 2.5, and 5.5 h post-dose. Memory functioning was measured only 1 h after administration. RESULTS: Both formulations severely impaired driving performance between 4 and 5 h after administration. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. CONCLUSIONS: The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate-release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.