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Ayahuasca Characterization, Metabolism in Humans, and Relevance to Endogenous N,N-Dimethyltryptamines

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Ayahuasca Characterization, Metabolism in Humans, and Relevance to Endogenous N,N-Dimethyltryptamines ______________________________________________________________________________________________www.neip.info AYAHUASCA CHARACTERIZATION, METABOLISM IN HUMANS, AND RELEVANCE TO ENDOGENOUS N,N-DIMETHYLTRYPTAMINES A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and School of Veterinary Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Interdepartmental Program in Veterinary Medical Sciences through the Department of Comparative Biomedical Sciences by Ethan Hamilton McIlhenny B.A., Skidmore College, 2006 M.S., Tulane University, 2008 August 2012 ______________________________________________________________________________________________www.neip.info Acknowledgments Infinite thanks, appreciation, and gratitude to my mother Bonnie, father Chaffe, brother Matthew, grandmothers Virginia and Beverly, and to all my extended family, friends, and loved ones. Without your support and the visionary guidance of my friend and advisor Dr. Steven Barker, none of this work would have been possible. Special thanks to Dr. Rick Strassman MD and the Cottonwood Research Foundation for helping me find and navigate this path. We acknowledge and are grateful for the collaborative research efforts and dedication of Dr. Jordi Riba and his lab which obtained the human urine and blood samples necessary for the included studies. We wish to dedicate this work to the memory of our friend and colleague, Dr. Manel J. Barbanoj. We acknowledge Dr. Leanna Standish for her diligent work in bringing ayahuasca towards clinical trials and collaborative efforts in supplying our lab with ayahuasca samples. We thank Dr. Dave E. Nichols, Dr. Laurent Micouin and Dr. Simon D. Brandt for generously providing analytical compounds. We thank Connie David, Izabela Lomnicka, Pam Waller and Marian Waguespack for technical support in lab. I thank my dissertation committee members Dr. George Strain, Dr. Arthur Penn, Dr. Joseph Francis, and Dr. Samuel Gilman. I thank the Louisiana State Board of Regents for the generous fellowship grant support they provided. I thank Dr. Luis Eduardo Luna, Dr. Dennis McKenna, Dr. Michael Winkelman and Dr. Ede Frecska MD for opportunity, friendship, and insights. I thank and acknowledge the plant teachers Ayahuasca and Chacruna for wisdom, teachings and healing. I express my eternal and infitie gratitude to the form and formless, to the water, earth, air, and fire for our feelings, sensations, thoughts, intuition, and intentionality, to the central source within and mysterious truth that surrounds, to the one shared unity and the many reflections of it. -Blessings, gratitude, love and light to all beings and all becomings in all places and all times. ii ______________________________________________________________________________________________www.neip.info Table of Contents Acknowledgments .........................................................................................................................ii List of Tables..................................................................................................................................vi List of Figures................................................................................................................................vii Abstract.........................................................................................................................................viii Chapter 1. Introduction ..................................................................................................................1 1.1 Semanitcs……………………………………………………………………….…….1 1.2 Historical and Social Context…………………………………………………….…..3 1.3 Ayahuasca……………………………………………………………………….……7 1.4 Chapter Contents……………………………………………………………………..9 1.5 References……………………………………………………………………………15 Chapter 2. Direct Analysis of Psychoactive Tryptamine and Harmala Alkaloids in the Amazonian Botanical Medicine Ayahuasca by Liquid Chromatography-Electrospray Ionization-Tandem MassSpectrometry………………………………………..............................21 2.1 Introduction……………………………………………………………………………....…22 2.2 Materials and Methods………………………………………………………………..25 2.2.1 Reagents and Chemicals…………………………………………………...25 2.2.2 Botanical Raw Material and Ayahuasca……………………………….…..25 2.2.3 Preparation of standards and samples for analysis………………………...26 2.2.4 LC-ESI-MS/MS analysis…………………………………………………..27 2.2.5 Calculations………………………………………………………………..28 2.3 Results……………………………………………………………………………….28 2.3.1 Validation of the Method………………………………………………….28 2.3.2 Characterization of ayahuasca preparations……………………………….34 2.4 Discussion……………………………………………………………………...……35 2.5 Conclusions………………………………………………………………...………..38 2.6 References……………………………………………………………………...……39 Chapter 3. Methodology for and the Determination of the Major Constituents and Metabolites of the Amazonian Botanical Medicine Ayahuasca in Human Urine…………..….42 3.1 Introduction………………………………………………………………….….…43 3.2 Experimental………………………………………………………………….….…45 3.2.1 Solvents and Standards……………………………………………..…….45 3.2.2 Preparation of Urine Samples……………………………………….……47 3.2.3 Freeze Dried Ayahuasca Administration and Urine Collection…….……48 3.2.4 Enzyme Hydrolysis………………………………………………….……48 3.2.5 Determination of Matrix Effects…………………………………………49 3.2.6 LC-ESI-MS/MS analysis…………………………………………………49 3.2.7 Determination of Inter- and Intra-assay Variation……………………….50 3.2.8 Calculations………………………………………………………………51 3.3 Results and Discussion……………………………………………………………..52 3.3.1 Evaluation of the Method…………………………………………….…..52 3.3.2 Matrix Effects……………………………………………………....……60 iii ______________________________________________________________________________________________www.neip.info 3.3.3 Major Constituents and Metabolites of Ayahuasca in Urine………….….60 3.4 References……………………………………………………………………….….67 Chapter 4. Methodology for Determining Major Constituents of Ayahuasca and Their Metabolites in Blood…………………………………………………………………………...73 4.1 Introduction…………………………………………………………………….…..74 4.2 Experimental…………………………………………………………………….….76 4.2.1 Standards and reagents…………………………………………………...76 4.2.2 Freeze Dried Ayahuasca Administration and Plasma Collection………...78 4.2.3 Sample preparation……………………………………………………….79 4.2.4 Determination of Matrix Effects…………………………………………80 4.2.5 Enzyme Hydrolysis……………………………………………………….80 4.2.6 LC-HESI-MS/MS analysis……………………………………………….81 4.2.7 Calculations………………………………………………………………84 4.3 Results and Discussion……………………………………………………………..85 4.3.1 Method Performance……………………………………………………..85 4.3.2 Matrix Effects……………………………………………………………92 4.3.3 Analysis of Administration Samples……………………………………..94 4.4 Conclusions………………………………………………………………………...96 4.5 References………………………………………………………………………….96 Chapter 5. Summary and Conclusions……………………………………………………...….100 5.1 Summary and Conclusions……………………………………………………..…..100 Appendix A: Cross-Cultural Variations in Psychoactive Alkaloid Content in Ayahuasca Teas Used in Spiritual Ceremonies……………………………………………………………108 A.1 Introduction………………………………………………………………...……110 A.2 Materials and methods……………………………………………………....……111 A.2.1 Materials……………………………………………………………...…111 A.2.2 Methods…………………………………………………………………111 A.3 Results……………………………………………………………………….…....113 A.3.1 DMT and 5-OH-DMT concentrations in ayahuasca teas……………….113 A.3.2 DMT, harmine, THH and harmol concentrations…………………...…..114 A.3.3 Beta-carboline alkaloid concentrations in ayahuasca teas……………....115 A.3.4 Bivariate and multivariate relationships among ayahuasca alkaloids…...116 A.4 Discussion…………………………………………………………………………120 A.5 Conclusions…………………………………………………………………..……121 A.6 Future Ayahuasca Characterization Publications……………………………...…..121 A.7 Future Publications to Prepare Ayahuasca for Clinical Trials…………………......122 A.8 References……………………………………………………………………….…123 Appendix B: Metabolism and Disposition of N,N-Dimethyltryptamine and Harmala Alkaloids After Oral Administration of Ayahuasca……………………………………………125 B.1 Introduction………………………………………………………………………...127 B.2 Materials and Methods……………………………………………………………..131 iv ______________________________________________________________________________________________www.neip.info B.2.1 Volunteers…………………………………………………………....…..131 B.2.2 Drugs……………………………………………………………..…..…..132 B.2.3 Study Design and Sample Collection…………………………….…...….132 B.2.4 Analytical Method…………………………………………………...…..133 B.2.5 Statistics…………………………………………………………..…..….134 B.3 Results and Discussion……………………………………………………….….…139 B.4 Conclusion………………………………………………………..………..…..…..146 B.5 References………………………………………………………………..…..……146 Appendix C: A Critical Review of Reports of Endogenous Psychedelic N, N-Dimethyltryptamines in Humans: 1955-2010………………………………………....….150 C.1 Introduction………………………………………………………………….…..…152 C.2 Historical Perspective………………………………………………………..…..…155 C.3 Study Review……………………………………………………………………....168 C.3.1 HDMT: urine…………………………………………………………..…168 C.3.2 HDMT: blood…………………………………………………………….169 C.3.3 HDMT: cerebrospinal fluid………………………………………………170 C.3.4 DMT: urine……………………………………………………………….170 C.3.5 DMT: blood………………………………………………………………171 C.3.6 DMT; cerebrospinal fluid…………………………………………..….…172 C.3.7 MDMT-DMT: urine……………………………………………...………172 C.3.8 MDMT-DMT: blood……………………………….………..……….…..172 C.3.9 MDMT-DMT: cerebrospinal fluid……………………………………….173 C.4 Discussion and Conclusions………………………………………...……...…..…..177 C.5 References…………………………………………………………………….……183 Appendix D: Permission of use………………………………………………….……....…….192 Vita .............................................................................................................................................205
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