DOCSLIB.ORG

Metabolic Pathways of the Psychotropic-Carboline Alkaloids, Harmaline and Harmine, by Liquid Chromatography/Mass Spectrometry and NMR Spectroscopy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Metabolic Pathways of the Psychotropic-Carboline Alkaloids, Harmaline and Harmine, by Liquid Chromatography/Mass Spectrometry and NMR Spectroscopy Food Chemistry 134 (2012) 1096–1105 Contents lists available at SciVerse ScienceDirect Food Chemistry journal homepage: www.elsevier.com/locate/foodchem Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy Ting Zhao a, Shan-Song Zheng a, Bin-Feng Zhang a,b,c, Yuan-Yuan Li a, S.W. Annie Bligh d, ⇑ ⇑ Chang-Hong Wang a,b,c, , Zheng-Tao Wang a,b,c, a Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201210, China b The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, 1200 Cailun Road, Shanghai 201210, China c Shanghai R&D Center for Standardization of Chinese Medicines, 199 Guoshoujing Road, Shanghai 201210, China d Institute for Health Research and Policy, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK article info abstract Article history: The b-carboline alkaloids, harmaline and harmine, are present in hallucinogenic plants Ayahuasca and Received 3 June 2011 Peganum harmala, and in a variety of foods. In order to establish the metabolic pathway and bioactivities Received in revised form 25 January 2012 of endogenous and xenobiotic bioactive b-carbolines, high-performance liquid chromatography, coupled Accepted 6 March 2012 with mass spectrometry, was used to identify these metabolites in human liver microsomes (HLMs) Available online 16 March 2012 in vitro and in rat urine and bile samples after oral administration of the alkaloids. Three metabolites of harmaline and two of harmine were found in the HLMs. Nine metabolites for harmaline and seven Keywords: metabolites for harmine, from the rat urine and bile samples, were identified. Among them, four Harmaline in vivo metabolites were isolated and fully characterised by NMR analysis. For the first time, harmaline Harmine Metabolites is shown transforming to harmine by oxidative dehydrogenation in rat. Five metabolic pathways were b-Carboline alkaloids therefore proposed, namely, oxidative dehydrogenation, 7-O-demethylation, hydroxylation, O-glucuro- nide conjugation and O-sulphate conjugation. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction such as harmane, harmine, harmaline and ibogaine can also be found in common plant-derived foodstuffs (e.g. wheat, rice, corn, The b-carboline alkaloids, harmaline and harmine, are the main barely, soy, beans, rye, grapes, mushrooms and vinegar), well- active components of the hallucinogenic plant, Ayahuasca, which is cooked meat, plant-derived beverages (e.g. wine, beer, whisky, used as an ingredient of the popular sacred and psychoactive brandy and sake), and plant-derived inhaled substances (e.g. to- drinks in South American Indian cultures. It is also known as Caapi, bacco) (Agüía, Peña-Farfala, Yáñez-Sedeño, & Pingarróna, 2007; Pinde, Natema or Yaje, which is widely used for prophecy, divina- Alves, Mendes, Oliveira, & Casal, 2010; Conning, 1989; Crotti, tion, and as a sacrament in the northern part of South America Gates, Lopes, & Lopes, 2010; Derakhshanfar, Oloumi, & Mirzaie, (Samoylenko et al., 2010). The b-carboline alkaloids also present 2010; Guan, Louis, & Zheng, 2001; Herraiz, Guillén, & Arán, in Peganum harmala, which has traditionally been used for ritual 2008). Because of their natural presence in the food chain and envi- and medicinal preparations in the Middle East, central Asia, and ronment, there appears to be a risk associated with extra exposure South America. According to previous reports, the entire plant to these b-carbolines from dietary sources, smoking, and consump- and seeds of P. harmala have been separately used to treat diseases tion of alcoholic beverages. In fact, the occurrence of b-carbolines such as cough, asthma, rheumatoid arthritis and swelling pain in human blood and excreta, beef and sardines under normal phys- (Cheng et al., 2010; Hemmateenejad, Abbaspour, Maghamia, Miri, iological conditions has been reported in the literature, which & Panjehshahin, 2006; Kartal, Altun, & Kurucu, 2003; Samoylenko implies that b-carboline alkaloids may be present in biological sys- et al., 2010; Sourkes, 1999; Zheng et al., 2009). The b-carbolines, tems (Guan et al., 2001; Herath, Mikell, Ferreira, & Khan, 2003; Riba et al., 2003). The b-carboline alkaloids have been of interest due to their ⇑ Corresponding authors. Address: The MOE Key Laboratory for Standardization psychotropic properties. These compounds affect the content of of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, 1200 neurotransmitters by strong reversible inhibition of monoamine Cailun Road, Zhangjiang Hi-Tech Park, Shanghai 201210, China. Tel.: +86 21 oxidase (Kim, Sablin, & Ramsay, 1997; Schwarz, Houghton, Rose, 51322511; fax: +86 21 51322519. E-mail addresses: [email protected] (C.-H. Wang), [email protected] Jenner, & Lees, 2003) and the inhibition of acetylcholinesterase (Z.-T. Wang). (Zheng et al., 2009, 2011). They also exhibit some pharmacological 0308-8146/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.foodchem.2012.03.024 T. Zhao et al. / Food Chemistry 134 (2012) 1096–1105 1097 actions, such as anti-tumour and analgesic effects (Farouk, Laroubi, donors (Mongolian). Reverse-phase silica gel (C18) and MCI Gel Aboufatima, Benharref, & Chait, 2008; Jahaniani, Ebrahimi, CHP20P(75–150 lm) for column chromatography were purchased Rahbar-Roshandel, & Mahmoudian, 2005; Wang, Liu, & Zheng, from Mitsubishi (Tokyo, Japan). The MG II C18 column (75 mm  2002), vasorelaxant activities (Astulla et al., 2008), and antimicro- 2.0 mm, i.d. 3 lm) was purchased from Shiseido (Tokyo, Japan). bial properties (Arshad, Neubauer, Hasnain, & Hess, 2008). Hence, DMSO-d6 was supplied by Armar Chemicals (Switzerland). b-carboline alkaloids have potential in the treatment of psychiatric A surveyor HPLC system (Thermo-Finnigan, San Jose, CA, USA) disorders and diseases. However, these compounds have some was used for sample separation. A Finnigan LCQ DECA XP, plus toxic effects especially in the central nervous system. For instance, ion-trap mass spectrometer equipped with an electrospray the structures of the N-methylated b-carboline alkaloids resemble ionisation (ESI) source, was used for mass analysis and detection N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and partic- (Thermo-Finnigan, San Jose, CA, USA). High resolution mass spec- ularly its neurotoxic metabolite, N-methyl-4-phenylpyridinium trometry (HRMS) was recorded using an ion mobility spectrometry (MPP+), may act as an endogenous or environmental neurotoxic (IMS)-mass spectrometry (MS) instrument (SYNAPT G2, Waters agent (Cobuzzi, Neafsey, & Collins, 1994). It was also found that Technologies, Milford, USA). A Bruker AV 400 MHz NMR spectrom- b-carboline alkaloids were co-mutagens in the presence of aro- eter (Faellanden, Switzerland) was used to record 1HNMR matic amines such as aniline, toluidine and inhibitors of mutagens (400 MHz), 13C NMR (100 MHz), HMBC and HSQC spectra. and carcinogens in mutagenic assays (Herraiz et al., 2008). The metabolic outcome and potential bio-activation of endoge- 2.2. Microsomal incubation with NADPH nous and xenobiotic bioactive b-carbolines are matters of research interest. However, not much is currently known about their Each incubation was performed in a 100 mM phosphate buffer metabolism. A previous study found that the main metabolic path- at pH 7.4 containing HLMs (final protein concentrations were ways of harmaline and harmine were O-demethylation mediated 1 mg/ml), the NADPH-generating system contained 10 mM glucose by CYP 2D6, CYP1A2 and CYP2C9, and hydroxylation mediated 6-phosphate, 1 mM NADP+, 4 mM magnesium chloride, and 1 unit/ by CYP1A2 and CYP1A1 (Yu, Idle, Krausz, Küpfer, & Gonzalez, ml of glucose 6-phosphate dehydrogenase, and various alkaloids 2003). Both in vivo and in vitro studies have revealed that the major (harmaline, harmine, harmalol, harmol) which were previously fate of harmaline and harmine was demethylation to form harma- dissolved in methanol (final methanol concentration was 1%, v/v) lol and harmol, respectively, which were subsequently excreted as with concentration 200 lM in a total volume of 100 ll. The reac- the glucuronide conjugate and sulphate conjugate (Ho, Estevez, tion system was incubated for 3 min at 37 °C before the reaction Fritchie, & Tansey, 1971; Mulder & Hagedoorn, 1974; Slotkin & was initiated by the addition of NADP+, and the incubation contin- DiStefano, 1970a, 1970b; Slotkin, DiStefano, & Au, 1970). Two ued at 37 °C for 60 min. The reaction was quenched by adding the hydroxylated metabolites were also found in human or mouse liver same volume of ice-cold acetonitrile and the reaction system was microsomes (Tweedie & Burke, 1987; Yu et al., 2003), but the posi- placed in an ice bath for 30 min. The incubation mixtures were tion of the hydroxyl group could not be definitively assigned. These then centrifuged for 10 min at 20,000g and an aliquot of the super- results are of further interest because of the biological features of natant was injected for LC-MSn analysis. these xenobiotic and endogenous bioactive alkaloids and their potential interactions with mutagens and carcinogens. Unambiguous identification of metabolites can usually only be 2.3. Microsomal incubation with UDPGA accomplished by spectroscopic characterisation, especially by MS and
Load more

Recommended publications
  • Long-Lasting Analgesic Effect of the Psychedelic Drug Changa: a Case Report
    CASE REPORT Journal of Psychedelic Studies 3(1), pp. 7–13 (2019) DOI: 10.1556/2054.2019.001 First published online February 12, 2019 Long-lasting analgesic effect of the psychedelic drug changa: A case report GENÍS ONA1* and SEBASTIÁN TRONCOSO2 1Department of Anthropology, Philosophy and Social Work, Universitat Rovira i Virgili, Tarragona, Spain 2Independent Researcher (Received: August 23, 2018; accepted: January 8, 2019) Background and aims: Pain is the most prevalent symptom of a health condition, and it is inappropriately treated in many cases. Here, we present a case report in which we observe a long-lasting analgesic effect produced by changa,a psychedelic drug that contains the psychoactive N,N-dimethyltryptamine and ground seeds of Peganum harmala, which are rich in β-carbolines. Methods: We describe the case and offer a brief review of supportive findings. Results: A long-lasting analgesic effect after the use of changa was reported. Possible analgesic mechanisms are discussed. We suggest that both pharmacological and non-pharmacological factors could be involved. Conclusion: These findings offer preliminary evidence of the analgesic effect of changa, but due to its complex pharmacological actions, involving many neurotransmitter systems, further research is needed in order to establish the specific mechanisms at work. Keywords: analgesic, pain, psychedelic, psychoactive, DMT, β-carboline alkaloids INTRODUCTION effects of ayahuasca usually last between 3 and 5 hr (McKenna & Riba, 2015), but the effects of smoked changa – The treatment of pain is one of the most significant chal- last about 15 30 min (Ott, 1994). lenges in the history of medicine. At present, there are still many challenges that hamper pain’s appropriate treatment, as recently stated by American Pain Society (Gereau et al., CASE DESCRIPTION 2014).
    [Show full text]
  • Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion and Pharmacokinetics
    TESI DOCTORAL HUMAN PHARMACOLOGY OF AYAHUASCA JORDI RIBA Barcelona, 2003 Director de la Tesi: DR. MANEL JOSEP BARBANOJ RODRÍGUEZ A la Núria, el Marc i l’Emma. No pasaremos en silencio una de las cosas que á nuestro modo de ver llamará la atención... toman un bejuco llamado Ayahuasca (bejuco de muerto ó almas) del cual hacen un lijero cocimiento...esta bebida es narcótica, como debe suponerse, i á pocos momentos empieza a producir los mas raros fenómenos...Yo, por mí, sé decir que cuando he tomado el Ayahuasca he sentido rodeos de cabeza, luego un viaje aéreo en el que recuerdo percibia las prespectivas mas deliciosas, grandes ciudades, elevadas torres, hermosos parques i otros objetos bellísimos; luego me figuraba abandonado en un bosque i acometido de algunas fieras, de las que me defendia; en seguida tenia sensación fuerte de sueño del cual recordaba con dolor i pesadez de cabeza, i algunas veces mal estar general. Manuel Villavicencio Geografía de la República del Ecuador (1858) Das, was den Indianer den “Aya-huasca-Trank” lieben macht, sind, abgesehen von den Traumgesichten, die auf sein persönliches Glück Bezug habenden Bilder, die sein inneres Auge während des narkotischen Zustandes schaut. Louis Lewin Phantastica (1927) Agraïments La present tesi doctoral constitueix la fase final d’una idea nascuda ara fa gairebé nou anys. El fet que aquest treball sobre la farmacologia humana de l’ayahuasca hagi estat una realitat es deu fonamentalment al suport constant del seu director, el Manel Barbanoj. Voldria expressar-li la meva gratitud pel seu recolzament entusiàstic d’aquest projecte, molt allunyat, per la natura del fàrmac objecte d’estudi, dels que fins al moment s’havien dut a terme a l’Àrea d’Investigació Farmacològica de l’Hospital de Sant Pau.
    [Show full text]
  • (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact
    pharmaceuticals Review Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact Andreia Machado Brito-da-Costa 1 , Diana Dias-da-Silva 1,2,* , Nelson G. M. Gomes 1,3 , Ricardo Jorge Dinis-Oliveira 1,2,4,* and Áurea Madureira-Carvalho 1,3 1 Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; [email protected] (A.M.B.-d.-C.); ngomes@ff.up.pt (N.G.M.G.); [email protected] (Á.M.-C.) 2 UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 3 LAQV-REQUIMTE, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 4 Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal * Correspondence: [email protected] (D.D.-d.-S.); [email protected] (R.J.D.-O.); Tel.: +351-224-157-216 (R.J.D.-O.) Received: 21 September 2020; Accepted: 20 October 2020; Published: 23 October 2020 Abstract: Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids.
    [Show full text]
  • PAPER Monoamine Oxidase Inhibition Is Unlikely to Be Relevant To
    International Journal of Obesity (2001) 25, 1454–1458 ß 2001 Nature Publishing Group All rights reserved 0307–0565/01 $15.00 www.nature.com/ijo PAPER Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release{ IC Kilpatrick1*, M Traut2 and DJ Heal1 1Knoll Limited Research and Development, Nottingham, UK; and 2Knoll GmbH, 50 Knollstrasse, D-67061, Ludwigshafen, Germany OBJECTIVE AND DESIGN: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAOA and MAOB in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAOA and MAOB, their respective target enzymes, with IC50 values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAOA and MAOB with IC50 values for each enzyme in the moderate to high micromolar range. For MAOA, the IC50 for phentermine was estimated to be 143 mM, that for S( þ )-fenfluramine, 265 mM and that for sertraline, 31 mM. For MAOB, example IC50s were as follows: phentermine (285 mM), S( þ )-fenfluramine (800 mM) and paroxetine (16 mM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine.
    [Show full text]
  • Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss
    Supplemental Material can be found at: /content/suppl/2020/12/18/73.1.202.DC1.html 1521-0081/73/1/202–277$35.00 https://doi.org/10.1124/pharmrev.120.000056 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:202–277, January 2021 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL NADER Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss Antonio Inserra, Danilo De Gregorio, and Gabriella Gobbi Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract ...................................................................................205 Significance Statement. ..................................................................205 I. Introduction . ..............................................................................205 A. Review Outline ........................................................................205 B. Psychiatric Disorders and the Need for Novel Pharmacotherapies .......................206 C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments . .....................................206 D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition ......208 Downloaded from E. Dissociative Anesthetics................................................................209 F. Empathogens-Entactogens . ............................................................209
    [Show full text]
  • Chemical Composition of Traditional and Analog Ayahuasca
    Journal of Psychoactive Drugs ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ujpd20 Chemical Composition of Traditional and Analog Ayahuasca Helle Kaasik , Rita C. Z. Souza , Flávia S. Zandonadi , Luís Fernando Tófoli & Alessandra Sussulini To cite this article: Helle Kaasik , Rita C. Z. Souza , Flávia S. Zandonadi , Luís Fernando Tófoli & Alessandra Sussulini (2020): Chemical Composition of Traditional and Analog Ayahuasca, Journal of Psychoactive Drugs, DOI: 10.1080/02791072.2020.1815911 To link to this article: https://doi.org/10.1080/02791072.2020.1815911 View supplementary material Published online: 08 Sep 2020. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ujpd20 JOURNAL OF PSYCHOACTIVE DRUGS https://doi.org/10.1080/02791072.2020.1815911 Chemical Composition of Traditional and Analog Ayahuasca Helle Kaasik a, Rita C. Z. Souzab, Flávia S. Zandonadib, Luís Fernando Tófoli c, and Alessandra Sussulinib aSchool of Theology and Religious Studies; and Institute of Physics, University of Tartu, Tartu, Estonia; bLaboratory of Bioanalytics and Integrated Omics (LaBIOmics), Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil; cInterdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil ABSTRACT ARTICLE HISTORY Traditional ayahuasca can be defined as a brew made from Amazonian vine Banisteriopsis caapi and Received 17 April 2020 Amazonian admixture plants. Ayahuasca is used by indigenous groups in Amazonia, as a sacrament Accepted 6 July 2020 in syncretic Brazilian religions, and in healing and spiritual ceremonies internationally.
    [Show full text]
  • 5/1 (2005) 41 - 4541
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by idUS. Depósito de Investigación Universidad de Sevilla Vol. 5/1 (2005) 41 - 4541 JOURNAL OF NATURAL REMEDIES Cytotoxic activity of methanolic extract and two alkaloids extracted from seeds of Peganum harmala L. Hicham Berrougui1,2*, Miguel López-Lázaro1, Carmen Martin-Cordero1, Mohamed Mamouchi2, Abdelkader Ettaib2, Maria Dolores Herrera1. 1. Department of Pharmacology School of Pharmacy. Séville, Spain. 2. School of Medicine and Pharmacy, UFR (Natural Substances), Rabat, Morocco. Abstract Objective: To study the cytotoxic activity of P. harmala. Materials and method: The alkaloids harmine and harmaline have been isolated from a methanolic extract from the seeds of P. harmala L. and have been characterized by spectroscopic-Mass and NMR methods. The cytotoxicity of the methanolic extract and both alkaloids has been investigated in the three human cancer cell lines UACC-62 (melanoma), TK- 10 (renal) and MCF-7 (breast) and then compared to the positive control effect of the etoposide. Results and conclusion: The methanolic extract and both alkaloids have inhibited the growth of these three cancer cell-lines and we have discussed possible mechanisms involved in their cytotoxicity. Keywords: Peganum harmala, harmine, harmaline, cytotoxicity, TK-10, MCF-7, UACC-62. 1. Introduction Peganum harmala L. (Zygophyllaceae), the so- convulsive or anticonvulsive actions and called harmal, grows spontaneously in binding to various receptors including 5-HT uncultivated and steppes areas in semiarid and receptors and the benzodiazepine binding site pre-deserted regions in south Spain and South- of GABAA receptors [10]. In addition, these East Morocco [1].
    [Show full text]
  • Hallucinogens: an Update
    National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Hallucinogens: An Update 146 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Hallucinogens: An Update Editors: Geraline C. Lin, Ph.D. National Institute on Drug Abuse Richard A. Glennon, Ph.D. Virginia Commonwealth University NIDA Research Monograph 146 1994 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGEMENT This monograph is based on the papers from a technical review on “Hallucinogens: An Update” held on July 13-14, 1992. The review meeting was sponsored by the National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company.
    [Show full text]
  • Update of the Generic Definition for Tryptamines
    ACMD Advisory Council on the Misuse of Drugs Chair: Professor Les Iversen Secretary: Zahi Sulaiman 2nd Floor (NW), Seacole Building 2 Marsham Street London SW1P 4DF Tel: 020 7035 1121 [email protected] Norman Baker MP, Minister for Crime Prevention Home Office 2 Marsham Street London SW1P 4DF 10 June 2014 Dear Minister, In December 2013, you commissioned the ACMD to begin a regular review of generic definitions under the Misuse of Drugs Act 1971, with the aim of capturing emerging new psychoactive substances. These drugs are variants of controlled drugs and fall outside the existing scope of the Misuse of Drugs Act 1971. The ACMD has considered evidence available on tryptamines in the context of the Misuse of Drugs Act 1971 and I enclose the Advisory Council’s advice and an expanded definition for tryptamine compounds with this letter. The ACMD’s NPS Committee has firstly reviewed previous research and existing controls to identify those tryptamines now seen to evade the existing controls. The ACMD has also reviewed data provided by the Home Office’s early warning systems and networks, clinical toxicology, prevalence and neuropharmacology in arriving at the expanded generic definition. This expanded generic definition will bring drugs such as alpha-methyltryptamine (AMT) as well as 5-MeO-DALT within the scope of the Misuse of Drugs Act 1971. These are highly potent hallucinogens which act on the 5HT2A receptor, in the same way as LSD. The ACMD therefore recommends that the tryptamines covered by the proposed expanded generic definition in this report, are controlled under the Misuse of Drugs Act (1971) as Class A substances.
    [Show full text]
  • Vasorelaxant Effects of Harmine and Harmaline Extracted from Peganum Harmala L. Seed's in Isolated Rat Aorta
    Pharmacological Research 54 (2006) 150–157 Vasorelaxant effects of harmine and harmaline extracted from Peganum harmala L. seed’s in isolated rat aorta Hicham Berrougui a,b,c,∗, Carmen Mart´ın-Cordero b, Abdelouahed Khalil c, Mohammed Hmamouchi a, Abdelkader Ettaib a, Elisa Marhuenda b, Mar´ıa Dolores Herrera b a UFR of Natural Products, University MedV, School of Medicine and Pharmacy, Rabat 10000, Morocco b Department of Pharmacology, University of Seville, School of Pharmacy, C/Professor Garc´ıa Gonz´alez no. 2, Seville 41012, Spain c Research Centre on Aging, Sherbrooke University, 1036 Belvedere South, Sherbrooke (Qc), Canada J1H 4C4 Accepted 7 April 2006 Abstract The present work describes the mechanisms involved in the vasorelaxant effect of harmine and harmaline. These alkaloids induce in a dose- dependent manner the relaxation in the aorta precontracted with noradrenaline or KCl. However, the removal of endothelium or pre-treatment of intact aortic ring with L-NAME (inhibitor of NOSe synthetase) or with indomethacin (non-specific inhibitor of cyclo-oxygenase), reduces significantly the vasorelaxant response of harmaline but not harmine. According to their IC50 values, prazosin (inhibitor of ␣-adrenorecepteors) reduces the vasorelaxant effect only of harmaline, whereas, pre-treatment with IBMX (non-specific inhibitor of phosphodiesterase) affects both the harmaline and harmine-responses. Inhibitions of L-type voltage-dependent Ca2+ channels (VOCs) in endothelium-intact aortic rings with diltiazem depress the relaxation evoked by harmaline as well as by harmine. Pre-treatment with harmaline or harmine (3, 10 or 30 ␮M) shifted the phenylephrine-induced dose response curves to the right and the maximum response was attenuated indicating that the antagonist effect of both alkaloids on ␣1-adrenorecepteors was non-competitive.
    [Show full text]
  • United States Department of Justice Drug Enforcement
    UNITED STATES DEPARTMENT OF JUSTICE DRUG ENFORCEMENT ADMINISTRATION In the Matter of ) ) Docket No. 84-48 MDMA SCHEDULING ) DIRECT TESTIMONY OF RICHARD A. GLENNON, Ph.D. I, Richard A. Glennon, make the following statement: I am a Professor in the Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth Univer- sity, Richmond, Virginia. I have been a member of the teaching staff at the Medical College of Virginia since 1975. I received my B.S. degree in Pharmacy, my M.S. in Medicinal Chemistry, and my Ph.D. in Medicinal Chemistry from the State University of New York at Buffalo in 1973. I was in a post-doctoral program in psychopharmacology at the State University of New York at Buffalo from 1973 to 1975. A copy of my curriculum vitae i_ attached as exhibit I. I have been involved in investigations of centrally-actlve drugs using a drug discrimination paradigm. The paradigm, or research model, Involves training animals, in this case rats, to distinguish drugs based upon recognizing the presence or absence of certain effects produced by a particular dose of a drug. The animals are trained over a period of time to press a lever when they recognize that substance or one that produces similar stimulus effects. This paradigm is especially suitable for the study of psychotomlmetlc agents. After the animals have been trained to discriminate between a particular drug and saline, their responses to dosages of other substances are measured. For example, rats are trained to discriminate amphetamine from saline. This is evidenced by rats pressing a specific lever more than 80% of the time when they receive amphetamine.
    [Show full text]
  • Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction
    pharmaceutics Review Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction Maria D. Auxtero 1, Susana Chalante 1,Mário R. Abade 1 , Rui Jorge 1,2,3 and Ana I. Fernandes 1,* 1 CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; [email protected] (M.D.A.); [email protected] (S.C.); [email protected] (M.R.A.); [email protected] (R.J.) 2 Polytechnic Institute of Santarém, School of Agriculture, Quinta do Galinheiro, 2001-904 Santarém, Portugal 3 CIEQV, Life Quality Research Centre, IPSantarém/IPLeiria, Avenida Dr. Mário Soares, 110, 2040-413 Rio Maior, Portugal * Correspondence: [email protected]; Tel.: +35-12-1294-6823 Abstract: Late-life mild cognitive impairment and dementia represent a significant burden on health- care systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treat- ment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmaco- logical interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration.
    [Show full text]