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AM-2201

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Volker Auwärter – 1st expert on this subject based on the ideXlab platform

  • Genotoxic properties of representatives of alkylindazoles and aminoalkyl-indoles which are consumed as synthetic cannabinoids.
    Food and Chemical Toxicology, 2015
    Co-Authors: Verena J. Koller, Volker Auwärter, Franziska Ferk, Halh Al-serori, Miroslav Mišík, Armen Nersesyan, Tamara Grummt, Siegfried Knasmüller

    Abstract:

    Abstract Synthetic cannabinoids (SCs) cause similar effects as cannabis and are sold in herbal mixtures. Recent investigations indicate that some of these drugs possess genotoxic properties. Therefore, we tested representatives of two groups, namely, aminoalkylindoles (AM-2201 and UR-144) and 1-alkylindazoles (5F-AKB-48 and AM-2201-IC) in single cell gel electrophoresis and micronucleus (MN) assays with human lymphocytes and in Salmonella/microsome assays. All drugs except AM-2201 caused DNA-migration, the LOELs were between 50 and 75 µM. Furthermore, all SCs caused inhibition of cell division and significant induction of MN which reflect structural and numerical chromosomal aberrations. The LOEL values were 50 µM for UR-144 and 5-AKB-48 and 75 µM for the other drugs. Also the levels of nucleoplasmatic bridges which are formed from dicentric chromosomes were elevated under identical conditions while the frequencies of nuclear buds were not affected. These findings show that representatives of both groups cause chromosomal damage while the negative results in Salmonella assays (in strains TA98, TA100, TA1535, TA1537 and TA102) in absence and presence of metabolic activation indicate that they do not induce gene mutations. Taken together, these findings indicate that SCs may cause adverse health effects in users as a consequence of damage of the genetic material.

  • O23: Hair analysis for synthetic cannabinoids: How does handling of herbal mixtures during forensic analysis affect the analyst’s hair concentrations?
    Toxicologie Analytique et Clinique, 2014
    Co-Authors: Volker Auwärter, Melanie Hutter, Merja A Neukamm, B. Moosmann

    Abstract:

    Introduction If narcotics police officers or other persons handling drug material at work are suspected of consuming drugs, hair analysis may be used to prove or refute such suspicion. However, it is known for many drugs that differentiation of actual drug use from external contamination can be challenging or sometimes impossible. The aim of this study was to evaluate the extent of external contamination caused by handling of synthetic cannabinoid containing drug material under realistic conditions in a forensic laboratory. Methods Hair of laboratory workers was systematically analyzed for synthetic cannabinoids with a validated LC-MS/MS method after a big seizure of legal high products had to be analyzed in our laboratory. Hair samples were taken two days after the last exposure and again one week later. In addition, hair samples of laboratory staff not directly in contact with the drug material and close relatives of exposed subjects were analyzed to check for cross contamination. Results All samples of persons who were in direct contact with drug material were tested positive for at least one of the synthetic cannabinoids (JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-307, JWH-368, AM-2201, AM-2201 indazole derivative, AM- 2232, MAM-2201, RCS-4, XLR-11, 5F-PB-22, RCS-4 ortho isomer). Concentrations ranged from trace amounts up to a maximum of 170 pg/mg (JWH-210) and roughly reflected duration and intensity of exposition. There was no significant decline in concentrations from sample 1 to sample 2 (one week later). Unexpectedly, also subjects without direct contact to drug material showed measurable hair concentrations. In one case, a hair sample (21 cm) was taken 10 weeks after the last exposition with plant material. In this case, relevant concentrations of 5F-PB-22 were detected with an increase of concentrations from distal to proximal segments (7.9 – 20 pg/mg). Conclusion Depending on duration and intensity of exposition, relevant concentrations of synthetic cannabinoids may be found in hair samples of persons exposed to these drugs at work. Unexpectedly, even cross contamination from an exposed person to a close relative may occur and lead to (false) positive hair findings. Concentrations caused by contamination are in the typical range found in known users of these drugs and could lead to wrong conclusions. In contrast, detection of metabolites could strongly suggest an actual consumption. However, we did not detect such metabolites so far even in samples of known consumers of synthetic cannabinoids showing extremely high concentrations of the unchanged compounds. Therefore, body fluids have to be analyzed to unambiguously prove use of these drugs.

  • Driving under the influence of synthetic cannabinoids (“Spice”): a case series
    International Journal of Legal Medicine, 2014
    Co-Authors: Frank Musshoff, Melanie Hutter, Stefan Kneisel, Burkhard Madea, Gerhard Kernbach-wighton, Wolfgang Bicker, Volker Auwärter

    Abstract:

    Recreational use of synthetic cannabinoid receptor agonists—so-called “Spice” products—became very popular during the last few years. Several reports on clinical symptoms and poisonings were published. Unfortunately, most of these reports do not contain any analytical data on synthetic cannabinoids in body fluids, and no or only a limited number of cases were reported concerning driving under the influence (DUI) of this kind of drugs. In this article, several cases of DUI of synthetic cannabinoids (AM-2201, JWH-018, JWH-019, JWH-122, JWH-210, JWH-307, MAM-2201 (JWH-122 5-fluoropentyl derivative), and UR-144) are presented, focusing on analytical results and signs of impairment documented by the police or the physicians who had taken the blood sample from the suspects. Consumption of synthetic cannabinoids can lead to impairment similar to typical performance deficits caused by cannabis use which are not compatible with safe driving. These deficits include centrally sedating effects and impairment of fine motor skills necessary for keeping the vehicle on track. Police as well as forensic toxicologists and other groups should become familiar with the effects of synthetic cannabinoid use, and be aware of the fact that drug users may shift to these “legal” alternatives due to their nondetectability by commonly used drug screening tests based on antibodies. Sophisticated screening procedures covering the complete range of available compounds or their metabolites have to be developed for both blood/serum and urine testing.

Stefan Kneisel – 2nd expert on this subject based on the ideXlab platform

  • Metabolism of Nine Synthetic Cannabinoid Receptor Agonists Encountered in Clinical Casework: Major in vivo Phase I Metabolites of AM-694, AM-2201, JWH-007, JWH-019, JWH-203, JWH-307, MAM-2201, UR-144 and XLR-11 in Human Urine Using LC-MS/MS
    Current Pharmaceutical Biotechnology, 2018
    Co-Authors: Melanie Hutter, Stefan Kneisel, Sebastian Broecker, Florian Franz, Simon D. Brandt, Auwärter

    Abstract:

    Background: `Herbal mixtures` containing synthetic cannabinoid receptor agonists (SCRAs) are promoted as legal alternative to marihuana and are easily available via the Internet. Keeping analytical methods for the detection of these SCRAs up-to-date is a continuous challenge for clinicians and toxicologists due to the high diversity of the chemical structures and the frequent emergence of new compounds. Since many SCRAs are extensively metabolized, analytical methods used for urine testing require previous identification of the major metabolites of each compound. Objective: The aim of this study was to identify the in vivo major metabolites of nine SCRAs (AM-694, AM-2201, JWH-007, JWH-019, JWH-203, JWH-307, MAM-2201, UR-144, XLR-11) for unambiguous detection of a drug uptake by analysis of urine samples. Method: Positive urine samples from patients of hospitals, detoxification and therapy centers as well as forensic-psychiatric clinics were analyzed by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-quadrupol time-of-flight mass spectrometry (LC-qToF-MS) for investigation of the in vivo major metabolites. Results: For all investigated SCRAs, monohydroxylation, dihydroxylation and/or formation of the N-pentanoic acid metabolites were among the most abundant metabolites detected in human urine samples. Substitution of the fluorine atom was observed to be an important metabolic reaction for compounds carrying an N-(5-fluoropentyl) chain. Dealkylated metabolites were not detected in vivo. Conclusion: The investigated metabolites facilitate the reliable detection of drug uptake by analysis of urine samples. For distinction between uptake of the fluorinated and the non-fluorinated analogs, the N-(4-hydroxypentyl) metabolite of the non-fluorinated analog was identified as a useful analytical target and consumption marker.

  • Driving under the influence of synthetic cannabinoids (“Spice”): a case series
    International Journal of Legal Medicine, 2014
    Co-Authors: Frank Musshoff, Melanie Hutter, Stefan Kneisel, Burkhard Madea, Gerhard Kernbach-wighton, Wolfgang Bicker, Volker Auwärter

    Abstract:

    Recreational use of synthetic cannabinoid receptor agonists—so-called “Spice” products—became very popular during the last few years. Several reports on clinical symptoms and poisonings were published. Unfortunately, most of these reports do not contain any analytical data on synthetic cannabinoids in body fluids, and no or only a limited number of cases were reported concerning driving under the influence (DUI) of this kind of drugs. In this article, several cases of DUI of synthetic cannabinoids (AM-2201, JWH-018, JWH-019, JWH-122, JWH-210, JWH-307, MAM-2201 (JWH-122 5-fluoropentyl derivative), and UR-144) are presented, focusing on analytical results and signs of impairment documented by the police or the physicians who had taken the blood sample from the suspects. Consumption of synthetic cannabinoids can lead to impairment similar to typical performance deficits caused by cannabis use which are not compatible with safe driving. These deficits include centrally sedating effects and impairment of fine motor skills necessary for keeping the vehicle on track. Police as well as forensic toxicologists and other groups should become familiar with the effects of synthetic cannabinoid use, and be aware of the fact that drug users may shift to these “legal” alternatives due to their nondetectability by commonly used drug screening tests based on antibodies. Sophisticated screening procedures covering the complete range of available compounds or their metabolites have to be developed for both blood/serum and urine testing.

  • Characteristics of the designer drug and synthetic cannabinoid receptor agonist AM-2201 regarding its chemistry and metabolism.
    Journal of Mass Spectrometry, 2013
    Co-Authors: Melanie Hutter, Stefan Kneisel, Bjoern Moosmann, Volker Auwärter

    Abstract:

    Aminoalkylindoles, a subclass of synthetic cannabinoid receptor agonists, show an extensive and complex metabolism in vivo, and due to their structural similarity, they can be challenging in terms of unambiguous assignment of metabolic patterns in urine samples to consumed substances. The situation may even be more complicated as these drugs are usually smoked, and the high temperature exposure may lead to formation of artifacts.

    Typical metabolites of JWH-018 (Naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone) were reportedly detected not only in urine samples collected after consumption of JWH-018 but also after AM-2201 (1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone) use. The aim of the presented study was to evaluate if typical JWH-018 metabolites can be formed metabolically in humans and if JWH-018 may be formed artifactually during smoking of AM-2201. Therefore, one of the authors ingested 5 mg of pure AM-2201, and serum as well as urine samples were analyzed subsequently. Additionally, the smoke condensate from a cigarette laced with pure AM-2201 was investigated. In addition, urine samples of patients after known consumption of AM-2201 or JWH-018 were evaluated.

    The results of the study prove that typical metabolites of JWH-018 and JWH-073 are built in humans after ingestion of AM-2201. However, the N-(4-hydroxypentyl) metabolite of JWH-018, which is the major metabolite after JWH-018 use, was not detected after the self-experiment. In the smoke condensate, small amounts of JWH-018 and JWH-022 (Naphthalen-1-yl[1-(pent-4-en-1-yl)-1H-indol-3-yl]methanone) were detected. Nevertheless, the results of our study suggest that the amounts absorbed by smoking do not significantly influence the metabolic pattern in urine samples.

    Therefore, the N-(4-hydroxypentyl) metabolite of JWH-018 can serve as a valuable marker to distinguish consume of products containing AM-2201 from JWH-018 use. Copyright © 2013 John Wiley & Sons, Ltd.

Tomoko Hamano – 3rd expert on this subject based on the ideXlab platform

  • Identification and quantitation of two new naphthoylindole drugs-of-abuse, (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202) and (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone, with other synthetic cannabinoids in unre
    Forensic Toxicology, 2012
    Co-Authors: Jun’ichi Nakajima, Misako Takahashi, Takako Seto, Masao Yoshida, Chieko Kanai, Jin Suzuki, Tomoko Hamano

    Abstract:

    During our continual surveillance of unregulated drugs in May–June 2011, we found two new compounds as adulterants in herbal products obtained at shops in the Tokyo area. These compounds were identified by liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a naphthoylindole (1-(5-hydroxypentyl)-1 H -indol-3-yl)(naphthalen-1-yl)methanone (AM-2202, 1 ), which is a side-chain hydroxyl analogue of JWH-018. The second compound was (1-(4-pentenyl)-1 H -indol-3-yl)(naphthalen-1-yl)methanone ( 2 ), which is side-chain double bond analogue of JWH-018. This is the first report to identify 1 and 2 in a commercial “herbal” product to our knowledge. For quantitation of the above compounds 1 and 2 , and chemical analysis for previously reported compounds (AM-2201, 3 ; JWH-203, 4 ; JWH-019, 7 ; JWH-210, 8 ; mitragynine, 9 ), each product was extracted with methanol under ultrasonication to prepare solutions for analysis by liquid chromatography with ultraviolet detection. For the sake of identifying JWH-203 ( 4 ) and its positional isomers [JWH-203-3-chloroisomer ( 5 ) and 4-chloroisomer ( 6 )] correctly, simultaneous liquid chromatography analysis on fluorocarbon-bonded silica gel column was performed. And a case report of commercially available products containing synthetic cannabinoids 7 and 8 , and a natural occurring alkaloid 9 , was also shown. Each of 6 commercially circulated products contained compounds 1 – 4 and 7 – 9 ; the amounts of the compounds ranged from 4.1 to 222 mg per pack.

  • Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and
    Forensic Toxicology, 2011
    Co-Authors: Jun’ichi Nakajima, Misako Takahashi, Takako Seto, Masao Yoshida, Chieko Kanai, Jin Suzuki, Ryouichi Nonaka, Tomoko Hamano

    Abstract:

    During our careful surveillance of unregulated drugs in January to February 2011, we found two new compounds used as adulterants in herbal products obtained via the Internet. These compounds were identified by liquid chromatography–mass spectrometry, gas chromatography-mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a benzoylindole (2-methoxyphenyl)(1-pentyl-1 H -indol-3-yl)methanone ( 1 ), which is a positional isomer of (4-methoxyphenyl)(1-pentyl-1 H -indol-3-yl)methanone (RCS-4, 4 ). The second compound was 1-(5-fluoropentyl-1 H -indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201, 2 ). The compound 2 has been reported to be a cannabinoid receptor agonist. Because the cannabimimetic effects of compounds 1 and 4 have not been reported to date, their biological activities were evaluated by measuring the activation of [^35S] guanosine-5′- O -(3-thio)-triphosphate binding to guanine nucleotide-binding proteins, together with those of other synthetic cannabimimetic compounds. For quantitation of the above two compounds ( 1 and 2 ) and previously identified compounds (AM-694, 3 ; JWH-122, 5 ; RCS-4, 4 ), each product was extracted with methanol under ultrasonication to prepare a sample solution for analysis by liquid chromatography with ultraviolet detection. Each of four commercial products contained some of cannabimimetic indoles 1 – 5 ; their contents ranged from 14.8 to 185 mg per pack.