A proposed approach to confirm heroin administration - Regional differences in heroin purity is a major factor.

In forensic toxicology, a marker of street heroin use is urgent especially in the absence of urinary 6-monoacetylmorphine. ATM4G, the Glucuronide of Acetylated product of Thebaine compound 4 Metabolite (ATM4), arising from byproducts of street heroin synthesis has been considered as a useful marker in some European studies. However, whether ATM4G is a universal marker particularly in Southeast Asia due to 'street' heroin with high purity, it's still unclear. To investigate putative markers for different regions, ATM4G and other metabolites including the Acetylated product of Thebaine compound 3 Metabolite (ATM3) and thebaol, also originated from thebaine were detected in 552 urine samples from heroin users in Taiwan. Results were compared with that from samples collected in the UK and Germany. Only a sulfo-conjugate of ATM4, ATM4S, was detected in 28 Taiwanese users using a sensitive MS3 method whilst out of 351 samples from the UK and Germany, ATM4G was present in 91. Thebaol-glucuronide was first time detected in 118. No markers were detected in urine following herbal medicine use or poppy seed ingestion. The presence of ATM4S/ATM4G might be affected by ethnicities and heroin supplied in regions. Thebaol-glucuronide is another putative marker with ATM4G and ATM4S for street heroin use.

Synthetic cannabinoids in hair-Prevalence of use in abstinence control programs for driver's license regranting in Germany.

Although the use, structural variety, and prevalence of synthetic cannabinoids (SCs) have steadily increased on the drug market, they are rarely analyzed in abstinence control programs for driver's license regranting. The aim of this study was to determine the SC prevalence in these programs by analyzing hair samples collected between March 2020 and March 2021 from various regions in Germany, mainly Bavaria (40%). Specimens were analyzed quantitatively for drugs of abuse and qualitatively for 107 SCs. Hair samples were screened by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and to search for unknown SC analogs, positive samples were additionally screened by liquid chromatography-high resolution time of flight mass spectrometry (LC-qTOF/MS). The analysis of 5097 hair samples resulted in 181 SC detections (3.6%), showing a wide range of 44 SCs, with up to 13 different compounds found in a single sample. The most prevalent compounds were 5F-MDMB-PICA and MDMB-4en-PINACA; furthermore, 10 new substances not initially covered by LC-MS/MS analysis were detected by LC-qTOF/MS. The SC positivity rate was comparable to cocaine (5.4%) and amphetamine (2.6%). Only in 35 cases (0.7%), SC analysis was requested by the clients, highlighting the insufficient coverage of SC consumption in the studied collective. In summary, hair sample analysis proved to be a valuable tool to monitor the use of SCs. In order to keep pace with newly emerging SC analogs, an up-to-date analytical method is essential. Prospectively, SCs should be more routinely screened in hair analysis for abstinence control to avoid cannabis substitution by SCs.

Evidence for gender differences in the Amphetamine/Methamphetamine ratio in the hair of subjects undergoing Fitness-to-Drive testing.

BACKGROUND AND AIMS: Retrospective analysis of hair testing data provides insights in drugs abuse patterns and improves results interpretation. Cases from subjects undergoing driving fitness assessment (2010-2020) were examined to evidence patterns in methamphetamine (MA) abuse. MATERIALS AND METHODS: All cases with positive MA (≥0.025 ng/mg) were included (n = 585). Data available were gender, age, MA and A (amphetamine) in hair (h), hair color/treatment, length of proximal hair. Cases with Ah/MAh ≤ 0.35 (n = 469) were arbitrarily selected to remove as many combined A, MA users. ANOVA was performed to detect Ah/MAh predictors. RESULTS: No predictors affected Ah/MAh. A bimodal frequency distribution was observed. We clustered cases in two groups (1, Ah/MAh 0.025-0.070; 2, Ah/MAh 0.071-0.120) and performed logistic regression. Only gender exhibited significant difference across groups (p = 0.0080). Odds ratio for females falling into group 2 was 2.86 times higher (CI97.5 1.34-6.44). CONCLUSION: Literature data support the hypothesis that the two Ah/MAh groups represent different phenotypes of the CYP2D6-mediated MA N-demethylation. Whether gender plays a role in such difference could not be confirmed. However, these results provide further suggestion of an association of gender and pharmacogenomics with MA disposition, requiring these factors to be considered in future research.

Digital health understanding and preparedness of medical students: a cross-sectional study.

Digitalisation is changing all areas of our daily life. This changing environment requires new competences from physicians in all specialities. This study systematically surveyed the knowledge, attitude, and interests of medical students. These results will help further develop the medical curriculum, as well as increase our understanding of future physicians by other healthcare market players. A web-based survey consisting of four sections was developed: Section one queried demographic data, section two assessed the current digital health knowledge of medical students, section three queried their attitudes about the future impact of digital health in medicine and section four assessed the recommendations medical students have for the medical curriculum in terms of digital health. This survey was distributed to all (11,978) student at all public Austrian medical schools. A total of 8.4% of the medical student population started the survey. At the knowledge self-assessment section, the medical students reached mean of 11.74 points (SD 4.42) out of a possible maximum of 32 (female mean 10.66/ SD 3.87, male mean 13.34/SD 4.50). The attitude section showed that students see digitalisation as a threat, especially with respect to the patient-physician relationship. The curriculum recommendation section showed a high interest for topics related to AI, a per study year increasing interest in impact of digital health in communication, as well as a decreasing interest in robotic related topics. The attitude towards digital health can be described as sceptical. To ensure that future physicians keep pace with this development and fulfil their responsibility towards the society, medical schools need to be more proactive to foster the understanding of medical students that digital health will persistently alter the medical practice.

LC-QTOF-MS Presumptive Identification of Synthetic Cannabinoids without Reference Chromatographic Retention/Mass Spectral Information. II. Evaluation of a Computational Approach for Predicting and Identifying Unknown High-Resolution Product Ion Mass Spectra.

Despite liquid chromatography-high-resolution tandem mass spectrometry (MS2) enables untargeted acquisition, data processing in toxicological screenings is almost invariably performed in targeted mode. We developed a computational approach based on open source chemometrics software that, starting from a suspected synthetic cannabinoid (SC) determined formula, searches for isomers in different new psychoactive substances web databases, predicts retention time (RT) and high-resolution MS2 spectrum, and compares them with the unknown providing a rank-ordered candidates list. R was applied on 105 SC measured data to develop and validate a multiple linear regression quantitative structure-activity relationship model predicting RT. Competitive Fragmentation Modeling for Metabolite Identification (CFM-ID) freeware was used to predict/compare spectra with Jaccard similarity index. Data-dependent acquisition was performed with an Agilent Infinity 1290 LC-6550 iFunnel Q-TOF MS with ZORBAX Eclipse-Plus C18 (100 × 2.1 mm2/1.8 µm) in water/acetonitrile/ammonium formate gradient. Ability of the combined RT/MS2 prediction to identify unknowns was evaluated on SC standards (with leave-one-out from the RT model) and on unexpected SC encountered in real cases. RT prediction reduced the number of isomers retrieved from a group of new psychoactive substances web databases to one-third (2,792 ± 3,358→845 ± 983) and differentiated between SC isomers when spectra were not selective (4F-MDMB-BUTINACA, 4F-MDMB-BUTINACA 2'-indazole isomer) or unavailable (4CN-Cumyl-B7AICA, 4CN-Cumyl-BUTINACA). When comparing 30/40 eV measured spectra of 99 SC against RT-selected, CFM-ID predicted spectra of isomers, the right candidate ranked 1st on median and 4th on average; 54% and 88% of times the right match ranked 1st or within the first 5 matches, respectively. To our knowledge, this is the first case of extensive chemometrics application to toxicological screening. In most cases, presumptive identification (being based on computation, it requires further information for confirmation) of unexpected SC was achieved without reference measured information. This method is currently the closest possible to true unbiased/untargeted screening. The bottleneck of the method is the processing time required to predict mass spectra (ca. 30-35 s/compound using a 64-bit 2.50-GHz Intel® Core™ i5-7200U CPU). However, strategies can be implemented to reduce prediction processing time.

LC-QTOF-MS Presumptive Identification of Synthetic Cannabinoids without Reference Chromatographic Retention/Mass Spectral Information. I. Reversed-Phase Retention Time QSPR Prediction as an Aid to Identification of New/Unknown Compounds.

The application of Quantitative Structure-Property Relationship (QSPR) modeling to the prediction of reversed-phase liquid chromatography retention behavior of synthetic cannabinoids (SC), and its use in aiding the untargeted identification of unknown SC are described in this paper. 1D, 2D molecular descriptors and fingerprints of 105 SC were calculated with PaDEL-Descriptor, selected with Boruta algorithm in R environment, and used to build-up a multiple linear regression model able to predict retention times, relative to JWH-018 N-pentanoic acid-d5 as internal standard, under the following conditions: Agilent ZORBAX Eclipse Plus C18 (100 mm × 2.1 mm I.D., 1.8 µm) column with Phenomenex SecurityGuard Ultra cartridge (C18, 10 mm × 2.1 mm I.D., < 2 µm) kept at 50°C; gradient elution with 5-mM ammonium formate buffer (pH 4 with formic acid) and acetonitrile with 0.01% formic acid, flow rate 0.5 mL/min. The model was validated by repeated k-fold cross-validation using two-thirds of the compounds as training set and one-third as test set (Q2 0.8593; root mean squared error, 0.087, ca. 0.56 min; mean absolute error, 0.060) and by predicting relative Retention Times (rRT) of 5 SC left completely out of the modeling study. Application of the model in routine work showed its capacity to discriminate isomers, to identify unexpected SC in combination with mass spectral information, and to reduce the length of the list of candidate isomers to ca. one-third, thus reducing significantly the time required for predicting high-resolution product ion spectra to be compared to the unknown using a computational Mass Spectrometry (MS) search/identification approach.

Identification of cytochrome P450 enzymes involved in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-3-ethoxypropanamine and N-(1-phenylcyclohexyl)-3-methoxypropanamine.

The involvement of human hepatic cytochrome P450 isoenzymes (P450s) in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) and N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) to the common metabolite N-(1-phenylcyclohexyl)-3-hydroxypropanamine (PCHPA) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLMs). Incubation samples were analyzed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry. Among the tested isoenzymes, P450 2B6, P450 2C19, P450 2D6, and P450 3A4 catalyzed PCEPA O-deethylation, and P450 2B6, P450 2C19, and P450 2D6 catalyzed PCMPA O-demethylation. According to the relative activity factor approach, these enzymes accounted for 22, 3, 30, and 45% of the net clearance for PCEPA and 51, 8, and 40% of the net clearance for PCMPA, respectively. At 1 microM PCEPA, the chemical inhibitors 4-(4-chlorobenzyl)pyridine for P450 2B6 and quinidine for P450 2D6 reduced metabolite formation in pooled HLMs by 37 and 73%, respectively, and at 10 microM PCEPA, they reduced metabolite formation by 57 and 26%, respectively. At 1 microM PCMPA, 4-(4-chlorobenzyl)pyridine and quinidine reduced metabolite formation in pooled HLMs by 25 and 39%, respectively, and at 10 microM PCMPA, they reduced metabolite formation by 62 and 27%, respectively. The experiments with the MAB inhibitory to P450 3A4 and the chemical inhibitor ketoconazole for P450 3A4 showed no inhibitory effect concerning PCEPA O-dealkylation. Experiments with HLMs from P450 2D6 poor metabolizers showed a reduction of metabolite formation as compared to pooled HLM of 73 and 25% (1 microM and 10 microM PCEPA) and 40 and 38% (1 microM and 10 microM PCMPA), respectively. In conclusion, the main metabolic step was catalyzed by different P450s.

New designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA): Studies on their metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.

Studies are described on the metabolism and the toxicological detection of the phencyclidine-derived designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA) in rat urine using gas chromatographic/mass spectrometric (GC/MS) techniques. The identified metabolites indicated that PCEEA and PCMEA were transformed to the same metabolites by N-dealkylation and O-dealkylation partially followed by oxidation of the resulting alcohol to the respective carboxylic acid and hydroxylation of the cyclohexyl ring at different positions and combinations of those. Finally, aromatic hydroxylation of the O-dealkylated metabolites was partially followed by hydroxylation of the cyclohexyl ring at different positions. All metabolites were partially excreted in conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of an intake of a common drug users' dose both of PCEEA and PCMEA in rat urine. Assuming similar metabolism in humans, the STA should be suitable for proof of an intake of PCEEA and PCMEA in human urine, although their differentiation is not possible due to common metabolites.

Metabolism and toxicological detection of a new designer drug, N-(1-phenylcyclohexyl)propanamine, in rat urine using gas chromatography-mass spectrometry.

Studies are described on the metabolism and the toxicological detection of the phencyclidine-derived designer drug N-(1-phenylcyclohexyl)-propanamine (PCPR) in rat urine using gas chromatographic-mass spectrometric techniques. The identified metabolites indicated that PCPR was metabolized by hydroxylation of the cyclohexyl ring at different positions, hydroxylation of the phenyl ring, N-dealkylation, and combinations of these steps. Parts of the metabolites were excreted in conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of an intake of a common drug users' dose of PCPR in rat urine. Assuming similar metabolism in humans, the STA should be suitable for proof of an intake of PCPR in human urine.

New designer drug N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.

Studies are described on the metabolism and toxicological detection of the phencyclidine-derived designer drug N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) in rat urine using gas chromatographic/mass spectrometric techniques. The identified metabolites indicated that PCEPA was metabolized by N-dealkylation, O-deethylation partially followed by oxidation of the resulting alcohol to the corresponding carboxylic acid, hydroxylation of the cyclohexyl ring at different positions of PCEPA, N-dealkyl PCEPA, O-deethyl PCEPA, and of the corresponding carboxylic acids. Finally, aromatic hydroxylation of PCEPA, the corresponding carboxylic acids, and O-deethyl PCEPA, the latter partially followed by oxidation to the corresponding carboxylic acid and hydroxylation of the cyclohexyl ring could be observed. All metabolites were partially excreted in the conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the detection in rat urine of an intake of a common drug users' dose of PCEPA. Assuming a similar metabolism in humans, the STA in human urine should be suitable as proof of intake of PCEPA.

GC-MS analysis of the designer drug α-pyrrolidinovalerophenone and its metabolites in urine and blood in an acute poisoning case.

α-Pyrrolidinovalerophenone (α-PVP) is a synthetic cathinone belonging to the group of "second generation" pyrrolidinophenones that becomes more and more popular as a designer psychostimulant. Here we provide toxicological analytical support for a severe poisoning with α-PVP. Serum and urine samples that were sent to our laboratory were subjected to a general unknown screening procedure. The procedure includes immunoassay-based screening of drugs of abuse in serum and systematic toxicological analysis of urine and serum after neutral and basic liquid-liquid extraction followed by gas chromatography-mass spectrometry (GC-MS). Whereas the immunoassay delivered negative results, analyzing the urine sample by GC-MS in full scan mode disclosed the presence of α-PVP and its metabolites α-(2″-oxo-pyrrolidino)valerophenone (2″-oxo-α-PVP) and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-ol (OH-α-PVP). In the acetylated urine sample we found additionally N,N-bis-dealkyl-PVP. In serum, α-PVP could be detected after solid phase extraction and a concentration of 29ng/mL was determined. Other forensic relevant substances were not detected. The presented data can explain the psychotic symptoms and behavioural pattern of the subject after abuse of α-PVP, leading to a clinical condition similar to excited delirium syndrome.

Acute poisoning involving the pyrrolidinophenone-type designer drug 4'-methyl-alpha-pyrrolidinohexanophenone (MPHP).

INTRODUCTION: The pyrrolidinophenone-type designer drug 4'-methyl-alpha-pyrrolidinohexanophenone (MPHP) is presumed to be a potent psychostimulant as the structurally related drug pyrovalerone. This is the first report of an acute poisoning involving MPHP. CASE HISTORY: A 27 year old man was admitted to hospital in an agitated state and with fractures of both feet after jumping from a window. He had reportedly snorted a powder supposed to be cocaine on the previous day and taken amyl nitrite several days before. He presented with pronounced rhabdomyolysis and had to be treated by repeated hemodialysis. Elevated liver parameters indicated toxic liver damage. TOXICOLOGICAL ANALYSIS: The presumed cocaine powder was analyzed by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography with diode array detection. The liquid and the urine samples were analyzed by headspace gas chromatography with flame ionization detection. Urine was submitted to enzymatic conjugate cleavage and further worked up by liquid-liquid extraction and acetylation or by mixed-mode solid-phase extraction (SPE) and trimethylsilylation. Serum was worked up by mixed-mode SPE. All extracts were analyzed by fullscan GC-MS. RESULTS: The powder and liquid were identified as MPHP and amyl nitrite, respectively. In the serum sample, MPHP was found in a concentration of approximately 100 ng/ml, while its 4'-carboxy metabolite was detected in urine. Amyl nitrite was not found in urine. CONCLUSION: The use of MPHP instead of cocaine is in line with its presumed stimulant properties. The presented data indicate that it can lead to serious poisoning with toxic liver damage and rhabdomyolysis.

Use of fission yeast heterologously expressing human cytochrome P450 2B6 in biotechnological synthesis of the designer drug metabolite N-(1-phenylcyclohexyl)-2-hydroxyethanamine.

Standards of drug metabolites are required for drug metabolism studies as a basis for toxicological risk assessment with respect to drug interactions and pharmacogenetic polymorphisms. They are further needed as reference compounds in analytical toxicology. However, metabolite standards are often not commercially available, particularly in the case of new designer drugs. As an alternative to often cumbersome chemical synthesis, human cytochrome P450 (CYP) isoenzymes heterologously expressed in the fission yeast Schizosaccharomyces pombe can be used for the biotechnological synthesis of drug metabolites. In the present study this concept was applied to the synthesis of N-(1-phenylcyclohexyl)-2-hydroxyethanamine (PCHEA), the common O-dealkyl metabolite of the designer drugs N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA) and N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA). After adding 250 micromol PCEEA x HCl (62 mg), a 1 l culture of CAD65 (S. pombe strain co-expressing human CYP reductase and CYP2B6) was fermented over 65 h (pH 8, 30 degrees C) and centrifuged. PCHEA and remaining parent drug were isolated from the supernatant by solid-phase extraction (SPE). The eluate was evaporated to dryness and reconstituted in HPLC solvent. Aliquots were separated by semi-preparative HPLC. From the respective fraction, PCHEA was extracted by liquid-liquid extraction and precipitated as hydrochloric salt. Approximately 80% of PCEEA was converted to PCHEA. The final yield of PCHEA x HCl was 9 mg (35 micromol). Its identity was confirmed by GC-MS, (1)H NMR and (13)C NMR. The product purity, as determined by HPLC-UV, was 95%.

Investigations on the cytochrome P450 (CYP) isoenzymes involved in the metabolism of the designer drugs N-(1-phenyl cyclohexyl)-2-ethoxyethanamine and N-(1-phenylcyclohexyl)-2-methoxyethanamine.

Investigations using insect cell microsomes with cDNA-expressed human cytochrome P450 (CYP)s and human liver microsomes (HLM) are reported on the CYP isoenzymes involved in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) to O-deethyl PCEEA and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA) to O-demethyl PCMEA. Gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry was used for the analysis of the incubation samples. PCEEA O-deethylation was catalyzed by CYP2B6, CYP2C9, CYP2C19, and CYP3A4, while PCMEA O-demethylation was catalyzed only by CYP2B6 and CYP2C19. Considering the relative activity factor approach, these enzymes accounted for 53%, 25%, 4%, and 18% of net clearance for PCEEA and 91% and 9% of net clearance for PCMEA, respectively. The chemical CYP2B6 inhibitor 4-(4-chlorobenzyl)pyridine (CBP) reduced the metabolite formation in pooled HLM by 63% at 1 microM PCEEA. At 10 microM PCEEA, CBP reduced metabolite formation by 61%, while inhibition of CYP3A4 by ketoconazole and inhibition of CYP2C9 by sulfaphenazole showed no inhibitory effect. At 1 microM PCMEA, CBP reduced metabolite formation in pooled HLM by 70% and at 10 microM PCMEA by 78%, respectively. In conclusion, the main metabolic step of both studied drugs was catalyzed by different CYPs.

New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.

The aim of the present study was to identify the metabolites of the new designer drug alpha-pyrrolidinovalerophenone (PVP) in rat urine using GC/MS techniques. Eleven metabolites of PVP could be identified suggesting the following metabolic steps: hydroxylation of the side chain followed by dehydrogenation to the corresponding ketone; hydroxylation of the 2''-position of the pyrrolidine ring followed by dehydrogenation to the corresponding lactam or followed by ring opening to the respective aliphatic aldehyde and further oxidation to the respective carboxylic acid; degradation of the pyrrolidine ring to the corresponding primary amine; and hydroxylation of the phenyl ring, most probably in the 4'-position. The authors' screening procedure for pyrrolidinophenones allowed the detection of PVP metabolites after application of a dose corresponding to a presumed user's dose. In addition, the involvement of nine different human cytochrome P450 (CYP) isoenzymes in the side chain hydroxylation of PVP was investigated and CYP 2B6, 2C19, 2D6, and 3A4 were found to catalyze this reaction.

Metabolism and toxicological detection of the designer drug N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) in rat urine using gas chromatography-mass spectrometry.

Studies on the metabolism and the toxicological detection of the phencyclidine-derived designer drug N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) in rat urine are described using gas chromatographic-mass spectrometric (GC-MS) techniques. Based on the identified metabolites, the following metabolic pathways could be postulated: N-dealkylation, O-demethylation partially followed by oxidation of the resulting alcohol to the corresponding carboxylic acid, hydroxylation of the cyclohexyl ring at different positions, and aromatic hydroxylation. The formed metabolites were identical to those of the homologue N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) with exception of the mono hydroxyl metabolites of PCEPA. All PCMPA metabolites were partially excreted in conjugated form. An intake of a common drug users' dose of PCMPA could be detected in rat urine by the authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation. The STA should be suitable for proof of an intake of PCMPA also in human urine assuming similar metabolism.

Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.

This review summarizes the major metabolic pathways of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin, morphine, and codeine, in humans including the involvement of isoenzymes. This knowledge may be important for predicting their possible interactions with other xenobiotics, understanding pharmaco-/toxicokinetic and pharmacogenetic variations, toxicological risk assessment, developing suitable toxicological analysis procedures, and finally for understanding certain pitfalls in drug testing. The detection times of these drugs and/or their metabolites in biological samples are summarized and the implications of the presented data on the possible interactions of drugs of abuse with other xenobiotics, ie, inhibition or induction of individual polymorphic and nonpolymorphic isoenzymes, discussed.