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Sebastian Dresen – One of the best experts on this subject based on the ideXlab platform.

  • development and validation of a liquid chromatography tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the Aminoalkylindole type and methanandamide in serum and its application to forensic samples
    Journal of Mass Spectrometry, 2011
    Co-Authors: Stefan Kneisel, Sebastian Dresen, Wolfgang Weinmann, Ralf Zimmermann, Volker Auwarter

    Abstract:

    After the discovery of synthetic cannabimimetic substances in ‘Spice’-like herbal mixtures marketed as ‘incense’ or ‘plant fertilizer’ the active compounds have been declared as controlled substances in several European countries. As expected, a monitoring of new herbal mixtures which continue to appear on the market revealed that shortly after control measures have been taken by legal authorities, other compounds were added to existing mixtures and to new products. Several compounds of the Aminoalkylindole type have been detected so far in herbal mixtures but still their consumption cannot be detected by commonly used drug-screening procedures, encouraging drug users to substitute cannabis with those products. There is a increasing demand on the part of police authorities, hospitals and psychiatrists for detection and quantification of synthetic cannabinoids in biological samples originating from psychiatric inpatients, emergency units or assessment of fitness to drive. Therefore, a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of JWH-015, JWH-018, JWH-073, JWH-081, JWH 200, JWH-250, WIN 55,212-2 and methanandamide and the detection of JWH-019 and JWH-020 in human serum has been developed and fully validated according to guidelines for forensic toxicological analyses. The method was successfully applied to 101 serum samples from 80 subjects provided by hospitals, detoxification and therapy centers, forensic psychiatric centers and police authorities. Fifty-seven samples or 56.4% were found positive for at least one Aminoalkylindole. JWH-019, JWH-020, JWH-200, WIN 55,212-2 and methanandamide were not detected in any of the analyzed samples.

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  • Development and validation of a liquid chromatography–tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the Aminoalkylindole type and methanandamide in serum and its application to forensic samples
    Journal of Mass Spectrometry, 2011
    Co-Authors: Sebastian Dresen, Stefan Kneisel, Wolfgang Weinmann, Ralf Zimmermann, Volker Auwarter

    Abstract:

    After the discovery of synthetic cannabimimetic substances in ‘Spice’-like herbal mixtures marketed as ‘incense’ or ‘plant fertilizer’ the active compounds have been declared as controlled substances in several European countries. As expected, a monitoring of new herbal mixtures which continue to appear on the market revealed that shortly after control measures have been taken by legal authorities, other compounds were added to existing mixtures and to new products. Several compounds of the Aminoalkylindole type have been detected so far in herbal mixtures but still their consumption cannot be detected by commonly used drug-screening procedures, encouraging drug users to substitute cannabis with those products. There is a increasing demand on the part of police authorities, hospitals and psychiatrists for detection and quantification of synthetic cannabinoids in biological samples originating from psychiatric inpatients, emergency units or assessment of fitness to drive. Therefore, a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of JWH-015, JWH-018, JWH-073, JWH-081, JWH 200, JWH-250, WIN 55,212-2 and methanandamide and the detection of JWH-019 and JWH-020 in human serum has been developed and fully validated according to guidelines for forensic toxicological analyses. The method was successfully applied to 101 serum samples from 80 subjects provided by hospitals, detoxification and therapy centers, forensic psychiatric centers and police authorities. Fifty-seven samples or 56.4% were found positive for at least one Aminoalkylindole. JWH-019, JWH-020, JWH-200, WIN 55,212-2 and methanandamide were not detected in any of the analyzed samples.

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  • Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds
    Journal of Mass Spectrometry, 2010
    Co-Authors: Sebastian Dresen, Ralf Zimmermann, Nerea Ferreirós, Michael Putz, Folker Westphal, Volker Auwarter

    Abstract:

    Herbal mixtures like ‘Spice’ with potentially bioactive ingredients were available in many European countries since 2004 and are still widely used as a substitute for cannabis, although merchandized as ‘herbal incense’. After gaining a high degree of popularity in 2008, big quantities of these drugs were sold. In December 2008, synthetic cannabinoids were identified in the mixtures which were not declared as ingredients: the C8 homolog of the non-classical cannabinoid CP-47,497 (CP-47,497-C8) and a cannabimimetic Aminoalkylindole called JWH-018. In February 2009, a few weeks after the German legislation put these compounds and further pharmacologically active homologs of CP-47,497 under control, another cannabinoid appeared in ‘incense’ products: the Aminoalkylindole JWH-073.

    In this paper, the results of monitoring of commercially available ‘incense’ products from June 2008 to September 2009 are presented. In this period of time, more than 140 samples of herbal mixtures were analyzed for bioactive ingredients and synthetic cannabimimetic substances in particular. The results show that the composition of many products changed repeatedly over time as a reaction to prohibition and prosecution of resellers. Therefore neither the reseller nor the consumer of these mixtures can predict the actual content of the ‘incense’ products. As long as there is no possibility of generic definitions in the controlled substances legislation, further designer cannabinoids will appear on the market as soon as the next legal step has been taken. This is affirmed by the recent identification of the Aminoalkylindoles JWH-250 and JWH-398. As further cannabinoids can be expected to occur in the near future, a continuous monitoring of these herbal mixtures is required.

    The identification of the synthetic opioid O-desmethyltramadol in a herbal mixture declared to contain ‘kratom’ proves that the concept of selling apparently natural products spiked with potentially dangerous synthetic chemicals/pharmaceuticals is a continuing trend on the market of ‘legal highs’. Copyright © 2010 John Wiley & Sons, Ltd.

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Alexandros Makriyannis – One of the best experts on this subject based on the ideXlab platform.

  • [INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related Aminoalkylindole analogs in rats.
    Behavioural Pharmacology, 2016
    Co-Authors: Torbjörn U. C. Järbe, Roger S. Gifford, Alexander M. Zvonok, Alexandros Makriyannis

    Abstract:

    The recent recreational use of synthetic cannabinoid ligands, collectively referred to as ‘Spice’, has raised concerns about their safety and possible differences in their biological effect(s) from marijuana/Δ-tetrahydrocannabinol (THC). AM2201, a highly efficacious, potent cannabinoid receptor 1 (CB1R) agonist, is a recently detected compound in ‘Spice’ preparations. Furthermore, structural analogs of AM2201 are now being found in ‘Spice’. The present studies were conducted to investigate their Δ-THC-like effects using drug (Δ-THC) discrimination in rats. Results show that the tested compounds were potent cannabinergics that generalized to the response to Δ-THC, with AM2201 being most potent, exhibiting a 14-fold potency difference over Δ-THC. The other analogs were between 2.5-fold and 4-fold more potent than THC. Surmountable antagonism of AM2201 with the selective CB1R antagonist/inverse agonist rimonabant also established that the discrimination is CB1R dependent. Time-course data reveal that AM2201 likely peaks rapidly with an in-vivo functional half-life of only 60 min. The present data confirm and extend previous observations regarding Δ-THC-like effects of ‘Spice’ components.

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  • Cannabinergic Aminoalkylindoles, including AM678=JWH018 found in ‘Spice’, examined using drug (Δ(9)-tetrahydrocannabinol) discrimination for rats.
    Behavioural Pharmacology, 2011
    Co-Authors: Torbjörn U. C. Järbe, Hongfeng Deng, Subramanian K. Vadivel, Alexandros Makriyannis

    Abstract:

    We examined four different cannabinergic Aminoalkylindole ligands, including one drug (AM678=JWH018) found in herbal ‘Spice’ concoctions, for their ability to substitute for Δ(9)-tetrahydrocannabinol (THC), and the ability of the cannabinoid receptor 1-selective antagonist/inverse agonist rimonabant to block the substitution, 30 and 90 min after intraperitoneal injection. Rats trained to discriminate the effects of vehicle from those produced by 3 mg/kg of THC were used. The order of potency was: AM5983≥AM678>AM2233>WIN55212-2 at both test intervals. AM5983 and AM678 appeared eight times more potent than THC, followed by AM2233 (about twice as potent as THC), and WIN55212-2 approximately THC at the 30-min test interval. The Aminoalkylindoles showed reduced potency (i.e. an increased ED50 value) at the longer injection-to-test interval of 90 min compared with testing at 30 min. The rightward shifts by coadministration of rimonabant were approximately 8-fold to 12-fold for AM5983 and AM678, compared with an approximately 3-fold rightward shift for the WIN55212-2 curve. AM2233 (1.8 mg/kg) substitution was also blocked by 1 mg/kg of rimonabant. In conclusion, AM5983 and AM678=JWH018 are potent cannabimimetics derived from an Aminoalkylindole template. WIN55212-2 seemed to interact differently with rimonabant, compared with either AM5983 or AM678, indicating potential differences in the mechanism(s) of action among cannabinergic Aminoalkylindoles.

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  • Discriminative stimulus functions of methanandamide and ∆^9-THC in rats: tests with Aminoalkylindoles (WIN55,212-2 and AM678) and ethanol
    Psychopharmacology, 2009
    Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Alexandros Makriyannis

    Abstract:

    Objective The aim of the study was to characterize in vivo the Aminoalkylindoles WIN55,212-2 (WIN) and AM678 (naphthalen-1-yl(1-pentyl-1 H -indol-3-yl)methanone) as cannabinoid receptor (CB_1R) ligands using drug discrimination. Tests also involved ∆^9-tetrahydrocannabinol (THC) and R -(+)-methanandamide (mAEA), a metabolically stable analog of the endogenous ligand anandamide, as well as the CB_1R selective antagonist/inverse agonist rimonabant; tests with ethanol assessed pharmacological specificity. We used two different drug discriminations (mAEA and THC) allowing us to explore potential differences in CB_1R activation which could be attributed to variations in their respective CB_1R signaling mechanisms. Methods There were two concurrently trained groups of rats. One group discriminated between i.p. injected vehicle and 10 mg/kg mAEA. The other group was trained to discriminate between vehicle and 1.8 mg/kg THC. Results Dose generalization curves for AM678, WIN55,212-2, THC, and mAEA suggested the following rank order of potency: AM678 > WIN55,212-2 ≥ THC > mAEA in both drug discrimination groups. Challenge by 1 mg/kg rimonabant resulted in shifts to the right of the generalization curves for the two Aminoalkylindoles (4.4-fold for AM678 and 11.3-fold for WIN in the mAEA group, whereas for the THC group, the corresponding values were 13 and 2.6, respectively), suggesting surmountable antagonism. Ethanol did not generalize in either of the two groups, suggesting pharmacological specificity. Conclusion Data are congruent with the general observation that there is substantial overlap in the discriminative stimulus effects of CB_1R ligands across different chemical classes. However, the quantitative differences in the interactions between the two Aminoalkylindoles and rimonabant in the two discrimination groups suggest subtle variations in the ligand–receptor activation(s).

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Volker Auwarter – One of the best experts 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, Franziska Ferk, Halh Al-serori, Miroslav Misik, Armen Nersesyan, Volker Auwarter, 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.

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  • Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8
    Toxicology and Applied Pharmacology, 2014
    Co-Authors: Verena J. Koller, Miroslav Misik, Volker Auwarter, Tamara Grummt, Bjoern Moosmann, Siegfried Knasmüller

    Abstract:

    Abstract Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by Aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥ 10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.

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  • development and validation of a liquid chromatography tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the Aminoalkylindole type and methanandamide in serum and its application to forensic samples
    Journal of Mass Spectrometry, 2011
    Co-Authors: Stefan Kneisel, Sebastian Dresen, Wolfgang Weinmann, Ralf Zimmermann, Volker Auwarter

    Abstract:

    After the discovery of synthetic cannabimimetic substances in ‘Spice’-like herbal mixtures marketed as ‘incense’ or ‘plant fertilizer’ the active compounds have been declared as controlled substances in several European countries. As expected, a monitoring of new herbal mixtures which continue to appear on the market revealed that shortly after control measures have been taken by legal authorities, other compounds were added to existing mixtures and to new products. Several compounds of the Aminoalkylindole type have been detected so far in herbal mixtures but still their consumption cannot be detected by commonly used drug-screening procedures, encouraging drug users to substitute cannabis with those products. There is a increasing demand on the part of police authorities, hospitals and psychiatrists for detection and quantification of synthetic cannabinoids in biological samples originating from psychiatric inpatients, emergency units or assessment of fitness to drive. Therefore, a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of JWH-015, JWH-018, JWH-073, JWH-081, JWH 200, JWH-250, WIN 55,212-2 and methanandamide and the detection of JWH-019 and JWH-020 in human serum has been developed and fully validated according to guidelines for forensic toxicological analyses. The method was successfully applied to 101 serum samples from 80 subjects provided by hospitals, detoxification and therapy centers, forensic psychiatric centers and police authorities. Fifty-seven samples or 56.4% were found positive for at least one Aminoalkylindole. JWH-019, JWH-020, JWH-200, WIN 55,212-2 and methanandamide were not detected in any of the analyzed samples.

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