A two-sample approach to retrograde extrapolation of blood THC concentrations - Is it feasible?

BACKGROUND: Retrograde extrapolation of drug concentrations in blood can be relevant in cases of drug-impaired driving and is regularly used in forensic toxicology in Norway. Δ9-tetrahydrocannabinol (THC) has complex, multi-compartmental pharmacokinetics, which makes retrograde extrapolation of blood THC concentrations problematic. In the present study, we evaluated an approach to retrograde extrapolation in which momentary rates of decrease of THC were estimated from two consecutive blood samples in apprehended drivers. MATERIAL AND METHODS: Data were collected from apprehended drivers in Norway 2000-2020. We included 548 cases in which THC was detected in two consecutive blood samples collected ≥ 20 min apart. THC concentrations were measured by GC-MS and UHPLC-MS/MS. In each case, THC concentrations and the time between the two sampling points (Δt) were used to estimate the rate constant k. The relationship between THC concentration and k was modelled by linear regression. RESULTS: The median Δt was 31 min (interquartile range, IQR = 9). The median blood THC concentration was 2.4 µg/L (IQR = 3.4) at the first sampling point and 2.3 µg/L (IQR =3.1) at the second. The concentration decreased in 62% and increased in 38% of all cases. However, considering measurement uncertainty, the changes were not statistically significant in 87% of cases. The mean of k was 0.12 h-1, corresponding to an apparent t1/2 of 6.0 h. The t1/2 predicted from linear regression of k against THC concentration ranged from 0.93 to 13 h for the highest and lowest concentrations observed (36 and 0.63 µg/L, respectively). The time from driving to blood collection had a median of 1.7 h (IQR = 1.5), and did not correlate with k. CONCLUSIONS: The apparent t1/2 of THC calculated from the mean of k was 6.0 h, which is shorter than the terminal elimination t1/2 suggested in previous population studies. This indicates that blood samples were often taken during the late distribution phase of THC. Because Δt was short relative to the rates of decrease expected in the late distribution and elimination phases, the underlying true concentration changes related to in vivo pharmacokinetics were small and masked by the relatively larger "false" changes introduced by random analytical and pre-analytical error. Therefore, individual values of k calculated from only two blood samples taken a short time apart are unreliable, and a two-sample approach to retrograde extrapolation of THC cannot be recommended.

Driving under the influence of zopiclone: Elimination between two consecutive blood samples.

AIM: Zopiclone is a widely used hypnotic drug which is frequently detected in apprehended drivers. For assessments in forensic cases, the elimination half-life (t1/2) of a drug is sometimes important. A t1/2 of 3.5-6.5 h for zopiclone is previously reported in healthy individuals, but different factors like age and drug-interactions can affect the t1/2 of zopiclone. The aim of this study was to describe concentrations of zopiclone and co-ingestion of additional drugs in apprehended drivers, and to investigate the t1/2 of zopiclone based on two consecutive blood samples. METHODS: Data was collected from apprehended drivers in Norway between 2003 and 2021. All cases where zopiclone was detected were included. In a subset of the material, two consecutive whole blood samples were collected ≥ 20 and < 60 min apart. Concentrations of zopiclone in blood were determined by LC-MS or UHPLC-MS/MS. The elimination and t1/2 of zopiclone was estimated from the concentration change of zopiclone and the time interval between the two consecutive blood samples, under the assumption of first order kinetics. RESULTS: The median concentration among all zopiclone positive cases was 0.044 mg/L (IQR 0.070 mg/L) (n = 2401). The most frequent additional drugs detected were ethanol (36%), diazepam (22%), amphetamine (14%) and THC (14%). In zopiclone-only cases (n = 364), the median concentration of zopiclone was 0.066 mg/L (IQR 0.115 mg/L). In 112 cases, two consecutive blood samples were collected. Of these, 28 cases showed increasing concentrations of zopiclone between the two sampling time points. Among the cases in which the concentration decreased (n = 84), the median C1 was 0.048 mg/L (IQR 0.062 mg/L) and the median C2 was 0.043 mg/L (IQR 0.056 mg/L). A Bayesian statistical model was used to obtain the posterior distribution of t1/2. The posterior median of t1/2 was estimated to 3.1 h (IQR=0.39 h) when including only the cases showing decreasing concentrations, and this increased to 3.8 h (IQR=0.52 h) when also including samples showing non outlying increase in concentrations. There was no statistically significant gender difference in the calculated half-lives (two-sided Mann-Whitney U test, p = .525). CONCLUSIONS: This study showed that zopiclone is frequently detected in apprehended drivers in supra therapeutic concentrations and poly drug cases. The elimination of zopiclone in blood from two consecutive blood samples indicated an apparent t1/2 of between 3.1 and 3.8 h, which is within the lower range of what previous experimental studies on healthy individuals have reported.

Nystagmus among suspected amphetamine impaired drivers.

Clinical signs of drug use can be helpful to identify which drug has been consumed. Amphetamine intake has traditionally not been considered to cause nystagmus. The aim of this study was to explore whether there is a relationship between amphetamine use and nystagmus in a population of apprehended drivers in a naturalistic setting. We evaluated drivers suspected of drug-impaired driving where blood samples were collected and a clinical test of impairment (CTI) was performed. Evaluation of nystagmus is one of the CTI subtests. The samples were analysed for alcohol and psychoactive drugs. Cases with a nystagmus test were recorded and amphetamine-only cases were compared with alcohol-only cases and with cases where alcohol or drugs were not detected, respectively. Samples from 507 amphetamine-only cases were compared to 485 alcohol-only cases and 205 drug-negative cases. The median blood amphetamine concentration was 0.37 mg/L and the median alcohol concentration was 1.57 g/kg. The proportion of cases with nystagmus was similar in amphetamine-only cases (21%) and drug-negative controls (25%), p = 0.273, but higher in alcohol-only cases (53%), p < 0.001. No association was found between the blood amphetamine concentration and degree of nystagmus (Spearman's ρ = 0.008, p = 0.860), whereas an association between blood alcohol concentration and degree of nystagmus was demonstrated (ρ = 0.249, p < 0.001). In conclusion, our study did not find that apprehended drivers using amphetamine had more frequently nystagmus than a control group that tested negative for alcohol and drugs, even at high amphetamine concentrations in blood. Hence, nystagmus should not be considered a tool for identifying amphetamine-induced impairment in drivers.

Relationship between betahydroxybutyrate (BHB) and acetone concentrations in postmortem blood and cause of death.

Unexpected death caused by diabetic or alcoholic ketoacidosis is easily overlooked due to the non-specific symptoms. Although the acid betahydroxybutyrate (BHB) is the most abundant ketone body formed in conditions with ketoacidosis, routine analysis in postmortem investigations often only includes the neutral ketone body acetone. This study aims to evaluate the usefulness of implementing routine BHB analysis in postmortem cases, by investigating the relationship between BHB and acetone concentrations in postmortem blood and the main cause of death. From our database of forensic autopsy cases examined from 2012 to 2015, there were 376 cases with BHB and/or acetone detected in postmortem blood that could be paired with data from the Norwegian Cause of Death Registry. Cases were categorized into three groups based on cause of death: "Diabetes-related" (n = 38), "Alcohol-related" (n = 35) and "Other" (n = 303). Analysis of BHB in blood was performed using UHPLC-MS/MS (limit of quantification (LOQ) 52 mg/L) and of acetone using HS-GC-FID (LOQ 87 mg/L). For the purpose of the study, the acetone method was also validated for a LOQ of 23 mg/L. The median BHB concentration was significantly higher in the group of diabetes-related deaths (671 mg/L, range 68-1311 mg/L) compared to the group of alcohol-related (304 mg/L, range 65-1555 mg/L, p <0.001) and other causes of deaths (113 mg/L, range 0-1402 mg/L, p <0.001). In seven deaths (1.9%), the BHB blood concentration was above the suggested pathological threshold of 250 mg/L, without detection of acetone in blood above 23 mg/L. In 15% of deaths by other causes than diabetes or alcohol, a pathologically significant BHB blood concentration was detected. Our results indicate that BHB is a more reliable marker of pathologically significant ketoacidosis than acetone, and we suggest that BHB should be routinely analyzed in postmortem investigations.

Unconscious man in his fifties with elevated anion gap. / Bevisstløs mann i 50-årene med økt aniongap.

BACKGROUND: The use of GHB is still widespread with many hospitalised overdose cases. CASE PRESENTATION: A man in his fifties was found unconscious in the street and brought to our Acute Admissions. When first examined he was still unconscious, hypothermic, had snoring respiration and smelled of alcohol. He was otherwise haemodynamically stable. Blood samples showed elevated osmolal and anion gaps. The increase in the osmol gap could be explained by the ethanol level of 210 mg/dL (46 mmol/L), but the reason for the increased anion gap was unknown. Flumazenil and naloxone were administered without effect. As the ethanol concentration alone was unlikely to explain the clinical picture, extended toxicological tests were performed. GHB in plasma was very high (5.0 mmol/L; 520 mg/L) even though the sample was taken almost 4 hours after admission. The GHB concentration (present as an anion) corresponded to the increased anion gap. The patient was comatose for approximately 12 hours, which is unusually long in GHB poisoning. INTERPRETATION: Intoxication with GHB is important to consider in comatose patients where other causes are excluded. Prolonged clinical course may be due to a saturation of the GHB metabolism after a large dose or ingestion of GBL or 1,4-butanediol, both of which are precursors to GHB.

Pharmacokinetics of Single Doses of Methadone and Buprenorphine in Blood and Oral Fluid in Healthy Volunteers and Correlation With Effects on Psychomotor and Cognitive Functions.

PURPOSE: We aimed to study the pharmacokinetics of methadone and buprenorphine in blood and oral fluid after single-dose administration and investigate correlations between concentrations in blood and neurocognitive functions. METHODS: A 5-way, double-blind, randomized, placebo-controlled, double-dummy, crossover study was performed to study the pharmacokinetics and neurocognitive effects of methadone (5 and 10 mg per oral) and buprenorphine (0.2 and 0.4 mg sublingual) in 22 healthy volunteers. Blood and oral fluid were collected throughout the test days, and drug concentrations in both matrices were analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. On-road driving testing, neurocognitive computerized tests, and subjective questionnaires were performed. RESULTS: Large individual variations in concentrations of methadone and buprenorphine in blood and oral fluid, and accordingly oral fluid/blood drug concentration ratios, were observed. The mean ratio 6.5 hours after drug administration was 2.0 (range, 0.49-7.39) for methadone after both doses. Buprenorphine was not detected above the limit of quantification in blood after 6.5 hours. No significant correlation between methadone concentration in blood and effect was found. Significant correlations were found between buprenorphine concentration in blood and standard deviation of lateral position in the driving test and some measures of reaction time, divided attention, balance, alertness, contentedness. and sleepiness. CONCLUSIONS: Concentrations of methadone and buprenorphine in blood and oral fluid showed large interindividual variations. No concentration-effect correlations were found for methadone, whereas low to moderate correlations were observed between buprenorphine concentration and driving, psychomotor function, and subjective rating of sleep and alertness.

A clinical trial on the acute effects of methadone and buprenorphine on actual driving and cognitive function of healthy volunteers.

AIMS: The present study assessed the acute effects of methadone and buprenorphine on actual on-road driving performance and neurocognitive function. METHODS: Methadone (5 and 10 mg per os) and buprenorphine (0.2 and 0.4 mg sublingual) were administered to 22 healthy volunteers in a five-way, double-blind, randomized, placebo-controlled, double-dummy, cross-over study. Driving performance was assessed with an on-road driving test. The primary outcome measure was standard deviation of lateral position (SDLP), a measure of road tracking control. Laboratory tests were used to measure cognitive function (e.g. reaction time and attention) and questionnaires were used to assess subjective measures of mood and sedation. RESULTS: There was no significant main effect of treatment on SDLP. Yet, analysis of individual drug-placebo contrast data revealed that buprenorphine 0.4 mg significantly increased SDLP. Driving impairment was mild and below the impairment threshold of a blood alcohol concentration of 0.5 mg ml-1 . Four participants stopped their driving test while under the influence of either opioid due to sleepiness. Both opioids produced impairments of cognitive task performance and increased sleepiness particularly at the highest dose. CONCLUSIONS: Analgesic doses of buprenorphine produced mild impairing effects on driving and related cognitive skills, while methadone impaired cognitive task performance but not driving performance. Large individual variations were observed for both drugs. Patients should be informed about the possibility of driving impairment when initiating opioid treatment.

Conversion factors for assessment of driving impairment after exposure to multiple benzodiazepines/z-hypnotics or opioids.

AIMS: Norway has introduced legal concentration limits in blood for 28 non-alcohol drugs in driving under the influence cases. As of 2016 this legislation also regulates the assessment of combined effects of multiple benzodiazepines and opioids. We herein describe the employed methodology for the equivalence tables for concentrations of benzodiazepines/z-hypnotics and opioids implemented in the Norwegian Road Traffic Act. METHODS: Legislative limits corresponding to impairment at blood alcohol concentrations (BAC) of 0.02%, 0.05% and 0.12% were established for 15 different benzodiazepines and opioids. This was based on a concept of a linear relationship between blood drug concentration and impairment in drug naïve users. Concentration ratios between these drugs were used to establish conversion factors and calculate net impairment using diazepam and morphine equivalents. RESULTS: Conversion factors were established for 14 benzodiazepines/z-hypnotics (alprazolam, bromazepam, clobazam, clonazepam, etizolam, flunitrazepam, lorazepam, nitrazepam, nordiazepam, oxazepam, phenazepam, temazepam, zolpidem and zopiclone) and two opioids (methadone and oxycodone). CONCLUSIONS: Conversion factors to calculate diazepam and morphine equivalents for benzodiazepines/z-hypnotics and selected opioids, respectively, have been operative in the Norwegian Road Traffic Act as of February 2016. Calculated equivalents can be applied by the courts to meter out sanctions.

Acute impairing effects of morphine related to driving: A systematic review of experimental studies to define blood morphine concentrations related to impairment in opioid-naïve subjects.

OBJECTIVE: The objective of this study was to look for dose- and concentration-effect relationships in experimental studies on single-dose administration of morphine on traffic-relevant behavioral tests by a systematic literature review and possibly to see whether a dose/concentration could be defined below which few or no tests would be affected. METHODS: Searches for corresponding literature were conducted using MEDLINE, EMBASE, and PsycINFO, throughout March of 2016. The search strategy consisted of words colligated to cognitive and psychomotor functions of relevance to driving, in relation to morphine administration. The tests were arranged in main groups, and tests showing impairment were categorized by doses as well as calculated plasma concentrations. RESULTS: Fifteen studies were included in the review. Impairment after the administration of a single intravenously dose of morphine was found in some of the tests on reaction time, attention, and visual functions. No impairment was observed in tests on psychomotor skills and en-/decoding. Tests on reaction time appeared to be less sensitive to the morphine administration, whereas tests on visual functions and attention appeared to be the most sensitive to the morphine administration. Single-dose administration of morphine with dosages up to 5 mg appeared to cause very few effects on traffic-relevant performance tasks. At higher dosages, impairment was found on various tasks but with no clear dose-effect relationship. Plasma morphine concentrations less than 50 nmol/L are most probably accompanied by few effects on traffic-relevant performance tasks. CONCLUSIONS: A plasma morphine concentration of 50 nmol/L (approximately 14.3 ng/mL) could represent an upper level, under which there is little accompanying road traffic risk. A single dose of 5 mg morphine IV and analgetic equivalence doses of fentanyl, hydromorphone, oxycodone, and oxymorphone are presented with the suggestion that few traffic-relevant effects will appear after such doses.

THC and CBD in blood samples and seizures in Norway: Does CBD affect THC-induced impairment in apprehended subjects?

BACKGROUND AND AIMS: Several publications have suggested increasing cannabis potency over the last decade, which, together with lower amounts of cannabidiol (CBD), could contribute to an increase in adverse effects after cannabis smoking. Naturalistic studies on tetrahydrocannabinol (THC) and CBD in blood samples are, however, missing. This study aimed to investigate the relationship between THC- and CBD concentrations in blood samples among cannabis users, and to compare cannabinoid concentrations with the outcome of a clinical test of impairment (CTI) and between traffic accidents and non-accident driving under the influence of drugs (DUID)-cases. Assessment of THC- and CBD contents in cannabis seizures was also included. METHODS: THC- and CBD concentrations in blood samples from subjects apprehended in Norway from April 2013-April 2015 were included (n=6134). A CTI result was compared with analytical findings in cases where only THC and/or CBD were detected (n=705). THC- and CBD content was measured in 41 cannabis seizures. RESULTS: Among THC-positive blood samples, 76% also tested positive for CBD. There was a strong correlation between THC- and CBD concentrations in blood samples (Pearson's r=0.714, p<0.0005). Subjects judged as impaired by a CTI had significantly higher THC- (p<0.001) and CBD (p=0.008) concentrations compared with not impaired subjects, but after multivariate analyses, impairment could only be related to THC concentration (p=0.004). Analyzing seizures revealed THC/CBD ratios of 2:1 for hashish and 200:1 for marijuana. CONCLUSIONS: More than ¾ of the blood samples testing positive for THC, among subjects apprehended in Norway, also tested positive for CBD, suggesting frequent consumption of high CBD cannabis products. The simultaneous presence of CBD in blood does, however, not appear to affect THC-induced impairment on a CTI. Seizure sample analysis did not reveal high potency cannabis products, and while CBD content appeared high in hashish, it was almost absent in marijuana.

Novel psychoactive substances. / Nye psykoaktive stoffer.

There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.

[Prevalence of injuries associated with the «russ¼ celebration in Norway]. / Forekomst av skader i russetiden.

BACKGROUND: Every year the Norwegian Institute of Public Health receives a number of enquiries from the media regarding the extent to which alcohol intake by upper secondary school leavers celebrating in their final spring term (the traditional Norwegian «russ¼ celebration) is a cause of injuries, and whether there are more injuries during this period. The purpose of this study is to investigate the prevalence of injuries in the «russ¼ celebration period. MATERIAL AND METHOD: Data from the Norwegian patient register (NPR) were used to investigate the prevalence of injuries in 16-, 19- and 21-year-olds from 2007 to 2011. The 19-year-olds represent those who celebrate «russ¼. Injuries recorded using ICD-10 codes were examined. The month of May and the period 20 April to 20 May were compared to the other months of the year. RESULTS: The 19-year-olds have significantly more injuries during the «russ¼ period compared to the 16- and 21-year-olds. In the «russ¼ period, the 19-year-olds accounted for 41.4% of the injuries, the 16-year-olds for 27.7% and the 21-year-olds for 30.9%. The 19-year-olds have more injuries in May compared to other months. There is a particular increase in the prevalence of head injuries. CONCLUSION: An increase was observed in the number of injuries among 19-year-olds associated with the period of the «russ¼ celebration compared to the rest of the year. There are no data available which describe the causes of the injuries. There is a need for better recording of the use of alcohol or intoxicants as a possible cause. Injuries treated by the specialist health services are probably of a more serious nature, and the study may indicate an increase in serious injuries among 19-year-olds during the «russ¼ celebration.

Drugged driving arrests in Norway before and after the implementation of per se law.

Norway introduced legislative limits for driving under the influence of drugs (DUID) February 1st, 2012, to harmonize with the legislation on driving under the influence of alcohol. Per se limits corresponding to blood alcohol concentrations (BACs) of 0.02% were established for 20 drugs and concentration limits for graded sanctions corresponding to BACs of 0.05% and 0.12% were established for 13 of these drugs as well. The new system is not applied to individuals with valid prescriptions for medicinal drugs. The aim of this study was to investigate if the implementation of legislative limits for drugs affected the number of blood samples taken from suspected drugged drivers, drug findings and the number of expert witness statement requests. The number of blood samples taken in suspected DUID cases increased by 20% after introduction of legislative limits (3320 cases in 2010 and 3970 in 2013). The number of samples with at least one drug above the per se limit corresponding to BAC of 0.02% increased by 17% (from 2646 in 2010 to 3090 in 2013), whereas the number of expert witness statements was reduced by the half (from 63.4% in 2010 and 28.7% in 2013).

Can patients receiving opioid maintenance therapy safely drive? A systematic review of epidemiological and experimental studies on driving ability with a focus on concomitant methadone or buprenorphine administration.

OBJECTIVE: To perform a systematic review of the present scientific literature on the treatment with methadone or buprenorphine related to (1) traffic accident risk in epidemiological studies and (2) their effects on cognitive and psychomotor functions of relevance to driving in experimental studies. METHODS: Searches for corresponding literature were conducted in MEDLINE, EMBASE, and PsycINFO throughout March and June of 2010. The search strategy consisted of words colligated to accident risk and culpability, in addition to cognitive and psychomotor functions of relevance to driving, all in relation to methadone or buprenorphine administration. In total, 59 studies were included. RESULTS: Early epidemiological studies found no substantial difference in motor vehicle accident risk between methadone maintenance therapy patients (MMPs) and control groups. However, more recent studies have found an increased risk of traffic accident involvement for both MMPs and buprenorphine maintenance therapy patients (BMPs). In experimental studies, impairments of cognitive and psychomotor functions have been observed among both MMPs and BMPs when compared to control groups. When comparing MMPs with BMPs, the latter appeared to be less impaired than MMPs, but this difference may be unrelated to the maintenance therapy. Further impairments have been observed among MMPs after single doses, after an additional versus regular daily dosing, in multiple versus single dosing, and after long-term treatment compared to baseline levels. All studies showed impairments among opioid-naïve subjects after the administration of a comparatively low and single dose of either methadone or buprenorphine. CONCLUSIONS: Both methadone and buprenorphine were confirmed as having impairing potentials in opioid-naïve subjects. At least some opioid maintenance therapy patients are observed having only slight impairments of relevance to driving. Knowing this when approaching the question of ability to drive, an individual evaluation of the driving performance, pertaining to the opioid maintained patient, may be the most useful and conclusive procedure.

[Effect and occurrence of synthetic cannabinoids]. / Syntetiske cannabinoider--effekt og forekomst.

BACKGROUND: ''Spice'' is the term used for various products that contain synthetic cannabinoids. In recent years a growing number of products have been reported on the illegal market, also in Norway. The substances are sold over the internet as 'legal' cannabis. A number of the substances have gradually been classified as narcotics, also in Norway, but new variants continue to be developed. An overview is provided here of current knowledge of the efficacy and occurrence of synthetic cannabinoids. METHOD: The article is based on a discretionary selection of relevant articles found by means of a literature search in PubMed and on reports from Norwegian and European authorities and research institutions. RESULTS: Synthetic cannabinoids are a large group of drugs of abuse that have an effect similar to cannabis, but may be considerably more potent. The contents of the various Spice products vary with respect to potency, purity and the number and types of additives, and this implies a risk of unintentional overdose. There are reports from abroad of cardiac infarction in teenagers, severe psychoses, anxiety, unconsciousness and deaths following use. INTERPRETATION: Synthetic cannabinoids are marketed over the internet as legal and harmless cannabis, but can cause severe intoxication and death. There is a considerable need for more knowledge about the action and harmful effects of these substances.