DOCSLIB.ORG

Using Dictyostelium Discoideum to Investigate the Mechanism of Action of Cannabigerol

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Using Dictyostelium Discoideum to Investigate the Mechanism of Action of Cannabigerol Therapeutic cannabinoids: Using Dictyostelium discoideum to investigate the mechanism of action of cannabigerol Joseph Oddy Research thesis submitted for the degree of Doctor of Philosophy at the Royal Holloway University of London in May 2020 1 Declaration of Authorship I, Joseph Laurence Damstra-Oddy, hereby declare that the work presented in this thesis is my own unless otherwise stated, and that all published work has been acknowledged. Furthermore, I affirm that I have neither fabricated nor falsified the results reported herein. Signed: Date: 22/05/2020 2 Abstract Cannabis has been used to treat many diseases for centuries. Recent medical interest has focused on the potential of cannabinoids to treat diseases such as multiple sclerosis, epilepsy, and cancer where research has focused on investigating cannabidiol (CBD). However, other cannabinoids, such as cannabigerol (CBG), remain poorly characterised and are being explored as potential treatments. The molecular mechanisms by which cannabinoids treat diseases remain unclear, despite suggested targets including adenosine, mTOR, transient receptor potential transporters and cannabinoid receptors. This study aimed to identify molecular mechanisms of CBG, using Dictyostelium discoideum as a model system and translating results to a clinical setting. Initially, a targeted approach was undertaken where the effects of CBG on adenosine transport (and DNA methylation) was investigated. From this approach, CBG elevated DNA methylation in D. discoideum dependent upon adenosine transport via the equilibrative nucleoside transporter 1 (ENT1). In addition, an unbiased approach was taken in which screening of a mutant library for CBG resistance identified inositol polyphosphate multikinase (IPMK), a known regulator of mTOR activity, as a potential target. Both CBG and CBD increased mTORC1 activity in wild type cells. Elevated expression of IPMK increased mTORC1 activity, but surprisingly, subsequent treatment with both CBG and CBD reduced mTORC1 activity, suggesting that cannabinoids functioned as pro-homeostatic regulators of mTORC1 activity through IPMK. Translating these results into mouse embryonic fibroblasts, CBG and CBD also increased mTORC1 activity in an IPMK-dependent manner. Finally, in primary human peripheral blood mononuclear cells (PBMCs) derived from healthy volunteers CBG and CBD also increased mTORC1 activity, but decreased mTORC1 activity in primary human PBMCs derived from patients with multiple sclerosis. Thus, this study identifies a pro-homeostatic role for CBG and CBD in mTORC1 regulation via IPMK, conserved between D. discoideum and humans, providing new insights into the potential therapeutic mechanism of these cannabinoids. 3 Contents Abstract ........................................................................................................................................ 3 Contents ………………………………………………………………………………………………………………………………… 4 List of Tables and Figures ............................................................................................................. 8 Abbreviations ............................................................................................................................. 10 Acknowledgements .................................................................................................................... 14 1 Introduction ............................................................................................................................ 15 1.1 Cannabinoids .................................................................................................................... 15 1.1.1 History of C. sativa .................................................................................................... 15 1.1.2 Economic Value of Cannabinoid-Based Therapeutics ............................................... 15 1.1.3 Chemistry of cannabinoids ........................................................................................ 15 1.1.4 Efficacy of THC and CBD in disease treatment .......................................................... 19 1.2 Mechanisms of action of cannabinoids ............................................................................ 31 1.2.1 Cannabinoid interaction with cannabinoid receptors ............................................... 31 1.2.2 Cannabinoid interaction with transient receptor potential channels ....................... 31 1.2.3 Cannabinoid interaction with adenosine transport and signalling ........................... 32 1.2.4 Cannabinoid interaction with mTOR signalling ......................................................... 34 1.1.3 CBG and therapeutic potential .................................................................................. 37 1.3 Dictyostelium discoideum as a pharmacogenetic model ................................................. 38 1.5 Aims and Objectives ......................................................................................................... 42 2 Methods .................................................................................................................................. 43 2.1 Assessment of relative research output for cannabinoids ........................................... 43 2.2 Storage of cell lines ...................................................................................................... 43 2.3 Maintenance of cell lines .............................................................................................. 43 2.4 Growth assays of D. discoideum cells ........................................................................... 43 2.5 Development assays of D. discoideum cells ................................................................. 44 2.6 Bioinformatics protein analysis .................................................................................... 44 2.7 Transfection of D. discoideum by electroporation ....................................................... 45 2.8 Polymerase chain reaction (PCR) amplification ............................................................ 45 4 2.9 Restriction digests ........................................................................................................ 45 2.10 Agarose gel electrophoresis ....................................................................................... 45 2.11 Bacterial transformation ............................................................................................ 46 2.12 Plasmid extraction from bacterial cells ...................................................................... 46 2.13 Extraction of genomic DNA ........................................................................................ 46 2.2.14 Creation of knockout cell lines in D. discoideum ..................................................... 47 2.2.15 Analysis of intra- and extracellular adenosine in microglia (carried out at Reading University) .......................................................................................................................... 48 2.2.16 Analysis of DNA methylation in D. discoideum ........................................................ 50 2.2.17 D. discoideum mutant screen .................................................................................. 50 2.2.18 qPCR analysis of CBG-resistant mutants ................................................................. 51 2.2.19 Creation of dIPMK-RFP and hIPMK-RFP cell lines and imaging (and attempt at ENT1- RFP) .................................................................................................................................... 51 2.2.20 RFP expression confirmation by Western Blot ........................................................ 52 2.2.21 Western blot analysis of mTORC1 activity in D. discoideum ................................... 52 2.2.22 Higher order inositol phosphate analysis in D. discoideum ..................................... 53 2.2.23 Mouse embryonic fibroblast cell culture ................................................................. 53 2.2.24 Western blot analysis of mTORC1 activity in mouse embryonic fibroblasts ........... 53 2.2.25 Primary peripheral blood mononuclear cell collection from human volunteers (carried out at Trinity College Dublin) ................................................................................ 54 2.2.26 Western blot analysis of mTORC1 activity in primary peripheral blood mononuclear cells ..................................................................................................................................... 54 2.2.27 Statistical analysis .................................................................................................... 55 Chapter 3: Examining adenosine transport regulation as a molecular mechanism of CBG ....... 56 3.1 Introduction ...................................................................................................................... 56 3.2 Results .............................................................................................................................. 57 3.2.1 Effects of CBG on Dictyostelium discoideum growth and development ................... 57 3.2.2 Examining adenosine transport modulation as a potential molecular mechanism of CBG ..................................................................................................................................... 58 5 3.2.3 Examining DNA methylation modulation as a potential molecular mechanism of CBG ...........................................................................................................................................
Load more

Recommended publications
  • Designing Microorganisms for Heterologous Biosynthesis of Cannabinoids Angelaˆ Carvalho1, Esben Halkjær Hansen1, Oliver Kayser2, Simon Carlsen1,∗ and Felix Stehle2
    FEMS Yeast Research, 17, 2017, fox037 doi: 10.1093/femsyr/fox037 Advance Access Publication Date: 4 June 2017 Minireview MINIREVIEW Designing microorganisms for heterologous biosynthesis of cannabinoids Angelaˆ Carvalho1, Esben Halkjær Hansen1, Oliver Kayser2, Simon Carlsen1,∗ and Felix Stehle2 1Evolva Biotech A/S, Lersø Parkalle´ 42-44, 2100, Copenhagen, Denmark and 2Laboratory of Technical Biochemistry, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 66, 44227 Dortmund, Germany ∗Corresponding author: Evolva Biotech A/S, Lersø Parkalle´ 42-44, 2100, Copenhagen, Denmark. Tel: +45-35-200-243; E-mail: [email protected] One sentence summary: In this review, the authors explore the use of synthetic biology as an alternative approach for the synthesis of pharmaceutical cannabinoids in a heterologous host organism. Editor: John Morrissey ABSTRACT During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem.
    [Show full text]
  • Recent Developments in Cannabis Chemistry
    Recent Developments in Cannabis Chemistry BY ALEXANDER T. SHULGIN, Ph.D. The marijuana plant Cannabis sativa contains a bewildering Introduction array of organic chemicals. As is true with other botanic species, there are representatives of almost all chemical classes present, including mono- and sesquiterpenes, carbohy- drates, aromatics, and a variety of nitrogenous compounds. Interest in the study of this plant has centered primarily on the resinous fraction, as it is this material that is invested with the pharmacological activity that is peculiar to the plant. This resin is secreted by the female plant as a protective agent during seed ripening, although it can be found as a microscopic exudate through the aerial portions of plants of either sex. The pure resin, hashish or charas, is the most potent fraction of the plant, and has served as the source material for most of the chemical studies. The family of chemicals that has been isolated from this source has been referred to as the cannabinoid group. It is unique amongst psychotropic materials from plants in that there are no alkaloids present. The fraction is totally nitro- gen-free. Rather, the set of compounds can be considered as analogs of the parent compound cannabinol (I), a fusion product of terpene and a substituted resorcinol. Beyond the scope of this present review are such questions as the distribution of these compounds within the plant, the bo- tanic variability resulting from geographic distribution, the diversity of pharmacological action assignable to the several Reprinted from Journal of Psychedelic Drugs, vol. II, no. 1, 197 1. 397 398 Marijuana: Medical Papers distinct compounds present, and the various preparations and customs of administration.
    [Show full text]
  • What Is Delta-8 THC?? Cannabinoid Chemistry 101
    What is Delta-8 THC?? Cannabinoid Chemistry 101 National Conference on Weights and Measures Annual Meeting - Rochester, NY Matthew D. Curran, Ph.D. July 21, 2021 Disclaimer Just to be clear… • I am a chemist and not a lawyer so: • This presentation will not discuss the legal aspects of Δ8-THC or DEA’s current position. • This presentation will not discuss whether Δ8-THC is considered “synthetic” or “naturally occurring.” • This is not a position statement on any issues before the NCWM. • Lastly, this should only be considered a scientific sharing exercise. Florida Department of Agriculture and Consumer Services 2 Cannabis in Florida Cannabis Syllabus • What is Cannabis? • “Mother” Cannabinoid • Decarboxylation • Relationship between CBD and THC • What does “Total” mean? • Dry Weight vs. Wet Weight • What does “Delta-9” mean? • Relationship between “Delta-8” and “Delta-9” • CBD to Delta-8 THC • Cannabinoid Chemistry 202… Florida Department of Agriculture and Consumer Services 3 Cannabis Cannabis • Cannabis sativa is the taxonomic name for the plant. • The concentration of Total Δ9-Tetrahydrocannabinol (Total Δ9-THC) is critical when considering the varieties of Cannabis sativa. • Hemp – (Total Δ9-THC) 0.3% or less • Not really a controversial term, “hemp” • Marijuana/cannabis – (Total Δ9-THC) Greater than 0.3% • Controversial term, “marijuana” • Some states prohibit the use of this term whereas some states have it in their laws. • Some states use the term “cannabis.” • Not italicized • Lower case “c” Florida Department of Agriculture and
    [Show full text]
  • WO 2017/139496 Al 17 August 2017 (17.08.2017) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/139496 Al 17 August 2017 (17.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 1/15 (2006.01) C12N 15/52 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/29 (2006.01) C12P 7/40 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 15/31 (2006.01) C12P 7/22 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, PCT/US20 17/0 17246 KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (22) International Filing Date: MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, ' February 2017 (09.02.2017) NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (25) Filing Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/293,050 February 2016 (09.02.2016) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: CEVOLVA BIOTECH, INC.
    [Show full text]
  • Cannabis Sativa L.) Phenotypes
    plants Article Metabolomic Analysis of Cannabinoid and Essential Oil Profiles in Different Hemp (Cannabis sativa L.) Phenotypes Marjeta Eržen 1, Iztok J. Košir 1 , Miha Ocvirk 1 , Samo Kreft 2 and Andreja Cerenakˇ 1,* 1 Slovenian Institute of Hop Research and Brewing, Cesta Žalskega tabora 2, 3310 Žalec, Slovenia; [email protected] (M.E.); [email protected] (I.J.K.); [email protected] (M.O.) 2 Faculty of Pharmacy, University of Ljubljana, Aškerˇcevacesta 7, 1000 Ljubljana, Slovenia; [email protected] * Correspondence: [email protected]; Tel.: +386-3-71-21-633 Abstract: Hemp (Cannabis sativa L.) cannabinoids and terpenoids have therapeutic effects on human and animal health. Cannabis plants can often have a relatively high heterogeneity, which leads to different phenotypes that have different chemical profiles despite being from the same variety. Little information exists about cannabinoid and terpenoid profiles in different hemp phenotypes within the same variety. For this study, 11 phenotypes from three different varieties (“Carmagnola” selected (CS), “Tiborszallasi” (TS), and “Finola” selection (FS)) were analyzed. The components of essential oil (29) were analyzed using gas chromatography with flame ionization detection (GC/FID), and 10 different cannabinoids of each phenotype were determined using high-performance liquid chromatography (HPLC). Principal component analysis (PCA) and analysis of variance (ANOVA) showed that according to the components of essential oil, FS and TS plants were more uniform than CS plants, where there were great differences between CI and CII phenotypes. The content of cannabinoid CBD-A was the highest in all four FS phenotypes. By comparing cannabinoid profiles, Citation: Eržen, M.; Košir, I.J.; Ocvirk, M.; Kreft, S.; Cerenak,ˇ A.
    [Show full text]
  • Cannabigerol Is a Potential Therapeutic Agent in a Novel Combined Therapy for Glioblastoma
    Supplemental material Cannabigerol is a potential therapeutic agent in a novel combined therapy for glioblastoma Tamara T. Lah, Metka Novak, Milagros A. Pena Almidon, Oliviero Marinelli, Barbara Žvar Baškovič, Bernarda Majc, Mateja Mlinar, Roman Bošnjak, Barbara Breznik, Roby Zomer, and Massimo Nabissi Figure S1. Biosynthesis and metabolism of cannabigerol (CBG). The enzyme prenyltransferase catalyses the conversion of olivetolic acid into CBG in the cannabis plant. CBG is the intermediate biosynthetic precursor of delta‐9‐tetrahydrocannabinol (THC)‐acid and cannabidiol (CBD)‐acid and is converted to THC, CBD, and cannabichromene (CBC), which is then converted into THC, CBD, or CBG by specific synthases (adapted from [30]). Cells 2021, 10, 340. https://doi.org/10.3390/cells10020340 www.mdpi.com/journal/cells Cells 2021, 10, 340 2 of 3 Figure S2. Cell death determination by flow cytometry using Annexin V‐FITC and propidium iodide staining. Cells (U87 and NCH44) were treated with IC50 concentrations of compounds CBG, CBD, and THC for 48 h. Cells were labelled with Annexin V‐FITC and propidium iodide and analysed by flow cytometry. The dot blots represent the results from three biological repeats. Table S1: High‐performance liquid chromatography purity results for the CBG, CBD, and THC solutions used in this study. Cannabinoids Cannabinoids Cannabinoids Concentration Concentration Concentration in CBG in CBD in CBD (mg/ml) (mg/ml) (mg/ml) solution solution solution CBDVA BDL* CBDVA BDL* CBDVA BDL* CBDV BDL* CBDV BDL* CBDV BDL* CBDA BDL*
    [Show full text]
  • Structural and Biochemical Characterization of Members of the Cannabinoid Biosynthetic Pathway to Inform Their Application in Synthetic Biology
    Structural and Biochemical Characterization of Members of the Cannabinoid Biosynthetic Pathway to Inform their Application in Synthetic Biology A thesis submitted to the University of Manchester for the degree of Master of Philosophy in the faculty of science and engineering 2017 Lewis J. Kearsey School of Chemistry 1 Contents List of tables .................................................................................................................................................................. 4 List of figures ................................................................................................................................................................ 4 List of abbreviations .................................................................................................................................................. 7 Abstract ........................................................................................................................................................................... 9 Declaration ................................................................................................................................................................. 10 Copyright statement ............................................................................................................................................... 10 Acknowledgements ................................................................................................................................................ 11 1. Introduction
    [Show full text]
  • Cannabinoid Profiles: a Crash Course in Cbga |
    Science (/archives/category/science/) Cannabinoid Profile: Cannabigerolic Acid (CBGa) (http://theleafonline.com/c/science/2014/08/cannabinoid­profiles­crash­course­cbga/) By: Mitchell Colbert (http://theleafonline.com/c/author/mitchellrcolbert/) August 5, 2014 Formula: C22H32O4 Molecular Mass: 360.48708 g/mol Decarboxylation Point: ???? Boiling Point: ???? LD50 (Lethal Dose): Currently Unknown, likely similar to CBG, 300mg/kg for mice (http://www.clearsynth.com/ docs/MSD­CS­N­01916.pdf) (Compare to Nicotine: for mice – 3mg/kg (http://www.news­ medical.net/health/Nicotine­Toxicology.aspx), for humans – 40–60 mg/kg (http://www.oregon.gov/pharmacy/Imports/Marijuana/StaffReview/ReschedulingCannabis­NOTES_3­10.pdf)), How THC Is Made Cannabigerolic acid (CBGa) (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6449999) is formed when geranyl pyrophosphate (http://en.wikipedia.org/wiki/Geranyl_pyrophosphate) combines with olivetolic acid (http://en.wikipedia.org/wiki/Olivetol) within the cannabis plant. It is thanks to CBGa that all other medicinal effects of cannabis are possible. Cannabigerolic acid (CBGa) can be thought of as the stem cell cannabinoid, which becomes THCa (http://theleafonline.com/c/science/2014/07/cannabinoid­profile­crash­course­thca/)/THC (http://theleafonline.com/c/science/2014/06/cannabinoid­profiles­crash­course­thc/), CBDa (http://theleafonline.com/c/science/2014/07/cannabinoid­profile­crash­course­cbda/)/CBD (http://theleafonline.com/c/science/2014/06/cannabinoid­profiles­crash­course­cbd/), CBCa/CBC (http://theleafonline.com/c/science/2014/07/cannabinoid­profile­crash­course­cbc/), and CBG (http://theleafonline.com/c/science/2014/07/cannabinoid­profile­crash­course­cbg/). It does this through different types of biosynthesis (http://en.wikipedia.org/wiki/Tetrahydrocannabinol#Biosynthesis), where chemicals combine to form new compounds, examples being the THC biosynthase (http://en.wikipedia.org/wiki/THC_acid_synthase) and the CBD biosynthase (http://en.wikipedia.org/wiki/Cannabidiolic_acid_synthase).
    [Show full text]
  • Cannabinoids – a Tutorial Review Psychoactivity, Regulation, Common and IUPAC Nomenclature, Structures and Abbreviations in Relation to Cannabidiol (CBD) Products
    Journal of the Association of Public Analysts (Online) 2021 49 001-028 Walker et al Cannabinoids – a Tutorial Review Psychoactivity, Regulation, Common and IUPAC Nomenclature, Structures and Abbreviations in Relation to Cannabidiol (CBD) Products M J Walker1, 2, D T Burns2, Ian Axford1 and GP Moss3 (1) Laboratory of the Government Chemist, LGC, Teddington, Middlesex, TW11 0LY, UK to whom correspondence should be sent: [email protected], [email protected] (2) Institute for Global Food Security, the Queen's University of Belfast, Belfast, BT9 5HN, Northern Ireland, UK (3) School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK Summary Public Analysts and other forensic scientists frequently deal with the analysis of cannabis or cannabinoids, the nomenclature and abbreviations for which can be confusing. More recently, cannabidiol, (CBD), has gained salience as an ingredient in food supplements and in some cosmetic products. Apart from medicines with a market authorisation (eg Epidiolex and Sativex) which contain CBD, CBD-containing edible products must be regarded as food or as a food supplement. In the light of Food Standards Agency (FSA) advice after 31 March 2021 only certain CBD products for which the FSA has a valid application will be allowed to remain on the market. They must also be compositionally safe, correctly labelled, and must not contain substances that fall under controlled drugs legislation in the light of any extant or future Home Office guidance. It is to be anticipated that surveillance and, if necessary, enforcement action will take place against any non-compliant CBD products on the market after 31 March 2021.
    [Show full text]
  • Cannabigerol and Cannabichromene in Cannabis Sativa L
    Acta Pharm. 71 (2021) 355–364 Mini-review https://doi.org/10.2478/acph-2021-0021 Cannabigerol and cannabichromene in Cannabis sativa L. MARJETA ZAGOŽEN1,* In addition to delta-9-tetrahydrocannabinol (THC) and 1 ANDREJA ČERENAK cannabidiol (CBD), other phytocannabinoids, such as can- SAMO KREFT2 nabigerol (CBG) and cannabichromene (CBC), also have 1 Department for Plants, Soil, and beneficial effects on human health. A high content of CBG Environment, Slovenian Institute of Hop is found in plants with the B0 genotype, whereas CBC is Research and Brewing, 3310 Zalec independent of the allelic chemotype locus B. In basic re- Slovenia search models such as mice or rats, CBG has demonstrated anticancer properties, particularly against breast cancer. 2 The Chair of Pharmaceutical Biology CBG has shown anti-inflammatory effects on murine colitis University of Ljubljana, Faculty of and on inflammatory bowel disease as well as stimulatory Pharmacy, Ljubljana, Slovenia effects on the feeding behaviors of mice. It has also exhibi- ted inhibition of aldose reductase, which is known to cause an accumulation of sorbitol and increase glucose levels in the blood, which may lead to diabetes. Cannabinoid CBC has also shown anti-inflammatory effects and reduced -hy permobility in the gut and has displayed potential in vitro effect on adult neural stem progenitor cells. CBC also exerts modest analgesic properties in rodents, as well as anti-fun- gal, anti-bacterial, pro-apoptotic, and anti-proliferative ef- fects in tumor cells. Accepted July 23, 2020 Keywords: cannabinoids, chemotype, health effects, hemp, Published online August 3, 2020 receptors INTRODUCTION Hemp (Cannabis sativa L.) is an important herbaceous species that has been used for textile fibers and rope, as a source of food, in medicine, and in agriculture for seeds, animal food, silage, fuel, and animal bedding (1).
    [Show full text]
  • Anxiety Disorder, Generalized
    From: [email protected] To: [email protected] Subject: Condition Petition for Thomas Rosenberger Date: Tuesday, December 31, 2019 5:12:55 PM Attachments: Question 2 GAD (3).pdf Question 5 GAD (2).pdf This message was sent from the Condition page on medicalmarijuana.ohio.gov. Box was check regarding file size being too large to upload. Action needed! Name: Thomas Rosenberger Address: 815 Grandview Ave Suite 400, Columbus, OH, 43215 Phone: (614) 706-3782 Email: [email protected] Specific Disease or Condition: Generalized Anxiety Disorder (GAD) Information from experts who specialize in the disease or condition. File larger than 3MB Relevant medical or scientific evidence pertaining to the disease or condition. See Attached Question 2 GAD (3).pdf Consideration of whether conventional medical therapies are insufficient to treat or alleviate the disease or condition. File larger than 3MB Evidence supporting the use of medical marijuana to treat or alleviate the disease or condition, including journal articles, peer-reviewed studies, and other types of medical or scientific documentation. File larger than 3MB Letters of support provided by physicians with knowledge of the disease or condition. This may include a letter provided by the physician treating the petitioner, if applicable. See attached file Question 5 GAD (2).pdf Question 1 Information from experts who specialize in the disease or condition Contents Overview – 3 Generalized Anxiety Disorder: Prevalance, Burden, and Cost to Society - 4 Final Agency Decision: Petitions to Establish Additional Debilitating Medical Conditions Under the New Jersey Medicinal Marijuana Program – New Jersey Department of Health - 17 Overview General Anxiety Disorder (GAD) is a debilitating condition that has proven difficult to treat.
    [Show full text]
  • Phytocannabinoids Origins and Biosynthesis Gülck, Thies; Møller, Birger Lindberg
    Phytocannabinoids Origins and Biosynthesis Gülck, Thies; Møller, Birger Lindberg Published in: Trends in Plant Science DOI: 10.1016/j.tplants.2020.05.005 Publication date: 2020 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC-ND Citation for published version (APA): Gülck, T., & Møller, B. L. (2020). Phytocannabinoids: Origins and Biosynthesis. Trends in Plant Science, 25(10), 985-1004. https://doi.org/10.1016/j.tplants.2020.05.005 Download date: 03. Dec. 2020 Trends in Plant Science Feature Review Phytocannabinoids: Origins and Biosynthesis Thies Gülck1,2,3,* and Birger Lindberg Møller1,2,3,* Phytocannabinoids are bioactive natural products found in some flowering Highlights plants, liverworts, and fungi that can be beneficial for the treatment of human Phytocannabinoids are bioactive terpe- ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabi- noids that were thought to be exclusive noids with desirable properties requires identification of the underlying genes to Cannabis sativa, but have now also been discovered in Rhododendron spe- and their expression in a suitable heterologous host. We provide an overview cies, some legumes, the liverwort genus of the structural classification of phytocannabinoids based on their decorated Radula,andsomefungi. resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Many cannabinoids display promising non-hallucinogenic bioactivities that are Rhododendron,andRadula species. We also highlight the potential in planta determined by the variable nature of the roles of phytocannabinoids and the opportunity for synthetic biology approaches side chain and prenyl group defined by based on combinatorial biochemistry and protein engineering to produce canna- the enzymes involved in their synthesis.
    [Show full text]