An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users.

OBJECTIVE: Previous research reported cognitive and psychomotor impairments in long-term users of benzodiazepine receptor agonists (BZRAs). This article explores the role of acute intoxication and clinical complaints. METHODS: Neurocognitive and on-road driving performance of 19 long-term (≥6 months) regular (≥twice weekly) BZRA users with estimated plasma concentrations, based on self-reported use, exceeding the therapeutic threshold (CBZRA +), and 31 long-term regular BZRA users below (CBZRA -), was compared to that of 76 controls. RESULTS: BZRA users performed worse on tasks of response speed, processing speed, and sustained attention. Age, but not CBZRA or self-reported clinical complaints, was a significant covariate. Road-tracking performance was explained by CBZRA only. The CBZRA  + group exhibited increased mean standard deviation of lateral position comparable to that at blood-alcohol concentrations of 0.5 g/L. CONCLUSIONS: Functional impairments in long-term BZRA users are not attributable to self-reported clinical complaints or estimated BZRA concentrations, except for road-tracking, which was impaired in CBZRA + users. Limitations to address are the lack of assessment of objective clinical complaints, acute task related stress, and actual BZRA plasma concentrations. In conclusion, the results confirm previous findings that demonstrate inferior performance across several psychomotor and neurocognitive domains in long-term BZRA users.

Driving performance and neurocognitive skills of long-term users of sedating antidepressants.

OBJECTIVE: To assess driving performance and neurocognitive skills of long-term users of sedating antidepressants, in comparison to healthy controls. METHODS: Thirty-eight long-term (>6 months) users of amitriptyline (n = 13) and mirtazapine (n = 25) were compared to 65 healthy controls. Driving performance was assessed using a 1-h standardised highway driving test in actual traffic, with road-tracking error (standard deviation of lateral position [SDLP]) being the primary measure. Secondary measures included neurocognitive tasks related to driving. Performance differences between groups were compared to those of blood alcohol concentrations of 0.5 mg/ml to determine clinical relevance. RESULTS: Compared to controls, mean increase in SDLP of all antidepressant users was not significant, nor clinically relevant (+0.75 cm, 95% CI: -0.83 cm; +2.33 cm). However, users treated less than 3 years (n = 20) did show a significant and clinically relevant increase in SDLP (+2.05 cm). No significant effects were observed on neurocognitive tasks for any user group, although large individual differences were present. Most results from neurocognitive tests were inconclusive, while a few parameters confirmed non-inferiority for users treated longer than 3 years. CONCLUSION: The impairing effects of antidepressant treatment on driving performance and neurocognition mitigate over time following long-term use of 3 years.

Driving performance and neurocognitive skills of long-term users of benzodiazepine anxiolytics and hypnotics.

OBJECTIVE: The aim of this study is to compare actual driving performance and skills related to driving of patients using benzodiazepine anxiolytics or hypnotics for at least 6 months to that of healthy controls. METHODS: Participants were 44 long-term users of benzodiazepine and benzodiazepine-related anxiolytics (n = 12) and hypnotics (n = 32) and 65 matched healthy controls. Performance was assessed using an on-the-road driving test measuring standard deviation of lateral position (SDLP, in cm) and a battery of neurocognitive tasks. Performance differences between groups were compared with a blood alcohol concentration of 0.5 mg/ml to determine clinical relevance. RESULTS: Compared with controls, SDLP was significantly increased in hypnotic users (+1.70 cm) but not in anxiolytic users (+1.48 cm). Anxiolytic and hypnotic users showed significant and clinically relevant impairment on neurocognitive task measuring executive functioning, vigilance, and reaction time. For patients using hypnotics for at least 3 years, no significant driving impairment was observed. CONCLUSION: Impairing effects of benzodiazepine hypnotics on driving performance may mitigate over time following longer term use (i.e. 3 years or more) although neurocognitive impairments may remain.

A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.

When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.

Effects of alcohol (BAC 0.5‰) and ecstasy (MDMA 100 mg) on simulated driving performance and traffic safety.

RATIONAL: An increasing number of fatal road-accidents have been reported in which ecstasy was found in the blood of drivers. Although, ecstasy is frequently found to have been used in combination with alcohol, studies on the acute effects of ecstasy co-administered with alcohol on driving performance are relatively rare. OBJECTIVE: The present study was designed to establish the extent of driver impairment as a consequence of ecstasy or combined ecstasy and alcohol use as compared to driving under the influence of 0.3‰, 0.5‰ and 0.8‰ alcohol. Furthermore, subjective performance was also assessed. RESULTS: Alcohol and ecstasy mainly influenced automated driving performance such as lateral and speed control. However, small to no effects of the substances were found on more complex driving behaviour. Overall, variance within the different driving measures was high especially when participants were treated with 3.4-methylenedioxy-methamphetamine (MDMA) and alcohol. Furthermore, equivalence testing showed that combined use may lead to impaired driving for some, but not all, drivers. Participants rated their own performance to be slightly worse than normal in both studies. Since driving was actually seriously deteriorated, this was a falsely positive assessment of their condition. CONCLUSIONS: The dissociation between subjective perceptions and objective performance decrements are important notions for traffic safety since this may affect a driver's judgement of whether or not it is safe to drive. For example, an intoxicated individual might decide to drive because the feelings of alertness caused by MDMA cloud the impairing effects of other drugs such as alcohol, thereby creating a potentially serious risk for traffic safety.

[Determination of blood/serum ratios of different forensically relevant analytes in authentic samples]. / Bestimmung der Blut/Serum-verhältnisse verschiedener forensisch relevanter Analyten in authentischen Proben.

For forensic toxicological investigations only whole blood, but no serum is often available. Pharmacokinetic data are helpful for interpreting the results, but most of these studies indicate serum or plasma concentrations. In order to obtain reliable conversion factors which also take intersubject variability into account, the blood/serum ratios (B/S) of oxycodone, morphine, fentanyl, hydromorphone, zopiclone, MDMA, dexamphetamine, alprazolam, risperidone and 9-hydroxyrisperidone were determined by LC-MS/MS using authentic samples. Blood and corresponding serum samples were obtained from driving studies performed with controlled or known dosages of the above drugs. The analytes were analysed in blood and serum and the following mean B/S ratios (relative standard deviations) were determined: oxycodone 1.48 (8.19 %); morphine 1.03 (3.59 %); fentanyl 0.87 (13.9 %); hydromorphone 1.04 (8.11 %); zopiclone 0.89 (16.1 %); MDMA 1.19 (8.04 %); dexamphetamine 0.89 (10.9 %); alprazolam 0.81 (5.84 %); risperidone 0.65 (7.52 %); 9-hydroxyrisperidone 0.73 (12.3 %). These mean values are largely in line with those reported in the literature. The B/S ratios did not appear to depend on partition coefficients, whereas there was strong evidence that B/S ratios decreased with increasing plasma protein binding.

Analysis of 3,4-methylenedioxymetamphetamine: whole blood versus dried blood spots.

Analysis of dried blood spots is an increasingly accepted method in therapeutic drug monitoring, whereas its application by analogy to forensic samples has not been studied in detail. Therefore, we investigated whether determination of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolite 3,4-methylendioxyamphetamine (MDA) from dried blood spots (DBS) is as reliable as that from whole blood specimens. Analysis was performed by liquid chromatography-tandem mass spectrometry following liquid-liquid extraction of blood and corresponding DBS samples from 20 volunteers participating in a controlled driving experiment under the influence of MDMA. The assay was checked for carryover, ion suppression/enhancement, linearity of response, lower limits of detection (LLOD) and quantitation, extraction efficiency and the within-run and between-run assay imprecision for both whole blood and DBS. The LLODs were 2.0 and 1.6 ng/mL for MDMA in whole blood and DBS, respectively, using a volume of 100 µL. LLODs of MDA were determined to be 0.25 ng/mL in whole blood specimens and 0.12 ng/mL in DBS. Extraction efficiency and imprecision did not differ significantly between the two methods for both MDMA and MDA. The mean concentration ratio of corresponding whole blood and DBS samples, t-test, and the Bland-Altman difference plot were used to test hypothesis of equality. Statistical analyses revealed that methods did not significantly differ for MDMA or MDA. Thus, DBS analysis has potential as a precise and inexpensive alternative to whole blood analysis of MDMA.

Drugs of abuse, driving and traffic safety.

Roadside studies indicate that 1-15% of drivers drive under the influence of one or more drugs of abuse. After drug use, drivers are more often culpable for an accident than non-users. Information on drugs and traffic safety comes from roadside studies, epidemiological research, experimental studies on driving-related skills, and on-the-road driving tests. Road-side studies show that drivers most frequently test positive for the use of alcohol and/or cannabis. These two drugs affect driving ability in a dose-dependent matter and result in poor vehicle control, especially when used in combination. Drivers on cocaine, ecstasy and amphetamine show no impairment on basic driving skills, but often overestimate their driving skills. In combination with impaired decision making, this increases risk taking during driving. Only few studies looked at the effects on driving of other drugs of abuse, such as ketamine, inhalants and anabolic steroids, but suggest a negative effect on driving performance. In conclusion, most drugs of abuse negatively affect driving ability, especially when used in combination with alcohol or another drug. It is of concern that a substantial number of drug users are not aware that their driving is impaired.