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The Propagation, Characterisation and Optimisation

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The Propagation, Characterisation and Optimisation THE PROPAGATION, CHARACTERISATION AND OPTIMISATION OF CANNABIS SATIVA L AS A PHYTOPHARMACEUTICAL A thesis submitted by David Potter JP MIBiol CBiol FLS CMIOSH In fulfilment of the requirement for the degree of Doctor of Philosophy (PhD) in Pharmaceutical Sciences Department of Pharmaceutical Science Research King’s College London March 2009 Abstract In response to known pharmacology, and an increasing weight of anecdotal evidence of efficacy, clinical trials have been performed to support the licensing of cannabis-based botanical medicines. The initial applications envisaged were the treatment of cancer pain, neuropathic pain and various symptoms associated with multiple sclerosis. With effective alternatives often unavailable, otherwise law-abiding UK patients have regularly turned to illicit cannabis for medical relief. The main active ingredients in this are the cannabinoids THC and CBD, but other pharmacologically active cannabinoids are also present. One study reported here quantifies these cannabinoids and assesses the likely implications for efficacy. Using light microscopy, studies are performed to expand current knowledge of the form and function of trichomes in Cannabis sativa L. Supporting chemical analyses ascertain what secondary metabolites are biosynthesised within these trichomes, and determines where and when this occurs. To comply with the demands of the pharmaceutical industry, and in marked contrast to illicit cannabis, a phytopharmaceutical feedstock must meet high expectations regarding the minimum and maximum content of a range of compounds. Specific studies are performed to ascertain how growing methods affect the secondary metabolite content. They also aim to find out how a tight specification can be met while satisfying commercial and environmental expectations. This involves studying plant development and secondary metabolite biosynthesis in both indoor and outdoor conditions. The first approved cannabis-based botanical medicine supported by this research is Sativex®. This became available in Canada in 2005 for the treatment of central neuropathic pain in multiple sclerosis and in 2007 for intractable cancer pain. The medicine is also available in the UK and many other countries on a ‘named patient basis’. This thesis has also supported the production of a range of other cannabinoids which are undergoing in-vitro and in-vivo testing. This could lead to the commercial production of an increasing range of phytopharmaceuticals. i Cannabis sativa L cv Gayle CBD Chemotype. Awarded European Plant Variety Rights EU 16301, 10th Oct 2005 To my best mate John Pook and those who cared for him at St Leonard’s Hospice, York ii Acknowledgements This PhD would not have been possible without the support of friends and colleagues, of which there are too many to comprehensively mention. My deep appreciation first goes to my dear friend and champion Dr Brian Whittle who, having convinced me to do the PhD, guided me on my ‘long road to Ithaka’. Enormous thanks goes too to my supervisor Professor Marc Brown for his faith in me and his support and patience throughout. I express my sincerest gratitude to GW Pharmaceuticals Ltd, particularly Dr Geoffrey Guy, for sponsoring this PhD. Special thanks goes to a fabulous team of botanical colleagues – Dr Etienne de Meijer, Dr Tim Wilkinson, Barry and Chris Mears, Keith Hines and Roger Phillips for supplying cannabis and moral support throughout the project. I am especially grateful to Kathy Hammond for diligently analysing so many of my samples and Heather North for administrative assistance and pastoral care. Down on the farm I am indebted to great friends John and Vicky Clinch, over whose kitchen table much of the PhD was planned. In addition to growing many of my crops, they assisted in overnight monitoring as plants were dried. In the interest of science they also tolerated the incredible mess as I made CBD-rich hashish in their kitchen. Aren’t our police wonderful? Much of the work would not have been possible without help from several constabularies, and I would like to thank officers Phil Painter, Jerry Prodger, Howard Chandler, Bill Stupples and Steve Holme for assisting me with my enquiries. Heartfelt thanks goes to an ex-colleague and fond friend Heather House, who was my co-speaker at several inspirational Multiple Sclerosis Group Meetings. My thanks go to Dr Peter Toomey for his services to St Leonards Hospice in York, and for the invitation to give a presentation at a memorable Yorkshire Pain Management Group Meeting at St Stephens College – an experience that opened my eyes to the dedicated work of those involved in pain control. Warm thanks go too to good friends Peter Smith for photographic assistance and Valerie Bolas for botanical illustrations, and to colleagues at Kings College London - especially Darragh Murnane and Yanjun Xhao. Finally, I thank my wife Jane for supporting my PhD application – and for her forebearance thereafter. iii List of Publications Potter, D.J., 2004. Growth and Morphology of Medicinal Cannabis. In Guy, G.W., Whittle, B.A. and Robson, P.J. (Eds.). The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press, London. pp. 17-54. Potter, D.J., Clark, P. and Brown M.B. 2008. Potency of Δ9-THC and other cannabinoids in cannabis in England in 2005: Implications for psychoactivity and pharmacology. J Forensic Sci 53 (1): 90-94. Russo, E.B., Jiang, H-E., Li, X., Sutton, A., Carboni, A., del Bianco, F., Mandolino, G., Potter, D.J., Zhao, Y.X., Bera, S., Zhang, Y-B., Lü, E-G., Ferguson, D.K., Hueber, F., Zhei, L-C., Liu, C-J., Wang Y-F., Li C-S. 2008. Phytochemical and genetic analyses of ancient cannabis from Central Asia. J. Exp. Bot. 59, 15, 4171-4182. iv Table of Contents Abstract.....................................................................................................................i Acknowlegements................................................................................................... iii List of Publications .................................................................................................. iv Table of Contents.....................................................................................................v List of Figures ....................................................................................................... xiii List of Tables........................................................................................................ xxii Abbreviations ......................................................................................................xxvii Chapter 1 INTRODUCTION.....................................................................................1 1.1 Plants as a source of medicines – past and presen .......................................1 1.2 Cannabis Botany ............................................................................................4 1.3 Cannabis Taxonomy ......................................................................................6 1.4 UK Medicinal Cannabis Use - History and Legal Complications. ................. 8 1.5 The influence of the BMA and the House on Lords Select Committee on Science and Technology on UK Cannabis Research..................................10 1.6 International Legal Attitudes to Medicinal Cannabis.....................................11 1.6.1USA ........................................................................................................12 1.6.2 Canada ..................................................................................................14 1.6.3 Mainland Europe....................................................................................14 1.6.4 Ireland....................................................................................................15 1.6.5 Australia.................................................................................................15 1.6.6 Japan.....................................................................................................15 1.7 The choice of active pharmaceutical ingredients (APIs)...............................15 1.8 Cannabinoid and terpene biosynthesis ........................................................17 1.9 Cannabinoid Receptors and Cannabinoid Pharmacology. ...........................21 1.10 Outline of Thesis ........................................................................................24 v CHAPTER 2 CHARACTERISATION OF ILLICIT CANNABIS IN THE UK.............27 2.1 INTRODUCTION..........................................................................................27 2.2 AIM AND OBJECTIVES ...............................................................................29 2.3 MATERIALS .................................................................................................29 2.3.1 Cannabis samples .................................................................................29 2.3.2 Microscopy, Photography and other Apparatus .....................................29 2.4 METHODS ...................................................................................................30 2.4.1 Collection of Representative Samples ...................................................30 2.4.2 Storage of illicit cannabis samples.........................................................30 2.4.3 Categorisation of the form of each sample ............................................30 2.4.3 Categorisation of the form of each sample ............................................30 2.4.3.1 Cannabis resin ................................................................................30
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