Influence of ethanol on the pharmacokinetic properties of Δ9-tetrahydrocannabinol in oral fluid.

Oral fluid (OF) tests aid in identifying drivers under the influence of drugs. In this study, 17 heavy cannabis users consumed alcohol to achieve steady blood alcohol concentrations of 0 to 0.7 g/L and smoked cannabis 3 h afterward. OF samples were obtained before and up to 4 h after smoking and on-site tests were performed (Dräger DrugTest 5000 and Securetec DrugWipe 5+). Maximum concentrations of tetrahydrocannabinol (THC) immediately after smoking (up to 44,412 ng/g) were below 4,300 (median 377) ng/g 1 h after smoking and less than 312 (median 88) ng/g 3 h later with 5 of 49 samples negative, suggesting that recent cannabis use might occasionally not be detectable. An influence of alcohol was not observed. Drinking 300 mL variably influenced THC concentrations (median only -29.6%), which suggests that drinking does not markedly affect on-site test performance. Many (92%) Dräger tests performed 4 h after smoking were still positive, indicating sufficient sensitivity for recent cannabis use. Differences in the results of a roadside study with DrugTest 5000 (sensitivity 84.8%, specificity 96.0%, accuracy 84.3%) could be explained by a higher number of true negatives, differences between OF and serum and differences between occasional and chronic users.

Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication.

RATIONALE: Experienced cannabis users demonstrate tolerance to some of the impairing acute effects of cannabis. OBJECTIVES: The present study investigates whether event-related potentials (ERPs) differ between occasional and heavy cannabis users after acute Δ9-tetrahydrocannabinol (THC) administration, as a result of tolerance. METHODS: Twelve occasional and 12 heavy cannabis users participated in a double-blind, placebo-controlled, crossover study. On two separate days, they smoked a joint containing 0 or 500 µg/kg body weight THC. ERPs were measured while subjects performed a divided attention task (DAT) and stop signal task (SST). RESULTS: In the DAT, THC significantly decreased P100 amplitude in occasional but not in heavy cannabis users. P300 amplitude in the DAT was significantly decreased by THC in both groups. The N200 peak in the SST was not affected by treatment in neither of the groups. Performance in the SST was impaired in both groups after THC treatment, whereas performance in the DAT was impaired by THC only in the occasional users group. CONCLUSIONS: The present study confirms that heavy cannabis users develop tolerance to some of the impairing behavioral effects of cannabis. This tolerance was also evident in the underlying ERPs, suggesting that tolerance demonstrated on performance level is not (completely) due to behavioral compensation.

Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users.

INTRODUCTION: Previous research has shown that heavy cannabis users develop tolerance to the impairing effects of Δ9-tetrahydrocannabinol (THC) on neurocognitive functions. Animal studies suggest that chronic cannabis consumption may also produce cross-tolerance for the impairing effects of alcohol, but supportive data in humans is scarce. PURPOSE: The present study was designed to assess tolerance and cross-tolerance to the neurocognitive effects of THC and alcohol in heavy cannabis users. METHODS: Twenty-one heavy cannabis users participated in a double-blind, placebo-controlled, three-way study. Subjects underwent three alcohol-dosing conditions that were designed to achieve a steady blood alcohol concentration of about 0, 0.5, and 0.7 mg/ml during a 5-h time window. In addition, subjects smoked a THC cigarette (400 µg/kg) at 3 h post-onset of alcohol dosing during every alcohol condition. Performance tests were conducted repeatedly between 0 and 7 h after onset of drinking and included measures of perceptual motor control (critical tracking task), dual task processing (divided-attention task), motor inhibition (stop-signal task), and cognition (Tower of London). RESULTS: Alcohol significantly impaired critical tracking, divided attention, and stop-signal performance. THC generally did not affect task performance. However, combined effects of THC and alcohol on divided attention were bigger than those by alcohol alone. CONCLUSION: In conclusion, the present study generally confirms that heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive task performance. Yet, heavy cannabis users did not develop cross-tolerance to the impairing effects of alcohol, and the presence of the latter even selectively potentiated THC effects on measures of divided attention.

Influence of ethanol on cannabinoid pharmacokinetic parameters in chronic users.

Cannabis is not only the most widely used illicit drug worldwide but is also regularly consumed along with ethanol. In previous studies, it was assumed that cannabis users develop cross-tolerance to ethanol effects. The present study was designed to compare the effects of ethanol in comparison to and in combination with a cannabis joint and investigate changes in pharmacokinetics. In this study, 19 heavy cannabis users participated and received three alcohol dosing conditions that were calculated to achieve steady blood alcohol concentrations (BAC) of about 0, 0.5 and 0.7 g/l during a 5-h time window. Subjects smoked a Δ(9)-tetrahydrocannabinol (THC) cigarette (400 µg/kg) 3 h post-onset of alcohol dosing. Blood samples were taken between 0 and 4 h after smoking. During the first hour, samples were collected every 15 min and every 30 min thereafter. Mean steady-state BACs reached 0, 0.36 and 0.5 g/l. The apparent elimination half-life of THC was slightly prolonged (1.59 vs. 1.93 h, p < 0.05) and the concentration 1 h after smoking was slightly lower (24 vs. 17 ng/ml, p < 0.05) with the higher ethanol dose. The prolonged THC elimination might be explained by a small ethanol-mediated change in distribution to and from deep compartments. Concentrations and pharmacokinetics of 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCA) were not significantly influenced by ethanol. However, THCA concentrations appeared lower in both ethanol conditions, which might also be attributable to changes in distribution. Though not significant in the present study, this might be relevant in the interpretation of cannabinoid concentrations in blood.

Pharmacokinetic properties of delta9-tetrahydrocannabinol in oral fluid of occasional and chronic users.

Saliva is of continuing interest in detecting the influence of drugs while driving. Commercial tests are currently available where cannabis detectability is a major challenge. The present study aids in the understanding of tetrahydrocannabinol (THC) pharmacokinetics in oral fluid. The oral fluid analyses exhibited no significant differences between 12 occasional users and 12 chronic users smoking a standardized cannabis joint, except for the maximum concentrations in the first samples (occasional users, 397- 6438 ng/g; chronic users 387-71,747 ng/g). THC was detectable in all samples with medians in the last samples (8 h) of 6.3 and 11.3 ng/g in occasional and chronic users, respectively. The elimination half-life in both groups was 1.6 +/- 0.4 h. A series of samples was obtained over a period of 8 h without actual drug use representing a later elimination phase. Of these oral fluid samples, only 4.3% were negative for THC despite positive serum, and 24.1% of serum samples were negative despite positive oral fluid. This confirms that THC is detectable for longer in oral fluid than in serum. The oral fluid-to-serum ratios were 0.3 to 425 (median 16.5) with no difference between chronic and occasional users. The large inter- and intraindividual variability observed precludes a reliable estimation of THC serum concentrations from oral fluid data using this collection device.

Relationship between oral fluid and blood concentrations of drugs of abuse in drivers suspected of driving under the influence of drugs.

In recent years, the interest in the use of oral fluid as a biological matrix has increased significantly, particularly for detecting driving under the influence of drugs (DUID). In this study, the relationship between the oral fluid and the blood concentrations of drugs of abuse in drivers suspected of DUID is discussed. Blood and oral fluid samples were collected from drivers suspected of DUID or stopped during random controls by the police in Belgium, Germany, Finland, and Norway for the ROSITA-2 project. The blood samples were analyzed by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), sometimes preceded by immunoassay screening of blood or urine samples. The oral fluid samples were analyzed by GC-MS or LC-MS(/MS). Scatter plots and trend lines of the blood and oral fluid concentrations and the median, mean, range, and SD of the oral fluid to blood (OF:B) ratios were calculated for amphetamines, benzodiazepines, cocaine, opiates, and Delta(9)-2 tetrahydrocannabinol. The ratios found in this study were comparable with those that were published previously, but the range was wider. The OF:B ratios of basic drugs such as amphetamines, cocaine, and opiates were >1 [amphetamine: median (range) 13 (0.5-182), methylenedioxyamphetamine: 4 (1-15), methylenedioxymethamphetamine: 6 (0.9-88), methamphetamine: 5 (2-23), cocaine: 22 (4-119), benzoylecgonine: 1 (0.2-11), morphine: 2 (0.8-6), and codeine: 10 (0.8-39)]. The ratios for benzodiazepines were very low, as could be expected as they are highly protein bound and weakly acidic, leading to low oral fluid concentrations [diazepam: 0.02 (0.01-0.15), nordiazepam: 0.04 (0.01-0.23), oxazepam: 0.05 (0.03-0.14), and temazepam: 0.1 (0.06-0.54)]. For tetrahydrocannabinol, an OF:B ratio of 15 was found (range 0.01-569). In this study, the time of last administration, the dose, and the route of administration were unknown. Nevertheless, the data reflect the variability of the OF:B ratios in drivers thought to be under the influence of drugs. The wide range of the ratios, however, does not allow reliable calculation of the blood concentrations from oral fluid concentrations.

Comparison of cannabinoid pharmacokinetic properties in occasional and heavy users smoking a marijuana or placebo joint.

Cannabinoid pharmacokinetics in occasional users is well studied, but the interpretation of data from heavy users is difficult. In the present study, blood pharmacokinetic properties were investigated in occasional and heavy users in cannabis and placebo conditions. The results obtained with occasional users were in contrast to those of the heavy users who admitted cannabis use on 4-25 occasions during the previous week. Of the 12 heavy users, 10 exhibited up to 12.3 microg/L Delta(9)-tetrahydrocannabinol (THC) prior to smoking. During the 8 h after smoking, the distribution and elimination patterns were comparable to those of the occasional users and the concentrations returned to 68-196% (median 110%) of the initial values. However, the maximal concentration and the areas under the curves were significantly higher with marked interindividual variation. In contrast to the cannabis conditions, the THC concentrations in the placebo phase decreased more slowly (elimination half-life 17.5-43.5 h vs. 1.0-5.9 h) in accordance with a late elimination phase. The elimination half-lives of 11-hydroxy-THC and 11-nor-9-carboxy-THC in th cannabis conditions (medians 3.1 h and 6.2 h, respectively) were longer than those of THC, which was different in the placebo phase (medians 7.2 h and 13.0 h, respectively). From the results, it must be cautioned that cannabinoid blood concentrations from heavy users in a late elimination phase may be difficult to distinguish from concentrations measured in occasional users after acute cannabis use.

Pharmacokinetic properties of delta9-tetrahydrocannabinol in serum and oral fluid.

In a study on the effects of smoked cannabis (18.2 +/- 2.8 mg as low and 36.5 +/- 5.6 mg as high dose) paired blood and oral fluid samples were collected from 10 study participants up to 6 h after smoking and analyzed for the cannabinoids Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (THC-OH) and 11-nor-9-carboxy-THC (THCA) using gas chromatography-mass spectrometry. Highest concentrations in serum were 47.8 +/- 35.0 and 79.1 +/- 42.5 microg/L at the end of smoking (low and high dose, respectively) and decreased to less than 1 microg/L during 6 h with elimination half-lives of 1.4 +/- 0.1 h calculated from 1 to 6 h, which is shorter than reported previously. The elimination half-lives of THC-OH (2.0 +/- 0.3 h) and THCA (3.4 +/- 0.9 h) were significantly higher. The THC concentrations in oral fluid were highest with 900 +/- 589 and 1041 +/- 652 microg/L (low and high dose, respectively) in the first sample collected at 0.25 h and decreased to 18 +/- 12 microg/L over 6 h with elimination half-lives of 1.5 +/- 0.6 h. The elimination half-life of THC in serum and oral fluid and between the two doses did not significantly differ. Oral fluid/serum ratios were 46 +/- 27 and 36 +/- 20 (low and high dose, respectively), which are higher than previously reported and might be based on sample collection and/or analytical issues. In conclusion, despite similar elimination rates of THC in serum and oral fluid, which appear incidental, the high differences in oral fluid/serum ratios are not a reliable basis for correlating THC concentrations in oral fluid and serum. The oral compartment and its kinetics for drugs, particularly THC, are not yet satisfactorily understood.

High-potency marijuana impairs executive function and inhibitory motor control.

Human performance studies have usually relied on low-potency marijuana (4% THC) for determining THC-induced impairment. The present study was designed to assess the effects of high-potency marijuana (13% THC) on human performance. In all, 20 recreational users of marijuana participated in a double-blind, placebo controlled, three way cross-over study. The treatments consisted of single doses of 0, 250, and 500 microg/kg THC. Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control (Critical tracking task), executive function (Tower of London) motor impulsivity (Stop signal task), and risk taking (Iowa gambling task). THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task. In addition, THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task. THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC x Time after smoking interaction. Effect sizes for performance impairments produced by THC 250 microg/kg were relatively low but generally increased by a factor of two in case of THC 500 microg/kg. These data suggest that high potency marijuana consistently impairs executive function and motor control. Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies.

Driving under the influence of drugs -- evaluation of analytical data of drugs in oral fluid, serum and urine, and correlation with impairment symptoms.

A study was performed to acquire urine, serum and oral fluid samples in cases of suspected driving under the influence of drugs of abuse. Oral fluid was collected using a novel sampling/testing device (Dräger DrugTest System). The aim of the study was to evaluate oral fluid and urine as a predictor of blood samples positive for drugs and impairment symptoms. Analysis for cannabinoids, amphetamine and its derivatives, opiates and cocaine was performed in urine using the Mahsan Kombi/DOA4-test, in serum using immunoassay and gas chromatography-mass spectrometry (GC-MS) confirmation and in oral fluid by GC-MS. Police and medical officer observations of impairment symptoms were rated and evaluated using a threshold value for the classification of driving inability. Accuracy in correlating drug detection in oral fluid and serum were >90% for all substances and also >90% in urine and serum except for THC (71.0%). Of the cases with oral fluid positive for any drug 97.1% of corresponding serum samples were also positive for at least one drug; of drug-positive urine samples this were only 82.4%. In 119 of 146 cases, impairment symptoms above threshold were observed (81.5%). Of the cases with drugs detected in serum, 19.1% appeared not impaired which were the same with drug-positive oral fluid while more persons with drug-positive urine samples appeared uninfluenced (32.7%). The data demonstrate that oral fluid is superior to urine in correlating with serum analytical data and impairment symptoms of drivers under the influence of drugs of abuse.

Screening for drugs of abuse in oral fluid--correlation of analysis results with serum in forensic cases.

The testing of saliva or oral fluid at the roadside could be a powerful tool to detect drivers under the influence of drugs and has several advantages over urine screening. In 177 cases of individuals suspected of driving under the influence of drugs, oral fluid was collected at the roadside and analyzed in parallel to serum samples. The study was performed to investigate the variability of oral fluid analysis results in relation to blood/serum. In 45% of the cases single-drug use was found, and in 50% poly-drug use was found. Cannabis was most prevalent (78%), and 70% of these individuals were also positive for tetrahydrocannabinol in serum. Overall, 97% of oral fluid samples positive for any substance were also positive in serum. Comparing data of oral fluid and serum for amphetamine, MDMA, morphine, benzoylecgonine, and tetrahydrocannabinol, the sensitivities were 100%, 97%, 87%, 87%, and 92%, respectively. Overall specificity and accuracy were in the range of 91-98%. Discrepancies between a negative oral fluid sample and a positive serum sample could be explained by analytical insensitivity in the lower volume of oral fluid analyzed (estimated for 0.1 mL confirmation vs. 1 mL of serum) or a shorter detection window in oral fluid. The low prevalence of discrepancies with positive oral fluid and negative serum results (2-9% of the cases) may be explained by persistent oral contamination especially for orally consumed drugs, like MDMA and cannabis. It is concluded that the detection of a psychoactive substance in oral fluid taken at the roadside is highly predictive for the detection of the corresponding drug or its metabolite in serum. Oral fluid testing is therefore suitable for the efficient confirmation of drug use of drivers suspected of being under the influence of drugs.

Poppy seed consumption and toxicological analysis of blood and urine samples.

Poppy seeds contain morphine in different amounts. Reported concentrations are up to 294 mg morphine/kg poppy seeds. Since penalties based on Street Traffic Law (parapgraph 24a StVG) in Germany (administrative offence) require definitive proof of morphine in blood samples, and the "Grenzwertkommission" in consultation with the Ministry of Transportation recommended a threshold of free morphine of 10 ng/mL, the question arose whether the consumption of poppy seeds can lead to a blood concentrations equal or higher than 10 ng/mL of free morphine. Therefore, five volunteers ate poppy seed products (50 mg morphine/kg poppy seeds). In urine, all on-site tests were enzyme immunologically positive for opiates and were positive to morphine by GC/MS. All the blood samples were negative to morphine by EIA and to free morphine by GC/MS. However, after hydrolysis, morphine was detected by GC/MS in all cases. Accordingly, in Germany, penalties based on parapgraph 24a StVG are not likely to cause road users any concerns should they have consumed poppy seeds. Driver Licensing Authorities, however, should be advised of this problem to avoid unjustified legal measures.

Improved and validated method for the determination of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC and 11-nor-9-carboxy-THC in serum, and in human liver microsomal preparations using gas chromatography-mass spectrometry.

A validated method for the quantification of Delta(9)-tetrahydrocannabinol (THC) and its main metabolites 11-hydroxy-tetrahydrocannabinol (OH-THC) and 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) in serum is presented. The substances were isolated by solid-phase extraction, derivatised by methylation, and analysed by means of GC-MS in the selected ion monitoring mode. Quantitation was achieved by the addition of deuterated analogues as internal standards. The method was linear up to 10 ng/ml for THC and OH-THC, and up to 50 ng/ml for THC-COOH. The limits of quantification were 0.62 ng/ml for THC, 0.68 ng/ml for OH-THC and 3.35 ng/ml for THC-COOH. The limits of detection for the least intensive ions were 0.52 ng/ml for THC, 0.49 ng/ml for OH-THC and 0.65 ng/ml for THC-COOH. The method was validated according to the requirements of the Journal of Chromatography B. The method has been routinely used on samples from drivers suspected of "driving under the influence". In addition to the forensic application, a cross-validation was carried out by applying the method developed for serum to human liver microsomal preparation samples.

Drugs of abuse monitoring in blood for control of driving under the influence of drugs.

Driving under the influence of drugs is an issue of growing concern in the industrialized countries as a risk and a cause for road accidents. In forensic toxicology, the increasing number of samples for determination of drugs in blood is mainly due to zero-tolerance laws in several countries and well-trained police officers who can better recognize drivers under the influence of drugs of abuse. This review describes procedures for detection of the following drugs of abuse in whole blood, plasma, and serum: amphetamine, methamphetamine, 3,4-methylenedioxy methamphetamine (MDMA), N-ethyl-3, 4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxyamphetamine (MDA), cannabinoids (delta-9-tetrahydrocannabinol [THC], 11-hydroxy-delta-9-THC, 11-nor-9-carboxy-delta-9-THC), cocaine, benzoylecgonine, ecgonine methyl ester, cocaethylene, the opiates (heroin, 6-monoacetylmorphine, morphine, or codeine), and methadone as well as gamma-hydroxybutyric acid (GHB), lysergic acid diethylamide (LSD), phencyclidine (PCP), and psilocybin/psilocin. For many of the analytes, sensitive immunologic methods for screening are available. Gas chromatography-mass spectrometry (GC-MS) is still the state-of-the-art method for confirmatory analysis or for screening and confirmation in one step. Liquid chromatography-mass spectrometry (LC-MS) procedures for such purposes are also included in this review. Basic data about the biosample assayed, internal standard, workup, GC or LC column and mobile phase, detection mode, reference data, and validation data of each procedure are summarized in two tables.