The Essential Medicinal Chemistry of Cannabidiol (CBD)
- Kathryn M. Nelson
Kathryn M. NelsonDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesMore by Kathryn M. Nelson
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- Jonathan Bisson
Jonathan BissonCenter for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by Jonathan Bisson
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- Gurpreet Singh
Gurpreet SinghDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesMore by Gurpreet Singh
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- James G. Graham
James G. GrahamCenter for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by James G. Graham
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- Shao-Nong Chen
Shao-Nong ChenCenter for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by Shao-Nong Chen
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- J. Brent Friesen
J. Brent FriesenCenter for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by J. Brent Friesen
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- Jayme L. Dahlin
Jayme L. DahlinDepartment of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United StatesHarvard Medical School, Boston, Massachusetts 02115, United StatesMore by Jayme L. Dahlin
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- Matthias Niemitz
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- Michael A. Walters
Michael A. WaltersDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesMore by Michael A. Walters
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- Guido F. Pauli*
Guido F. PauliCenter for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesMore by Guido F. Pauli
Abstract
This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD’s reputation as a cure-all puts it in the same class as other “natural” panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the “natural” label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
Introduction
What’s in the Name?
Aims of This Perspective
Ten Facts about CBD
(1) | CBD is a promoter of DDI (drug–drug interactions) and potentiates the action of many drugs (5–10 μM). (10) |
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(2) | CBD is a membrane interactor: it promiscuously affects ion channels by membrane pressure and direct binding (0.1–5 μM). (11,12) |
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(3) | CBD has a strong “meaning effect”: individuals expect it to work. (13) |
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(4) | CBD is 6% orally bioavailable by some reports. (14) |
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(5) | CBD’s typical dose in nonmedicinal products is much lower than that used in clinical trials and in prescriptions (25 mg in a typical nonmedicinal product versus 150–1500 mg/day clinical trials). (15) |
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(6) | “CBD has the potential to harm you” (similar to other drugs). (16) |
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(7) | CBD can be converted to THC by chemical means but appears not to convert to THC under physiological conditions (vide infra). |
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(8) | CBD is currently considered an illegal supplement (“It is currently illegal to market CBD by adding it to a food or labeling it as a dietary supplement”). (16) |
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(9) | “CBD” is a popular product label but often misleading: frequently “CBD” products contain many other chemically complex ingredients in addition to varying, sometimes small, amounts of CBD. Valid CBD label-claims require rigorous analytical characterization of its identity, purity, and stability (elements of residual complexity; vide infra) rather than blanket statements such as “pure” or “natural”. |
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(10) | CBD has not displayed meaningful activity on its own in a double-blinded, placebo-controlled clinical trial. Trials that underlie claims of a wide range of health have predominantly used CBD as minor ingredient or part of adjunctive therapy schemes that coadminister other substances/preparations, often seeking to leverage “botanical synergy” (also involving residual complexity; vide infra). This is also important considering that CBD displays strong DDIs (vide infra). |
Natural Product (Bio-)Chemistry Overview
CBD Is Just One Molecule in the Vast Chemical Space of Cannabinoids
Biosynthetic Pathways
CBD Residual Complexity, Purity, Identity, and Quality Control
Regulatory Overview
Material | Definition |
---|---|
Cannabis | Plant of the Cannabaceae family that produces biologically active cannabinoids, some of which are controlled under the Controlled Substances Act (CSA) since 1970 (39) |
Marijuana | Cannabis plant that produces THC at 20%+ levels |
Hemp | The plant Cannabis sativa L. and any part of the plant and all derivatives thereof with a THC content of <0.3% (dry weight). (39) Hemp can contain as much as 20% or more CBD. |
Hemp seeds/oil | Whole seeds or oil, containing fatty acid esters, that is expressed or extracted from seeds. These products contain 0% THC and trace levels of CBD. |
Cannabinoids | Family of chemicals that act on the endocannabinoid system. The Cannabis plant synthesizes many cannabinoids, such as THC and CBD. |
THC | Δ9-Tetrahydrocannabinol, a cannabinoid used for medicinal purposes and nonmedicinally for its (intoxicating) CNS effects. CAS no. 1972-08-3 |
CBD | Cannabidiol, a cannabinoid with an undefined mechanism of action. Biosynthetically related to THC. Not intoxicating even at high doses. CAS no. 13956-29-1 |
Cannabis-derived products for medicinal use | Medicinal products containing cannabis or cannabinoids derived from the Cannabis plant (e.g., THC and/or CBD in well-defined proportions) |
Synthetic cannabinoids for medicinal use | Medicinal products containing synthetically produced cannabinoids that typically mimic the effects of THC |
Nonmedicinal CBD products | Products containing CBD that are widely sold as herbal remedies but are not regulated as medicinal products |
Nonmedicinal cannabis | Material from the Cannabis plant that is not regulated as a medicinal product, widely used for its (intoxicating) CNS effects |
Nonmedicinal synthetic cannabinoids | Synthetic cannabinoids that are typically not structurally related to naturally occurring cannabinoids and are not currently recognized for medicinal use (e.g., synthetic cannabinoid receptor agonists, found in products such as “spice”) |
“Under the FD&C Act [note: Food, Drug, and Cosmetic Act, 1938], any product intended to have a therapeutic or medical use, and any product (other than a food) that is intended to affect the structure or function of the body of humans or animals, is a drug. Drugs must generally either receive premarket approval by the FDA through the New Drug Application (NDA) process or conform to a “monograph” for a particular drug category, as established by FDA’s Over-the-Counter (OTC) Drug Review. CBD was not an ingredient considered under the OTC drug review. An unapproved new drug cannot be distributed or sold in interstate commerce. FDA continues to be concerned at the proliferation of products asserting to contain CBD that are marketed for therapeutic or medical uses although they have not been approved by FDA. Often such products are sold online and are therefore available throughout the country. Selling unapproved products with unsubstantiated therapeutic claims is not only a violation of the law, but also can put patients at risk, as these products have not been proven to be safe or effective. This deceptive marketing of unproven treatments also raises significant public health concerns, because patients and other consumers may be influenced not to use approved therapies to treat serious and even fatal diseases. Unlike drugs approved by FDA, products that have not been subject to FDA review as part of the drug approval process have not been evaluated as to whether they work, what the proper dosage may be if they do work, how they could interact with other drugs, or whether they have dangerous side effects or other safety concerns.” (39)
Conversion of CBD to THC
Bioactivity of Simple CBD Analogs
Pharmacology
CBD Receptor Activity
Interaction of CBD with CYPs
Bioassay Interferences of CBD
Property | Value |
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MW | 314.47 g/mol |
log P | 5.91 |
ClogP | 6.64 |
tPSA | 40.46 Å2s |
H-bond donors | 2 |
H-bond acceptors | 2 |
rotatable bonds | 6 |
ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicology
Absorption
avg dose (mg) | avg Tmax (h) | avg Cmax (ng/mL) | avg Cmax (nM) | F (%) (if reported) | |
---|---|---|---|---|---|
low oral doseb | 14 ± 15 | 1.9 ± 1.2 | 2.8 ± 2.2 | 0.9 | |
high oral dosec | 525 ± 340 | 3.1 ± 0.3 | 131.9 ± 82.5 | 41.5 | |
inhalation dosed | 3.5 ± 5.5 | 0.3 ± 0.3 | 35.3 ± 41.3 | 11.1 | 31 |
Analysis of 50 reported studies of CBD dosing that included reported plasma levels.
Dose range: 1.5–20 mg.
Dose range: 100–800 mg.
Dose range: 1.5–20 mg.
Distribution
Metabolism
Excretion
Toxicology
CBD Ki (μM) | |
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CYP1A1 | 0.16 |
CYP1A2 | 2.69 |
CYP1B1 | 3.63 |
CYP2A6 | 55.0 |
CYP2B6 | 0.69 |
CYP2C9 | 5.60 |
CYP2C11 | 20.7 |
CYP2C19 | 0.79 |
CYP2D6 | 2.42 |
CYP3A4 | 1.00 |
CYP3A5 | 0.19 |
CYP3A7 | 12.3 |
CYP17 | 124 |
Clinical Trials
“Recently, there have been several scientifically rigorous, double-blind, placebo-controlled randomized clinical trials of one specific pharmaceutical-grade, purified, highly concentrated CBD for patients with refractory epilepsy that have been published. Studies evaluating the pharmacokinetics and potential drug–drug interactions with this formulation have also been published or presented at epilepsy congresses. These trials demonstrated that this one pharmaceutical-grade CBD is moderately effective in the treatment of patients with seizures in both Lennox–Gastaut syndrome (LGS) and Dravet syndrome. However, these studies also showed that CBD has more side effects than placebo and revealed previously unrecognized drug–drug interactions.” (116)
(1) | What was the exact identity and purity of the CBD used? Note that APIs are distinct from crude preparations (such as plant extracts) and that residual complexity (including significant content in, for example, THC; vide supra) is relevant and will confound the study results. |
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(2) | Was the trial placebo-controlled? |
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(3) | Was the trial double-blinded? |
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(4) | Was the statistical analysis plan published before the trial? (124) |
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(5) | Did the authors claim significance of the results? |
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(6) | If CBD was used in combination, was the possibility of DDIs considered? Is the coadministered agent metabolized by CYPs? |
Summary
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00724.
Quantum-mechanical 1H NMR characterization of CBD using HiFSA, psychoactive drug screening program activity of CBD, and pharmacological methods for evaluation of CBD (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Biographies
Acknowledgments
The Ki determinations, receptor binding profiles, agonist and/or antagonist functional data, HERG data, MDR1 data, etc. as appropriate were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract HHSN-271-2018-00023-C (NIMH PDSP), directed by Dr. Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD, U.S. The authors acknowledge the following financial support: J.L.D. through Grant T32 HL007627 from NHLBI/NIH; J.B., J.G.G., S.-N.C., and G.F.P. through Grants U41 AT008706 and P50 AT000155 jointly from ODS/NIH and NCCIH/NIH. Furthermore, the authors acknowledge the collegial spirit of Drs. Young-Hae Choi and Rob Verpoorte, University of Leiden, for kindly sharing their historic raw NMR data. J.L.D. gratefully acknowledges Drs. Parnian Lak and Brian Shoichet for performing DLS experiments. We kindly acknowledge the Research Open Access Publishing (ROAAP) Fund of the University of Illinois at Chicago for financial support towards the open access publishing fee for this article. Finally, the authors thank M. Backmann for help in creating the figure for the graphical abstract. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the funders.
Abbreviations Used
CBD | cannabidiol |
DDI | drug–drug interaction |
DHI | drug–herbal interaction |
FDA | Food and Drug Administration |
HiFSA | 1H iterative full spin analysis |
IMP | invalid metabolic panacea |
OTC | over-the-counter |
THC | Δ9-tetrahydrocannabinol |
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This article references 131 other publications.
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3Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem. 2017, 60 (5), 1620– 1637, DOI: 10.1021/acs.jmedchem.6b00975Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFKjsA%253D%253D&md5=dfb16371e0ef27d4111628203c6acc09The Essential Medicinal Chemistry of CurcuminNelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Curcumin is a constituent (3-5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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4Dietz, B. M.; Chen, S.-N.; Alvarenga, R. F. R.; Dong, H.; Nikolić, D.; Biendl, M.; van Breemen, R. B.; Bolton, J. L.; Pauli, G. F. DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women’s Health. J. Nat. Prod. 2017, 80, 2284– 2294, DOI: 10.1021/acs.jnatprod.7b00284Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlaqs73E&md5=61580fe2c5ca4e8319b799d40a719b0aDESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women's HealthDietz, Birgit M.; Chen, Shao-Nong; Alvarenga, Rene F. Ramos; Dong, Huali; Nikolic, Dejan; Biendl, Martin; van Breemen, Richard B.; Bolton, Judy L.; Pauli, Guido F.Journal of Natural Products (2017), 80 (8), 2284-2294CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Botanical dietary supplements contain multiple bioactive compds. that target numerous biol. pathways. The lack of uniform standardization requirements is one reason that inconsistent clin. effects are reported frequently. The multifaceted biol. interactions of active principles can be disentangled by a coupled pharmacol./phytochem. approach using specialized ("knock-out") exts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent sepn., Humulus lupulus exts. were designed for pre- and postmenopausal women by contg. various amts. of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Anal. of their estrogenic (alk. phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concns. provided evidence for the interdependence of the biol. effects. A designed postmenopausal hop ext. was prepd. to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An ext. designed for premenopausal women contains reduced 8-PN levels and high XH concns. to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concns. of bioactive compds. in botanical exts. for potentially improved efficacy and safety.
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5Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy Effects of Herb Extracts: Pharmacokinetics and Pharmacodynamic Basis. Fitoterapia 2014, 92, 133– 147, DOI: 10.1016/j.fitote.2013.10.010Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2qsg%253D%253D&md5=cd39ee817d4b79de0642d10b904ee64bSynergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basisYang, Yong; Zhang, Zaiqi; Li, Shuping; Ye, Xiaoli; Li, Xuegang; He, KaiFitoterapia (2014), 92 (), 133-147CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)A review. Herbal medicine, esp. traditional Chinese medicine and Ayurvedic medicine have played and still play an important role in fighting against various diseases. Emerging clin. studies regarding traditional Chinese medicine have provided convincing evidence for the first time to gain credibility and reputation outside China. Although synergistic therapeutic actions of herbal ingredients have been frequently reported, few reports have offered clear underlying mechanisms. This might be the main reason for the conflicting views with respect to the therapeutic efficacy of medicinal herbs. Therefore, this paper reviews the herb synergisms reported in the recent literature and discusses thoroughly the mechanisms underlying synergistic actions of herbal ingredients. The authors conducted an electronic literature search to detect articles published mainly in the last five years. Articles were included if they pertained to synergy research of ethnomedicines or the active compds. derived from them, included verification of synergy effects using modern anal. tools and mol.-biol. methods. Results have revealed that the multi-component nature of medicinal herbs makes them particularly suitable for treating complex diseases and offers great potential for exhibiting synergistic actions. The mechanisms underlying synergistic therapeutic actions of herb medicines are (1): different agents may regulate either the same or different target in various pathways, and therefore cooperate in an agonistic, synergistic way; (2): regulate the enzymes and transporters that are involved in hepatic and intestinal metab. to improve oral drug bioavailability; (3): overcome the drug resistance mechanisms of microbial and cancer cells; and (4): eliminate the adverse effects and enhance pharmacol. potency of agents by "processing" or by drug-drug interaction. The exploration of synergistic mechanisms of herbal ingredients will not only help researchers to discover new phytomedicines or drug combinations but also help to avoid the possible neg. synergy. Further clin. research is required for verifying these reported drug combinations and discovered synergistic mechanisms.
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6Caesar, L. K.; Cech, N. B. Synergy and Antagonism in Natural Product Extracts: When 1 + 1 Does Not Equal 2. Nat. Prod. Rep. 2019, 36, 869– 888, DOI: 10.1039/C9NP00011AGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFKqsrfO&md5=6329e8cce673f78a847a41e8a703131eSynergy and antagonism in natural product extracts: when 1 + 1 does not equal 2Caesar, Lindsay K.; Cech, Nadja B.Natural Product Reports (2019), 36 (6), 869-888CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Covering: 2000 to 2019According to a 2012 survey from the Centers for Disease Control and Prevention, approx. 18% of the U. S. population uses natural products (including plant-based or botanical prepns.) for treatment or prevention of disease. The use of plant-based medicines is even more prevalent in developing countries, where for many they constitute the primary health care modality. Proponents of the medicinal use of natural product mixts. often claim that they are more effective than purified compds. due to beneficial "synergistic" interactions. A less-discussed phenomenon, antagonism, in which effects of active constituents are masked by other compds. in a complex mixt., also occurs in natural product mixts. Synergy and antagonism are notoriously difficult to study in a rigorous fashion, particularly given that natural products chem. research methodol. is typically devoted to reducing complexity and identifying single active constituents for drug development. This report represents a crit. review with commentary about the current state of the scientific literature as it relates to studying combination effects (including both synergy and antagonism) in natural product exts. We provide particular emphasis on anal. and Big Data approaches for identifying synergistic or antagonistic combinations and elucidating the mechanisms that underlie their interactions. Specific case studies of botanicals in which synergistic interactions have been documented are also discussed. The topic of synergy is important given that consumer use of botanical natural products and assocd. safety concerns continue to garner attention by the public and the media. Guidance by the natural products community is needed to provide strategies for effective evaluation of safety and toxicity of botanical mixts. and to drive discovery in botanical natural product research.
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7Friesen, J. B.; Liu, Y.; Chen, S.-N.; McAlpine, J. B.; Pauli, G. F. Selective Depletion and Enrichment of Constituents in “Curcumin” and Other Curcuma longa Preparations. J. Nat. Prod. 2019, 82, 621– 630, DOI: 10.1021/acs.jnatprod.9b00020Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktlOjsLk%253D&md5=02f3df013c782b59bae7478d95298de1Selective Depletion and Enrichment of Constituents in "Curcumin" and Other Curcuma longa PreparationsFriesen, J. Brent; Liu, Yang; Chen, Shao-Nong; McAlpine, James B.; Pauli, Guido F.Journal of Natural Products (2019), 82 (3), 621-630CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Much uncertainty exists in science and herbal products referencing turmeric (T), turmeric ext. (TE), curcuminoid-enriched turmeric ext. (CTE), further processed curcuminoid-enriched materials (CEM), or curcumin as a single-chem. entity. To facilitate the rational chem. and biol. assessment of turmeric-derived NPs, we introduced the DESIGNER approach of Depleting and Enriching Select Ingredients to Generate Normalized Ext. Resources to Curcuma longa prepns. Countercurrent sepn. of a com. CTE yielded four key materials-lipophilic metabolites; purified curcumin ("purcumin"); a mixt. of curcumin, demethoxycurcumin, and bisdemethoxycurcumin ("purcuminoids"); and hydrophilic metabolites-and enabled prodn. of a curcuminoid-free TE ("nocumin"). Their characterization utilized TLC, 1H (q)NMR spectroscopy, and HPLC.
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8Zuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimarães, F. S. Cannabidiol, a Cannabis sativa Constituent, as an Antipsychotic Drug. Braz. J. Med. Biol. Res. 2006, 39, 421– 429, DOI: 10.1590/S0100-879X2006000400001Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvFGjtbk%253D&md5=67836b59cdf13217813f2daa43242797Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drugZuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimaraes, F. S.Brazilian Journal of Medical and Biological Research (2006), 39 (4), 421-429CODEN: BJMRDK; ISSN:0100-879X. (Associacao Brasileira de Divulgacao Cientifica)A review. A high dose of Δ9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of Δ9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochem. techniques which suggested that CBD has a pharmacol. profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addn., open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clin. trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.
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9Mogil, J. S. Laboratory Environmental Factors and Pain Behavior: The Relevance of Unknown Unknowns to Reproducibility and Translation. Lab Anim. 2017, 46, 136– 141, DOI: 10.1038/laban.1223Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czpslyhug%253D%253D&md5=4338f12be20a5765890467f3da8e401eLaboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translationMogil Jeffrey SLab animal (2017), 46 (4), 136-141 ISSN:.The poor record of basic-to-clinical translation in recent decades has led to speculation that preclinical research is "irreproducible", and this irreproducibility in turn has largely been attributed to deficiencies in reporting and statistical practices. There are, however, a number of other reasonable explanations of both poor translation and difficulties in one laboratory replicating the results of another. This article examines these explanations as they pertain to preclinical pain research. I submit that many instances of apparent irreproducibility are actually attributable to interactions between the phenomena and interventions under study and "latent" environmental factors affecting the rodent subjects. These environmental variables-often causing stress, and related to both animal husbandry and the specific testing context-differ greatly between labs, and continue to be identified, suggesting that our knowledge of their existence is far from complete. In pain research in particular, laboratory stressors can produce great variability of unpredictable direction, as stress is known to produce increases (stress-induced hyperalgesia) or decreases (stress-induced analgesia) in pain depending on its parameters. Much greater attention needs to be paid to the study of the laboratory environment if replication and translation are to be improved.
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10Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2019, 8, 1009– 1031, DOI: 10.1002/cpdd.665Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVOhtr7M&md5=1c152b54ce3a70e65dca8bbfe90ee164A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy SubjectsMorrison, Gilmour; Crockett, Julie; Blakey, Graham; Sommerville, KennethClinical Pharmacology in Drug Development (2019), 8 (8), 1009-1031CODEN: CPDDAH; ISSN:2160-7648. (John Wiley & Sons, Inc.)GW Pharmaceuticals' formulation of highly purified cannabidiol oral soln. is approved in the United States for seizures assocd. with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure, N-desmethylclobazam exposure increased, stiripentol exposure increased slightly, while no clin. relevant effect on valproate exposure was obsd. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure, without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clin. significant safety findings.
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11Ghovanloo, M.-R.; Shuart, N. G.; Mezeyova, J.; Dean, R. A.; Ruben, P. C.; Goodchild, S. J. Inhibitory Effects of Cannabidiol on Voltage-Dependent Sodium Currents. J. Biol. Chem. 2018, 293, 16546– 16558, DOI: 10.1074/jbc.RA118.004929Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVSlt7%252FE&md5=40b508435c5e7d9b7e220e8e05a03d54Inhibitory effects of cannabidiol on voltage-dependent sodium currentsGhovanloo, Mohammad-Reza; Shuart, Noah Gregory; Mezeyova, Janette; Dean, Richard A.; Ruben, Peter C.; Goodchild, Samuel J.Journal of Biological Chemistry (2018), 293 (43), 16546-16558CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A review. Cannabis sativa contains many related compds. known as phytocannabinoids. The main psychoactive and nonpsychoactive compds. are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), resp. Much of the evidence for clin. efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiol. of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concns. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temp.-dependent, with potency increasing at lower temps. We conclude that CBD's mode of action likely involves (1) compd. partitioning in lipid membranes, which alters membrane fluidity affecting gating, and (2) undetd. direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.
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12Watkins, A. R. Cannabinoid Interactions with Ion Channels and Receptors. Channels 2019, 13, 162– 167, DOI: 10.1080/19336950.2019.1615824Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7lslWlsg%253D%253D&md5=7ee0ebb3aee6565c669dab8692c2eb3eCannabinoid interactions with ion channels and receptorsWatkins Abeline RoseChannels (Austin, Tex.) (2019), 13 (1), 162-167 ISSN:.Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Nav). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Nav. Nav are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Nav potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.
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13Gertsch, J. The Intricate Influence of the Placebo Effect on Medical Cannabis and Cannabinoids. Med. Cannabis Cannabinoids 2018, 1, 60– 64, DOI: 10.1159/000489291Google ScholarThere is no corresponding record for this reference.
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14WHO CBD Report May 2018. Cannabidiol (CBD). Critical Review Report. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf?ua=1 (accessed Oct 25, 2019).Google ScholarThere is no corresponding record for this reference.
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15Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365, DOI: 10.3389/fphar.2018.01365Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVGmtL%252FM&md5=75d60a2ef4d2866558759c1ec05a02efA systematic review on the pharmacokinetics of cannabidiol in humansMillar, Sophie A.; Stone, Nicole L.; Yates, Andrew S.; O'Sullivan, Saoirse E.Frontiers in Pharmacology (2018), 9 (), 1365CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2-5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the abs. bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Anal. and understanding of properties such as bioavailability and half-life is crit. to future therapeutic success, and robust data from a variety of formulations is required.
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16Office of the Commissioner. What to Know About Products Containing Cannabis and CBD. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis (accessed Apr 23, 2020).Google ScholarThere is no corresponding record for this reference.
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17Gaoni, Y.; Mechoulam, R. Hashish—VII: The Isomerization of Cannabidiol to Tetrahydrocannabinols. Tetrahedron 1966, 22, 1481– 1488, DOI: 10.1016/S0040-4020(01)99446-3Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xkt1Sqt74%253D&md5=f4842df46ea46da10b951ce4d84a6a82Hashish. VII. Isomerization of cannabidiol to tetrahydrocannabinolsGaoni, Y.; Mechoulam, R.Tetrahedron (1966), 22 (4), 1481-8CODEN: TETRAB; ISSN:0040-4020.cf. CA 63, 2919c, 9849a. Depending on the reaction conditions used, the physiol. active products obtained by Adams on isomerization of the inactive cannabidiol with acids are shown to be either Δ1(6)-tetrahydrocannabinol (I) or a mixt. of I, Δ1-tetrahydrocannabinol and the 2 isomers of 1 ethoxyhexahydrocannabinol.
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18Gutman, A. L.; Etinger, M.; Fedotev, I.; Khanolkar, R. Methods for Purifying Trans-(−)-Δ9-Tetrahydrocannabinol and Trans-(+)-Δ9-Tetrahydrocannabinol. U.S. Patent 8383842, 2006.Google ScholarThere is no corresponding record for this reference.
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19Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes. J. Nat. Prod. 2016, 79, 324– 331, DOI: 10.1021/acs.jnatprod.5b00949Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVynt7s%253D&md5=22ba257f20240b854d5a271d30d002baEvolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different ChemotypesAizpurua-Olaizola, Oier; Soydaner, Umut; Ozturk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, AresatzJournal of Natural Products (2016), 79 (2), 324-331CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The evolution of major cannabinoids and terpenes during the growth of Cannabis sativa plants was studied. In this work, seven different plants were selected: three each from chemotypes I and III and one from chemotype II. Fifty clones of each mother plant were grown indoors under controlled conditions. Every week, three plants from each variety were cut and dried, and the leaves and flowers were analyzed sep. Eight major cannabinoids were analyzed via HPLC-DAD, and 28 terpenes were quantified using GC-FID and verified via GC-MS. The chemotypes of the plants, as defined by the tetrahydrocannabinolic acid/cannabidiolic acid (THCA/CBDA) ratio, were clear from the beginning and stable during growth. The concns. of the major cannabinoids and terpenes were detd., and different patterns were found among the chemotypes. In particular, the plants from chemotypes II and III needed more time to reach peak prodn. of THCA, CBDA, and monoterpenes. Differences in the cannabigerolic acid development among the different chemotypes and between monoterpene and sesquiterpene evolution patterns were also obsd. Plants of different chemotypes were clearly differentiated by their terpene content, and characteristic terpenes of each chemotype were identified.
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20Basas-Jaumandreu, J.; de Las Heras, F. X. C. GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa. Planta Med. 2020, 86, 338– 347, DOI: 10.1055/a-1110-1045Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlaht7c%253D&md5=bc6cd94ef2fb2d1addd0d006ab574534GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativaBasas-Jaumandreu, Josep; de las Heras, F. Xavier C.Planta Medica (2020), 86 (5), 338-347CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)Phytochem. investigation of the lipids extd. from seeds of Cannabis sativaby GC-MS showed 43 cannabinoids, 16 of which are new. The ext. is dominated by Δ 9-tetrahydrocannabinolic acid (A) and its neutral deriv. trans-Δ 9-tetrahydrocannabinol-C 5(THC) Cisand trans-Δ 9-tetrahydrocannabinol-C 7isomers with an ethyl-pentyl branched chain together with minor amts. of trans-Δ 9-tetrahydrocannabinol with a methyl-pentyl C 6branched side chain were identified as new natural compds. Four cannabichromene isomers with a C 5side chain are postulated to be derived from the double bond migration at the terminal isoprenyl unit. C 7cannabichromene together with the neutral and acidic forms of cannabinol-C 7were also detected. The mass spectrum of these homologues as trimethylsilyl (TMS) derivs. are presented, and the fragmentation patterns are discussed.
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21Luo, X.; Reiter, M. A.; d’Espaux, L.; Wong, J.; Denby, C. M.; Lechner, A.; Zhang, Y.; Grzybowski, A. T.; Harth, S.; Lin, W.; Lee, H.; Yu, C.; Shin, J.; Deng, K.; Benites, V. T.; Wang, G.; Baidoo, E. E. K.; Chen, Y.; Dev, I.; Petzold, C. J.; Keasling, J. D. Complete Biosynthesis of Cannabinoids and Their Unnatural Analogues in Yeast. Nature 2019, 567, 123– 126, DOI: 10.1038/s41586-019-0978-9Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmsVyqtbg%253D&md5=7cb609e2be139b5158982daf739a6491Complete biosynthesis of cannabinoids and their unnatural analogues in yeastLuo, Xiaozhou; Reiter, Michael A.; d'Espaux, Leo; Wong, Jeff; Denby, Charles M.; Lechner, Anna; Zhang, Yunfeng; Grzybowski, Adrian T.; Harth, Simon; Lin, Weiyin; Lee, Hyunsu; Yu, Changhua; Shin, John; Deng, Kai; Benites, Veronica T.; Wang, George; Baidoo, Edward E. K.; Chen, Yan; Dev, Ishaan; Petzold, Christopher J.; Keasling, Jay D.Nature (London, United Kingdom) (2019), 567 (7746), 123-126CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia. Some cannabinoids, the hallmark constituents of Cannabis, and their analogs have been investigated extensively for their potential medical applications. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids, and their structural complexity, which limits bulk chem. synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogs. Feeding different fatty acids to our engineered strains yielded cannabinoid analogs with modifications in the part of the mol. that is known to alter receptor binding affinity and potency. We also demonstrated that our biol. system could be complemented by simple synthetic chem. to further expand the accessible chem. space. Our work presents a platform for the prodn. of natural and unnatural cannabinoids that will allow for more rigorous study of these compds. and could be used in the development of treatments for a variety of human health problems.
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22Kumari, S.; Pundhir, S.; Priya, P.; Jeena, G.; Punetha, A.; Chawla, K.; Firdos Jafaree, Z.; Mondal, S.; Yadav, G. EssOilDB: A Database of Essential Oils Reflecting Terpene Composition and Variability in the Plant Kingdom. Database 2014, 2014, bau120 DOI: 10.1093/database/bau120Google ScholarThere is no corresponding record for this reference.
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23Degenhardt, F.; Stehle, F.; Kayser, O. The Biosynthesis of Cannabinoids. In Handbook of Cannabis and Related Pathologies. Biology, Pharmacology, Diagnosis, and Treatment; Preedy, V. R., Ed.; Elsevier: London, 2017; pp 13– 23.Google ScholarThere is no corresponding record for this reference.
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24Pauli, G. F.; Chen, S.-N.; Simmler, C.; Lankin, D. C.; Gödecke, T.; Jaki, B. U.; Friesen, J. B.; McAlpine, J. B.; Napolitano, J. G. Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity Assay. J. Med. Chem. 2014, 57, 9220– 9231, DOI: 10.1021/jm500734aGoogle Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslahsLzF&md5=78900d0b03e31739e50c04c63c55dba7Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity AssayPauli, Guido F.; Chen, Shao-Nong; Simmler, Charlotte; Lankin, David C.; Godecke, Tanja; Jaki, Birgit U.; Friesen, J. Brent; McAlpine, James B.; Napolitano, Jose G.Journal of Medicinal Chemistry (2014), 57 (22), 9220-9231CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. In any biomedical and chem. context, a truthful description of chem. constitution requires coverage of both structure and purity. This qualification affects all drug mols., regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly crit. in discovery programs and whenever chem. is linked with biol. and/or therapeutic outcome. Compared with chromatog. and elemental anal., quant. NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Abs. qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical 1H qNMR (qHNMR) procedures with simultaneous qual. and (abs.) quant. capability. This study reviews underlying concepts, provides a framework for std. qHNMR purity assays, and shows how adequate accuracy and precision are achieved for the intended use of the material.
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25Martin Emanuele, R.; Shattock-Gordon, T.; Williford, T.; Andres, M.; Andres, P. New Solid Forms of Cannabidiol and Uses Thereof. World Intellectual Property Organization. WO 2019118360 A1, 2019.Google ScholarThere is no corresponding record for this reference.
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26Mechoulam, R.; Hanuš, L. Cannabidiol: An Overview of Some Chemical and Pharmacological Aspects. Part I: Chemical Aspects. Chem. Phys. Lipids 2002, 121, 35– 43, DOI: 10.1016/S0009-3084(02)00144-5Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xpslansrg%253D&md5=928634dca87b012a94252b05170a8c0aCannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspectsMechoulam, Raphael; Hanus, LumirChemistry and Physics of Lipids (2002), 121 (1-2), 35-43CODEN: CPLIA4; ISSN:0009-3084. (Elsevier Science Ltd.)A review. Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chem. of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
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27Popovic, A.; Morelato, M.; Roux, C.; Beavis, A. Review of the Most Common Chemometric Techniques in Illicit Drug Profiling. Forensic Sci. Int. 2019, 302, 109911, DOI: 10.1016/j.forsciint.2019.109911Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFCmsL3K&md5=3d3759d9a3dd3f720b411706bb299c76Review of the most common chemometric techniques in illicit drug profilingPopovic, Ana; Morelato, Marie; Roux, Claude; Beavis, AlisonForensic Science International (2019), 302 (), 109911CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)A review. The information generated through drug profiling can be used to infer a common source between one or several seizures as well as drug trafficking routes to provide insights into drug markets. Although well established, it is time-consuming and ineffective to compare all drug profiles manually. In recent years, there has been a push to automate processes to enable a more efficient comparison of illicit drug specimens. Various chemometric methods have been employed to compare and interpret forensic case data promptly. The intelligence that is produced can be used by decision-makers to disrupt or reduce the impact of illicit drug markets. This review highlights the most common chemometric techniques used in drug profiling and more specifically, the most efficient comparison metrics and pattern recognition techniques outlined in the literature.
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28O’Neil, M. J. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; Royal Society of Chemistry: Cambridge, U.K., 2013; 2707.Google ScholarThere is no corresponding record for this reference.
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29Pauli, G. F.; Gödecke, T.; Jaki, B. U.; Lankin, D. C. Quantitative 1H NMR. Development and Potential of an Analytical Method: An Update. J. Nat. Prod. 2012, 75, 834– 851, DOI: 10.1021/np200993kGoogle Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltFGisLw%253D&md5=aaee4e1fe38121ba9e222c5e6d661269Quantitative 1H NMR. Development and Potential of an Analytical Method: An UpdatePauli, Guido F.; Godecke, Tanja; Jaki, Birgit U.; Lankin, David C.Journal of Natural Products (2012), 75 (4), 834-851CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review. Covering the literature from mid-2004 until the end of 2011, this review continues a previous literature overview on quant. 1H NMR (qHNMR) methodol. and its applications in the anal. of natural products. Among the foremost advantages of qHNMR is its accurate function with external calibration, the lack of any requirement for identical ref. materials, a high precision and accuracy when properly validated, and an ability to quantitate multiple analytes simultaneously. As a result of the inclusion of over 170 new refs., this updated review summarizes a wealth of detailed experiential evidence and newly developed methodol. that supports qHNMR as a valuable and unbiased anal. tool for natural product and other areas of research.
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30Hazekamp, A.; Choi, Y. H.; Verpoorte, R. Quantitative Analysis of Cannabinoids from Cannabis sativa Using 1H-NMR. Chem. Pharm. Bull. 2004, 52, 718– 721, DOI: 10.1248/cpb.52.718Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXltFKqsL4%253D&md5=571f3c33fef65c66e2fb174c4e4e0da8Quantitative analysis of cannabinoids from Cannabis sativa using 1H-NMRHazekamp, Arno; Choi, Young Hae; Verpoorte, RobertChemical & Pharmaceutical Bulletin (2004), 52 (6), 718-721CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A 1H-NMR method has been developed for the quant. anal. of pure cannabinoids and for cannabinoids present in Cannabis sativa plant material without any chromatog. purifn. The expt. was performed by the anal. of singlets in the range of δ 4.0-7.0 in the 1H-NMR spectrum, in which distinguishable signals of each cannabinoid are shown. Quantitation was performed by calcg. the relative ratio of the peak area of selected proton signals of the target compds. to the known amt. of the internal std., anthracene. For this method no ref. compds. are needed. It allows rapid and simple quantitation of cannabinoids with a final anal. time of only 5 min without the need for a pre-purifn. step.
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31Siciliano, C.; Bartella, L.; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A. 1H NMR Quantification of Cannabidiol (CBD) in Industrial Products Derived from Cannabis sativa L. (hemp) Seeds - IOPscience. IOP Conf. Ser.: Mater. Sci. Eng. 2019, 572, 012010, DOI: 10.1088/1757-899X/572/1/012010Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVajsA%253D%253D&md5=c61b5657c5c2d4b40bc43770bcc9803e1H NMR quantification of cannabidiol (CBD) in industrial products derived from Cannabis sativa L. (hemp) seedsSiciliano, C.; Bartella, Lucia; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A.IOP Conference Series: Materials Science and Engineering (2019), 572 (International Conference on Innovative Research: ICIR EUROINVENT 2019), 012010CODEN: ICSMGW; ISSN:1757-899X. (IOP Publishing Ltd.)A practicable and reliable quant. proton NMR (1H qNMR) method was developed and evaluated for the qual. and quant. detn. of cannabidiol (CBD), the principal and most important among cannabinoids in Cannabis sativa L. (hemp), and present in food products and animal feeding derived from the industrial processing of hemp seeds. Specificity, sensitivity, linearity range, precision, accuracy, LOD and LOQ of the method proved to be entirely satisfactory. This spectroscopic method uses the unlabeled residual solvent of CDCl3 as the "intrinsic" internal std. The develop procedure might also be applied to measure levels of all the other lawful natural cannabinoids in com. productions obtained from hemp seeds. Moreover, the rapid and relatively economical quantification of CBD could be of great importance, because it is possible to candidate this cannabinoid to the role of a mol. marker attesting food processing quality.
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32Choules, M. P.; Bisson, J.; Simmler, C.; McAlpine, J. B.; Giancaspro, G.; Bzhelyansky, A.; Niemitz, M.; Pauli, G. F. NMR Reveals an Undeclared Constituent in Custom Synthetic Peptides. J. Pharm. Biomed. Anal. 2020, 178, 112915, DOI: 10.1016/j.jpba.2019.112915Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVyht7nM&md5=8641a2f32d8a85596e4e3faf5b27170dNMR reveals an undeclared constituent in custom synthetic peptidesChoules, Mary P.; Bisson, Jonathan; Simmler, Charlotte; McAlpine, James B.; Giancaspro, Gabriel; Bzhelyansky, Anton; Niemitz, Matthias; Pauli, Guido F.Journal of Pharmaceutical and Biomedical Analysis (2020), 178 (), 112915CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)Whereas generic, LC-based pharmaceutical control quality procedures depend largely on the detection mode and can be particularly 'blind' to certain impurities, NMR is a more versatile and, thus, often more judicious detector. While adulteration presents ever-evolving challenges for the anal. of active pharmaceutical ingredients (APIs) and finished products sold in the worldwide (online) marketplace, research chems. are usually trusted rather than being considered flawed or even adulterated. This report shows how NMR anal. uncovered the unanticipated presence of substantial amts. of mannitol (20 and 43% wt./wt.) as undeclared constituent in two custom synthetic peptides, DR and DRVYI, that were sourced com. Quant. 1H NMR (qHNMR) readily detected the contaminant, even on a 60 MHz benchtop instrument, and quantified the highly polar and UV-transparent adulterant. Quantum-mech. 1H iterative Full Spin Anal. (HiFSA) not only achieved unambiguous identification of both the mannitol and the peptides, but also confirmed the quant. results. The cases show that exptl. verification supersedes trust in both pharmaceutical and research QC. They also highlight the promising utility of both established high-field and recently re-evolving low-field benchtop qHNMR. The unanticipated findings remind manufacturers and researchers alike about the advantages of including/performing NMR and qNMR with routine CofA documentation and/or verification of research grade chems. Esp. when done jointly, this can greatly improve confidence in research and help streamline the pharmaceutical QC toolbox.
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33Bisson, J.; Simmler, C.; Chen, S.-N.; Friesen, J. B.; Lankin, D. C.; McAlpine, J. B.; Pauli, G. F. Dissemination of Original NMR Data Enhances Reproducibility and Integrity in Chemical Research. Nat. Prod. Rep. 2016, 33, 1028– 1033, DOI: 10.1039/C6NP00022CGoogle Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XosValtrs%253D&md5=6f67b234eacdee2ba368ad0667e6f96bDissemination of original NMR data enhances reproducibility and integrity in chemical researchBisson, Jonathan; Simmler, Charlotte; Chen, Shao-Nong; Friesen, J. Brent; Lankin, David C.; McAlpine, James B.; Pauli, Guido F.Natural Product Reports (2016), 33 (9), 1028-1033CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)The notion of data transparency is gaining a strong awareness among the scientific community. The availability of raw data is actually regarded as a fundamental way to advance science by promoting both integrity and reproducibility of research outcomes. Particularly, in the field of natural product and chem. research, NMR spectroscopy is a fundamental tool for structural elucidation and quantification (qNMR). As such, the accessibility of original NMR data, i.e., Free Induction Decays (FIDs), fosters transparency in chem. research and optimizes both peer review and reproducibility of reports by offering the fundamental tools to perform efficient structural verification. Although original NMR data are known to contain a wealth of information, they are rarely accessible along with published data. This viewpoint discusses the relevance of the availability of original NMR data as part of good research practices not only to promote structural correctness, but also to enhance traceability and reproducibility of both chem. and biol. results.
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34McAlpine, J. B.; Chen, S.-N.; Kutateladze, A.; MacMillan, J. B.; Appendino, G.; Barison, A.; Beniddir, M. A.; Biavatti, M. W.; Blüml, S.; Boufridi, A.; Butler, M. S.; Capon, R. J.; Choi, Y. H.; Coppage, D.; Crews, P.; Crimmins, M. T.; Csete, M.; Dewapriya, P.; Egan, J. M.; Garson, M. J.; Genta-Jouve, G.; Gerwick, W. H.; Gross, H.; Harper, M. K.; Hermanto, P.; Hook, J. M.; Hunter, L.; Jeannerat, D.; Ji, N.-Y.; Johnson, T. A.; Kingston, D. G. I.; Koshino, H.; Lee, H.-W.; Lewin, G.; Li, J.; Linington, R. G.; Liu, M.; McPhail, K. L.; Molinski, T. F.; Moore, B. S.; Nam, J.-W.; Neupane, R. P.; Niemitz, M.; Nuzillard, J.-M.; Oberlies, N. H.; Ocampos, F. M. M.; Pan, G.; Quinn, R. J.; Reddy, D. S.; Renault, J.-H.; Rivera-Chávez, J.; Robien, W.; Saunders, C. M.; Schmidt, T. J.; Seger, C.; Shen, B.; Steinbeck, C.; Stuppner, H.; Sturm, S.; Taglialatela-Scafati, O.; Tantillo, D. J.; Verpoorte, R.; Wang, B.-G.; Williams, C. M.; Williams, P. G.; Wist, J.; Yue, J.-M.; Zhang, C.; Xu, Z.; Simmler, C.; Lankin, D. C.; Bisson, J.; Pauli, G. F. The Value of Universally Available Raw NMR Data for Transparency, Reproducibility, and Integrity in Natural Product Research. Nat. Prod. Rep. 2019, 36, 35– 107, DOI: 10.1039/C7NP00064BGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlamsrzP&md5=5ca1ec7156152f70e83356b1e198f83eThe value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product researchMcAlpine, James B.; Chen, Shao-Nong; Kutateladze, Andrei; MacMillan, John B.; Appendino, Giovanni; Barison, Andersson; Beniddir, Mehdi A.; Biavatti, Maique W.; Bluml, Stefan; Boufridi, Asmaa; Butler, Mark S.; Capon, Robert J.; Choi, Young H.; Coppage, David; Crews, Phillip; Crimmins, Michael T.; Csete, Marie; Dewapriya, Pradeep; Egan, Joseph M.; Garson, Mary J.; Genta-Jouve, Gregory; Gerwick, William H.; Gross, Harald; Harper, Mary Kay; Hermanto, Precilia; Hook, James M.; Hunter, Luke; Jeannerat, Damien; Ji, Nai-Yun; Johnson, Tyler A.; Kingston, David G. I.; Koshino, Hiroyuki; Lee, Hsiau-Wei; Lewin, Guy; Li, Jie; Linington, Roger G.; Liu, Miaomiao; McPhail, Kerry L.; Molinski, Tadeusz F.; Moore, Bradley S.; Nam, Joo-Won; Neupane, Ram P.; Niemitz, Matthias; Nuzillard, Jean-Marc; Oberlies, Nicholas H.; Ocampos, Fernanda M. M.; Pan, Guohui; Quinn, Ronald J.; Reddy, D. Sai; Renault, Jean-Hugues; Rivera-Chavez, Jose; Robien, Wolfgang; Saunders, Carla M.; Schmidt, Thomas J.; Seger, Christoph; Shen, Ben; Steinbeck, Christoph; Stuppner, Hermann; Sturm, Sonja; Taglialatela-Scafati, Orazio; Tantillo, Dean J.; Verpoorte, Robert; Wang, Bin-Gui; Williams, Craig M.; Williams, Philip G.; Wist, Julien; Yue, Jian-Min; Zhang, Chen; Xu, Zhengren; Simmler, Charlotte; Lankin, David C.; Bisson, Jonathan; Pauli, Guido F.Natural Product Reports (2019), 36 (1), 35-107CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw NMR (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and assocd. fields of chem. and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of exptl. protocols, augment the reproducibility of reported outcomes, including biol. studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
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35Choules, M. P.; Klein, L. L.; Lankin, D. C.; McAlpine, J. B.; Cho, S.-H.; Cheng, J.; Lee, H.; Suh, J.-W.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin. J. Org. Chem. 2018, 83, 6664– 6672, DOI: 10.1021/acs.joc.8b00988Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvFanu78%253D&md5=ae7081d9e1a29208a81a2a0a06969906Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and RufomycinChoules, Mary P.; Klein, Larry L.; Lankin, David C.; McAlpine, James B.; Cho, Sang-Hyun; Cheng, Jinhua; Lee, Hanki; Suh, Joo-Won; Jaki, Birgit U.; Franzblau, Scott G.; Pauli, Guido F.Journal of Organic Chemistry (2018), 83 (12), 6664-6672CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Residual complexity (RC) involves the impact of subtle but crit. structural and biol. features on drug lead validation, including unexplained effects related to unidentified impurities. RC commonly plagues drug discovery efforts due to the inherent imperfections of chromatog. sepn. methods. The new diketopiperazine, rufomyazine (6), and the previously known antibiotic, rufomycin (7), represent a prototypical case of RC that (almost) resulted in the misassignment of biol. activity. The case exemplifies that impurities well below the natural abundance of 13C (1.1%) can be highly relevant and calls for advanced anal. characterization of drug leads with extended molar dynamic ranges of >1:1,000 using qNMR and LC-MS. Isolated from an actinomycete strain, 6 was originally found to be active against Mycobacterium tuberculosis with a min. inhibitory concn. (MIC) of 2 μg/mL and high selectivity. As a part of lead validation, the dipeptide was synthesized and surprisingly found to be inactive. The initially obsd. activity was eventually attributed to a very minor contamination (0.24% [m/m]) with a highly active cyclic peptide (MIC ∼ 0.02 μM), subsequently identified as an analog of 7. This study illustrates the serious implications RC can exert on org. chem. and drug discovery, and what efforts are vital to improve lead validation and efficiency, esp. in NP-related drug discovery programs.
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36Pauli, G. F.; Chen, S.-N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study. J. Nat. Prod. 2012, 75, 1243– 1255, DOI: 10.1021/np300066qGoogle Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsVeru70%253D&md5=15d145c2988692d26558d6d4361337d9Analysis and Purification of Bioactive Natural Products: The AnaPurNa StudyPauli, Guido F.; Chen, Shao-Nong; Friesen, J. Brent; McAlpine, James B.; Jaki, Birgit U.Journal of Natural Products (2012), 75 (6), 1243-1255CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review on the survey of anal. methodol. such as chromatog. and spectroscopy used for isolation and purity assessment of bioactive natural products (NPs), which have been employed in the almost 2000 publications in the recent years.
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37Citti, C.; Linciano, P.; Forni, F.; Vandelli, M. A.; Gigli, G.; Laganà, A.; Cannazza, G. Analysis of Impurities of Cannabidiol from Hemp. Isolation, Characterization and Synthesis of Cannabidibutol, the Novel Cannabidiol Butyl Analog. J. Pharm. Biomed. Anal. 2019, 175, 112752, DOI: 10.1016/j.jpba.2019.06.049Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVajt77O&md5=9b4cdb8a8e76150ebd70a648598a2284Analysis of impurities of cannabidiol from hemp. Isolation, characterization and synthesis of cannabidibutol, the novel cannabidiol butyl analogCitti, Cinzia; Linciano, Pasquale; Forni, Flavio; Vandelli, Maria Angela; Gigli, Giuseppe; Lagana, Aldo; Cannazza, GiuseppeJournal of Pharmaceutical and Biomedical Analysis (2019), 175 (), 112752CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)Cannabidiol (CBD), one of the two major active principles present in Cannabis sativa, is gaining great interest among the scientific community for its pharmaceutical, nutraceutical and cosmetic applications. CBD can be prepd. either by chem. synthesis or extn. from Cannabis sativa (hemp). The latter is more convenient from several points of view, including environmental and economic, but mainly for the absence of harmful org. solvents generally employed in the chem. synthesis. Although CBD produced by hemp extn. is the most widely employed, it carries two major impurities. The first one is the already known cannabidivarin (CBDV), whereas the second one is supposed to be the Bu analog of CBD with a four-term alkyl side chain. In this work, we report the isolation by semi-preparative liq. chromatog. and the unambiguous identification of this second impurity. A comprehensive spectroscopic characterization, including NMR, UV, IR, CD and high-resoln. mass spectrometry (HRMS), was carried out on this natural cannabinoid. In order to confirm its abs. configuration and chem. structure, the stereoisomer (1R,6R) of the supposed cannabinoid was synthesized and the physicochem. and spectroscopic properties, along with the stereochem., matched those of the natural isolated mol. According to the International Nonproprietary Name, we suggested the name of cannabidibutol (CBDB) for this cannabinoid. Lastly, an HPLC-UV method was developed and validated for the qual. and quant. detn. of CBDV and CBDB in samples of CBD extd. from hemp and produced according to Good Manufg. Practices regulations for pharmaceutical and cosmetic use.
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38Freeman, T. P.; Hindocha, C.; Green, S. F.; Bloomfield, M. A. P. Medicinal Use of Cannabis Based Products and Cannabinoids. BMJ. 2019, 365, l1141 DOI: 10.1136/bmj.l1141Google ScholarThere is no corresponding record for this reference.
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39Office of the Commissioner. FDA Regulation of Cannabis and Cannabis-Derived Products: Q&A. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd (accessed Apr 22, 2020).Google ScholarThere is no corresponding record for this reference.
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40Office of the Commissioner. FDA and Cannabis: Research and Drug Approval Process. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process (accessed Apr 22, 2020).Google ScholarThere is no corresponding record for this reference.
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41Biosciences, G. EPIDIOLEX (cannabidiol) oral solution, CV prescribing information; revised 12/2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed Dec 19, 2019).Google ScholarThere is no corresponding record for this reference.
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42Office of the Commissioner. Warning Letters and Test Results for Cannabidiol-Related Products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products (accessed Apr 27, 2020).Google ScholarThere is no corresponding record for this reference.
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43Jacob, A.; Todd, A. R. 119. Cannabis Indica. Part II. Isolation of Cannabidiol from Egyptian Hashish. Observations on the Structure of Cannabinol. J. Chem. Soc. 1940, 649– 653, DOI: 10.1039/jr9400000649Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3cXjs1SgsA%253D%253D&md5=7f05442ba9a7024a106ac13fc4dd9fc1Cannabis indica. II. Isolation of cannabidiol from Egyptian hashish. Observations on the structure of cannabinolJacob, A.; Todd, A. R.Journal of the Chemical Society (1940), (), 649-53CODEN: JCSOA9; ISSN:0368-1769.cf. C. A. 33, 5073.3; 34, 3441.2. Cannabidiol (I), C21H30O2, a typical constituent of American hemp resin (Adams, Hunt and Clark, C. A. 34, 1635.7), has been isolated from hashish of Egyptian origin, where it was accompanied by an approx. equal amt. of cannabinol (II). Extn. of 500 g. of the drug with 3 l. petr. ether (b. 40-60°) at room temp. gives 70 g. of a thick brown oil; a MeOH soln. (350 cc.) deposits 3 g. of a cryst. hydrocarbon; evapn. of the MeOH gives 60 g. of oil which, distd. at 10-3 mm. in a mol. still, gives 28.4 g. of a resin at 110-30°; this resin was esterified with p-O2NC6H4COCl and the portion insol. in petr. ether was taken up in a mixt. of 30% C6H6 and 70% petr. ether and passed through Al2O3; washing with the mixed solvent and crystn. of the product from EtOH give 5 g. of the p-nitrobenzoate of II, m. 159-60°; the remainder of the material on the Al2O3 was removed with Me2CO, hydrolyzed and transformed into the bis-3,5-dinitrobenzoate (4 g.) of I, m. 106-7°. II gives an intense blue color with 2,6-dichloroquinone chloroimine, indicating that the p-position to the phenolic OH group is unsubstituted; the absorption spectrum of II in EtOH shows a max. at 2850 A. (ε mol. = 16,790); this agrees with the presence of a di-Ph chromophoric system. I contains 2 double bonds; its absorption spectrum in EtOH has a max. at 2775 A. (ε mol. = 1350); thus neither of the double bonds can be conjugated with the arom. nucleus. Possible formulas for II are proposed, based on the color reactions. Both I and II appear to be inactive in the Gayer test in rabbits.
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44Adams, R.; Baker, B. R.; Wearn, R. B. Structure of Cannabinol. III. Synthesis of Cannabinol, 1-Hydroxy-3-N-Amyl-6,6,9-Trimethyl-6-dibenzopyran1. J. Am. Chem. Soc. 1940, 62, 2204– 2207, DOI: 10.1021/ja01865a083Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3cXktlaktQ%253D%253D&md5=3de762ddb6d9d67935dff0b3c2a14b07Structure of cannabinol. III. Synthesis of cannabinol, 1-hydroxy-3-amyl-6,6,9-trimethyl-6-dibenzopyranAdams, Roger; Baker, B. R.; Wearn, R. B.Journal of the American Chemical Society (1940), 62 (), 2204-7CODEN: JACSAT; ISSN:0002-7863.o-BrC6H4CO2H, menthone, EtONa and Cu(OAc)2 in abs. EtOH, refluxed 5 h., give 1-keto-3,3-dimethyl-1,2,3,4-tetrahydro-6-dibenzopyrone, m. 145-6° (m. ps. cor.). Olivetol is reduced by H and Raney Ni at 125° (initial pressure of 2800 lbs.) in about 1 min., giving 70-5% of dihydro.ovrddot.odlivetol (5-amyl-1,3-cyclohexanedione) (I), m. 70-1°; a synthesis from AmCHO in 29% is also reported, hexylideneacetone reacting with CH2(CO2Et)2 and EtONa. Condensation of 4,2-MeBrC6H3CO2H and I with EtONa and Cu(OAc)2 gives 78% of 1-keto-3-amyl-9-methyl-1,2,3,4-tetrahydro-6-dibenzopyrone (II), m. 95-6°; heating 10.4 g. II and 1.13 g. S at 250° for 25 min. yields 34% (with 43% recovery of II) of 1-hydroxy-3-amyl-9-methyl-6-dibenzopyrone (III), m. 186°. Reaction of III with MeMgI gives 75% of cannabinol (IV), m. 76-7°. IV was characterized by its Ac deriv., m. 75-6°, its 1-p-nitrobenzoxy deriv., yellow, m. 165-6°, and its 1-m-nitrobenzenesulfonoxy deriv., yellow, m. 127-9°. 5-Ethyl-3-hepten-2-one and CHNa(CO2Et)2 give 5-diethylmethyl-1,3-cyclohexanedione, m. 104-5°; the following compds. were prepd. as above: 1-keto-3-diethylmethyl-9-methyl-1,2,3,4-tetrahydro-6-dibenzopyrone, m. 111-12°; 1-hydroxy-3-diethylmethyl-9-methyl-6-dibenzopyrone, m. 217-18° (Ac deriv., m. 128-30°); 1-hydroxy-3-diethylmethyl-6,6,9-trimethyl-6-dibenzopyran, m. 133-4° (Ac deriv., m. 103°; 1-p-nitrobenzoxy deriv., yellow, m. 171°).
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45Jones, P. G.; Falvello, L.; Kennard, O.; Sheldrick, G. M.; Mechoulam, R. Cannabidiol. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 3211– 3214, DOI: 10.1107/S0567740877010577Google ScholarThere is no corresponding record for this reference.
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46Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F. P.; Pichini, S. Evaluation of Cannabinoids Concentration and Stability in Standardized Preparations of Cannabis Tea and Cannabis Oil by Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry. Clin. Chem. Lab. Med. 2017, 55, 1555– 1563, DOI: 10.1515/cclm-2016-1060Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlymtLnP&md5=58e5d46a27508b7b9539bf8740109296Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometryPacifici, Roberta; Marchei, Emilia; Salvatore, Francesco; Guandalini, Luca; Busardo, Francesco Paolo; Pichini, SimonaClinical Chemistry and Laboratory Medicine (2017), 55 (10), 1555-1563CODEN: CCLMFW; ISSN:1434-6621. (Walter de Gruyter GmbH)Background: : Cannabis has been used since ancient times to relieve neuropathic pain, to lower intraocular pressure, to increase appetite and finally to decrease nausea and vomiting. The combination of the psychoactive cannabis alkaloid Δ9-tetrahydrocannabinol (THC) with the non-psychotropic alkaloids cannabidiol (CBD) and cannabinol (CBN) demonstrated a higher activity than THC alone. The Italian National Institute of Health sought to establish conditions and indications on how to correctly use nationally produced cannabis to guarantee therapeutic continuity in individuals treated with medical cannabis. Methods: : The evaluation of cannabinoids concn. and stability in standardized prepns. of cannabis tea and cannabis oil was conducted using an easy and fast ultra-high performance liq. chromatog. tandem mass spectrometry (UHPLC-MS/MS) assay. Results: : Extn. efficiency of oil was significantly higher than that of water with respect to the different cannabinoids. This was esp. obsd. in the case of the pharmacol. active THC, CBD and their acidic precursors. Fifteen minutes boiling was sufficient to achieve the highest concns. of cannabinoids in the cannabis tea solns. At ambient temp., a significant THC and CBD decrease to 50% or less of the initial concn. was obsd. over 3 and 7 days, resp. When refrigerated at 4 °C, similar decreasing profiles were obsd. for the two compds. The cannabinoids profile in cannabis oil obtained after pre-heating the flowering tops at 145 °C for 30 min in a static oven resulted in a complete decarboxylation of cannabinoid acids CBDA and THCA-A. Nevertheless, it was apparent that heat not only decarboxylated acidic compds., but also significantly increased the final concns. of cannabinoids in oil. The stability of cannabinoids in oil samples was higher than that in tea samples since the max. decrease (72% of initial concn.) was obsd. in THC coming from unheated flowering tops at ambient temp. In the case of the other cannabinoids, at ambient and refrigerated temps., 80%-85% of the initial concns. were measured up to 14 days after oil prepn. Conclusions: : As the first and most important aim of the different cannabis prepns. is to guarantee therapeutic continuity in treated individuals, a strictly standardized prepn. protocol is necessary to assure the availability of a homogeneous product of defined stability.
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47Watanabe, K.; Usami, N.; Yamamoto, I.; Yoshimura, H. Inhibitory Effect of Cannabidiol Hydroxy-Quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice. J. Pharmacobio-Dyn. 1991, 14, 421– 427, DOI: 10.1248/bpb1978.14.421Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmsVOru7w%253D&md5=552b340763e94c5aa31539d328dbbcc3Inhibitory effect of cannabidiol hydroxyquinone, an oxidative product of cannabidiol, on the hepatic microsomal drug-metabolizing enzymes of miceWatanabe, Kazuhito; Usami, Noriyuki; Yamamoto, Ikuo; Yoshimura, HidetoshiJournal of Pharmacobio-Dynamics (1991), 14 (7), 421-7CODEN: JOPHDQ; ISSN:0386-846X.Cannabidiol hydroxyquinone (I) was identified as an air oxidn. product of cannabidiol (CBD). The in vitro incubation of mouse hepatic microsomes with I resulted in a decrease of cytochrome P 450 content. I inhibited the hepatic microsomal drug-metabolizing enzymes of mice. This inhibitory effect was stronger than that of CBD. I (150 μM) inhibited aniline hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase in the microsomes by 70, 52 and 77%, resp., whereas the same concn. of CBD caused the inhibition by 39, 30 and 26%, resp. I (91.5 μM) decreased total heme content by 21% and free SH groups by 11% in the microsomes. The results indicate that I which is an oxidn. product of CBD, inhibits the hepatic microsomal drug-metabolizing enzymes through the decrease of cytochrome P 450 content.
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48Webster, G. R. B.; Sarna, L. P.; Mechoulam, R. Conversion of CBD to Delta8-THC and Delta9-THC. United States Patent 2004/0143126 A1, 2004.Google ScholarThere is no corresponding record for this reference.
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49Merrick, J.; Lane, B.; Sebree, T.; Yaksh, T.; O’Neill, C.; Banks, S. L. Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. Cannabis Cannabinoid Res. 2016, 1, 102– 112, DOI: 10.1089/can.2015.0004Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsrc%253D&md5=70ba0946c6b284e95185364f3ed72bd5Identification of psychoactive degradants of cannabidiol in simulated gastric and physiological fluidMerrick, John; Lane, Brian; Sebree, Terri; Yaksh, Tony; O'Neill, Carol; Banks, Stan L.Cannabis and Cannabinoid Research (2016), 1 (1), 102-112CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quant. exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concn. range used in this study. CBD was spiked into media contg. 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatog. with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degrdn. followed first-order kinetics at a rate const. of -0.031 min-1 (R2 = 0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiol. buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral anal., mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic ref. stds. Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics obsd. in this study allowed estd. levels to be calcd. and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiol. response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.
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50Nahler, G.; Grotenhermen, F.; Zuardi, A. W.; Crippa, J. A. S. A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Cannabis Cannabinoid Res. 2017, 2, 81– 86, DOI: 10.1089/can.2017.0009Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGltrw%253D&md5=1f0013e56bc11e05534521ca0f30d691A conversion of oral cannabidiol to delta9-tetrahydrocannabinol seems not to occur in humansNahler, Gerhard; Grotenhermen, Franjo; Zuardi, Antonio Waldo; Crippa, Jose A. S.Cannabis and Cannabinoid Research (2017), 2 (1), 81-86CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9-tetrahydrocannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the exptl. conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiol. conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions. Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been obsd. to occur in vivo, even after high doses of oral CBD. In addn., the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concn. difficulties, nausea, tachycardia) has not been obsd. after treatment with CBD in double-blind, randomized, controlled clin. trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact.
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51Watanabe, K.; Itokawa, Y.; Yamaori, S.; Funahashi, T.; Kimura, T.; Kaji, T.; Usami, N.; Yamamoto, I. Conversion of Cannabidiol to Δ9-Tetrahydrocannabinol and Related Cannabinoids in Artificial Gastric Juice, and Their Pharmacological Effects in Mice. Forensic Toxicol. 2007, 25, 16– 21, DOI: 10.1007/s11419-007-0021-yGoogle Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotleksLo%253D&md5=84e82b6d8735058caaf1781dfe96dfbfConversion of cannabidiol to Δ9-tetrahydrocannabinol and related cannabinoids in artificial gastric juice, and their pharmacological effects in miceWatanabe, Kazuhito; Itokawa, Yuka; Yamaori, Satoshi; Funahashi, Tatsuya; Kimura, Toshiyuki; Kaji, Toshiyuki; Usami, Noriyuki; Yamamoto, IkuoForensic Toxicology (2007), 25 (1), 16-21CODEN: FTOOAU ISSN:. (Springer Tokyo)Cannabidiol (CBD), a nonpsychoactive cannabinoid, was found to be converted to 9α-hydroxy-hexahydrocannabinol (9α-OH-HHC) and 8-hydroxy-iso-hexahydrocannabinol (8-OH-iso-HHC) together with Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive cannabinoid, and cannabinol in artificial gastric juice. These cannabinoids were identified by gas chromatog.-mass spectrometry (GC-MS) by comparison with the spectral data of the authentic compds. Pharmacol. effects of 9α-OH-HHC and 8-OH-iso-HHC in mice were examd. using catalepsy, hypothermia, pentobarbital-induced sleep prolongation, and antinociception against acetic acid-induced writhing as indexes. The ED50 values (ED producing a 50% redn. of control; mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the cataleptogenic effect were 8.0 and 30.4, resp. 8-OH-iso-HHC (10mg/kg, i.v.) produced a significant hypothermia from 15 to 90min after administration, although 9α-OH-HHC failed to induce such an effect at the same dose. However, both HHCs (10mg/kg, i.v.) significantly prolonged pentobarbital-induced sleeping time by 1.8 to 8.0 times as compared with the control soln. with 1% Tween 80-saline. The ED50 values (mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the antinociceptive effect were 14.1 and 39.4, resp. The present study demonstrated that CBD can be converted to Δ9-THC and its related cannabinoids, 9α-OH-HHC and 8-OH-iso-HHC, in artificial gastric juice, and that these HHCs show Δ9-THC-like effects in mice, although their pharmacol. effects were less potent than those of Δ9-THC.
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52Grotenhermen, F.; Russo, E.; Zuardi, A. W. Even High Doses of Oral Cannabidiol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016; 1(1): 102–112; DOI: 10.1089/can.2015.0004. Cannabis Cannabinoid Res. 2017, 2, 1– 4, DOI: 10.1089/can.2016.0036Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsbo%253D&md5=94db2af2e70d52b34dda35a823f88783Even high doses of oral cannabidiol do not cause THC-like effects in humans: comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102-112; DOI: 10.1089/can.2015.0004Grotenhermen, Franjo; Russo, Ethan; Zuardi, Antonio WaldoCannabis and Cannabinoid Research (2017), 2 (1), 1-4CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)This short communication examines the question whether the exptl. data presented in a study by Merrick et al. are of clin. relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that "the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a pos. physiol. response. They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clin. data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychol., psychomotor, cognitive, or phys. effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clin. studies. In addn., administration of CBD did not result in detectable THC blood concns. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.
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53Lachenmeier, D. W.; Habel, S.; Fischer, B.; Herbi, F.; Zerbe, Y.; Bock, V.; Rajcic de Rezende, T.; Walch, S. G.; Sproll, C. Are Side Effects of Cannabidiol (CBD) Products Caused by Tetrahydrocannabinol (THC) Contamination?. F1000Research 2019, 8, 1394, DOI: 10.12688/f1000research.19931.3Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387otVarsw%253D%253D&md5=20573609b25bc14518c1653d202a71adAre side effects of cannabidiol (CBD) products caused by tetrahydrocannabinol (THC) contamination?Lachenmeier Dirk W; Habel Stephanie; Fischer Berit; Herbi Frauke; Zerbe Yvonne; Bock Verena; Rajcic de Rezende Tabata; Walch Stephan G; Sproll ConstanzeF1000Research (2019), 8 (), 1394 ISSN:.Cannabidiol (CBD)-containing products are widely marketed as over the counter products, mostly as food supplements, to avoid the strict rules of medicinal products. Side-effects reported in anecdotal consumer reports or during clinical studies were first assumed to be due to hydrolytic conversion of CBD to psychotropic Δ (9)-tetrahydrocannabinol (Δ (9)-THC) in the stomach after oral consumption. However, research of pure CBD solutions stored in simulated gastric juice or subjected to various storage conditions such as heat and light with specific liquid chromatographic/tandem mass spectrometric (LC/MS/MS) and ultra-high pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UPLC-QTOF) analyses was unable to confirm THC formation. Another hypothesis for the side-effects of CBD products may be residual Δ (9)-THC concentrations in the products as contamination, because most of them are based on crude hemp extracts containing the full spectrum of cannabinoids besides CBD. Analyses of 67 food products of the German market (mostly CBD oils) confirmed this hypothesis: 17 products (25%) contained Δ (9)-THC above the lowest observed adverse effects level (2.5 mg/day). Inversely, CBD was present in the products below the no observed adverse effect level. Hence, it may be assumed that the adverse effects of some commercial CBD products are based on a low-dose effect of Δ (9)-THC and not due to effects of CBD itself. The safety, efficacy and purity of commercial CBD products is highly questionable, and all of the products in our sample collection showed various non-conformities to European food law such as unsafe Δ (9)-THC levels, full-spectrum hemp extracts as non-approved novel food ingredients, non-approved health claims, and deficits in mandatory food labelling requirements. In view of the growing market for such lifestyle products, the effectiveness of the instrument of food business operators' own responsibility for product safety must obviously be challenged.
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54Mascal, M.; Hafezi, N.; Wang, D.; Hu, Y.; Serra, G.; Dallas, M. L.; Spencer, J. P. E. Synthetic, Non-Intoxicating 8,9-Dihydrocannabidiol for the Mitigation of Seizures. Sci. Rep. 2019, 9, 7778, DOI: 10.1038/s41598-019-44056-yGoogle Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7pt1Sgsw%253D%253D&md5=607e1c75768f18a1587a78b7af89fb6aSynthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizuresMascal Mark; Hafezi Nema; Wang Deping; Hu Yuhan; Serra Gessica; Dallas Mark L; Spencer Jeremy P EScientific reports (2019), 9 (1), 7778 ISSN:.There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of Δ(9)-tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation.
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55Ben-Shabat, S.; Hanus, L. O.; Katzavian, G.; Gallily, R. New Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory Activity. J. Med. Chem. 2006, 49, 1113– 1117, DOI: 10.1021/jm050709mGoogle Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitV2jsQ%253D%253D&md5=5a10e739ac11ac63db66c0eed3dcb6cdNew Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory ActivityBen-Shabat, Shimon; Hanus, Lumir O.; Katzavian, Galia; Gallily, RuthJournal of Medicinal Chemistry (2006), 49 (3), 1113-1117CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cannabidiol (CBD) and cannabidiol dimethylheptyl (CBD-DMH) were hydrogenated to give four different epimers. The new derivs. were evaluated for their ability to modulate the prodn. of reactive oxygen intermediates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-α) by murine macrophages, and for their binding to the cannabinoid receptor (CB1). Surprisingly, we found that these derivs. exhibit good binding to CB1. In addn. hydrogenated CBD and CBD-DMH demonstrate bioactivities different from their original compds.
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56Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D. E.; Brandi, I.; Moriello, A. S.; Davis, J. B.; Mechoulam, R.; Di Marzo, V. Molecular Targets for Cannabidiol and Its Synthetic Analogues: Effect on Vanilloid VR1 Receptors and on the Cellular Uptake and Enzymatic Hydrolysis of Anandamide. Br. J. Pharmacol. 2001, 134, 845– 852, DOI: 10.1038/sj.bjp.0704327Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlChsbk%253D&md5=f79cc419ce01e535d1ed5346edb4e775Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamideBisogno, Tiziana; Hanus, Lumir; De Petrocellis, Luciano; Tchilibon, Susanna; Ponde, Datta E.; Brandi, Ines; Moriello, Aniello Schiano; Davis, John B.; Mechoulam, Raphael; Di Marzo, VincenzoBritish Journal of Pharmacology (2001), 134 (4), 845-852CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)(-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible mol. targets of this compd. We investigated whether CBD and some of its derivs. interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogs, obtained by exchanging the C-7 Me group of CBD with a hydroxy-Me or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concns. in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalyzed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogs, stimulated VR1 with EC50=3.2-3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67-70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compds. were not additive. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (-)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (-)-7-hydroxy-CBD (IC50=34 μM), but not the other analogs (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacol. effects of CBD and its analogs. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
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57Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam, R. Enantiomeric Cannabidiol Derivatives: Synthesis and Binding to Cannabinoid Receptors. Org. Biomol. Chem. 2005, 3 (6), 1116– 1123, DOI: 10.1039/b416943cGoogle Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvF2jsr0%253D&md5=47dfb860e82ef35d36a9504306b08d1fEnantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptorsHanus, Lumir O.; Tchilibon, Susanna; Ponde, Datta E.; Breuer, Aviva; Fride, Ester; Mechoulam, RaphaelOrganic & Biomolecular Chemistry (2005), 3 (6), 1116-1123CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiol. effects of therapeutic importance. We have reported that CBD derivs. in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compds. in the enantiomeric (+)-CBD series. The starting materials were the resp. CBD enantiomers and their DMH homologs. The binding of these compds. to the CB1 and CB2 cannabinoid receptors are compared. Surprisingly, contrary to the compds. in the (-) series, which do not bind to the receptors, most of the derivs. in the (+) series bind to the CB1 receptor in the low nanomole range. Some of these compds. also bind weakly to the CB2 receptor.
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58Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin, L. S.; Martin, B. R. Pharmacology and Stereoselectivity of Structurally Novel Cannabinoids in Mice. J. Pharmacol. Exp. Ther. 1988, 247, 1046– 1051Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXovVSisg%253D%253D&md5=32c7696e1333349d245d52bb07f18426Pharmacology and stereoselectivity of structurally novel cannabinoids in miceLittle, Patrick J.; Compton, David R.; Johnson, M. Ross; Melvin, Lawrence S.; Martin, Billy R.Journal of Pharmacology and Experimental Therapeutics (1988), 247 (3), 1046-51CODEN: JPETAB; ISSN:0022-3565.The pharmacol. effects of 3 stereoisomeric pairs of structurally novel cannabinoids were tested after i.v. administration in mice for depression of spontaneous activity and the prodn. of hypothermia, antinociception, and catalepsy. The (-)-enantiomers were as much as 770 times more potent than Δ9-6a,10a-trans-tetrahydrocannabinol and were 7-2000 times more potent than their resp. (+)-enantiomers. The order of potency for cannabinoid-induced effects was spontaneous activity > antinociception > hypothermia ≥ catalepsy. Levonantradol was active between 0.123-1.5 mg/kg, whereas dextronantradol, its (+)-enantiomer, was inactive. (-)-CP 55,244 and (-)-CP 55,940, analogs which lack the dihydropyran ring, were 5-775 times more potent than Δ9-6a,10a-trans-tetrahydrocannabinol and 30-2000 times more potent than their resp. (+)-enantiomers. Some sepn. of effects was demonstrated with (+)-CP 55,243 and (+)-CP 56,667, which were inactive in producing hypothermia and catalepsy but were active in the spontaneous activity and tail-flick procedures. The high degree of enantioselectivity and potency of these nonclassical cannabinoids are indicative of a highly specific mechanism of action such as a receptor.
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59Kinney, W. A.; McDonnell, M. E.; Zhong, H. M.; Liu, C.; Yang, L.; Ling, W.; Qian, T.; Chen, Y.; Cai, Z.; Petkanas, D.; Brenneman, D. E. Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS Med. Chem. Lett. 2016, 7, 424– 428, DOI: 10.1021/acsmedchemlett.6b00009Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVWmt7Y%253D&md5=32249f294f3baf8d6ffa0ffd743ab0c8Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and PermeabilityKinney, William A.; McDonnell, Mark E.; Zhong, Hua Marlon; Liu, Chaomin; Yang, Lanyi; Ling, Wei; Qian, Tao; Chen, Yu; Cai, Zhijie; Petkanas, Dean; Brenneman, Douglas E.ACS Medicinal Chemistry Letters (2016), 7 (4), 424-428CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurol. disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clin. relevant concns. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.
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60BioSpace. Kannalife, Inc. Further Elucidates Mechanism of Action Behind KLS-13019, the Company’s Leading Drug Candidate for the Potential Treatment of Neuropathic Pain. BioSpace. https://www.biospace.com/article/kannalife-inc-further-elucidates-mechanism-of-action-behind-kls-13019-the-company-s-leading-drug-candidate-for-the-potential-treatment-of-neuropathic-pain/ (accessed Apr 27, 2020).Google ScholarThere is no corresponding record for this reference.
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61Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T.-L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A. The Novel Endocannabinoid Receptor GPR55 Is Activated by Atypical Cannabinoids but Does Not Mediate Their Vasodilator Effects. Br. J. Pharmacol. 2007, 152, 825– 831, DOI: 10.1038/sj.bjp.0707419Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ejt7vE&md5=9e389e9b687d2ce27817ff44b5a6e513The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effectsJohns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T-L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A.British Journal of Pharmacology (2007), 152 (5), 825-831CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified 'CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator 'CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents. Human recombinant GPR55 was expressed in HEK293T cells and specific GTPγS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myog. were used to det. GPR55 dependence of atypical cannabinoid-induced hemodynamic and vasodilator responses. Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPγS activity (EC50 approx. 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20±2%, KO 26±5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approx. 3 μM for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains. These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents.
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62Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P. J. The Orphan Receptor GPR55 Is a Novel Cannabinoid Receptor. Br. J. Pharmacol. 2007, 152, 1092– 1101, DOI: 10.1038/sj.bjp.0707460Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlCrsbnI&md5=de00567034c31dd815548fdef069f5daThe orphan receptor GPR55 is a novel cannabinoid receptorRyberg, E.; Larsson, N.; Sjoegren, S.; Hjorth, S.; Hermansson, N-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P. J.British Journal of Pharmacology (2007), 152 (7), 1092-1101CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Background: The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a no. of groups in recent years has provided evidence that the system is more complicated and addnl. receptor types should exist to explain ligand activity in a no. of physiol. processes. Exptl. approach: Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPγS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was detd. and further demonstrated by measuring activity of downstream signaling pathways. Key results: We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP 55940. In addn. endocannabinoids including anandamide and virodhamine activate GTPγS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Gα13 and can mediate activation of rhoA, cdc42 and rac1. Conclusions: These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiol. function(s).
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63Romero-Zerbo, S. Y.; Rafacho, A.; Díaz-Arteaga, A.; Suárez, J.; Quesada, I.; Imbernon, M.; Ross, R. A.; Dieguez, C.; Rodríguez de Fonseca, F.; Nogueiras, R.; Nadal, A.; Bermúdez-Silva, F. J. A Role for the Putative Cannabinoid Receptor GPR55 in the Islets of Langerhans. J. Endocrinol. 2011, 211, 177– 185, DOI: 10.1530/JOE-11-0166Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqtLrO&md5=5c5988f648273fd5b0c9c928fdf50554A role for the putative cannabinoid receptor GPR55 in the islets of LangerhansRomero-Zerbo, Silvana Y.; Rafacho, Alex; Diaz-Arteaga, Adenis; Suarez, Juan; Quesada, Ivan; Imbernon, Monica; Ross, Ruth A.; Dieguez, Carlos; Rodriguez de Fonseca, Fernando; Nogueiras, Ruben; Nadal, Angel; Bermudez-Silva, Francisco J.Journal of Endocrinology (2011), 211 (2), 177-185CODEN: JOENAK; ISSN:0022-0795. (BioScientifica Ltd.)The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clin. practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacol. is still enigmatic and its physiol. role is largely unexplored, with no reports investigating its putative role in metab. Thus, we aim to investigate in rats the presence, distribution and putative physiol. role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting β-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients and insulin secretion stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo expts. showed that GPR55 activation increases glucose tolerance and plasma insulin levels, suggesting an in vivo physiol. relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.
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64Console-Bram, L.; Brailoiu, E.; Brailoiu, G. C.; Sharir, H.; Abood, M. E. Activation of GPR18 by Cannabinoid Compounds: A Tale of Biased Agonism. Br. J. Pharmacol. 2014, 171, 3908– 3917, DOI: 10.1111/bph.12746Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WmsrjN&md5=4685930ff193dd4c44fea180be190dcbActivation of GPR18 by cannabinoid compounds: a tale of biased agonismConsole-Bram, Linda; Brailoiu, Eugen; Brailoiu, Gabriela Cristina; Sharir, Haleli; Abood, Mary E.British Journal of Pharmacology (2014), 171 (16), 3908-3917CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : GPR18 is a candidate cannabinoid receptor, but its classification as such is controversial. The rationale of the study presented herein was to consider the effects of N-arachidonoyl glycine (NAGly) and cannabinoids via differential G-protein coupled pathways, in addn. to β-arrestin signalling. Cellular localization of GPR18 receptors was also examd. Exptl. Approach : Calcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addn., using the DiscoveRx PathHunter CHO-K1 GPR18 β-arrestin cell line, recruitment of β-arrestin was quantified. Key Results : Concn.-dependent increases in intracellular calcium and ERK1/2 phosphorylation were obsd. in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and Δ9-tetrahydrocannabinol (Δ9-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either Gαq or Gαi/o inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of β-arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only Δ9-THC produced a concn.-dependent response. The localization of GPR18 receptors within the HEK293/GPR18 cells is both intracellular, and on the plasma membrane. Conclusions and Implications : These findings suggest that GPR18 activation involves several signal transduction pathways indicative of biased agonism, thereby providing a plausible explanation for the apparent discrepancies in GPR18 activation found in the literature. Addnl., the results presented herein provide further evidence for GPR18 as a candidate cannabinoid receptor.
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65Morales, P.; Reggio, P. H. CBD: A New Hope?. ACS Med. Chem. Lett. 2019, 10, 694– 695, DOI: 10.1021/acsmedchemlett.9b00127Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXotlSjsL0%253D&md5=781d92a79b5d878220c0caea1f129600CBD: A New Hope?Morales, Paula; Reggio, Patricia H.ACS Medicinal Chemistry Letters (2019), 10 (5), 694-695CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. The nonpsychoactive phytocannabinoid, CBD, was recently approved by the Food and Drug Administration for the treatment of children with drug-resistant epilepsy. This milestone opens new avenues for cannabinoid research. In this Viewpoint, we provide an overview of recent progress in the field highlighting mol. insights into CBD's mechanism of action, as well as its therapeutic potential.
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66Pertwee, R. G. Pharmacological and Therapeutic Targets for Δ9 Tetrahydrocannabinol and Cannabidiol. Euphytica 2004, 140, 73– 82, DOI: 10.1007/s10681-004-4756-9Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitFertrs%253D&md5=a8126492162a6539259e301fb3c296c8Pharmacological and therapeutic targets for Δ9 tetrahydrocannabinol and cannabidiolPertwee, Roger G.Euphytica (2004), 140 (1-2), 73-82CODEN: EUPHAA; ISSN:0014-2336. (Kluwer Academic Publishers)A review. Cannabis is the unique source of a set of at least 66 compds. known collectively as cannabinoids. Of these, most is known about the pharmacol. of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, and about cannabidiol (CBD), which lacks psychoactivity. Accordingly, this paper focuses on the pharmacol. and therapeutic targets of these two cannabinoids. Many of the effects of Δ9-THC are mediated by cannabinoid receptors of which at least two types, CB1 and CB2, are present in mammalian tissues. Endogenous agonists for cannabinoid receptors have also been discovered. CB1 receptors are present at the terminals of central and peripheral neurons, where they modulate transmitter release. They also exist in some non-neuronal cells. CB2 receptors are expressed mainly by immune cells, one of their roles being to alter cytokine release. Δ9-THC also appears to have non-CB1, non-CB2 pharmacol. targets. It is already licensed for clin. use in the U.S.A. as an anti-emetic and appetite stimulant and both Δ9-THC and Δ9-THC-rich cannabis exts. show therapeutic potential as neuroprotective and anticancer agents and for the management of glaucoma, pain and various kinds of motor dysfunction assocd., for example, with multiple sclerosis and spinal cord injury. CBD has much less affinity for CB1 and CB2 receptors than Δ9-THC and its pharmacol. actions have been less well characterized. Potential clin. applications of CBD and CBD-rich cannabis exts. include the prodn. of anti-inflammatory and neuroprotective effects, the management of epilepsy, anxiety disorders, glaucoma and nausea, and the modulation of some effects of Δ9-THC.
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67Morales, P.; Hurst, D. P.; Reggio, P. H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017, 103, 103– 131, DOI: 10.1007/978-3-319-45541-9_4Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFWntbzL&md5=d5d97efcecf866c4f2f5c31b56ef502cMolecular targets of the phytocannabinoids: a complex pictureMorales, Paula; Hurst, Dow P.; Reggio, Patricia H.Progress in the Chemistry of Organic Natural Products (2017), 103 (Phytocannabinoids), 103-131CODEN: POPRDK; ISSN:2192-4309. (Springer International Publishing AG)A review. This article discusses about mol. pharmacol. of phytocannabinoids, including (-)-trans-Δ9-tetrahydrocannabinol and cannabidiol from perspective of targets at which these important compds. act.
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68Brzozowska, N.; Li, K. M.; Wang, X. S.; Booth, J.; Stuart, J.; McGregor, I. S.; Arnold, J. C. ABC Transporters P-Gp and Bcrp Do Not Limit the Brain Uptake of the Novel Antipsychotic and Anticonvulsant Drug Cannabidiol in Mice. PeerJ 2016, 4, e2081 DOI: 10.7717/peerj.2081Google ScholarThere is no corresponding record for this reference.
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69Kathmann, M.; Flau, K.; Redmer, A.; Tränkle, C.; Schlicker, E. Cannabidiol Is an Allosteric Modulator at Mu- and Delta-Opioid Receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 2006, 372, 354– 361, DOI: 10.1007/s00210-006-0033-xGoogle Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhslOkurg%253D&md5=4fc34432ddf9968bcf4c761e4438597fCannabidiol is an allosteric modulator at mu- and delta-opioid receptorsKathmann, Markus; Flau, Karsten; Redmer, Agnes; Traenkle, Christian; Schlicker, EberhardNaunyn-Schmiedeberg's Archives of Pharmacology (2006), 372 (5), 354-361CODEN: NSAPCC; ISSN:0028-1298. (Springer)The mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of satn. binding expts. The aim of the present study was to examine whether cannabidiol is an allosteric modulator at this receptor, using kinetic binding studies, which are particularly sensitive for the measurement of allosteric interactions at G protein-coupled receptors. In addn., we studied whether such a mechanism also extends to the delta opioid receptor. For comparison, (-)-Δ9-tetrahydrocannabinol (THC; another major constituent of cannabis) and rimonabant (a cannabinoid CB1 receptor antagonist) were studied. In mu opioid receptor binding studies on rat cerebral cortex membrane homogenates, the agonist 3H-DAMGO bound to a homogeneous class of binding sites with a KD of 0.68±0.02 nM and a Bmax of 203±7 fmol/mg protein. The dissocn. of 3H-DAMGO induced by naloxone 10 μM (half life time of 7±1 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 12 and 2, resp. The resp. pEC50 values for a half-max. elevation of the dissocn. rate const. koff were 4.38 and 4.67; 3H-DAMGO dissocn. was not affected by rimonabant 10 μM. In delta opioid receptor binding studies on rat cerebral cortex membrane homogenates, the antagonist 3H-naltrindole bound to a homogeneous class of binding sites with a KD of 0.24±0.02 nM and a Bmax of 352±22 fmol/mg protein. The dissocn. of 3H-naltrindole induced by naltrindole 10 μM (half life time of 119±3 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 2, each. The resp. pEC50 values were 4.10 and 5.00; 3H-naltrindole dissocn. was not affected by rimonabant 10 μM. The present study shows that cannabidiol is an allosteric modulator at mu and delta opioid receptors. This property is shared by THC but not by rimonabant.
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70Russo, E. B.; Burnett, A.; Hall, B.; Parker, K. K. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem. Res. 2005, 30, 1037– 1043, DOI: 10.1007/s11064-005-6978-1Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKmsbrE&md5=af83825950fd487bf72f78ac6d003656Agonistic Properties of Cannabidiol at 5-HT1a ReceptorsRusso, Ethan B.; Burnett, Andrea; Hall, Brian; Parker, Keith K.Neurochemical Research (2005), 30 (8), 1037-1043CODEN: NEREDZ; ISSN:0364-3190. (Springer)Cannabidiol (CBD) is a major, biol. active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concn.-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concn. range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPγS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is neg. coupled to cAMP prodn., both CBD and 5-HT decrease cAMP concn. at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Addnl. work is required to compare CBD's potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.
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71Chen, G.; Chen, Y.; Yang, N.; Zhu, X.; Sun, L.; Li, G. Interaction between Curcumin and Mimetic Biomembrane. Sci. China: Life Sci. 2012, 55, 527– 532, DOI: 10.1007/s11427-012-4317-8Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVeisb8%253D&md5=64c80bb2adc6375b2b1ee2735969ec2eInteraction between curcumin and mimetic biomembraneChen, Gui Fang; Chen, Yang Yang; Yang, Na Na; Zhu, Xue Jun; Sun, Li Zhou; Li, Gen XiScience China: Life Sciences (2012), 55 (6), 527-532CODEN: SCLSCJ; ISSN:1674-7305. (Science China Press)Curcumin, a major bioactive compd. in turmeric, has a broad spectrum of antioxidant, anticarcinogenic, antimutagenic and anti-inflammatory properties. At the mol. level, curcumin modulates many structurally unrelated membrane proteins through several signaling pathways. Curcumin has been suggested to change the properties of cell membranes and affect the membrane-bound proteins indirectly; however, the detailed mechanism has yet to be investigated. In this paper, self-assembled bilayer lipid membranes are artificially constructed on the surface of a gold electrode to mimic biomembranes, and interaction between the supported membranes and curcumin is studied electrochem. Results show that curcumin interacts with the membranes strongly, in a concn.-dependent manner. At low concns., curcumin tends to insert into the outer monolayer only, while at high concns., it may also begin to penetrate the inner monolayer. The results obtained in this work may enhance our understanding of the effect of curcumin, and possibly flavonoids, on cell membranes and membrane proteins.
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72Ingólfsson, H. I.; Thakur, P.; Herold, K. F.; Hobart, E. A.; Ramsey, N. B.; Periole, X.; de Jong, D. H.; Zwama, M.; Yilmaz, D.; Hall, K.; Maretzky, T.; Hemmings, H. C., Jr.; Blobel, C.; Marrink, S. J.; Koçer, A.; Sack, J. T.; Andersen, O. S. Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function. ACS Chem. Biol. 2014, 9, 1788– 1798, DOI: 10.1021/cb500086eGoogle Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlyqt7s%253D&md5=b61876239e926b652adea2e130627bc3Phytochemicals Perturb Membranes and Promiscuously Alter Protein FunctionIngolfsson, Helgi I.; Thakur, Pratima; Herold, Karl F.; Hobart, E. Ashley; Ramsey, Nicole B.; Periole, Xavier; de Jong, Djurre H.; Zwama, Martijn; Yilmaz, Duygu; Hall, Katherine; Maretzky, Thorsten; Hemmings, Hugh C.; Blobel, Carl; Marrink, Siewert J.; Kocer, Armagan; Sack, Jon T.; Andersen, Olaf S.ACS Chemical Biology (2014), 9 (8), 1788-1798CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A wide variety of phytochems. are consumed for their perceived health benefits. Many of these phytochems. have been found to alter numerous cell functions, but the mechanisms underlying their biol. activity tend to be poorly understood. Phenolic phytochems. are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examd. five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochems. alters lipid bilayer properties and the function of diverse membrane proteins. Mol. dynamics simulations show that these phytochems. modify bilayer properties by localizing to the bilayer/soln. interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochems., consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochems. are due to cell membrane perturbations, rather than specific protein binding.
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73Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E. Evaluation of Binding in a Transfected Cell Line Expressing a Peripheral Cannabinoid Receptor (CB2): Identification of Cannabinoid Receptor Subtype Selective Ligands. J. Pharmacol. Exp. Ther. 1996, 278, 989– 999Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtVSjs74%253D&md5=d765777f3b8763afa042ea068ffd7a28Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligandsShowalter, Vincent M.; Compton, David R.; Martin, Billy R.; Abood, Mary E.Journal of Pharmacology and Experimental Therapeutics (1996), 278 (3), 989-999CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compds. displaying distinct affinities for either cannabinoid receptor. The binding affinities for either cannabinoids tested previously at the CB1 receptor were detd. at cloned human CB1 and CB2 receptors using a filtration assay. In addn., possible allosteric regulation of the CB2 receptor was examd. Sodium and a GTP analog elicited a concn.-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3±14 nM) was confirmed to be in approx. the same range as that of Δ9-THC (Ki = 36.4±10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities detd. in the brain. Although most of the chosen compds. did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride}. In addn., WIN-55,212-2 {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone} and a closely related Pr indole analog were shown to be 6.75- and 27.5-fold selective, resp., for the CB2 receptor. These ligands can now serve as a basis for the design of compds. with even greater selectivity.
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74Watkinson, A.; Chapman, S. C. E.; Horne, R. Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo Analgesia. J. Pain 2017, 18 (8), 908– 922, DOI: 10.1016/j.jpain.2017.02.435Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czkvVaguw%253D%253D&md5=f9ec1259bbf93f3cbaad033a005d02b4Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo AnalgesiaWatkinson Andrew; Chapman Sarah C E; Horne RobThe journal of pain : official journal of the American Pain Society (2017), 18 (8), 908-922 ISSN:.This study examined whether placebo responses were predicted by a theoretical model of specific and general treatment beliefs. Using a randomized crossover, experimental design (168 healthy individuals) we assessed whether responses to a cold pressor task were influenced by 2 placebo creams described as pharmaceutical versus natural. We assessed whether placebo responses were predicted by pretreatment beliefs about the treatments (placebo) and by beliefs about the pain. The efficacy of pharmaceutical as well as natural placebos in reducing pain intensity was predicted by aspects of pain catastrophizing including feelings of helplessness (pharmaceutical: B = .03, P < .01, natural: B = .02, P < .05) and magnification of pain (pharmaceutical: B = .04, P < .05, natural: B = .05, P < .05) but also by pretreatment necessity beliefs (pharmaceutical: B = .21, P < .01, natural: B = .16, P < .05) and, for the pharmaceutical condition, by more general beliefs about personal sensitivity to pharmaceuticals (B = .14, P < .05). Treatment necessity beliefs also partially mediated the effects of helplessness on placebo responses. Treatment necessity beliefs for the pharmaceutical placebo were influenced by general pharmaceutical beliefs whereas necessity beliefs for the natural placebo were informed by general background beliefs about holistic treatments. Our findings show that treatment beliefs influence the placebo effect suggesting that they may offer an additional approach for understanding the placebo effect. PERSPECTIVE: Placebo effects contribute to responses to active analgesics. Understanding how beliefs about different types of treatment influence placebo analgesia may be useful in understanding variations in treatment response. Using the cold pressor paradigm we found that placebo analgesia was influenced by beliefs about natural remedies, pharmaceutical medicines, and about pain.
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75Trainor, G. L. Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications. In Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.; Academic Press: San Diego, CA, 2007; Vol. 42, Chapter 31, pp 489– 502.Google ScholarThere is no corresponding record for this reference.
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76Tayo, B.; Taylor, L.; Sahebkar, F.; Morrison, G. A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment. Clin. Pharmacokinet. 2020, 59, 747– 755, DOI: 10.1007/s40262-019-00841-6Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlyntr7N&md5=eed4a2caf04a836d61680f63c79bd583A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal ImpairmentTayo, Bola; Taylor, Lesley; Sahebkar, Farhad; Morrison, GilmourClinical Pharmacokinetics (2020), 59 (6), 747-755CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Introduction: As patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment. Methods: The pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral soln. (Epidiolex in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment (n = 8/group) relative to matched subjects with normal renal function (n = 8). Blood samples were collected until 48 h post-dose and evaluated by liq. chromatog. with tandem mass spectrometry. Anal. of variance was used to compare primary pharmacokinetic parameters (max. measured plasma concn. [Cmax], oral clearance of drug from plasma [CL/F], renal clearance [CLR], area under the plasma concn.-time curve [AUC] from time zero to last measurable concn. [AUCt], and AUC from time zero to infinity [AUC∞]); descriptive anal. was used for secondary pharmacokinetic parameters (time to Cmax [tmax], terminal [elimination] half-life [t1/2], cumulative amt. excreted from time zero to the last quantifiable sample [Aelast], and fraction of the systemically available drug excreted into the urine [fe]). Results: No statistically significant differences were obsd. in Cmax, AUCt, AUC∞, or tmax values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for Cmax values ranged from 0.68 to 1.35. No differences were obsd. for other secondary parameters (Aelast and fe). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine anal. for CBD recorded no appreciable amt., and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Lab., phys. examn., vital sign, and 12-lead ECG findings were not clin. significant. Conclusion: Renal impairment had no effect on the metab. of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function.
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77Liu, X.; Wright, M.; Hop, C. E. C. A. Rational Use of Plasma Protein and Tissue Binding Data in Drug Design. J. Med. Chem. 2014, 57, 8238– 8248, DOI: 10.1021/jm5007935Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Git77M&md5=53ffbdb88ddf500a90a0eee14b0e641fRational Use of Plasma Protein and Tissue Binding Data in Drug DesignLiu, Xingrong; Wright, Matthew; Hop, Cornelis E. C. A.Journal of Medicinal Chemistry (2014), 57 (20), 8238-8248CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. It is a commonly accepted assumption that only unbound drug mols. are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compd. structure to increase in vivo unbound drug concn. In this review, theor. analyses and exptl. observations are presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concn. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concn. Instead, low intrinsic clearance leads to high in vivo unbound plasma concn., and low efflux transport activity at the blood-brain barrier leads to high unbound brain concn. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design.
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78Wheless, J. W.; Dlugos, D.; Miller, I.; Oh, D. A.; Parikh, N.; Phillips, S.; Renfroe, J. B.; Roberts, C. M.; Saeed, I.; Sparagana, S. P.; Yu, J.; Cilio, M. R. INS011-14-029 Study Investigators. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy. CNS Drugs 2019, 33, 593– 604, DOI: 10.1007/s40263-019-00624-4Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqsbrO&md5=77382c061afe9bed0c1abfd22b76f22aPharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant EpilepsyWheless, James W.; Dlugos, Dennis; Miller, Ian; Oh, D. Alexander; Parikh, Neha; Phillips, Steven; Renfroe, J. Ben; Roberts, Colin M.; Saeed, Isra; Sparagana, Steven P.; Yu, Jin; Cilio, Maria RobertaCNS Drugs (2019), 33 (6), 593-604CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral soln. in pediatric patients with treatment-resistant epilepsy. In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral soln. administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concns. of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral soln. (mean age, 7.6 years). The age compn. was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral soln. dosing, but overall exposure varied. Approx. 2-6 days of twice-daily dosing provided steady-state concns. of cannabidiol. A bidirectional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral soln. resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concns. were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral soln. compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral soln. compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral soln. was obsd. but decreased with multiple doses. Short-term administration was generally safe and well tolerated.
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79Geffrey, A. L.; Pollack, S. F.; Bruno, P. L.; Thiele, E. A. Drug-Drug Interaction between Clobazam and Cannabidiol in Children with Refractory Epilepsy. Epilepsia 2015, 56, 1246– 1251, DOI: 10.1111/epi.13060Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yqsbbN&md5=c171eff89dbe4e84f61281a180562e51Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsyGeffrey, Alexandra L.; Pollack, Sarah F.; Bruno, Patricia L.; Thiele, Elizabeth A.Epilepsia (2015), 56 (8), 1246-1251CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P 450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demog. information was collected for each subject including age, sex, and etiol. of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB,N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. We report elevated CLB and nCLB levels in these subjects. The mean (± std. deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 wk); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 wk). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose redn. Monitoring of CLB and nCLB levels is necessary for clin. care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
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80Bergmann, K. R.; Broekhuizen, K.; Groeneveld, G. J. Clinical Trial Simulations of the Interaction between Cannabidiol and Clobazam and Effect on Drop-Seizure Frequency. Br. J. Clin. Pharmacol. 2020, 86, 380– 385, DOI: 10.1111/bcp.14158Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtVWktbY%253D&md5=3eb64ada7f6d50e1b7fab644f7174b64Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequencyBergmann, Kirsten Riber; Broekhuizen, Karen; Groeneveld, Geert JanBritish Journal of Clinical Pharmacology (2020), 86 (2), 380-385CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clin. trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median redn. in drop-seizure frequency and a variability in the percent redn. similar to the placebo group. The results show that the effect of cannabidiol on the median redn. in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.
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81Huddart, R.; Leeder, J. S.; Altman, R. B.; Klein, T. E. PharmGKB Summary: Clobazam Pathway, Pharmacokinetics. Pharmacogenet. Genomics 2018, 28, 110– 115, DOI: 10.1097/FPC.0000000000000327Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFGgs7c%253D&md5=894998d3164b98a20be437af9d2314d2PharmGKB summary: clobazam pathway, pharmacokineticsHuddart, Rachel; Leeder, J. Steven; Altman, Russ B.; Klein, Teri E.Pharmacogenetics and Genomics (2018), 28 (4), 110-115CODEN: PGHEAI; ISSN:1744-6872. (Lippincott Williams & Wilkins)There is no expanded citation for this reference.
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82Calculation of Molecular Properties and Bioactivity Core. https://www.molinspiration.com/cgi-bin/properties (accessed Jul 4, 2020).Google ScholarThere is no corresponding record for this reference.
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83Thorne, N.; Auld, D. S.; Inglese, J. Apparent Activity in High-Throughput Screening: Origins of Compound-Dependent Assay Interference. Curr. Opin. Chem. Biol. 2010, 14, 315– 324, DOI: 10.1016/j.cbpa.2010.03.020Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvVWqsL8%253D&md5=4d3dd71f66ce937002874106edaff12eApparent activity in high-throughput screening: origins of compound-dependent assay interferenceThorne, Natasha; Auld, Douglas S.; Inglese, JamesCurrent Opinion in Chemical Biology (2010), 14 (3), 315-324CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)A review. Expansive compd. collections made up of structurally heterogeneous chems., the activities of which are largely undefined, present challenging problems for high-throughput screening (HTS). Foremost is differentiating whether the activity for a given compd. in an assay is directed against the targeted biol., or is the result of surreptitious compd. activity involving the assay detection system. Such compd. interference can be esp. difficult to identify if it is reproducible and concn.-dependent - characteristics generally attributed to compds. with genuine activity. While reactive chem. groups on compds. were once thought to be the primary source of compd. interference in assays used in HTS, recent work suggests that other factors, such as compd. aggregation, may play a more significant role in many assay formats. Considerable progress has been made to profile representative compd. libraries in an effort to identify chem. classes susceptible to producing compd. interference, such as compds. commonly found to inhibit the reporter enzyme firefly luciferase. Such work has also led to the development of practices that have the potential to significantly reduce compd. interference, for example, through the addn. of non-ionic detergent to assay buffer to reduce aggregation-based inhibition.
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84Elbaz, M.; Nasser, M. W.; Ravi, J.; Wani, N. A.; Ahirwar, D. K.; Zhao, H.; Oghumu, S.; Satoskar, A. R.; Shilo, K.; Carson, W. E., 3rd; Ganju, R. K. Modulation of the Tumor Microenvironment and Inhibition of EGF/EGFR Pathway: Novel Anti-Tumor Mechanisms of Cannabidiol in Breast Cancer. Mol. Oncol. 2015, 9, 906– 919, DOI: 10.1016/j.molonc.2014.12.010Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVaktbg%253D&md5=20fc63b1ce328066e37db731b7998cbeModulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancerElbaz, Mohamad; Nasser, Mohd W.; Ravi, Janani; Wani, Nissar A.; Ahirwar, Dinesh K.; Zhao, Helong; Oghumu, Steve; Satoskar, Abhay R.; Shilo, Konstantin; Carson, Wiliam E., III; Ganju, Ramesh K.Molecular Oncology (2015), 9 (4), 906-919CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)The anti-tumor role and mechanisms of Cannabidiol (CBD), a non-psychotropic cannabinoid compd., are not well studied esp. in triple-neg. breast cancer (TNBC). In the present study, we analyzed CBD's anti-tumorigenic activity against highly aggressive breast cancer cell lines including TNBC subtype. We show here -for the first time-that CBD significantly inhibits epidermal growth factor (EGF)-induced proliferation and chemotaxis of breast cancer cells. Further studies revealed that CBD inhibits EGF-induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion. In addn., we demonstrated that CBD inhibits tumor growth and metastasis in different mouse model systems. Anal. of mol. mechanisms revealed that CBD significantly inhibits the recruitment of tumor-assocd. macrophages in primary tumor stroma and secondary lung metastases. Similarly, our in vitro studies showed a significant redn. in the no. of migrated RAW 264.7 cells towards the conditioned medium of CBD-treated cancer cells. The conditioned medium of CBD-treated cancer cells also showed lower levels of GM-CSF and CCL3 cytokines which are important for macrophage recruitment and activation. In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment. These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are assocd. with poor prognosis and low survival rates.
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85Solinas, M.; Massi, P.; Cantelmo, A. R.; Cattaneo, M. G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L. M.; Noonan, D. M.; Albini, A.; Parolaro, D. Cannabidiol Inhibits Angiogenesis by Multiple Mechanisms. Br. J. Pharmacol. 2012, 167, 1218– 1231, DOI: 10.1111/j.1476-5381.2012.02050.xGoogle Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKktL7O&md5=892900b2b76a23f2064a76465dacb9ceCannabidiol inhibits angiogenesis by multiple mechanismsSolinas, M.; Massi, P.; Cantelmo, A. R.; Cattaneo, M. G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L. M.; Noonan, D. M.; Albini, A.; Parolaro, D.British Journal of Pharmacology (2012), 167 (6), 1218-1231CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumors, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumors in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favorable pharmacol. and toxicol. profile, here, we evaluated the ability of CBD to modulate tumor angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS anal. - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were assocd. with the down-modulation of several angiogenesis-related mols. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumor and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.
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86Ohlsson, A.; Lindgren, J. E.; Andersson, S.; Agurell, S.; Gillespie, H.; Hollister, L. E. Single-Dose Kinetics of Deuterium-Labelled Cannabidiol in Man after Smoking and Intravenous Administration. Biol. Mass Spectrom. 1986, 13, 77– 83, DOI: 10.1002/bms.1200130206Google ScholarThere is no corresponding record for this reference.
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87Samara, E.; Bialer, M.; Mechoulam, R. Pharmacokinetics of Cannabidiol in Dogs. Drug Metab. Dispos. 1988, 16, 469– 472Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXksVOkurg%253D&md5=943104b7f2f03cd8c6b88313c36d5fb6Pharmacokinetics of cannabidiol in dogsSamara, Emil; Bialer, Meir; Mechoulam, RaphaelDrug Metabolism and Disposition (1988), 16 (3), 469-72CODEN: DMDSAI; ISSN:0090-9556.Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of 2 i.v. doses (45 and 90 mg) and 1 oral dose (180 mg) to dogs. After i.v. administration, CBD was rapidly distributed, followed by a prolonged elimination. It had a terminal half-life of 9 h. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 L/h (after the 45-mg dose) and 16 L/h (after the 90-mg dose). This clearance value, after its normalization to blood clearance using math. equations, approaches the value of the hepatic blood flow; the extn. ratio in the liver was 0.74. CBD had a large vol. of distribution, ∼100 L. In the dose range of 45-90 mg, the increase in the area under the concn.-time curve was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CbD in this dose range was not dose dependent. In 3 of the 6 dogs studied, CBD could not be detected in the plasma after oral administration. In the other 3, the oral bioavailability ranged 13-19%. Thus, CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a 1st-pass effect.
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88Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Single and Multiple Dose Pharmacokinetics of THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 1135– 1147, DOI: 10.1007/s00228-012-1441-0Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVajtL8%253D&md5=7b2eef902736fa6d5b1633dc94524addA phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal sprayStott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W.European Journal of Clinical Pharmacology (2013), 69 (5), 1135-1147CODEN: EJCPAS; ISSN:0031-6970. (Springer)Purpose A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Methods Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a min. of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatog.-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Results Δ9-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concn. (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concn. (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. Conclusions The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.
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89Deiana, S.; Watanabe, A.; Yamasaki, Y.; Amada, N.; Arthur, M.; Fleming, S.; Woodcock, H.; Dorward, P.; Pigliacampo, B.; Close, S.; Platt, B.; Riedel, G. Plasma and Brain Pharmacokinetic Profile of Cannabidiol (CBD), Cannabidivarine (CBDV), Δ9-Tetrahydrocannabivarin (THCV) and Cannabigerol (CBG) in Rats and Mice Following Oral and Intraperitoneal Administration and CBD Action on Obsessive-Compulsive Behaviour. Psychopharmacology 2012, 219, 859– 873, DOI: 10.1007/s00213-011-2415-0Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVajtLw%253D&md5=48622e6b81ae35d7f7ab26165f4c43daPlasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviourDeiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Arthur, Marlene; Fleming, Shona; Woodcock, Hilary; Dorward, Patricia; Pigliacampo, Barbara; Close, Steve; Platt, Bettina; Riedel, GernotPsychopharmacology (Heidelberg, Germany) (2012), 219 (3), 859-873CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurol. and neurodegenerative disorders. Consistent with these medicinal properties, extd. cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clin. testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Objectives and methods: We here detd. pharmacokinetic profiles of the above phytocannabinoids after acute single-dose i.p. and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, i.p. and oral) was further assessed using a marble burying test in mice. Results: All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioral anomalies, led to higher brain penetration than cremophor after oral, but not i.p. exposure. In mice, cremophor-based i.p. administration always attained higher plasma and brain concns., independent of substance given. In rats, oral administration offered higher brain concns. for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ9-THCV (30 mg/kg) and CBG (120 mg/kg), for which the i.p. route was more effective. CBD inhibited obsessive-compulsive behavior in a time-dependent manner matching its pharmacokinetic profile. Conclusions: These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for detn. of drug effects under in vivo conditions.
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90Huestis, M. A. Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9-Tetrahydrocannibinol, Cannabidiol and Cannabinol. In Cannabinoids; Pertwee, R. G., Ed.; Springer: Berlin, 2005; pp 657– 690.Google ScholarThere is no corresponding record for this reference.
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91Jiang, R.; Yamaori, S.; Takeda, S.; Yamamoto, I.; Watanabe, K. Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol by Human Liver Microsomes. Life Sci. 2011, 89, 165– 170, DOI: 10.1016/j.lfs.2011.05.018Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVaitbo%253D&md5=47a747f9f56840ca296c1dc1382b1bbcIdentification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomesJiang, Rongrong; Yamaori, Satoshi; Takeda, Shuso; Yamamoto, Ikuo; Watanabe, KazuhitoLife Sciences (2011), 89 (5-6), 165-170CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by exptl. animals and humans. However, human hepatic enzymes responsible for the CBD metab. remain to be elucidated. In this study, we examd. in vitro metab. of CBD with human liver microsomes (HLMs) to clarify cytochrome P 450 (CYP) isoforms involved in the CBD oxidns. Oxidns. of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatog./mass spectrometry. CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1''-OH-, 2''-OH-, 3''-OH-, 4''-OH-, and 5''-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4''-OH-CBDs were the major ones as estd. from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivs. of the metabolites. 7 Of 14 recombinant human CYP enzymes examd. (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4''-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4''-hydroxylations of CBD in HLMs.
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92Ujváry, I.; Hanuš, L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016, 1, 90– 101, DOI: 10.1089/can.2015.0012Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGmurg%253D&md5=b5823918b361a30b30faef84c7440dd4Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapyUjvary, Istvan; Hanus, LumirCannabis and Cannabinoid Research (2016), 1 (1), 90-101CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)A review. Cannabidiol (CBD), the main nonpsychoactive constituent of Cannabis sativa, has shown a wide range of therapeutically promising pharmacol. effects either as a sole drug or in combination with other drugs in adjunctive therapy. However, the targets involved in the therapeutic effects of CBD appear to be elusive. Furthermore, scarce information is available on the biol. activity of its human metabolites which, when formed in pharmacol. relevant concn., might contribute to or even account for the obsd. therapeutic effects. The present overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD in humans, reviews studies on the biol. activity of CBD metabolites either in vitro or in vivo, and discusses relevant drug-drug interactions. To facilitate further research in the area, the reported syntheses of CBD metabolites are also catalogued.
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93Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 2018, 32, 1053– 1067, DOI: 10.1007/s40263-018-0578-5Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVaqtLzN&md5=09e1f5ac19da1b63c1774385794de7d8A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy SubjectsTaylor, Lesley; Gidal, Barry; Blakey, Graham; Tayo, Bola; Morrison, GilmourCNS Drugs (2018), 32 (11), 1053-1067CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)This trial assessed the safety, tolerability and PK of CBD oral soln. in healthy adult volunteers, as well as the effect of food on CBD PK parameters. The study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD) [n = 6 per group]/placebo multiple dose (750 or 1500 mg CBD and food effect) (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned. Results: CBD was generally well tolerated. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to max. plasma concn. (tmax) was approx. 4-5 h. Oral clearance of CBD was high (1111-1909 L/h) and apparent vol. of distribution was large (20,963-42,849 L). CBD reached steady state after approx. 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. CBD elimination was multiphasic; the terminal elimination half-life was approx. 60 h after 750 and 1500 mg CBD twice daily; and effective half-life ests. ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, resp.; there was no effect of food on tmax or terminal half-life. Conclusion: CBD was generally well tolerated. The safety and PK profile support twice-daily administration of CBD.
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94Harvey, D. J.; Mechoulam, R. Metabolites of Cannabidiol Identified in Human Urine. Xenobiotica 1990, 20, 303– 320, DOI: 10.3109/00498259009046849Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXktlChtbg%253D&md5=aaedfccd73632b2585f08d8de01bdd55Metabolites of cannabidiol identified in human urineHarvey, D. J.; Mechoulam, R.Xenobiotica (1990), 20 (3), 303-20CODEN: XENOBH; ISSN:0049-8254.Urine from a dystonic patient treated with cannabidiol (I) was examd. by gas chromatog.-mass spectrometry for I metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and Me ester/TMS derivs. and as the TMS derivs. of the product of lithium aluminum deuteride redn. Thirty-three metabolites were identified in addn. to unmetabolized I, and a further four metabolites were partially characterized. The major metabolic route was hydroxylation and oxidn. at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivs. of I-7-oic acid. Other metabolites, mainly acids, were formed by β-oxidn. and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was I-oic acid contg. a hydroxyethyl side-chain. Two 8,9-dihydroxy compds., presumably derived from the corresponding epoxide were identified. Also present were several cyclized cannabinoids including Δ-6- and Δ-1-tetrahydrocannabinol and cannabinol. This is the first metabolic study of I in humans, most obsd. metabolic routes were typical of those found for I and related cannabinoids in other species.
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95Watanabe, K.; Usami, N.; Osada, S.; Narimatsu, S.; Yamamoto, I.; Yoshimura, H. Cannabidiol Metabolism Revisited: Tentative Identification of Novel Decarbonylated Metabolites of Cannabidiol Formed by Human Liver Microsomes and Recombinant Cytochrome P450 3A4. Forensic Toxicol. 2019, 37, 449– 455, DOI: 10.1007/s11419-019-00467-0Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltlOisrk%253D&md5=2ebef566215818c91b0d755f1a9e933eCannabidiol metabolism revisited: tentative identification of novel decarbonylated metabolites of cannabidiol formed by human liver microsomes and recombinant cytochrome P450 3A4Watanabe, Kazuhito; Usami, Noriyuki; Osada, Shigehiro; Narimatsu, Shizuo; Yamamoto, Ikuo; Yoshimura, HidetoshiForensic Toxicology (2019), 37 (2), 449-455CODEN: FTOOAU; ISSN:1860-8965. (Springer Japan)The purpose of the present study was to identify the structures of cannabidiol (CBD) metabolites during CO formation by human liver microsomes and human recombinant cytochrome P 450 (CYP) enzymes. CBD was NADPH-dependently metabolized by human liver microsomes and human recombinant CYP enzymes. Less-polar metabolites were analyzed by gas chromatog.-mass spectrometry monitoring, and their estd. mol. ions were m/z 286, 358 and 481 after non-derivatization, trimethylsilylation and pentafluorobenzyl oxime formation, resp. We tentatively identified novel decarbonylated metabolites of CBD as keto-enol tautomers. Among eight major recombinant human CYP enzymes, only CYP3A4 catalyzed the formation of decarbonylated metabolites. CBD was biotransformed to two decarbonylated metabolites, an enol-form (cyclopentadienol structure), and a keto-form (cyclopentenone structure) by human liver microsomes and CYP3A4.
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96Harvey, D. J.; Samara, E.; Mechoulam, R. Urinary Metabolites of Cannabidiol in Dog, Rat and Man and Their Identification by Gas Chromatography-Mass Spectrometry. J. Chromatogr., Biomed. Appl. 1991, 562, 299– 322, DOI: 10.1016/0378-4347(91)80587-3Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhtlGnu74%253D&md5=171a4fec2044447fb0d554283b1293deUrinary metabolites of cannabidiol in dog, rat and man and their identification by gas chromatography-mass spectrometryHarvey, D. J.; Samara, E.; Mechoulam, R.Journal of Chromatography, Biomedical Applications (1991), 562 (1-2), 299-322CODEN: JCBADL; ISSN:0378-4347.Urinary metabolites of cannabidiol (I) (CBD), a non-psychoactive cannabinoid of potential therapeutic interest, were extd. from dog, rat, and human urine, concd. by chromatog. on Sephadex LH-20 and examd. by gas chromatog.-mass spectrometry as trimethylsilyl (TMS), [2H9]TMS, Me ester-TMS and methyloxime-TMS derivs. Fragmentation of the metabolites under electron-impact gave structurally informative fragment ions; computer-generated single-ion plots of these diagnostic ions were used extensively to aid metabolite identification. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concn. in human urine, in the free state and as its glucuronide. In dog, unusual glucoside conjugates of 3 metabolites (4''- and 5''-hydroxy- and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all 3 species were mainly acids. Side-chain hydroxylated derivs. of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species, the major oxidized metabolites were the products of β-oxidn. with further hydroxylation at C-6. A related, but undefined pathway resulted in loss of 3 carbon atoms from the side-chain of CBD in man with prodn. of 2''-hydroxy-tris,nor-CBD-7-oic acid. Metab. by the epoxide-diol pathway, resulting in dihydro-diol formation from the Δ-8 double bond, gave metabolites in dog and human urine. Thus, CBD could be used as a probe of the mechanism of several types of biotransformation: particularly those related to carboxylic acid metab. as intermediates of the type not usually seen with endogenous compds. were excreted in substantial concn.
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97Wray, L.; Stott, C.; Jones, N.; Wright, S. Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model. Cannabis Cannabinoid Res. 2017, 2, 282– 287, DOI: 10.1089/can.2017.0032Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsL8%253D&md5=3f7a433910a828aad279d32356fefa9aCannabidiol does not convert to Δ9-tetrahydrocannabinol in an in vivo animal modelWray, Louise; Stott, Colin; Jones, Nicholas; Wright, StephenCannabis and Cannabinoid Research (2017), 2 (1), 282-287CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Introduction: Cannabidiol (CBD) can convert to Δ[sup]9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N = 3) in 15mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liq. chromatog. with tandem mass spectrometry anal. detd. CBD, THC, and 11-hydroxy-THC (11-OH-THC) concns. Lower limits of quantification: plasma CBD = 1 ng/mL, plasma THC and 11-OH-THC = 0.5 ng/mL, GI tract CBD = 2 ng/mL, and GI tract THC and 11-OH-THC = 1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concns. (Cmax) of CBD were obsd. between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean Cmax CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clin. studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h · ng/mL) and 5 (881 h · ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concns. reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clin. relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.
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98Palazzoli, F.; Citti, C.; Licata, M.; Vilella, A.; Manca, L.; Zoli, M.; Vandelli, M. A.; Forni, F.; Cannazza, G. Development of a Simple and Sensitive Liquid Chromatography Triple Quadrupole Mass Spectrometry (LC-MS/MS) Method for the Determination of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Its Metabolites in Rat Whole Blood after Oral Administration of a Single High Dose of CBD. J. Pharm. Biomed. Anal. 2018, 150, 25– 32, DOI: 10.1016/j.jpba.2017.11.054Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWgsLjN&md5=96eadfaa892555f3d58190f24ab0d709Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBDPalazzoli, Federica; Citti, Cinzia; Licata, Manuela; Vilella, Antonietta; Manca, Letizia; Zoli, Michele; Vandelli, Maria Angela; Forni, Flavio; Cannazza, GiuseppeJournal of Pharmaceutical and Biomedical Analysis (2018), 150 (), 25-32CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The investigation of the possible conversion of cannabidiol (CBD) into Δ9-tetrahydrocannabinol (THC) in vivo after oral administration of CBD is reported herein since recent publications suggested a rapid conversion in simulated gastric fluid. To this end, single high dose of CBD (50 mg/kg) was administered orally to rats and their blood was collected after 3 and 6 h. A highly sensitive and selective LC-MS/MS method was developed and fully validated in compliance with the Scientific Working Group of Forensic Toxicol. (SWGTOX) std. practices for method validation in forensic toxicol. This method also involved the optimization of cannabinoids and their metabolites extn. to remove co-eluting phospholipids and increase the sensitivity of the MS detection. Neither THC nor its metabolites were detected in rat whole blood after 3 or 6 h from CBD administration. After oral administration, the amt. of CBD dissolved in olive oil was higher than that absorbed from an ethanolic soln. After oral administration, the amt. of CBD dissolved in olive oil was higher than that absorbed from an ethanolic soln.
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99Guy, G. W.; Flint, M. E. A Single Centre, Placebo-Controlled, Four Period, Crossover, Tolerability Study Assessing, Pharmacodynamic Effects, Pharmacokinetic Characteristics and Cognitive Profiles of a Single Dose of Three Formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), Plus a Two Period Tolerability Study Comparing Pharmacodynamic Effects and Pharmacokinetic Characteristics of a Single Dose of a Cannabis Based Medicine Extract Given via Two Administration Routes (GWPD9901 EXT). J. Cannabis Ther. 2004, 3, 35– 77, DOI: 10.1300/J175v03n03_03Google ScholarThere is no corresponding record for this reference.
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100Atsmon, J.; Cherniakov, I.; Izgelov, D.; Hoffman, A.; Domb, A. J.; Deutsch, L.; Deutsch, F.; Heffetz, D.; Sacks, H. PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers. J. Pharm. Sci. 2018, 107, 1423– 1429, DOI: 10.1016/j.xphs.2017.12.020Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeitbk%253D&md5=fd9e6fa3dfb90bca10d5b0a4c2984727PTL401, a New Formulation Based on Pro-nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy VolunteersAtsmon, Jacob; Cherniakov, Irina; Izgelov, Dvora; Hoffman, Amnon; Domb, Abraham J.; Deutsch, Lisa; Deutsch, Frederic; Heffetz, Daphna; Sacks, HagitJournal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107 (5), 1423-1429CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)There is a growing clin. interest in developing and commercializing pharmaceutical-grade cannabinoid products, contg. primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metab. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed ref. oromucosal spray (Sativex). Fourteen healthy male volunteers received, on sep. treatment days, either a single dose of PTL401 or an equiv. dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma Cmax than the equiv. dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, resp.). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clin. studies with this formulation.
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101Consroe, P.; Kennedy, K.; Schram, K. Assay of Plasma Cannabidiol by Capillary Gas Chromatography/ion Trap Mass Spectroscopy Following High-Dose Repeated Daily Oral Administration in Humans. Pharmacol., Biochem. Behav. 1991, 40, 517– 522, DOI: 10.1016/0091-3057(91)90357-8Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XjsFOqsg%253D%253D&md5=d8b64eaedffa9333da04bbce7a57bb8fAssay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humansConsroe, Paul; Kennedy, Kurt; Schram, KarlPharmacology, Biochemistry and Behavior (1991), 40 (3), 517-22CODEN: PBBHAU; ISSN:0091-3057.Plasma levels of cannabidiol (CBD) were ascertained weekly in 14 Huntington's disease patients undergoing a double-blind, placebo-controlled, crossover trial of oral CBD (10 mg/kg/day = about 700 mg/day) for 6 wk. The assay procedure involved trimethylsilyl (TMS) derivatization of CBD and the internal std. delta-6-tetrahydrocannabinol (THC), capillary column gas chromatog., ion trap mass spectroscopy in pos. ion chem. ionization mode using isobutane, and calcns. of CBD levels based on peak ion intensity of the 387 M + H peak of delta-6-THC-TMS and the 459 M + H peak of CBD-2TMS. The sensitivity of the assay was about 500 pg/mL, and the precision was about 10-15%. Mean plasma levels of CBD ranged 5.9-11.2 ng/mL over the 6 wk of CBD administration. CBD levels averaged 1.5 ng/mL one week after CBD was discontinued, and were virtually undetectable thereafter. The elimination half-life of CBD was estd. to be about 2-5 days, and there were no differences between genders for half-life or CBD levels. Addnl., no plasma delta-1-THC, the major psychoactive cannabinoid of marijuana, was detected in any subject.
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102Wall, M. E.; Brine, D. R.; Perez-Reyes, M. Metabolism of Cannabinoids in Man. In The Pharmacology of Marihuana; Braude, M. C., Szara, S., Eds.; Raven Press: New York, 1976; pp 93– 113.Google ScholarThere is no corresponding record for this reference.
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103Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Effect of Food on the Single Dose Bioavailability of the THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 825– 834, DOI: 10.1007/s00228-012-1393-4Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s%252FjvFGjsA%253D%253D&md5=dccda46c8c7793a7e244cb94f26cfee4A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal sprayStott C G; White L; Wright S; Wilbraham D; Guy G WEuropean journal of clinical pharmacology (2013), 69 (4), 825-34 ISSN:.PURPOSE: To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. METHODS: Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). RESULTS: Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. CONCLUSIONS: The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.
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104Stout, S. M.; Cimino, N. M. Exogenous Cannabinoids as Substrates, Inhibitors, and Inducers of Human Drug Metabolizing Enzymes: A Systematic Review. Drug Metab. Rev. 2014, 46 (1), 86– 95, DOI: 10.3109/03602532.2013.849268Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVylu7Y%253D&md5=0d774cda3a4fa7cc3d50413e20e241c3Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic reviewStout, Stephen M.; Cimino, Nina M.Drug Metabolism Reviews (2014), 46 (1), 86-95CODEN: DMTRAR; ISSN:0360-2532. (Informa Healthcare)A review. Exogenous cannabinoids are structurally and pharmacol. diverse compds. that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compds. to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clin. care and drug interactions. In vitro data were identified that characterize cytochrome P 450 (CYP-450) enzymes as potential significant contributors to the primary metab. of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metab. of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metab. Clin. pharmacogenetic data further support CYP2C9 as a significant contributor to THC metab., and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis ext. further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis ext. with omeprazole suggests a less significant role of CYP2C19 in CBD metab. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clin. significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metab., although the role of cannabinoids specifically in eliciting this effect is questionable.
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105Zendulka, O.; Dovrtělová, G.; Nosková, K.; Turjap, M.; Šulcová, A.; Hanuš, L.; Juřica, J. Cannabinoids and Cytochrome P450 Interactions. Curr. Drug Metab. 2016, 17, 206– 226, DOI: 10.2174/1389200217666151210142051Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVGns7c%253D&md5=8018bdfd8377dabbd8c33932e8039f55Cannabinoids and Cytochrome P450 InteractionsZendulka, Ond|ej; Dovrt|lova, Gabriela; Noskova, Kristyna; Turjap, Miroslav; Sulcova, Alexandra; Hanus, Lumir; Ju|ica, JanCurrent Drug Metabolism (2016), 17 (3), 206-226CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Objective: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P 450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. Methods: We performed a structured search of bibliog. and drug databases for peer-reviewed literature using focused review questions. Results: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metab. and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro expts. document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clin. relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.
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106Benowitz, N. L.; Nguyen, T. L.; Jones, R. T.; Herning, R. I.; Bachman, J. Metabolic and Psychophysiologic Studies of Cannabidiol-Hexobarbital Interaction. Clin. Pharmacol. Ther. 1980, 28, 115– 120, DOI: 10.1038/clpt.1980.139Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXlt1GrsL4%253D&md5=104f81a3dee4aa0f4d62c604381bbc61Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interactionBenowitz, Neal L.; Nguyen Trong Lang; Jones, Reese T.; Herning, Ronald I.; Bachman, JohnClinical Pharmacology & Therapeutics (St. Louis, MO, United States) (1980), 28 (1), 115-20CODEN: CLPTAT; ISSN:0009-9236.The administration of cannabidiol (CBD)(I) [13956-29-1] (600 mg/day orally for 5-12 days), inhibited hexobarbital (II) [50-09-9] metab. in normal subjects. Hexobarbital oral clearance was 36% lower and the apparent vol. of distribution was 35% smaller, with no change in half-life during CBD. In subjects who received i.v. and oral hexobarbital, systemic clearance was 36% lower whereas bioavailability was 10% greater during CBD. Hexobarbital increased fatigue and tremor, impaired eye-tracking performance, and altered the EEG. Hexobarbital effects were not affected by CBD. Inhibition of metab. of other drugs should be considered when large amts. of CBD are taken or when CBD is used for therapy.
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107Garberg, H. T.; Solberg, R.; Barlinn, J.; Martinez-Orgado, J.; Løberg, E.-M.; Saugstad, O. D. High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets. Neonatology 2017, 112, 143– 149, DOI: 10.1159/000471786Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ygtrvP&md5=722d7deb5e6ac02dfef48145f8ca49e0High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in PigletsGarberg, Havard T.; Solberg, Ronnaug; Barlinn, Jon; Martinez-Orgado, Jose; Loberg, Else-Marit; Saugstad, Ola DidrikNeonatology (2017), 112 (2), 143-149CODEN: NEONCC; ISSN:1661-7800. (S. Karger AG)Background: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. Objective: To assess the safety and potential neuroprotective effects of high-dose CBD. Methods: Anesthetized newborn piglets underwent global HI by ventilation with 8% O2 until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to i.v. treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for anal. Results: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant neg. correlation between the plasma concn. of CBD and hypotension during drug infusion was obsd. (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathol. score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. Conclusions: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.
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108Murphy, S. K.; Itchon-Ramos, N.; Visco, Z.; Huang, Z.; Grenier, C.; Schrott, R.; Acharya, K.; Boudreau, M.-H.; Price, T. M.; Raburn, D. J.; Corcoran, D. L.; Lucas, J. E.; Mitchell, J. T.; McClernon, F. J.; Cauley, M.; Hall, B. J.; Levin, E. D.; Kollins, S. H. Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm. Epigenetics 2018, 13, 1208– 1221, DOI: 10.1080/15592294.2018.1554521Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnlslSnsw%253D%253D&md5=53a0321ca720a68e539e5540ef28a9ecCannabinoid exposure and altered DNA methylation in rat and human spermMurphy Susan K; Visco Zachary; Huang Zhiqing; Grenier Carole; Acharya Kelly; Boudreau Marie-Helene; Price Thomas M; Raburn Douglas J; Itchon-Ramos Nilda; Mitchell John T; McClernon F Joseph; Levin Edward D; Kollins Scott H; Schrott Rose; Corcoran David L; Lucas Joseph E; Cauley Marty; Hall Brandon JEpigenetics (2018), 13 (12), 1208-1221 ISSN:.Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.
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109Reece, A. S.; Hulse, G. K. Impacts of Cannabinoid Epigenetics on Human Development: Reflections on Murphy et. al. ‘Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm Epigenetics 2018; 13: 1208-1221’. Epigenetics 2019, 14, 1041– 1056, DOI: 10.1080/15592294.2019.1633868Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzmtFaguw%253D%253D&md5=5f715a99a6ffa633e0153481e01c2db0Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. 'cannabinoid exposure and altered DNA methylation in rat and human sperm' epigenetics 2018; 13: 1208-1221Reece Albert Stuart; Hulse Gary Kenneth; Reece Albert Stuart; Hulse Gary KennethEpigenetics (2019), 14 (11), 1041-1056 ISSN:.Recent data from the Kollins lab ('Cannabinoid exposure and altered DNA methylation in rat and human sperm' Epigenetics 2018; 13: 1208-1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers. The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis. Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required.
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110Carvalho, R. K.; Santos, M. L.; Souza, M. R.; Rocha, T. L.; Guimarães, F. S.; Anselmo-Franci, J. A.; Mazaro-Costa, R. Chronic Exposure to Cannabidiol Induces Reproductive Toxicity in Male Swiss Mice. J. Appl. Toxicol. 2018, 38, 1215– 1223, DOI: 10.1002/jat.3631Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsFOmsrs%253D&md5=8a3906504e6ec3809df124c2f6920201Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss miceCarvalho, Renata K.; Santos, Monaliza L.; Souza, Maingredy R.; Rocha, Thiago L.; Guimaraes, Francisco S.; Anselmo-Franci, Janete A.; Mazaro-Costa, RenataJournal of Applied Toxicology (2018), 38 (9), 1215-1223CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)Children and adults with frequent and severe episodes of epilepsy that do not respond to std. treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reprodn. has not been fully examd. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21-day-old male Swiss mice at doses of 15 and 30 mg kg-1 daily (CBD 15 and 30 groups, resp.), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: wt. of reproductive organs, testosterone concn., spermatogenesis, histomorphometry, daily sperm prodn. and its morphol. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiol. normal range (240-1100 ng dl-1). CBD treatment induced a significant increase in the frequency of stages I-IV and V-VI of spermatogenesis, and a decrease in the frequency of stages VII-VIII and XII. A significant decrease in the no. of Sertoli cells was obsd. only in the CBD 30 group. In both CBD groups the no. of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were obsd. in the medial region of flagellum. These results indicated that chronic CBD exposure was assocd. with changes in the male reproductive system, suggesting its reproductive toxicity.
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111Ewing, L. E.; Skinner, C. M.; Quick, C. M.; Kennon-McGill, S.; McGill, M. R.; Walker, L. A.; ElSohly, M. A.; Gurley, B. J.; Koturbash, I. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. Molecules 2019, 24, 1694, DOI: 10.3390/molecules24091694Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvF2mur4%253D&md5=7765d8d50b685310fa53d7ede40ccc9dHepatotoxicity of a Cannabidiol-rich cannabis extract in the mouse modelEwing, Laura E.; Skinner, Charles M.; Quick, Charles M.; Kennon-McGill, Stefanie; McGill, Mitchell R.; Walker, Larry A.; ElSohly, Mahmoud A.; Gurley, Bill J.; Koturbash, IgorMolecules (2019), 24 (9), 1694CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-wk-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equiv. doses (MED) of the max. recommended human maintenance dose of CBD in EPIDIOLEX (20 mg/kg). In the acute study, significant increases in liver-to-body wt. (LBW) ratios, plasma ALT, AST, and total bilirubin were obsd. for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metab. pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways assocd. with lipid and xenobiotic metab. raises serious concerns about potential drug interactions as well as the safety of CBD.
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112Russo, C.; Ferk, F.; Mišík, M.; Ropek, N.; Nersesyan, A.; Mejri, D.; Holzmann, K.; Lavorgna, M.; Isidori, M.; Knasmüller, S. Low Doses of Widely Consumed Cannabinoids (Cannabidiol and Cannabidivarin) Cause DNA Damage and Chromosomal Aberrations in Human-Derived Cells. Arch. Toxicol. 2019, 93, 179– 188, DOI: 10.1007/s00204-018-2322-9Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFygtbnL&md5=05f7839670d83b5101bc85aa36344236Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cellsRusso, Chiara; Ferk, Franziska; Misik, Miroslav; Ropek, Nathalie; Nersesyan, Armen; Mejri, Doris; Holzmann, Klaus; Lavorgna, Margherita; Isidori, Marina; Knasmuller, SiegfriedArchives of Toxicology (2019), 93 (1), 179-188CODEN: ARTODN; ISSN:0340-5761. (Springer)Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amts. worldwide in cannabis exts., as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compds. induced DNA damage in single cell gel electrophoresis (SCGE) expts. in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 μM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Addnl. expts. indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compds. Our findings show that low concns. of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.
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113Devinsky, O.; Patel, A. D.; Cross, J. H.; Villanueva, V.; Wirrell, E. C.; Privitera, M.; Greenwood, S. M.; Roberts, C.; Checketts, D.; VanLandingham, K. E.; Zuberi, S. M. GWPCARE3 Study Group. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N. Engl. J. Med. 2018, 378, 1888– 1897, DOI: 10.1056/NEJMoa1714631Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVCrt7jL&md5=6789d5c955c809a35801238a217c53f6Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndromeDevinsky, Orrin; Patel, Anup D.; Cross, J. Helen; Villanueva, Vicente; Wirrell, Elaine C.; Privitera, Michael; Greenwood, Sam M.; Roberts, Claire; Checketts, Daniel; Van Landingham, Kevan E.; Zuberi, Sameer M.New England Journal of Medicine (2018), 378 (20), 1888-1897CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)We investigated efficacy, safety of cannabidiol added to regimen of conventional antiepileptic medication to treat drop seizures in patients with Lennox-Gastaut syndrome. We randomly assigned patients with Lennox-Gastaut syndrome who had two or more drop seizures per wk during 28-day baseline period to receive cannabidiol oral soln. at a dose of either 20 mg per kg of body wt. or 10 mg per kg or matching placebo, administered in 2 equally divided doses daily for 14 wk. Primary outcome was percentage change from baseline in frequency of drop seizures during the treatment period. During 28-day baseline period, median no. of drop seizures was 85 in all trial groups combined. Median percent redn. from baseline in drop-seizure frequency during treatment period was 41.9% in 20-mg cannabidiol group, 37.2% in 10-mg cannabidiol group, and 17.2% in placebo group. Most common adverse events among patients in cannabidiol groups were somnolence, decreased appetite, diarrhea. 14 Patients who received cannabidiol had elevated liver aminotransferase concns. Among children, adults with the Lennox-Gastaut syndrome, the addn. of cannabidiol at a dose of 10 mg or 20 mg per kg per day to a conventional antiepileptic regimen resulted in greater redns. in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferases.
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114Gaston, T. E.; Bebin, E. M.; Cutter, G. R.; Liu, Y.; Szaflarski, J. P. UAB CBD Program. Interactions between Cannabidiol and Commonly Used Antiepileptic Drugs. Epilepsia 2017, 58, 1586– 1592, DOI: 10.1111/epi.13852Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOit7bM&md5=5ad7017993c10c448f8d64103e2925c1Interactions between cannabidiol and commonly used antiepileptic drugsGaston, Tyler E.; Bebin, E. Martina; Cutter, Gary R.; Liu, Yuliang; Szaflarski, Jerzy P.Epilepsia (2017), 58 (9), 1586-1592CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Summary : Objective : To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. Methods : In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 wk by 5 mg/kg/day up to a max. of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was detd. that a clin. symptom or lab. result was related to a potential interaction. The Mixed Procedure was used to det. if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial anal. were plotted for mean change in serum level over time. Subanalyses were performed to det. if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Results : Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significance : Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.
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115Groeneveld, G. J.; Martin, J. H. Parasitic Pharmacology: A Plausible Mechanism of Action for Cannabidiol. Br. J. Clin. Pharmacol. 2020, 86, 189– 191, DOI: 10.1111/bcp.14028Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzlvVaisQ%253D%253D&md5=6018dd17f8ffe625275c15cc94d30080Parasitic pharmacology: A plausible mechanism of action for cannabidiolGroeneveld Geert Jan; Groeneveld Geert Jan; Martin Jennifer H; Martin Jennifer HBritish journal of clinical pharmacology (2020), 86 (2), 189-191 ISSN:.There is no expanded citation for this reference.
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116American Epilepsy Foundation. AES Position Statement on Cannabis as a Treatment for Patients with Epileptic Seizures; American Epilepsy Foundation, 2019. https://www.aesnet.org/sites/default/files/file_attach/42981132_cannabis_position_statement_updated_2.19.19.pdf (accessed Dec 19, 2019).Google ScholarThere is no corresponding record for this reference.
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117MacKeen, D. What Are the Benefits of CBD? N. Y. Times 2019 (October 16).Google ScholarThere is no corresponding record for this reference.
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118Popejoy, S. Is CBD for Aging a Potential Fountain of Youth? CBGenius. https://www.cbgenius.net/2019/06/18/is-cbd-for-aging-a-potential-fountain-of-youth/ (accessed Jul 4, 2020).Google ScholarThere is no corresponding record for this reference.
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119Freeman, J. Does CBD Oil Really Help Treat Arthritis Pain? Rheumatoid Arthritis. https://www.rheumatoidarthritis.org/cbd-oil/ (accessed Jul. 4, 2020).Google ScholarThere is no corresponding record for this reference.
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120Skrobin, N., The Fresh Toast. Cannabis: Optimal Treatment Method for Post-Concussion Syndrome Symptoms. Chicago Tribune 2019 (August 30).Google ScholarThere is no corresponding record for this reference.
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121Johnson, J. CBD for Weight Loss: Does It Work? https://www.medicalnewstoday.com/articles/324733 (accessed Jul 4, 2020).Google ScholarThere is no corresponding record for this reference.
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122Kubala, J.. 7 Benefits and Uses of CBD Oil (Plus Side Effects). https://www.healthline.com/nutrition/cbd-oil-benefits (accessed Jul 4, 2020).Google ScholarThere is no corresponding record for this reference.
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123Bonaccorso, S.; Ricciardi, A.; Zangani, C.; Chiappini, S.; Schifano, F. Cannabidiol (CBD) Use in Psychiatric Disorders: A Systematic Review. NeuroToxicology 2019, 74, 282– 298, DOI: 10.1016/j.neuro.2019.08.002Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ymtbnE&md5=2efa8d86969ee9ca64d901c32ba2cc64Cannabidiol (CBD) use in psychiatric disorders: A systematic reviewBonaccorso, Stefania; Ricciardi, Angelo; Zangani, Caroline; Chiappini, Stefania; Schifano, FabrizioNeuroToxicology (2019), 74 (), 282-298CODEN: NRTXDN; ISSN:0161-813X. (Elsevier Inc.)A review. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathol. conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstr.'s screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathol. conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
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124Hiemstra, B.; Keus, F.; Wetterslev, J.; Gluud, C.; van der Horst, I. C. C. DEBATE-Statistical Analysis Plans for Observational Studies. BMC Med. Res. Methodol. 2019, 19 (1), 233, DOI: 10.1186/s12874-019-0879-5Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mfot1Gjug%253D%253D&md5=48b47e89a91f8e32771b6c74fefc41a3DEBATE-statistical analysis plans for observational studiesHiemstra Bart; Keus Frederik; Wetterslev Jorn; Gluud Christian; van der Horst Iwan C CBMC medical research methodology (2019), 19 (1), 233 ISSN:.BACKGROUND: All clinical research benefits from transparency and validity. Transparency and validity of studies may increase by prospective registration of protocols and by publication of statistical analysis plans (SAPs) before data have been accessed to discern data-driven analyses from pre-planned analyses. MAIN MESSAGE: Like clinical trials, recommendations for SAPs for observational studies increase the transparency and validity of findings. We appraised the applicability of recently developed guidelines for the content of SAPs for clinical trials to SAPs for observational studies. Of the 32 items recommended for a SAP for a clinical trial, 30 items (94%) were identically applicable to a SAP for our observational study. Power estimations and adjustments for multiplicity are equally important in observational studies and clinical trials as both types of studies usually address multiple hypotheses. Only two clinical trial items (6%) regarding issues of randomisation and definition of adherence to the intervention did not seem applicable to observational studies. We suggest to include one new item specifically applicable to observational studies to be addressed in a SAP, describing how adjustment for possible confounders will be handled in the analyses. CONCLUSION: With only few amendments, the guidelines for SAP of a clinical trial can be applied to a SAP for an observational study. We suggest SAPs should be equally required for observational studies and clinical trials to increase their transparency and validity.
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125The Skyline Agency. CBD Oil & Cannabinol Tincture Products from Medterra CBD. https://medterracbd.com/product-cbd-oil-tincture (accessed Jul 7, 2020).Google ScholarThere is no corresponding record for this reference.
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126Moerman, D. E.; Jonas, W. B. Deconstructing the Placebo Effect and Finding the Meaning Response. Ann. Intern. Med. 2002, 136, 471– 476, DOI: 10.7326/0003-4819-136-6-200203190-00011Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387mvVyksw%253D%253D&md5=81d68eb21291815c01381bbb30a4f1d7Deconstructing the placebo effect and finding the meaning responseMoerman Daniel E; Jonas Wayne BAnnals of internal medicine (2002), 136 (6), 471-6 ISSN:.We provide a new perspective with which to understand what for a half century has been known as the "placebo effect." We argue that, as currently used, the concept includes much that has nothing to do with placebos, confusing the most interesting and important aspects of the phenomenon. We propose a new way to understand those aspects of medical care, plus a broad range of additional human experiences, by focusing on the idea of "meaning," to which people, when they are sick, often respond. We review several of the many areas in medicine in which meaning affects illness or healing and introduce the idea of the "meaning response." We suggest that use of this formulation, rather than the fixation on inert placebos, will probably lead to far greater insight into how treatment works and perhaps to real improvements in human well-being.
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127Benedetti, F. Placebo Effects: From the Neurobiological Paradigm to Translational Implications. Neuron 2014, 84, 623– 637, DOI: 10.1016/j.neuron.2014.10.023Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvV2mtrfE&md5=0cb297b6ae7d878559b8c43c36692042Placebo Effects: From the Neurobiological Paradigm to Translational ImplicationsBenedetti, FabrizioNeuron (2014), 84 (3), 623-637CODEN: NERNET; ISSN:0896-6273. (Cell Press)Today we are witnessing a new science of placebo, a complex discipline that encompasses several exptl. approaches and translational implications. Modern neurobiol. tools have been used to answer important questions in placebo research, such as the top-down modulation of sensory and motor systems as well as the influence of cognition, emotions, and learning on symptoms, diseases, and responses to treatments. What we have learned is that there is not one single placebo effect, but many. This review highlights the translational implications of this new knowledge, ranging from clin. trial design to medical practice to social and ethical issues.
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128Hopp, C. Past and Future Research at National Center for Complementary and Integrative Health with Respect to Botanicals. HerbalGram 2015, 107, 44– 51Google ScholarThere is no corresponding record for this reference.
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129Geller, S. E.; Shulman, L. P.; van Breemen, R. B.; Banuvar, S.; Zhou, Y.; Epstein, G.; Hedayat, S.; Nikolic, D.; Krause, E. C.; Piersen, C. E.; Bolton, J. L.; Pauli, G. F.; Farnsworth, N. R. Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial. Menopause 2009, 16, 1156– 1166, DOI: 10.1097/gme.0b013e3181ace49bGoogle Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MjkslGmsw%253D%253D&md5=0c9d2bd07ee6a27ed3c4e374632a5a30Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trialGeller Stacie E; Shulman Lee P; van Breemen Richard B; Banuvar Suzanne; Zhou Ying; Epstein Geena; Hedayat Samad; Nikolic Dejan; Krause Elizabeth C; Piersen Colleen E; Bolton Judy L; Pauli Guido F; Farnsworth Norman RMenopause (New York, N.Y.) (2009), 16 (6), 1156-66 ISSN:.OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of black cohosh and red clover compared with placebo for the relief of menopausal vasomotor symptoms. METHODS: This study was a randomized, four-arm, double-blind clinical trial of standardized black cohosh, red clover, placebo, and 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA; n = 89). Primary outcome measures were reduction in vasomotor symptoms (hot flashes and night sweats) by black cohosh and red clover compared with placebo; secondary outcomes included safety evaluation, reduction of somatic symptoms, relief of sexual dysfunction, and overall improvement in quality of life. RESULTS: Reductions in number of vasomotor symptoms after a 12-month intervention were as follows: black cohosh (34%), red clover (57%), placebo (63%), and CEE/MPA (94%), with only CEE/MPA differing significantly from placebo. Black cohosh and red clover did not significantly reduce the frequency of vasomotor symptoms as compared with placebo. Secondary measures indicated that both botanicals were safe as administered. In general, there were no improvements in other menopausal symptoms. CONCLUSIONS: Compared with placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms. Safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months.
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130Sorkin, B. C.; Kuszak, A. J.; Bloss, G.; Fukagawa, N. K.; Hoffman, F. A.; Jafari, M.; Barrett, B.; Brown, P. N.; Bushman, F. D.; Casper, S. J.; Chilton, F. H.; Coffey, C. S.; Ferruzzi, M. G.; Hopp, D. C.; Kiely, M.; Lakens, D.; MacMillan, J. B.; Meltzer, D. O.; Pahor, M.; Paul, J.; Pritchett-Corning, K.; Quinney, S. K.; Rehermann, B.; Setchell, K. D. R.; Sipes, N. S.; Stephens, J. M.; Taylor, D. L.; Tiriac, H.; Walters, M. A.; Xi, D.; Zappalá, G.; Pauli, G. F. Improving Natural Product Research Translation: From Source to Clinical Trial. FASEB J. 2020, 34, 41– 65, DOI: 10.1096/fj.201902143RGoogle Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFehsL8%253D&md5=19537e9297cca959ebd3405e66fc9b1aImproving natural product research translation: From source to clinical trialSorkin, Barbara C.; Kuszak, Adam J.; Bloss, Gregory; Fukagawa, Naomi K.; Hoffman, Freddie Ann; Jafari, Mahtab; Barrett, Bruce; Brown, Paula N.; Bushman, Frederic D.; Casper, Steven J.; Chilton, Floyd H.; Coffey, Christopher S.; Ferruzzi, Mario G.; Hopp, D. Craig; Kiely, Mairead; Lakens, Daniel; MacMillan, John B.; Meltzer, David O.; Pahor, Marco; Paul, Jeffrey; Pritchett-Corning, Kathleen; Quinney, Sara K.; Rehermann, Barbara; Setchell, Kenneth D. R.; Sipes, Nisha S.; Stephens, Jacqueline M.; Taylor, D. Lansing; Tiriac, Herve; Walters, Michael A.; Xi, Dan; Zappala, Giovanna; Pauli, Guido F.FASEB Journal (2020), 34 (1), 41-65CODEN: FAJOEC; ISSN:1530-6860. (John Wiley & Sons, Inc.)While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclin. NP research is not consistently translating into actionable clin. trial (CT) outcomes. Generally considered the gold std. for assessing safety and efficacy, CTs, esp. phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a . Participants emphasized that replicability and likelihood of successful translation depend on rigor in exptl. design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clin. predictive validity; controls for exptl. artifacts, esp. for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clin. trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.
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131Brown, J. D. Cannabidiol as Prophylaxis for SARS-CoV-2 and COVID-19? Unfounded Claims versus Potential Risks of Medications during the Pandemic. Res. Social Adm. Pharm. 2020, DOI: 10.1016/j.sapharm.2020.03.020Google ScholarThere is no corresponding record for this reference.
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This article references 131 other publications.
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1Cannabidiol Market Size Analysis. CBD Industry Growth Report, 2025. https://www.grandviewresearch.com/industry-analysis/cannabidiol-cbd-market (accessed Apr 22, 2020).There is no corresponding record for this reference.
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2Dorbian, I. CBD Market Could Reach $20 Billion By 2024, Says New Study. Forbes May 20, 2019.There is no corresponding record for this reference.
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3Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem. 2017, 60 (5), 1620– 1637, DOI: 10.1021/acs.jmedchem.6b009753https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFKjsA%253D%253D&md5=dfb16371e0ef27d4111628203c6acc09The Essential Medicinal Chemistry of CurcuminNelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Curcumin is a constituent (3-5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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4Dietz, B. M.; Chen, S.-N.; Alvarenga, R. F. R.; Dong, H.; Nikolić, D.; Biendl, M.; van Breemen, R. B.; Bolton, J. L.; Pauli, G. F. DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women’s Health. J. Nat. Prod. 2017, 80, 2284– 2294, DOI: 10.1021/acs.jnatprod.7b002844https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlaqs73E&md5=61580fe2c5ca4e8319b799d40a719b0aDESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women's HealthDietz, Birgit M.; Chen, Shao-Nong; Alvarenga, Rene F. Ramos; Dong, Huali; Nikolic, Dejan; Biendl, Martin; van Breemen, Richard B.; Bolton, Judy L.; Pauli, Guido F.Journal of Natural Products (2017), 80 (8), 2284-2294CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Botanical dietary supplements contain multiple bioactive compds. that target numerous biol. pathways. The lack of uniform standardization requirements is one reason that inconsistent clin. effects are reported frequently. The multifaceted biol. interactions of active principles can be disentangled by a coupled pharmacol./phytochem. approach using specialized ("knock-out") exts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent sepn., Humulus lupulus exts. were designed for pre- and postmenopausal women by contg. various amts. of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Anal. of their estrogenic (alk. phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concns. provided evidence for the interdependence of the biol. effects. A designed postmenopausal hop ext. was prepd. to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An ext. designed for premenopausal women contains reduced 8-PN levels and high XH concns. to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concns. of bioactive compds. in botanical exts. for potentially improved efficacy and safety.
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5Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy Effects of Herb Extracts: Pharmacokinetics and Pharmacodynamic Basis. Fitoterapia 2014, 92, 133– 147, DOI: 10.1016/j.fitote.2013.10.0105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2qsg%253D%253D&md5=cd39ee817d4b79de0642d10b904ee64bSynergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basisYang, Yong; Zhang, Zaiqi; Li, Shuping; Ye, Xiaoli; Li, Xuegang; He, KaiFitoterapia (2014), 92 (), 133-147CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)A review. Herbal medicine, esp. traditional Chinese medicine and Ayurvedic medicine have played and still play an important role in fighting against various diseases. Emerging clin. studies regarding traditional Chinese medicine have provided convincing evidence for the first time to gain credibility and reputation outside China. Although synergistic therapeutic actions of herbal ingredients have been frequently reported, few reports have offered clear underlying mechanisms. This might be the main reason for the conflicting views with respect to the therapeutic efficacy of medicinal herbs. Therefore, this paper reviews the herb synergisms reported in the recent literature and discusses thoroughly the mechanisms underlying synergistic actions of herbal ingredients. The authors conducted an electronic literature search to detect articles published mainly in the last five years. Articles were included if they pertained to synergy research of ethnomedicines or the active compds. derived from them, included verification of synergy effects using modern anal. tools and mol.-biol. methods. Results have revealed that the multi-component nature of medicinal herbs makes them particularly suitable for treating complex diseases and offers great potential for exhibiting synergistic actions. The mechanisms underlying synergistic therapeutic actions of herb medicines are (1): different agents may regulate either the same or different target in various pathways, and therefore cooperate in an agonistic, synergistic way; (2): regulate the enzymes and transporters that are involved in hepatic and intestinal metab. to improve oral drug bioavailability; (3): overcome the drug resistance mechanisms of microbial and cancer cells; and (4): eliminate the adverse effects and enhance pharmacol. potency of agents by "processing" or by drug-drug interaction. The exploration of synergistic mechanisms of herbal ingredients will not only help researchers to discover new phytomedicines or drug combinations but also help to avoid the possible neg. synergy. Further clin. research is required for verifying these reported drug combinations and discovered synergistic mechanisms.
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6Caesar, L. K.; Cech, N. B. Synergy and Antagonism in Natural Product Extracts: When 1 + 1 Does Not Equal 2. Nat. Prod. Rep. 2019, 36, 869– 888, DOI: 10.1039/C9NP00011A6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFKqsrfO&md5=6329e8cce673f78a847a41e8a703131eSynergy and antagonism in natural product extracts: when 1 + 1 does not equal 2Caesar, Lindsay K.; Cech, Nadja B.Natural Product Reports (2019), 36 (6), 869-888CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Covering: 2000 to 2019According to a 2012 survey from the Centers for Disease Control and Prevention, approx. 18% of the U. S. population uses natural products (including plant-based or botanical prepns.) for treatment or prevention of disease. The use of plant-based medicines is even more prevalent in developing countries, where for many they constitute the primary health care modality. Proponents of the medicinal use of natural product mixts. often claim that they are more effective than purified compds. due to beneficial "synergistic" interactions. A less-discussed phenomenon, antagonism, in which effects of active constituents are masked by other compds. in a complex mixt., also occurs in natural product mixts. Synergy and antagonism are notoriously difficult to study in a rigorous fashion, particularly given that natural products chem. research methodol. is typically devoted to reducing complexity and identifying single active constituents for drug development. This report represents a crit. review with commentary about the current state of the scientific literature as it relates to studying combination effects (including both synergy and antagonism) in natural product exts. We provide particular emphasis on anal. and Big Data approaches for identifying synergistic or antagonistic combinations and elucidating the mechanisms that underlie their interactions. Specific case studies of botanicals in which synergistic interactions have been documented are also discussed. The topic of synergy is important given that consumer use of botanical natural products and assocd. safety concerns continue to garner attention by the public and the media. Guidance by the natural products community is needed to provide strategies for effective evaluation of safety and toxicity of botanical mixts. and to drive discovery in botanical natural product research.
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7Friesen, J. B.; Liu, Y.; Chen, S.-N.; McAlpine, J. B.; Pauli, G. F. Selective Depletion and Enrichment of Constituents in “Curcumin” and Other Curcuma longa Preparations. J. Nat. Prod. 2019, 82, 621– 630, DOI: 10.1021/acs.jnatprod.9b000207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktlOjsLk%253D&md5=02f3df013c782b59bae7478d95298de1Selective Depletion and Enrichment of Constituents in "Curcumin" and Other Curcuma longa PreparationsFriesen, J. Brent; Liu, Yang; Chen, Shao-Nong; McAlpine, James B.; Pauli, Guido F.Journal of Natural Products (2019), 82 (3), 621-630CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Much uncertainty exists in science and herbal products referencing turmeric (T), turmeric ext. (TE), curcuminoid-enriched turmeric ext. (CTE), further processed curcuminoid-enriched materials (CEM), or curcumin as a single-chem. entity. To facilitate the rational chem. and biol. assessment of turmeric-derived NPs, we introduced the DESIGNER approach of Depleting and Enriching Select Ingredients to Generate Normalized Ext. Resources to Curcuma longa prepns. Countercurrent sepn. of a com. CTE yielded four key materials-lipophilic metabolites; purified curcumin ("purcumin"); a mixt. of curcumin, demethoxycurcumin, and bisdemethoxycurcumin ("purcuminoids"); and hydrophilic metabolites-and enabled prodn. of a curcuminoid-free TE ("nocumin"). Their characterization utilized TLC, 1H (q)NMR spectroscopy, and HPLC.
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8Zuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimarães, F. S. Cannabidiol, a Cannabis sativa Constituent, as an Antipsychotic Drug. Braz. J. Med. Biol. Res. 2006, 39, 421– 429, DOI: 10.1590/S0100-879X20060004000018https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvFGjtbk%253D&md5=67836b59cdf13217813f2daa43242797Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drugZuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimaraes, F. S.Brazilian Journal of Medical and Biological Research (2006), 39 (4), 421-429CODEN: BJMRDK; ISSN:0100-879X. (Associacao Brasileira de Divulgacao Cientifica)A review. A high dose of Δ9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of Δ9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochem. techniques which suggested that CBD has a pharmacol. profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addn., open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clin. trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.
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9Mogil, J. S. Laboratory Environmental Factors and Pain Behavior: The Relevance of Unknown Unknowns to Reproducibility and Translation. Lab Anim. 2017, 46, 136– 141, DOI: 10.1038/laban.12239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czpslyhug%253D%253D&md5=4338f12be20a5765890467f3da8e401eLaboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translationMogil Jeffrey SLab animal (2017), 46 (4), 136-141 ISSN:.The poor record of basic-to-clinical translation in recent decades has led to speculation that preclinical research is "irreproducible", and this irreproducibility in turn has largely been attributed to deficiencies in reporting and statistical practices. There are, however, a number of other reasonable explanations of both poor translation and difficulties in one laboratory replicating the results of another. This article examines these explanations as they pertain to preclinical pain research. I submit that many instances of apparent irreproducibility are actually attributable to interactions between the phenomena and interventions under study and "latent" environmental factors affecting the rodent subjects. These environmental variables-often causing stress, and related to both animal husbandry and the specific testing context-differ greatly between labs, and continue to be identified, suggesting that our knowledge of their existence is far from complete. In pain research in particular, laboratory stressors can produce great variability of unpredictable direction, as stress is known to produce increases (stress-induced hyperalgesia) or decreases (stress-induced analgesia) in pain depending on its parameters. Much greater attention needs to be paid to the study of the laboratory environment if replication and translation are to be improved.
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10Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2019, 8, 1009– 1031, DOI: 10.1002/cpdd.66510https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVOhtr7M&md5=1c152b54ce3a70e65dca8bbfe90ee164A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy SubjectsMorrison, Gilmour; Crockett, Julie; Blakey, Graham; Sommerville, KennethClinical Pharmacology in Drug Development (2019), 8 (8), 1009-1031CODEN: CPDDAH; ISSN:2160-7648. (John Wiley & Sons, Inc.)GW Pharmaceuticals' formulation of highly purified cannabidiol oral soln. is approved in the United States for seizures assocd. with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure, N-desmethylclobazam exposure increased, stiripentol exposure increased slightly, while no clin. relevant effect on valproate exposure was obsd. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure, without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clin. significant safety findings.
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11Ghovanloo, M.-R.; Shuart, N. G.; Mezeyova, J.; Dean, R. A.; Ruben, P. C.; Goodchild, S. J. Inhibitory Effects of Cannabidiol on Voltage-Dependent Sodium Currents. J. Biol. Chem. 2018, 293, 16546– 16558, DOI: 10.1074/jbc.RA118.00492911https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVSlt7%252FE&md5=40b508435c5e7d9b7e220e8e05a03d54Inhibitory effects of cannabidiol on voltage-dependent sodium currentsGhovanloo, Mohammad-Reza; Shuart, Noah Gregory; Mezeyova, Janette; Dean, Richard A.; Ruben, Peter C.; Goodchild, Samuel J.Journal of Biological Chemistry (2018), 293 (43), 16546-16558CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A review. Cannabis sativa contains many related compds. known as phytocannabinoids. The main psychoactive and nonpsychoactive compds. are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), resp. Much of the evidence for clin. efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiol. of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concns. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temp.-dependent, with potency increasing at lower temps. We conclude that CBD's mode of action likely involves (1) compd. partitioning in lipid membranes, which alters membrane fluidity affecting gating, and (2) undetd. direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.
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12Watkins, A. R. Cannabinoid Interactions with Ion Channels and Receptors. Channels 2019, 13, 162– 167, DOI: 10.1080/19336950.2019.161582412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7lslWlsg%253D%253D&md5=7ee0ebb3aee6565c669dab8692c2eb3eCannabinoid interactions with ion channels and receptorsWatkins Abeline RoseChannels (Austin, Tex.) (2019), 13 (1), 162-167 ISSN:.Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Nav). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Nav. Nav are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Nav potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.
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13Gertsch, J. The Intricate Influence of the Placebo Effect on Medical Cannabis and Cannabinoids. Med. Cannabis Cannabinoids 2018, 1, 60– 64, DOI: 10.1159/000489291There is no corresponding record for this reference.
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14WHO CBD Report May 2018. Cannabidiol (CBD). Critical Review Report. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf?ua=1 (accessed Oct 25, 2019).There is no corresponding record for this reference.
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15Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365, DOI: 10.3389/fphar.2018.0136515https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVGmtL%252FM&md5=75d60a2ef4d2866558759c1ec05a02efA systematic review on the pharmacokinetics of cannabidiol in humansMillar, Sophie A.; Stone, Nicole L.; Yates, Andrew S.; O'Sullivan, Saoirse E.Frontiers in Pharmacology (2018), 9 (), 1365CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2-5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the abs. bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Anal. and understanding of properties such as bioavailability and half-life is crit. to future therapeutic success, and robust data from a variety of formulations is required.
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16Office of the Commissioner. What to Know About Products Containing Cannabis and CBD. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis (accessed Apr 23, 2020).There is no corresponding record for this reference.
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17Gaoni, Y.; Mechoulam, R. Hashish—VII: The Isomerization of Cannabidiol to Tetrahydrocannabinols. Tetrahedron 1966, 22, 1481– 1488, DOI: 10.1016/S0040-4020(01)99446-317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xkt1Sqt74%253D&md5=f4842df46ea46da10b951ce4d84a6a82Hashish. VII. Isomerization of cannabidiol to tetrahydrocannabinolsGaoni, Y.; Mechoulam, R.Tetrahedron (1966), 22 (4), 1481-8CODEN: TETRAB; ISSN:0040-4020.cf. CA 63, 2919c, 9849a. Depending on the reaction conditions used, the physiol. active products obtained by Adams on isomerization of the inactive cannabidiol with acids are shown to be either Δ1(6)-tetrahydrocannabinol (I) or a mixt. of I, Δ1-tetrahydrocannabinol and the 2 isomers of 1 ethoxyhexahydrocannabinol.
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18Gutman, A. L.; Etinger, M.; Fedotev, I.; Khanolkar, R. Methods for Purifying Trans-(−)-Δ9-Tetrahydrocannabinol and Trans-(+)-Δ9-Tetrahydrocannabinol. U.S. Patent 8383842, 2006.There is no corresponding record for this reference.
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19Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes. J. Nat. Prod. 2016, 79, 324– 331, DOI: 10.1021/acs.jnatprod.5b0094919https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVynt7s%253D&md5=22ba257f20240b854d5a271d30d002baEvolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different ChemotypesAizpurua-Olaizola, Oier; Soydaner, Umut; Ozturk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, AresatzJournal of Natural Products (2016), 79 (2), 324-331CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The evolution of major cannabinoids and terpenes during the growth of Cannabis sativa plants was studied. In this work, seven different plants were selected: three each from chemotypes I and III and one from chemotype II. Fifty clones of each mother plant were grown indoors under controlled conditions. Every week, three plants from each variety were cut and dried, and the leaves and flowers were analyzed sep. Eight major cannabinoids were analyzed via HPLC-DAD, and 28 terpenes were quantified using GC-FID and verified via GC-MS. The chemotypes of the plants, as defined by the tetrahydrocannabinolic acid/cannabidiolic acid (THCA/CBDA) ratio, were clear from the beginning and stable during growth. The concns. of the major cannabinoids and terpenes were detd., and different patterns were found among the chemotypes. In particular, the plants from chemotypes II and III needed more time to reach peak prodn. of THCA, CBDA, and monoterpenes. Differences in the cannabigerolic acid development among the different chemotypes and between monoterpene and sesquiterpene evolution patterns were also obsd. Plants of different chemotypes were clearly differentiated by their terpene content, and characteristic terpenes of each chemotype were identified.
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20Basas-Jaumandreu, J.; de Las Heras, F. X. C. GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa. Planta Med. 2020, 86, 338– 347, DOI: 10.1055/a-1110-104520https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlaht7c%253D&md5=bc6cd94ef2fb2d1addd0d006ab574534GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativaBasas-Jaumandreu, Josep; de las Heras, F. Xavier C.Planta Medica (2020), 86 (5), 338-347CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)Phytochem. investigation of the lipids extd. from seeds of Cannabis sativaby GC-MS showed 43 cannabinoids, 16 of which are new. The ext. is dominated by Δ 9-tetrahydrocannabinolic acid (A) and its neutral deriv. trans-Δ 9-tetrahydrocannabinol-C 5(THC) Cisand trans-Δ 9-tetrahydrocannabinol-C 7isomers with an ethyl-pentyl branched chain together with minor amts. of trans-Δ 9-tetrahydrocannabinol with a methyl-pentyl C 6branched side chain were identified as new natural compds. Four cannabichromene isomers with a C 5side chain are postulated to be derived from the double bond migration at the terminal isoprenyl unit. C 7cannabichromene together with the neutral and acidic forms of cannabinol-C 7were also detected. The mass spectrum of these homologues as trimethylsilyl (TMS) derivs. are presented, and the fragmentation patterns are discussed.
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21Luo, X.; Reiter, M. A.; d’Espaux, L.; Wong, J.; Denby, C. M.; Lechner, A.; Zhang, Y.; Grzybowski, A. T.; Harth, S.; Lin, W.; Lee, H.; Yu, C.; Shin, J.; Deng, K.; Benites, V. T.; Wang, G.; Baidoo, E. E. K.; Chen, Y.; Dev, I.; Petzold, C. J.; Keasling, J. D. Complete Biosynthesis of Cannabinoids and Their Unnatural Analogues in Yeast. Nature 2019, 567, 123– 126, DOI: 10.1038/s41586-019-0978-921https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmsVyqtbg%253D&md5=7cb609e2be139b5158982daf739a6491Complete biosynthesis of cannabinoids and their unnatural analogues in yeastLuo, Xiaozhou; Reiter, Michael A.; d'Espaux, Leo; Wong, Jeff; Denby, Charles M.; Lechner, Anna; Zhang, Yunfeng; Grzybowski, Adrian T.; Harth, Simon; Lin, Weiyin; Lee, Hyunsu; Yu, Changhua; Shin, John; Deng, Kai; Benites, Veronica T.; Wang, George; Baidoo, Edward E. K.; Chen, Yan; Dev, Ishaan; Petzold, Christopher J.; Keasling, Jay D.Nature (London, United Kingdom) (2019), 567 (7746), 123-126CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia. Some cannabinoids, the hallmark constituents of Cannabis, and their analogs have been investigated extensively for their potential medical applications. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids, and their structural complexity, which limits bulk chem. synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogs. Feeding different fatty acids to our engineered strains yielded cannabinoid analogs with modifications in the part of the mol. that is known to alter receptor binding affinity and potency. We also demonstrated that our biol. system could be complemented by simple synthetic chem. to further expand the accessible chem. space. Our work presents a platform for the prodn. of natural and unnatural cannabinoids that will allow for more rigorous study of these compds. and could be used in the development of treatments for a variety of human health problems.
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22Kumari, S.; Pundhir, S.; Priya, P.; Jeena, G.; Punetha, A.; Chawla, K.; Firdos Jafaree, Z.; Mondal, S.; Yadav, G. EssOilDB: A Database of Essential Oils Reflecting Terpene Composition and Variability in the Plant Kingdom. Database 2014, 2014, bau120 DOI: 10.1093/database/bau120There is no corresponding record for this reference.
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23Degenhardt, F.; Stehle, F.; Kayser, O. The Biosynthesis of Cannabinoids. In Handbook of Cannabis and Related Pathologies. Biology, Pharmacology, Diagnosis, and Treatment; Preedy, V. R., Ed.; Elsevier: London, 2017; pp 13– 23.There is no corresponding record for this reference.
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24Pauli, G. F.; Chen, S.-N.; Simmler, C.; Lankin, D. C.; Gödecke, T.; Jaki, B. U.; Friesen, J. B.; McAlpine, J. B.; Napolitano, J. G. Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity Assay. J. Med. Chem. 2014, 57, 9220– 9231, DOI: 10.1021/jm500734a24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslahsLzF&md5=78900d0b03e31739e50c04c63c55dba7Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity AssayPauli, Guido F.; Chen, Shao-Nong; Simmler, Charlotte; Lankin, David C.; Godecke, Tanja; Jaki, Birgit U.; Friesen, J. Brent; McAlpine, James B.; Napolitano, Jose G.Journal of Medicinal Chemistry (2014), 57 (22), 9220-9231CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. In any biomedical and chem. context, a truthful description of chem. constitution requires coverage of both structure and purity. This qualification affects all drug mols., regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly crit. in discovery programs and whenever chem. is linked with biol. and/or therapeutic outcome. Compared with chromatog. and elemental anal., quant. NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Abs. qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical 1H qNMR (qHNMR) procedures with simultaneous qual. and (abs.) quant. capability. This study reviews underlying concepts, provides a framework for std. qHNMR purity assays, and shows how adequate accuracy and precision are achieved for the intended use of the material.
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25Martin Emanuele, R.; Shattock-Gordon, T.; Williford, T.; Andres, M.; Andres, P. New Solid Forms of Cannabidiol and Uses Thereof. World Intellectual Property Organization. WO 2019118360 A1, 2019.There is no corresponding record for this reference.
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26Mechoulam, R.; Hanuš, L. Cannabidiol: An Overview of Some Chemical and Pharmacological Aspects. Part I: Chemical Aspects. Chem. Phys. Lipids 2002, 121, 35– 43, DOI: 10.1016/S0009-3084(02)00144-526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xpslansrg%253D&md5=928634dca87b012a94252b05170a8c0aCannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspectsMechoulam, Raphael; Hanus, LumirChemistry and Physics of Lipids (2002), 121 (1-2), 35-43CODEN: CPLIA4; ISSN:0009-3084. (Elsevier Science Ltd.)A review. Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chem. of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
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27Popovic, A.; Morelato, M.; Roux, C.; Beavis, A. Review of the Most Common Chemometric Techniques in Illicit Drug Profiling. Forensic Sci. Int. 2019, 302, 109911, DOI: 10.1016/j.forsciint.2019.10991127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFCmsL3K&md5=3d3759d9a3dd3f720b411706bb299c76Review of the most common chemometric techniques in illicit drug profilingPopovic, Ana; Morelato, Marie; Roux, Claude; Beavis, AlisonForensic Science International (2019), 302 (), 109911CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)A review. The information generated through drug profiling can be used to infer a common source between one or several seizures as well as drug trafficking routes to provide insights into drug markets. Although well established, it is time-consuming and ineffective to compare all drug profiles manually. In recent years, there has been a push to automate processes to enable a more efficient comparison of illicit drug specimens. Various chemometric methods have been employed to compare and interpret forensic case data promptly. The intelligence that is produced can be used by decision-makers to disrupt or reduce the impact of illicit drug markets. This review highlights the most common chemometric techniques used in drug profiling and more specifically, the most efficient comparison metrics and pattern recognition techniques outlined in the literature.
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28O’Neil, M. J. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; Royal Society of Chemistry: Cambridge, U.K., 2013; 2707.There is no corresponding record for this reference.
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29Pauli, G. F.; Gödecke, T.; Jaki, B. U.; Lankin, D. C. Quantitative 1H NMR. Development and Potential of an Analytical Method: An Update. J. Nat. Prod. 2012, 75, 834– 851, DOI: 10.1021/np200993k29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltFGisLw%253D&md5=aaee4e1fe38121ba9e222c5e6d661269Quantitative 1H NMR. Development and Potential of an Analytical Method: An UpdatePauli, Guido F.; Godecke, Tanja; Jaki, Birgit U.; Lankin, David C.Journal of Natural Products (2012), 75 (4), 834-851CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review. Covering the literature from mid-2004 until the end of 2011, this review continues a previous literature overview on quant. 1H NMR (qHNMR) methodol. and its applications in the anal. of natural products. Among the foremost advantages of qHNMR is its accurate function with external calibration, the lack of any requirement for identical ref. materials, a high precision and accuracy when properly validated, and an ability to quantitate multiple analytes simultaneously. As a result of the inclusion of over 170 new refs., this updated review summarizes a wealth of detailed experiential evidence and newly developed methodol. that supports qHNMR as a valuable and unbiased anal. tool for natural product and other areas of research.
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30Hazekamp, A.; Choi, Y. H.; Verpoorte, R. Quantitative Analysis of Cannabinoids from Cannabis sativa Using 1H-NMR. Chem. Pharm. Bull. 2004, 52, 718– 721, DOI: 10.1248/cpb.52.71830https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXltFKqsL4%253D&md5=571f3c33fef65c66e2fb174c4e4e0da8Quantitative analysis of cannabinoids from Cannabis sativa using 1H-NMRHazekamp, Arno; Choi, Young Hae; Verpoorte, RobertChemical & Pharmaceutical Bulletin (2004), 52 (6), 718-721CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A 1H-NMR method has been developed for the quant. anal. of pure cannabinoids and for cannabinoids present in Cannabis sativa plant material without any chromatog. purifn. The expt. was performed by the anal. of singlets in the range of δ 4.0-7.0 in the 1H-NMR spectrum, in which distinguishable signals of each cannabinoid are shown. Quantitation was performed by calcg. the relative ratio of the peak area of selected proton signals of the target compds. to the known amt. of the internal std., anthracene. For this method no ref. compds. are needed. It allows rapid and simple quantitation of cannabinoids with a final anal. time of only 5 min without the need for a pre-purifn. step.
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31Siciliano, C.; Bartella, L.; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A. 1H NMR Quantification of Cannabidiol (CBD) in Industrial Products Derived from Cannabis sativa L. (hemp) Seeds - IOPscience. IOP Conf. Ser.: Mater. Sci. Eng. 2019, 572, 012010, DOI: 10.1088/1757-899X/572/1/01201031https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVajsA%253D%253D&md5=c61b5657c5c2d4b40bc43770bcc9803e1H NMR quantification of cannabidiol (CBD) in industrial products derived from Cannabis sativa L. (hemp) seedsSiciliano, C.; Bartella, Lucia; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A.IOP Conference Series: Materials Science and Engineering (2019), 572 (International Conference on Innovative Research: ICIR EUROINVENT 2019), 012010CODEN: ICSMGW; ISSN:1757-899X. (IOP Publishing Ltd.)A practicable and reliable quant. proton NMR (1H qNMR) method was developed and evaluated for the qual. and quant. detn. of cannabidiol (CBD), the principal and most important among cannabinoids in Cannabis sativa L. (hemp), and present in food products and animal feeding derived from the industrial processing of hemp seeds. Specificity, sensitivity, linearity range, precision, accuracy, LOD and LOQ of the method proved to be entirely satisfactory. This spectroscopic method uses the unlabeled residual solvent of CDCl3 as the "intrinsic" internal std. The develop procedure might also be applied to measure levels of all the other lawful natural cannabinoids in com. productions obtained from hemp seeds. Moreover, the rapid and relatively economical quantification of CBD could be of great importance, because it is possible to candidate this cannabinoid to the role of a mol. marker attesting food processing quality.
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32Choules, M. P.; Bisson, J.; Simmler, C.; McAlpine, J. B.; Giancaspro, G.; Bzhelyansky, A.; Niemitz, M.; Pauli, G. F. NMR Reveals an Undeclared Constituent in Custom Synthetic Peptides. J. Pharm. Biomed. Anal. 2020, 178, 112915, DOI: 10.1016/j.jpba.2019.11291532https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVyht7nM&md5=8641a2f32d8a85596e4e3faf5b27170dNMR reveals an undeclared constituent in custom synthetic peptidesChoules, Mary P.; Bisson, Jonathan; Simmler, Charlotte; McAlpine, James B.; Giancaspro, Gabriel; Bzhelyansky, Anton; Niemitz, Matthias; Pauli, Guido F.Journal of Pharmaceutical and Biomedical Analysis (2020), 178 (), 112915CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)Whereas generic, LC-based pharmaceutical control quality procedures depend largely on the detection mode and can be particularly 'blind' to certain impurities, NMR is a more versatile and, thus, often more judicious detector. While adulteration presents ever-evolving challenges for the anal. of active pharmaceutical ingredients (APIs) and finished products sold in the worldwide (online) marketplace, research chems. are usually trusted rather than being considered flawed or even adulterated. This report shows how NMR anal. uncovered the unanticipated presence of substantial amts. of mannitol (20 and 43% wt./wt.) as undeclared constituent in two custom synthetic peptides, DR and DRVYI, that were sourced com. Quant. 1H NMR (qHNMR) readily detected the contaminant, even on a 60 MHz benchtop instrument, and quantified the highly polar and UV-transparent adulterant. Quantum-mech. 1H iterative Full Spin Anal. (HiFSA) not only achieved unambiguous identification of both the mannitol and the peptides, but also confirmed the quant. results. The cases show that exptl. verification supersedes trust in both pharmaceutical and research QC. They also highlight the promising utility of both established high-field and recently re-evolving low-field benchtop qHNMR. The unanticipated findings remind manufacturers and researchers alike about the advantages of including/performing NMR and qNMR with routine CofA documentation and/or verification of research grade chems. Esp. when done jointly, this can greatly improve confidence in research and help streamline the pharmaceutical QC toolbox.
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33Bisson, J.; Simmler, C.; Chen, S.-N.; Friesen, J. B.; Lankin, D. C.; McAlpine, J. B.; Pauli, G. F. Dissemination of Original NMR Data Enhances Reproducibility and Integrity in Chemical Research. Nat. Prod. Rep. 2016, 33, 1028– 1033, DOI: 10.1039/C6NP00022C33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XosValtrs%253D&md5=6f67b234eacdee2ba368ad0667e6f96bDissemination of original NMR data enhances reproducibility and integrity in chemical researchBisson, Jonathan; Simmler, Charlotte; Chen, Shao-Nong; Friesen, J. Brent; Lankin, David C.; McAlpine, James B.; Pauli, Guido F.Natural Product Reports (2016), 33 (9), 1028-1033CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)The notion of data transparency is gaining a strong awareness among the scientific community. The availability of raw data is actually regarded as a fundamental way to advance science by promoting both integrity and reproducibility of research outcomes. Particularly, in the field of natural product and chem. research, NMR spectroscopy is a fundamental tool for structural elucidation and quantification (qNMR). As such, the accessibility of original NMR data, i.e., Free Induction Decays (FIDs), fosters transparency in chem. research and optimizes both peer review and reproducibility of reports by offering the fundamental tools to perform efficient structural verification. Although original NMR data are known to contain a wealth of information, they are rarely accessible along with published data. This viewpoint discusses the relevance of the availability of original NMR data as part of good research practices not only to promote structural correctness, but also to enhance traceability and reproducibility of both chem. and biol. results.
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34McAlpine, J. B.; Chen, S.-N.; Kutateladze, A.; MacMillan, J. B.; Appendino, G.; Barison, A.; Beniddir, M. A.; Biavatti, M. W.; Blüml, S.; Boufridi, A.; Butler, M. S.; Capon, R. J.; Choi, Y. H.; Coppage, D.; Crews, P.; Crimmins, M. T.; Csete, M.; Dewapriya, P.; Egan, J. M.; Garson, M. J.; Genta-Jouve, G.; Gerwick, W. H.; Gross, H.; Harper, M. K.; Hermanto, P.; Hook, J. M.; Hunter, L.; Jeannerat, D.; Ji, N.-Y.; Johnson, T. A.; Kingston, D. G. I.; Koshino, H.; Lee, H.-W.; Lewin, G.; Li, J.; Linington, R. G.; Liu, M.; McPhail, K. L.; Molinski, T. F.; Moore, B. S.; Nam, J.-W.; Neupane, R. P.; Niemitz, M.; Nuzillard, J.-M.; Oberlies, N. H.; Ocampos, F. M. M.; Pan, G.; Quinn, R. J.; Reddy, D. S.; Renault, J.-H.; Rivera-Chávez, J.; Robien, W.; Saunders, C. M.; Schmidt, T. J.; Seger, C.; Shen, B.; Steinbeck, C.; Stuppner, H.; Sturm, S.; Taglialatela-Scafati, O.; Tantillo, D. J.; Verpoorte, R.; Wang, B.-G.; Williams, C. M.; Williams, P. G.; Wist, J.; Yue, J.-M.; Zhang, C.; Xu, Z.; Simmler, C.; Lankin, D. C.; Bisson, J.; Pauli, G. F. The Value of Universally Available Raw NMR Data for Transparency, Reproducibility, and Integrity in Natural Product Research. Nat. Prod. Rep. 2019, 36, 35– 107, DOI: 10.1039/C7NP00064B34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlamsrzP&md5=5ca1ec7156152f70e83356b1e198f83eThe value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product researchMcAlpine, James B.; Chen, Shao-Nong; Kutateladze, Andrei; MacMillan, John B.; Appendino, Giovanni; Barison, Andersson; Beniddir, Mehdi A.; Biavatti, Maique W.; Bluml, Stefan; Boufridi, Asmaa; Butler, Mark S.; Capon, Robert J.; Choi, Young H.; Coppage, David; Crews, Phillip; Crimmins, Michael T.; Csete, Marie; Dewapriya, Pradeep; Egan, Joseph M.; Garson, Mary J.; Genta-Jouve, Gregory; Gerwick, William H.; Gross, Harald; Harper, Mary Kay; Hermanto, Precilia; Hook, James M.; Hunter, Luke; Jeannerat, Damien; Ji, Nai-Yun; Johnson, Tyler A.; Kingston, David G. I.; Koshino, Hiroyuki; Lee, Hsiau-Wei; Lewin, Guy; Li, Jie; Linington, Roger G.; Liu, Miaomiao; McPhail, Kerry L.; Molinski, Tadeusz F.; Moore, Bradley S.; Nam, Joo-Won; Neupane, Ram P.; Niemitz, Matthias; Nuzillard, Jean-Marc; Oberlies, Nicholas H.; Ocampos, Fernanda M. M.; Pan, Guohui; Quinn, Ronald J.; Reddy, D. Sai; Renault, Jean-Hugues; Rivera-Chavez, Jose; Robien, Wolfgang; Saunders, Carla M.; Schmidt, Thomas J.; Seger, Christoph; Shen, Ben; Steinbeck, Christoph; Stuppner, Hermann; Sturm, Sonja; Taglialatela-Scafati, Orazio; Tantillo, Dean J.; Verpoorte, Robert; Wang, Bin-Gui; Williams, Craig M.; Williams, Philip G.; Wist, Julien; Yue, Jian-Min; Zhang, Chen; Xu, Zhengren; Simmler, Charlotte; Lankin, David C.; Bisson, Jonathan; Pauli, Guido F.Natural Product Reports (2019), 36 (1), 35-107CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw NMR (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and assocd. fields of chem. and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of exptl. protocols, augment the reproducibility of reported outcomes, including biol. studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
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35Choules, M. P.; Klein, L. L.; Lankin, D. C.; McAlpine, J. B.; Cho, S.-H.; Cheng, J.; Lee, H.; Suh, J.-W.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin. J. Org. Chem. 2018, 83, 6664– 6672, DOI: 10.1021/acs.joc.8b0098835https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvFanu78%253D&md5=ae7081d9e1a29208a81a2a0a06969906Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and RufomycinChoules, Mary P.; Klein, Larry L.; Lankin, David C.; McAlpine, James B.; Cho, Sang-Hyun; Cheng, Jinhua; Lee, Hanki; Suh, Joo-Won; Jaki, Birgit U.; Franzblau, Scott G.; Pauli, Guido F.Journal of Organic Chemistry (2018), 83 (12), 6664-6672CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Residual complexity (RC) involves the impact of subtle but crit. structural and biol. features on drug lead validation, including unexplained effects related to unidentified impurities. RC commonly plagues drug discovery efforts due to the inherent imperfections of chromatog. sepn. methods. The new diketopiperazine, rufomyazine (6), and the previously known antibiotic, rufomycin (7), represent a prototypical case of RC that (almost) resulted in the misassignment of biol. activity. The case exemplifies that impurities well below the natural abundance of 13C (1.1%) can be highly relevant and calls for advanced anal. characterization of drug leads with extended molar dynamic ranges of >1:1,000 using qNMR and LC-MS. Isolated from an actinomycete strain, 6 was originally found to be active against Mycobacterium tuberculosis with a min. inhibitory concn. (MIC) of 2 μg/mL and high selectivity. As a part of lead validation, the dipeptide was synthesized and surprisingly found to be inactive. The initially obsd. activity was eventually attributed to a very minor contamination (0.24% [m/m]) with a highly active cyclic peptide (MIC ∼ 0.02 μM), subsequently identified as an analog of 7. This study illustrates the serious implications RC can exert on org. chem. and drug discovery, and what efforts are vital to improve lead validation and efficiency, esp. in NP-related drug discovery programs.
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36Pauli, G. F.; Chen, S.-N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study. J. Nat. Prod. 2012, 75, 1243– 1255, DOI: 10.1021/np300066q36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsVeru70%253D&md5=15d145c2988692d26558d6d4361337d9Analysis and Purification of Bioactive Natural Products: The AnaPurNa StudyPauli, Guido F.; Chen, Shao-Nong; Friesen, J. Brent; McAlpine, James B.; Jaki, Birgit U.Journal of Natural Products (2012), 75 (6), 1243-1255CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review on the survey of anal. methodol. such as chromatog. and spectroscopy used for isolation and purity assessment of bioactive natural products (NPs), which have been employed in the almost 2000 publications in the recent years.
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37Citti, C.; Linciano, P.; Forni, F.; Vandelli, M. A.; Gigli, G.; Laganà, A.; Cannazza, G. Analysis of Impurities of Cannabidiol from Hemp. Isolation, Characterization and Synthesis of Cannabidibutol, the Novel Cannabidiol Butyl Analog. J. Pharm. Biomed. Anal. 2019, 175, 112752, DOI: 10.1016/j.jpba.2019.06.04937https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVajt77O&md5=9b4cdb8a8e76150ebd70a648598a2284Analysis of impurities of cannabidiol from hemp. Isolation, characterization and synthesis of cannabidibutol, the novel cannabidiol butyl analogCitti, Cinzia; Linciano, Pasquale; Forni, Flavio; Vandelli, Maria Angela; Gigli, Giuseppe; Lagana, Aldo; Cannazza, GiuseppeJournal of Pharmaceutical and Biomedical Analysis (2019), 175 (), 112752CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)Cannabidiol (CBD), one of the two major active principles present in Cannabis sativa, is gaining great interest among the scientific community for its pharmaceutical, nutraceutical and cosmetic applications. CBD can be prepd. either by chem. synthesis or extn. from Cannabis sativa (hemp). The latter is more convenient from several points of view, including environmental and economic, but mainly for the absence of harmful org. solvents generally employed in the chem. synthesis. Although CBD produced by hemp extn. is the most widely employed, it carries two major impurities. The first one is the already known cannabidivarin (CBDV), whereas the second one is supposed to be the Bu analog of CBD with a four-term alkyl side chain. In this work, we report the isolation by semi-preparative liq. chromatog. and the unambiguous identification of this second impurity. A comprehensive spectroscopic characterization, including NMR, UV, IR, CD and high-resoln. mass spectrometry (HRMS), was carried out on this natural cannabinoid. In order to confirm its abs. configuration and chem. structure, the stereoisomer (1R,6R) of the supposed cannabinoid was synthesized and the physicochem. and spectroscopic properties, along with the stereochem., matched those of the natural isolated mol. According to the International Nonproprietary Name, we suggested the name of cannabidibutol (CBDB) for this cannabinoid. Lastly, an HPLC-UV method was developed and validated for the qual. and quant. detn. of CBDV and CBDB in samples of CBD extd. from hemp and produced according to Good Manufg. Practices regulations for pharmaceutical and cosmetic use.
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38Freeman, T. P.; Hindocha, C.; Green, S. F.; Bloomfield, M. A. P. Medicinal Use of Cannabis Based Products and Cannabinoids. BMJ. 2019, 365, l1141 DOI: 10.1136/bmj.l1141There is no corresponding record for this reference.
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39Office of the Commissioner. FDA Regulation of Cannabis and Cannabis-Derived Products: Q&A. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd (accessed Apr 22, 2020).There is no corresponding record for this reference.
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40Office of the Commissioner. FDA and Cannabis: Research and Drug Approval Process. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process (accessed Apr 22, 2020).There is no corresponding record for this reference.
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41Biosciences, G. EPIDIOLEX (cannabidiol) oral solution, CV prescribing information; revised 12/2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed Dec 19, 2019).There is no corresponding record for this reference.
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42Office of the Commissioner. Warning Letters and Test Results for Cannabidiol-Related Products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products (accessed Apr 27, 2020).There is no corresponding record for this reference.
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43Jacob, A.; Todd, A. R. 119. Cannabis Indica. Part II. Isolation of Cannabidiol from Egyptian Hashish. Observations on the Structure of Cannabinol. J. Chem. Soc. 1940, 649– 653, DOI: 10.1039/jr940000064943https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3cXjs1SgsA%253D%253D&md5=7f05442ba9a7024a106ac13fc4dd9fc1Cannabis indica. II. Isolation of cannabidiol from Egyptian hashish. Observations on the structure of cannabinolJacob, A.; Todd, A. R.Journal of the Chemical Society (1940), (), 649-53CODEN: JCSOA9; ISSN:0368-1769.cf. C. A. 33, 5073.3; 34, 3441.2. Cannabidiol (I), C21H30O2, a typical constituent of American hemp resin (Adams, Hunt and Clark, C. A. 34, 1635.7), has been isolated from hashish of Egyptian origin, where it was accompanied by an approx. equal amt. of cannabinol (II). Extn. of 500 g. of the drug with 3 l. petr. ether (b. 40-60°) at room temp. gives 70 g. of a thick brown oil; a MeOH soln. (350 cc.) deposits 3 g. of a cryst. hydrocarbon; evapn. of the MeOH gives 60 g. of oil which, distd. at 10-3 mm. in a mol. still, gives 28.4 g. of a resin at 110-30°; this resin was esterified with p-O2NC6H4COCl and the portion insol. in petr. ether was taken up in a mixt. of 30% C6H6 and 70% petr. ether and passed through Al2O3; washing with the mixed solvent and crystn. of the product from EtOH give 5 g. of the p-nitrobenzoate of II, m. 159-60°; the remainder of the material on the Al2O3 was removed with Me2CO, hydrolyzed and transformed into the bis-3,5-dinitrobenzoate (4 g.) of I, m. 106-7°. II gives an intense blue color with 2,6-dichloroquinone chloroimine, indicating that the p-position to the phenolic OH group is unsubstituted; the absorption spectrum of II in EtOH shows a max. at 2850 A. (ε mol. = 16,790); this agrees with the presence of a di-Ph chromophoric system. I contains 2 double bonds; its absorption spectrum in EtOH has a max. at 2775 A. (ε mol. = 1350); thus neither of the double bonds can be conjugated with the arom. nucleus. Possible formulas for II are proposed, based on the color reactions. Both I and II appear to be inactive in the Gayer test in rabbits.
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44Adams, R.; Baker, B. R.; Wearn, R. B. Structure of Cannabinol. III. Synthesis of Cannabinol, 1-Hydroxy-3-N-Amyl-6,6,9-Trimethyl-6-dibenzopyran1. J. Am. Chem. Soc. 1940, 62, 2204– 2207, DOI: 10.1021/ja01865a08344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3cXktlaktQ%253D%253D&md5=3de762ddb6d9d67935dff0b3c2a14b07Structure of cannabinol. III. Synthesis of cannabinol, 1-hydroxy-3-amyl-6,6,9-trimethyl-6-dibenzopyranAdams, Roger; Baker, B. R.; Wearn, R. B.Journal of the American Chemical Society (1940), 62 (), 2204-7CODEN: JACSAT; ISSN:0002-7863.o-BrC6H4CO2H, menthone, EtONa and Cu(OAc)2 in abs. EtOH, refluxed 5 h., give 1-keto-3,3-dimethyl-1,2,3,4-tetrahydro-6-dibenzopyrone, m. 145-6° (m. ps. cor.). Olivetol is reduced by H and Raney Ni at 125° (initial pressure of 2800 lbs.) in about 1 min., giving 70-5% of dihydro.ovrddot.odlivetol (5-amyl-1,3-cyclohexanedione) (I), m. 70-1°; a synthesis from AmCHO in 29% is also reported, hexylideneacetone reacting with CH2(CO2Et)2 and EtONa. Condensation of 4,2-MeBrC6H3CO2H and I with EtONa and Cu(OAc)2 gives 78% of 1-keto-3-amyl-9-methyl-1,2,3,4-tetrahydro-6-dibenzopyrone (II), m. 95-6°; heating 10.4 g. II and 1.13 g. S at 250° for 25 min. yields 34% (with 43% recovery of II) of 1-hydroxy-3-amyl-9-methyl-6-dibenzopyrone (III), m. 186°. Reaction of III with MeMgI gives 75% of cannabinol (IV), m. 76-7°. IV was characterized by its Ac deriv., m. 75-6°, its 1-p-nitrobenzoxy deriv., yellow, m. 165-6°, and its 1-m-nitrobenzenesulfonoxy deriv., yellow, m. 127-9°. 5-Ethyl-3-hepten-2-one and CHNa(CO2Et)2 give 5-diethylmethyl-1,3-cyclohexanedione, m. 104-5°; the following compds. were prepd. as above: 1-keto-3-diethylmethyl-9-methyl-1,2,3,4-tetrahydro-6-dibenzopyrone, m. 111-12°; 1-hydroxy-3-diethylmethyl-9-methyl-6-dibenzopyrone, m. 217-18° (Ac deriv., m. 128-30°); 1-hydroxy-3-diethylmethyl-6,6,9-trimethyl-6-dibenzopyran, m. 133-4° (Ac deriv., m. 103°; 1-p-nitrobenzoxy deriv., yellow, m. 171°).
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45Jones, P. G.; Falvello, L.; Kennard, O.; Sheldrick, G. M.; Mechoulam, R. Cannabidiol. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 3211– 3214, DOI: 10.1107/S0567740877010577There is no corresponding record for this reference.
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46Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F. P.; Pichini, S. Evaluation of Cannabinoids Concentration and Stability in Standardized Preparations of Cannabis Tea and Cannabis Oil by Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry. Clin. Chem. Lab. Med. 2017, 55, 1555– 1563, DOI: 10.1515/cclm-2016-106046https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlymtLnP&md5=58e5d46a27508b7b9539bf8740109296Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometryPacifici, Roberta; Marchei, Emilia; Salvatore, Francesco; Guandalini, Luca; Busardo, Francesco Paolo; Pichini, SimonaClinical Chemistry and Laboratory Medicine (2017), 55 (10), 1555-1563CODEN: CCLMFW; ISSN:1434-6621. (Walter de Gruyter GmbH)Background: : Cannabis has been used since ancient times to relieve neuropathic pain, to lower intraocular pressure, to increase appetite and finally to decrease nausea and vomiting. The combination of the psychoactive cannabis alkaloid Δ9-tetrahydrocannabinol (THC) with the non-psychotropic alkaloids cannabidiol (CBD) and cannabinol (CBN) demonstrated a higher activity than THC alone. The Italian National Institute of Health sought to establish conditions and indications on how to correctly use nationally produced cannabis to guarantee therapeutic continuity in individuals treated with medical cannabis. Methods: : The evaluation of cannabinoids concn. and stability in standardized prepns. of cannabis tea and cannabis oil was conducted using an easy and fast ultra-high performance liq. chromatog. tandem mass spectrometry (UHPLC-MS/MS) assay. Results: : Extn. efficiency of oil was significantly higher than that of water with respect to the different cannabinoids. This was esp. obsd. in the case of the pharmacol. active THC, CBD and their acidic precursors. Fifteen minutes boiling was sufficient to achieve the highest concns. of cannabinoids in the cannabis tea solns. At ambient temp., a significant THC and CBD decrease to 50% or less of the initial concn. was obsd. over 3 and 7 days, resp. When refrigerated at 4 °C, similar decreasing profiles were obsd. for the two compds. The cannabinoids profile in cannabis oil obtained after pre-heating the flowering tops at 145 °C for 30 min in a static oven resulted in a complete decarboxylation of cannabinoid acids CBDA and THCA-A. Nevertheless, it was apparent that heat not only decarboxylated acidic compds., but also significantly increased the final concns. of cannabinoids in oil. The stability of cannabinoids in oil samples was higher than that in tea samples since the max. decrease (72% of initial concn.) was obsd. in THC coming from unheated flowering tops at ambient temp. In the case of the other cannabinoids, at ambient and refrigerated temps., 80%-85% of the initial concns. were measured up to 14 days after oil prepn. Conclusions: : As the first and most important aim of the different cannabis prepns. is to guarantee therapeutic continuity in treated individuals, a strictly standardized prepn. protocol is necessary to assure the availability of a homogeneous product of defined stability.
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47Watanabe, K.; Usami, N.; Yamamoto, I.; Yoshimura, H. Inhibitory Effect of Cannabidiol Hydroxy-Quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice. J. Pharmacobio-Dyn. 1991, 14, 421– 427, DOI: 10.1248/bpb1978.14.42147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmsVOru7w%253D&md5=552b340763e94c5aa31539d328dbbcc3Inhibitory effect of cannabidiol hydroxyquinone, an oxidative product of cannabidiol, on the hepatic microsomal drug-metabolizing enzymes of miceWatanabe, Kazuhito; Usami, Noriyuki; Yamamoto, Ikuo; Yoshimura, HidetoshiJournal of Pharmacobio-Dynamics (1991), 14 (7), 421-7CODEN: JOPHDQ; ISSN:0386-846X.Cannabidiol hydroxyquinone (I) was identified as an air oxidn. product of cannabidiol (CBD). The in vitro incubation of mouse hepatic microsomes with I resulted in a decrease of cytochrome P 450 content. I inhibited the hepatic microsomal drug-metabolizing enzymes of mice. This inhibitory effect was stronger than that of CBD. I (150 μM) inhibited aniline hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase in the microsomes by 70, 52 and 77%, resp., whereas the same concn. of CBD caused the inhibition by 39, 30 and 26%, resp. I (91.5 μM) decreased total heme content by 21% and free SH groups by 11% in the microsomes. The results indicate that I which is an oxidn. product of CBD, inhibits the hepatic microsomal drug-metabolizing enzymes through the decrease of cytochrome P 450 content.
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48Webster, G. R. B.; Sarna, L. P.; Mechoulam, R. Conversion of CBD to Delta8-THC and Delta9-THC. United States Patent 2004/0143126 A1, 2004.There is no corresponding record for this reference.
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49Merrick, J.; Lane, B.; Sebree, T.; Yaksh, T.; O’Neill, C.; Banks, S. L. Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. Cannabis Cannabinoid Res. 2016, 1, 102– 112, DOI: 10.1089/can.2015.000449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsrc%253D&md5=70ba0946c6b284e95185364f3ed72bd5Identification of psychoactive degradants of cannabidiol in simulated gastric and physiological fluidMerrick, John; Lane, Brian; Sebree, Terri; Yaksh, Tony; O'Neill, Carol; Banks, Stan L.Cannabis and Cannabinoid Research (2016), 1 (1), 102-112CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quant. exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concn. range used in this study. CBD was spiked into media contg. 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatog. with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degrdn. followed first-order kinetics at a rate const. of -0.031 min-1 (R2 = 0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiol. buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral anal., mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic ref. stds. Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics obsd. in this study allowed estd. levels to be calcd. and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiol. response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.
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50Nahler, G.; Grotenhermen, F.; Zuardi, A. W.; Crippa, J. A. S. A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Cannabis Cannabinoid Res. 2017, 2, 81– 86, DOI: 10.1089/can.2017.000950https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGltrw%253D&md5=1f0013e56bc11e05534521ca0f30d691A conversion of oral cannabidiol to delta9-tetrahydrocannabinol seems not to occur in humansNahler, Gerhard; Grotenhermen, Franjo; Zuardi, Antonio Waldo; Crippa, Jose A. S.Cannabis and Cannabinoid Research (2017), 2 (1), 81-86CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9-tetrahydrocannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the exptl. conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiol. conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions. Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been obsd. to occur in vivo, even after high doses of oral CBD. In addn., the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concn. difficulties, nausea, tachycardia) has not been obsd. after treatment with CBD in double-blind, randomized, controlled clin. trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact.
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51Watanabe, K.; Itokawa, Y.; Yamaori, S.; Funahashi, T.; Kimura, T.; Kaji, T.; Usami, N.; Yamamoto, I. Conversion of Cannabidiol to Δ9-Tetrahydrocannabinol and Related Cannabinoids in Artificial Gastric Juice, and Their Pharmacological Effects in Mice. Forensic Toxicol. 2007, 25, 16– 21, DOI: 10.1007/s11419-007-0021-y51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotleksLo%253D&md5=84e82b6d8735058caaf1781dfe96dfbfConversion of cannabidiol to Δ9-tetrahydrocannabinol and related cannabinoids in artificial gastric juice, and their pharmacological effects in miceWatanabe, Kazuhito; Itokawa, Yuka; Yamaori, Satoshi; Funahashi, Tatsuya; Kimura, Toshiyuki; Kaji, Toshiyuki; Usami, Noriyuki; Yamamoto, IkuoForensic Toxicology (2007), 25 (1), 16-21CODEN: FTOOAU ISSN:. (Springer Tokyo)Cannabidiol (CBD), a nonpsychoactive cannabinoid, was found to be converted to 9α-hydroxy-hexahydrocannabinol (9α-OH-HHC) and 8-hydroxy-iso-hexahydrocannabinol (8-OH-iso-HHC) together with Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive cannabinoid, and cannabinol in artificial gastric juice. These cannabinoids were identified by gas chromatog.-mass spectrometry (GC-MS) by comparison with the spectral data of the authentic compds. Pharmacol. effects of 9α-OH-HHC and 8-OH-iso-HHC in mice were examd. using catalepsy, hypothermia, pentobarbital-induced sleep prolongation, and antinociception against acetic acid-induced writhing as indexes. The ED50 values (ED producing a 50% redn. of control; mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the cataleptogenic effect were 8.0 and 30.4, resp. 8-OH-iso-HHC (10mg/kg, i.v.) produced a significant hypothermia from 15 to 90min after administration, although 9α-OH-HHC failed to induce such an effect at the same dose. However, both HHCs (10mg/kg, i.v.) significantly prolonged pentobarbital-induced sleeping time by 1.8 to 8.0 times as compared with the control soln. with 1% Tween 80-saline. The ED50 values (mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the antinociceptive effect were 14.1 and 39.4, resp. The present study demonstrated that CBD can be converted to Δ9-THC and its related cannabinoids, 9α-OH-HHC and 8-OH-iso-HHC, in artificial gastric juice, and that these HHCs show Δ9-THC-like effects in mice, although their pharmacol. effects were less potent than those of Δ9-THC.
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52Grotenhermen, F.; Russo, E.; Zuardi, A. W. Even High Doses of Oral Cannabidiol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016; 1(1): 102–112; DOI: 10.1089/can.2015.0004. Cannabis Cannabinoid Res. 2017, 2, 1– 4, DOI: 10.1089/can.2016.003652https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsbo%253D&md5=94db2af2e70d52b34dda35a823f88783Even high doses of oral cannabidiol do not cause THC-like effects in humans: comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102-112; DOI: 10.1089/can.2015.0004Grotenhermen, Franjo; Russo, Ethan; Zuardi, Antonio WaldoCannabis and Cannabinoid Research (2017), 2 (1), 1-4CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)This short communication examines the question whether the exptl. data presented in a study by Merrick et al. are of clin. relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that "the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a pos. physiol. response. They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clin. data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychol., psychomotor, cognitive, or phys. effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clin. studies. In addn., administration of CBD did not result in detectable THC blood concns. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.
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53Lachenmeier, D. W.; Habel, S.; Fischer, B.; Herbi, F.; Zerbe, Y.; Bock, V.; Rajcic de Rezende, T.; Walch, S. G.; Sproll, C. Are Side Effects of Cannabidiol (CBD) Products Caused by Tetrahydrocannabinol (THC) Contamination?. F1000Research 2019, 8, 1394, DOI: 10.12688/f1000research.19931.353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387otVarsw%253D%253D&md5=20573609b25bc14518c1653d202a71adAre side effects of cannabidiol (CBD) products caused by tetrahydrocannabinol (THC) contamination?Lachenmeier Dirk W; Habel Stephanie; Fischer Berit; Herbi Frauke; Zerbe Yvonne; Bock Verena; Rajcic de Rezende Tabata; Walch Stephan G; Sproll ConstanzeF1000Research (2019), 8 (), 1394 ISSN:.Cannabidiol (CBD)-containing products are widely marketed as over the counter products, mostly as food supplements, to avoid the strict rules of medicinal products. Side-effects reported in anecdotal consumer reports or during clinical studies were first assumed to be due to hydrolytic conversion of CBD to psychotropic Δ (9)-tetrahydrocannabinol (Δ (9)-THC) in the stomach after oral consumption. However, research of pure CBD solutions stored in simulated gastric juice or subjected to various storage conditions such as heat and light with specific liquid chromatographic/tandem mass spectrometric (LC/MS/MS) and ultra-high pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UPLC-QTOF) analyses was unable to confirm THC formation. Another hypothesis for the side-effects of CBD products may be residual Δ (9)-THC concentrations in the products as contamination, because most of them are based on crude hemp extracts containing the full spectrum of cannabinoids besides CBD. Analyses of 67 food products of the German market (mostly CBD oils) confirmed this hypothesis: 17 products (25%) contained Δ (9)-THC above the lowest observed adverse effects level (2.5 mg/day). Inversely, CBD was present in the products below the no observed adverse effect level. Hence, it may be assumed that the adverse effects of some commercial CBD products are based on a low-dose effect of Δ (9)-THC and not due to effects of CBD itself. The safety, efficacy and purity of commercial CBD products is highly questionable, and all of the products in our sample collection showed various non-conformities to European food law such as unsafe Δ (9)-THC levels, full-spectrum hemp extracts as non-approved novel food ingredients, non-approved health claims, and deficits in mandatory food labelling requirements. In view of the growing market for such lifestyle products, the effectiveness of the instrument of food business operators' own responsibility for product safety must obviously be challenged.
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54Mascal, M.; Hafezi, N.; Wang, D.; Hu, Y.; Serra, G.; Dallas, M. L.; Spencer, J. P. E. Synthetic, Non-Intoxicating 8,9-Dihydrocannabidiol for the Mitigation of Seizures. Sci. Rep. 2019, 9, 7778, DOI: 10.1038/s41598-019-44056-y54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7pt1Sgsw%253D%253D&md5=607e1c75768f18a1587a78b7af89fb6aSynthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizuresMascal Mark; Hafezi Nema; Wang Deping; Hu Yuhan; Serra Gessica; Dallas Mark L; Spencer Jeremy P EScientific reports (2019), 9 (1), 7778 ISSN:.There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of Δ(9)-tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation.
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55Ben-Shabat, S.; Hanus, L. O.; Katzavian, G.; Gallily, R. New Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory Activity. J. Med. Chem. 2006, 49, 1113– 1117, DOI: 10.1021/jm050709m55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitV2jsQ%253D%253D&md5=5a10e739ac11ac63db66c0eed3dcb6cdNew Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory ActivityBen-Shabat, Shimon; Hanus, Lumir O.; Katzavian, Galia; Gallily, RuthJournal of Medicinal Chemistry (2006), 49 (3), 1113-1117CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cannabidiol (CBD) and cannabidiol dimethylheptyl (CBD-DMH) were hydrogenated to give four different epimers. The new derivs. were evaluated for their ability to modulate the prodn. of reactive oxygen intermediates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-α) by murine macrophages, and for their binding to the cannabinoid receptor (CB1). Surprisingly, we found that these derivs. exhibit good binding to CB1. In addn. hydrogenated CBD and CBD-DMH demonstrate bioactivities different from their original compds.
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56Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D. E.; Brandi, I.; Moriello, A. S.; Davis, J. B.; Mechoulam, R.; Di Marzo, V. Molecular Targets for Cannabidiol and Its Synthetic Analogues: Effect on Vanilloid VR1 Receptors and on the Cellular Uptake and Enzymatic Hydrolysis of Anandamide. Br. J. Pharmacol. 2001, 134, 845– 852, DOI: 10.1038/sj.bjp.070432756https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlChsbk%253D&md5=f79cc419ce01e535d1ed5346edb4e775Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamideBisogno, Tiziana; Hanus, Lumir; De Petrocellis, Luciano; Tchilibon, Susanna; Ponde, Datta E.; Brandi, Ines; Moriello, Aniello Schiano; Davis, John B.; Mechoulam, Raphael; Di Marzo, VincenzoBritish Journal of Pharmacology (2001), 134 (4), 845-852CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)(-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible mol. targets of this compd. We investigated whether CBD and some of its derivs. interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogs, obtained by exchanging the C-7 Me group of CBD with a hydroxy-Me or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concns. in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalyzed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogs, stimulated VR1 with EC50=3.2-3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67-70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compds. were not additive. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (-)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (-)-7-hydroxy-CBD (IC50=34 μM), but not the other analogs (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacol. effects of CBD and its analogs. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
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57Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam, R. Enantiomeric Cannabidiol Derivatives: Synthesis and Binding to Cannabinoid Receptors. Org. Biomol. Chem. 2005, 3 (6), 1116– 1123, DOI: 10.1039/b416943c57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvF2jsr0%253D&md5=47dfb860e82ef35d36a9504306b08d1fEnantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptorsHanus, Lumir O.; Tchilibon, Susanna; Ponde, Datta E.; Breuer, Aviva; Fride, Ester; Mechoulam, RaphaelOrganic & Biomolecular Chemistry (2005), 3 (6), 1116-1123CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiol. effects of therapeutic importance. We have reported that CBD derivs. in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compds. in the enantiomeric (+)-CBD series. The starting materials were the resp. CBD enantiomers and their DMH homologs. The binding of these compds. to the CB1 and CB2 cannabinoid receptors are compared. Surprisingly, contrary to the compds. in the (-) series, which do not bind to the receptors, most of the derivs. in the (+) series bind to the CB1 receptor in the low nanomole range. Some of these compds. also bind weakly to the CB2 receptor.
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58Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin, L. S.; Martin, B. R. Pharmacology and Stereoselectivity of Structurally Novel Cannabinoids in Mice. J. Pharmacol. Exp. Ther. 1988, 247, 1046– 105158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXovVSisg%253D%253D&md5=32c7696e1333349d245d52bb07f18426Pharmacology and stereoselectivity of structurally novel cannabinoids in miceLittle, Patrick J.; Compton, David R.; Johnson, M. Ross; Melvin, Lawrence S.; Martin, Billy R.Journal of Pharmacology and Experimental Therapeutics (1988), 247 (3), 1046-51CODEN: JPETAB; ISSN:0022-3565.The pharmacol. effects of 3 stereoisomeric pairs of structurally novel cannabinoids were tested after i.v. administration in mice for depression of spontaneous activity and the prodn. of hypothermia, antinociception, and catalepsy. The (-)-enantiomers were as much as 770 times more potent than Δ9-6a,10a-trans-tetrahydrocannabinol and were 7-2000 times more potent than their resp. (+)-enantiomers. The order of potency for cannabinoid-induced effects was spontaneous activity > antinociception > hypothermia ≥ catalepsy. Levonantradol was active between 0.123-1.5 mg/kg, whereas dextronantradol, its (+)-enantiomer, was inactive. (-)-CP 55,244 and (-)-CP 55,940, analogs which lack the dihydropyran ring, were 5-775 times more potent than Δ9-6a,10a-trans-tetrahydrocannabinol and 30-2000 times more potent than their resp. (+)-enantiomers. Some sepn. of effects was demonstrated with (+)-CP 55,243 and (+)-CP 56,667, which were inactive in producing hypothermia and catalepsy but were active in the spontaneous activity and tail-flick procedures. The high degree of enantioselectivity and potency of these nonclassical cannabinoids are indicative of a highly specific mechanism of action such as a receptor.
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59Kinney, W. A.; McDonnell, M. E.; Zhong, H. M.; Liu, C.; Yang, L.; Ling, W.; Qian, T.; Chen, Y.; Cai, Z.; Petkanas, D.; Brenneman, D. E. Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS Med. Chem. Lett. 2016, 7, 424– 428, DOI: 10.1021/acsmedchemlett.6b0000959https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVWmt7Y%253D&md5=32249f294f3baf8d6ffa0ffd743ab0c8Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and PermeabilityKinney, William A.; McDonnell, Mark E.; Zhong, Hua Marlon; Liu, Chaomin; Yang, Lanyi; Ling, Wei; Qian, Tao; Chen, Yu; Cai, Zhijie; Petkanas, Dean; Brenneman, Douglas E.ACS Medicinal Chemistry Letters (2016), 7 (4), 424-428CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurol. disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clin. relevant concns. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.
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60BioSpace. Kannalife, Inc. Further Elucidates Mechanism of Action Behind KLS-13019, the Company’s Leading Drug Candidate for the Potential Treatment of Neuropathic Pain. BioSpace. https://www.biospace.com/article/kannalife-inc-further-elucidates-mechanism-of-action-behind-kls-13019-the-company-s-leading-drug-candidate-for-the-potential-treatment-of-neuropathic-pain/ (accessed Apr 27, 2020).There is no corresponding record for this reference.
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61Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T.-L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A. The Novel Endocannabinoid Receptor GPR55 Is Activated by Atypical Cannabinoids but Does Not Mediate Their Vasodilator Effects. Br. J. Pharmacol. 2007, 152, 825– 831, DOI: 10.1038/sj.bjp.070741961https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ejt7vE&md5=9e389e9b687d2ce27817ff44b5a6e513The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effectsJohns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T-L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A.British Journal of Pharmacology (2007), 152 (5), 825-831CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified 'CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator 'CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents. Human recombinant GPR55 was expressed in HEK293T cells and specific GTPγS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myog. were used to det. GPR55 dependence of atypical cannabinoid-induced hemodynamic and vasodilator responses. Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPγS activity (EC50 approx. 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20±2%, KO 26±5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approx. 3 μM for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains. These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents.
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62Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P. J. The Orphan Receptor GPR55 Is a Novel Cannabinoid Receptor. Br. J. Pharmacol. 2007, 152, 1092– 1101, DOI: 10.1038/sj.bjp.070746062https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlCrsbnI&md5=de00567034c31dd815548fdef069f5daThe orphan receptor GPR55 is a novel cannabinoid receptorRyberg, E.; Larsson, N.; Sjoegren, S.; Hjorth, S.; Hermansson, N-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P. J.British Journal of Pharmacology (2007), 152 (7), 1092-1101CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Background: The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a no. of groups in recent years has provided evidence that the system is more complicated and addnl. receptor types should exist to explain ligand activity in a no. of physiol. processes. Exptl. approach: Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPγS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was detd. and further demonstrated by measuring activity of downstream signaling pathways. Key results: We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP 55940. In addn. endocannabinoids including anandamide and virodhamine activate GTPγS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Gα13 and can mediate activation of rhoA, cdc42 and rac1. Conclusions: These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiol. function(s).
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63Romero-Zerbo, S. Y.; Rafacho, A.; Díaz-Arteaga, A.; Suárez, J.; Quesada, I.; Imbernon, M.; Ross, R. A.; Dieguez, C.; Rodríguez de Fonseca, F.; Nogueiras, R.; Nadal, A.; Bermúdez-Silva, F. J. A Role for the Putative Cannabinoid Receptor GPR55 in the Islets of Langerhans. J. Endocrinol. 2011, 211, 177– 185, DOI: 10.1530/JOE-11-016663https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqtLrO&md5=5c5988f648273fd5b0c9c928fdf50554A role for the putative cannabinoid receptor GPR55 in the islets of LangerhansRomero-Zerbo, Silvana Y.; Rafacho, Alex; Diaz-Arteaga, Adenis; Suarez, Juan; Quesada, Ivan; Imbernon, Monica; Ross, Ruth A.; Dieguez, Carlos; Rodriguez de Fonseca, Fernando; Nogueiras, Ruben; Nadal, Angel; Bermudez-Silva, Francisco J.Journal of Endocrinology (2011), 211 (2), 177-185CODEN: JOENAK; ISSN:0022-0795. (BioScientifica Ltd.)The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clin. practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacol. is still enigmatic and its physiol. role is largely unexplored, with no reports investigating its putative role in metab. Thus, we aim to investigate in rats the presence, distribution and putative physiol. role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting β-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients and insulin secretion stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo expts. showed that GPR55 activation increases glucose tolerance and plasma insulin levels, suggesting an in vivo physiol. relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.
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64Console-Bram, L.; Brailoiu, E.; Brailoiu, G. C.; Sharir, H.; Abood, M. E. Activation of GPR18 by Cannabinoid Compounds: A Tale of Biased Agonism. Br. J. Pharmacol. 2014, 171, 3908– 3917, DOI: 10.1111/bph.1274664https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WmsrjN&md5=4685930ff193dd4c44fea180be190dcbActivation of GPR18 by cannabinoid compounds: a tale of biased agonismConsole-Bram, Linda; Brailoiu, Eugen; Brailoiu, Gabriela Cristina; Sharir, Haleli; Abood, Mary E.British Journal of Pharmacology (2014), 171 (16), 3908-3917CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : GPR18 is a candidate cannabinoid receptor, but its classification as such is controversial. The rationale of the study presented herein was to consider the effects of N-arachidonoyl glycine (NAGly) and cannabinoids via differential G-protein coupled pathways, in addn. to β-arrestin signalling. Cellular localization of GPR18 receptors was also examd. Exptl. Approach : Calcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addn., using the DiscoveRx PathHunter CHO-K1 GPR18 β-arrestin cell line, recruitment of β-arrestin was quantified. Key Results : Concn.-dependent increases in intracellular calcium and ERK1/2 phosphorylation were obsd. in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and Δ9-tetrahydrocannabinol (Δ9-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either Gαq or Gαi/o inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of β-arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only Δ9-THC produced a concn.-dependent response. The localization of GPR18 receptors within the HEK293/GPR18 cells is both intracellular, and on the plasma membrane. Conclusions and Implications : These findings suggest that GPR18 activation involves several signal transduction pathways indicative of biased agonism, thereby providing a plausible explanation for the apparent discrepancies in GPR18 activation found in the literature. Addnl., the results presented herein provide further evidence for GPR18 as a candidate cannabinoid receptor.
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65Morales, P.; Reggio, P. H. CBD: A New Hope?. ACS Med. Chem. Lett. 2019, 10, 694– 695, DOI: 10.1021/acsmedchemlett.9b0012765https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXotlSjsL0%253D&md5=781d92a79b5d878220c0caea1f129600CBD: A New Hope?Morales, Paula; Reggio, Patricia H.ACS Medicinal Chemistry Letters (2019), 10 (5), 694-695CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. The nonpsychoactive phytocannabinoid, CBD, was recently approved by the Food and Drug Administration for the treatment of children with drug-resistant epilepsy. This milestone opens new avenues for cannabinoid research. In this Viewpoint, we provide an overview of recent progress in the field highlighting mol. insights into CBD's mechanism of action, as well as its therapeutic potential.
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66Pertwee, R. G. Pharmacological and Therapeutic Targets for Δ9 Tetrahydrocannabinol and Cannabidiol. Euphytica 2004, 140, 73– 82, DOI: 10.1007/s10681-004-4756-966https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitFertrs%253D&md5=a8126492162a6539259e301fb3c296c8Pharmacological and therapeutic targets for Δ9 tetrahydrocannabinol and cannabidiolPertwee, Roger G.Euphytica (2004), 140 (1-2), 73-82CODEN: EUPHAA; ISSN:0014-2336. (Kluwer Academic Publishers)A review. Cannabis is the unique source of a set of at least 66 compds. known collectively as cannabinoids. Of these, most is known about the pharmacol. of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, and about cannabidiol (CBD), which lacks psychoactivity. Accordingly, this paper focuses on the pharmacol. and therapeutic targets of these two cannabinoids. Many of the effects of Δ9-THC are mediated by cannabinoid receptors of which at least two types, CB1 and CB2, are present in mammalian tissues. Endogenous agonists for cannabinoid receptors have also been discovered. CB1 receptors are present at the terminals of central and peripheral neurons, where they modulate transmitter release. They also exist in some non-neuronal cells. CB2 receptors are expressed mainly by immune cells, one of their roles being to alter cytokine release. Δ9-THC also appears to have non-CB1, non-CB2 pharmacol. targets. It is already licensed for clin. use in the U.S.A. as an anti-emetic and appetite stimulant and both Δ9-THC and Δ9-THC-rich cannabis exts. show therapeutic potential as neuroprotective and anticancer agents and for the management of glaucoma, pain and various kinds of motor dysfunction assocd., for example, with multiple sclerosis and spinal cord injury. CBD has much less affinity for CB1 and CB2 receptors than Δ9-THC and its pharmacol. actions have been less well characterized. Potential clin. applications of CBD and CBD-rich cannabis exts. include the prodn. of anti-inflammatory and neuroprotective effects, the management of epilepsy, anxiety disorders, glaucoma and nausea, and the modulation of some effects of Δ9-THC.
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67Morales, P.; Hurst, D. P.; Reggio, P. H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017, 103, 103– 131, DOI: 10.1007/978-3-319-45541-9_467https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFWntbzL&md5=d5d97efcecf866c4f2f5c31b56ef502cMolecular targets of the phytocannabinoids: a complex pictureMorales, Paula; Hurst, Dow P.; Reggio, Patricia H.Progress in the Chemistry of Organic Natural Products (2017), 103 (Phytocannabinoids), 103-131CODEN: POPRDK; ISSN:2192-4309. (Springer International Publishing AG)A review. This article discusses about mol. pharmacol. of phytocannabinoids, including (-)-trans-Δ9-tetrahydrocannabinol and cannabidiol from perspective of targets at which these important compds. act.
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68Brzozowska, N.; Li, K. M.; Wang, X. S.; Booth, J.; Stuart, J.; McGregor, I. S.; Arnold, J. C. ABC Transporters P-Gp and Bcrp Do Not Limit the Brain Uptake of the Novel Antipsychotic and Anticonvulsant Drug Cannabidiol in Mice. PeerJ 2016, 4, e2081 DOI: 10.7717/peerj.2081There is no corresponding record for this reference.
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69Kathmann, M.; Flau, K.; Redmer, A.; Tränkle, C.; Schlicker, E. Cannabidiol Is an Allosteric Modulator at Mu- and Delta-Opioid Receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 2006, 372, 354– 361, DOI: 10.1007/s00210-006-0033-x69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhslOkurg%253D&md5=4fc34432ddf9968bcf4c761e4438597fCannabidiol is an allosteric modulator at mu- and delta-opioid receptorsKathmann, Markus; Flau, Karsten; Redmer, Agnes; Traenkle, Christian; Schlicker, EberhardNaunyn-Schmiedeberg's Archives of Pharmacology (2006), 372 (5), 354-361CODEN: NSAPCC; ISSN:0028-1298. (Springer)The mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of satn. binding expts. The aim of the present study was to examine whether cannabidiol is an allosteric modulator at this receptor, using kinetic binding studies, which are particularly sensitive for the measurement of allosteric interactions at G protein-coupled receptors. In addn., we studied whether such a mechanism also extends to the delta opioid receptor. For comparison, (-)-Δ9-tetrahydrocannabinol (THC; another major constituent of cannabis) and rimonabant (a cannabinoid CB1 receptor antagonist) were studied. In mu opioid receptor binding studies on rat cerebral cortex membrane homogenates, the agonist 3H-DAMGO bound to a homogeneous class of binding sites with a KD of 0.68±0.02 nM and a Bmax of 203±7 fmol/mg protein. The dissocn. of 3H-DAMGO induced by naloxone 10 μM (half life time of 7±1 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 12 and 2, resp. The resp. pEC50 values for a half-max. elevation of the dissocn. rate const. koff were 4.38 and 4.67; 3H-DAMGO dissocn. was not affected by rimonabant 10 μM. In delta opioid receptor binding studies on rat cerebral cortex membrane homogenates, the antagonist 3H-naltrindole bound to a homogeneous class of binding sites with a KD of 0.24±0.02 nM and a Bmax of 352±22 fmol/mg protein. The dissocn. of 3H-naltrindole induced by naltrindole 10 μM (half life time of 119±3 min) was accelerated by cannabidiol and THC (at 100 μM, each) by a factor of 2, each. The resp. pEC50 values were 4.10 and 5.00; 3H-naltrindole dissocn. was not affected by rimonabant 10 μM. The present study shows that cannabidiol is an allosteric modulator at mu and delta opioid receptors. This property is shared by THC but not by rimonabant.
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70Russo, E. B.; Burnett, A.; Hall, B.; Parker, K. K. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem. Res. 2005, 30, 1037– 1043, DOI: 10.1007/s11064-005-6978-170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKmsbrE&md5=af83825950fd487bf72f78ac6d003656Agonistic Properties of Cannabidiol at 5-HT1a ReceptorsRusso, Ethan B.; Burnett, Andrea; Hall, Brian; Parker, Keith K.Neurochemical Research (2005), 30 (8), 1037-1043CODEN: NEREDZ; ISSN:0364-3190. (Springer)Cannabidiol (CBD) is a major, biol. active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concn.-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concn. range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPγS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is neg. coupled to cAMP prodn., both CBD and 5-HT decrease cAMP concn. at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Addnl. work is required to compare CBD's potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.
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71Chen, G.; Chen, Y.; Yang, N.; Zhu, X.; Sun, L.; Li, G. Interaction between Curcumin and Mimetic Biomembrane. Sci. China: Life Sci. 2012, 55, 527– 532, DOI: 10.1007/s11427-012-4317-871https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVeisb8%253D&md5=64c80bb2adc6375b2b1ee2735969ec2eInteraction between curcumin and mimetic biomembraneChen, Gui Fang; Chen, Yang Yang; Yang, Na Na; Zhu, Xue Jun; Sun, Li Zhou; Li, Gen XiScience China: Life Sciences (2012), 55 (6), 527-532CODEN: SCLSCJ; ISSN:1674-7305. (Science China Press)Curcumin, a major bioactive compd. in turmeric, has a broad spectrum of antioxidant, anticarcinogenic, antimutagenic and anti-inflammatory properties. At the mol. level, curcumin modulates many structurally unrelated membrane proteins through several signaling pathways. Curcumin has been suggested to change the properties of cell membranes and affect the membrane-bound proteins indirectly; however, the detailed mechanism has yet to be investigated. In this paper, self-assembled bilayer lipid membranes are artificially constructed on the surface of a gold electrode to mimic biomembranes, and interaction between the supported membranes and curcumin is studied electrochem. Results show that curcumin interacts with the membranes strongly, in a concn.-dependent manner. At low concns., curcumin tends to insert into the outer monolayer only, while at high concns., it may also begin to penetrate the inner monolayer. The results obtained in this work may enhance our understanding of the effect of curcumin, and possibly flavonoids, on cell membranes and membrane proteins.
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72Ingólfsson, H. I.; Thakur, P.; Herold, K. F.; Hobart, E. A.; Ramsey, N. B.; Periole, X.; de Jong, D. H.; Zwama, M.; Yilmaz, D.; Hall, K.; Maretzky, T.; Hemmings, H. C., Jr.; Blobel, C.; Marrink, S. J.; Koçer, A.; Sack, J. T.; Andersen, O. S. Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function. ACS Chem. Biol. 2014, 9, 1788– 1798, DOI: 10.1021/cb500086e72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlyqt7s%253D&md5=b61876239e926b652adea2e130627bc3Phytochemicals Perturb Membranes and Promiscuously Alter Protein FunctionIngolfsson, Helgi I.; Thakur, Pratima; Herold, Karl F.; Hobart, E. Ashley; Ramsey, Nicole B.; Periole, Xavier; de Jong, Djurre H.; Zwama, Martijn; Yilmaz, Duygu; Hall, Katherine; Maretzky, Thorsten; Hemmings, Hugh C.; Blobel, Carl; Marrink, Siewert J.; Kocer, Armagan; Sack, Jon T.; Andersen, Olaf S.ACS Chemical Biology (2014), 9 (8), 1788-1798CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A wide variety of phytochems. are consumed for their perceived health benefits. Many of these phytochems. have been found to alter numerous cell functions, but the mechanisms underlying their biol. activity tend to be poorly understood. Phenolic phytochems. are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examd. five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochems. alters lipid bilayer properties and the function of diverse membrane proteins. Mol. dynamics simulations show that these phytochems. modify bilayer properties by localizing to the bilayer/soln. interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochems., consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochems. are due to cell membrane perturbations, rather than specific protein binding.
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73Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E. Evaluation of Binding in a Transfected Cell Line Expressing a Peripheral Cannabinoid Receptor (CB2): Identification of Cannabinoid Receptor Subtype Selective Ligands. J. Pharmacol. Exp. Ther. 1996, 278, 989– 99973https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtVSjs74%253D&md5=d765777f3b8763afa042ea068ffd7a28Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligandsShowalter, Vincent M.; Compton, David R.; Martin, Billy R.; Abood, Mary E.Journal of Pharmacology and Experimental Therapeutics (1996), 278 (3), 989-999CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compds. displaying distinct affinities for either cannabinoid receptor. The binding affinities for either cannabinoids tested previously at the CB1 receptor were detd. at cloned human CB1 and CB2 receptors using a filtration assay. In addn., possible allosteric regulation of the CB2 receptor was examd. Sodium and a GTP analog elicited a concn.-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3±14 nM) was confirmed to be in approx. the same range as that of Δ9-THC (Ki = 36.4±10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities detd. in the brain. Although most of the chosen compds. did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride}. In addn., WIN-55,212-2 {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone} and a closely related Pr indole analog were shown to be 6.75- and 27.5-fold selective, resp., for the CB2 receptor. These ligands can now serve as a basis for the design of compds. with even greater selectivity.
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74Watkinson, A.; Chapman, S. C. E.; Horne, R. Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo Analgesia. J. Pain 2017, 18 (8), 908– 922, DOI: 10.1016/j.jpain.2017.02.43574https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czkvVaguw%253D%253D&md5=f9ec1259bbf93f3cbaad033a005d02b4Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo AnalgesiaWatkinson Andrew; Chapman Sarah C E; Horne RobThe journal of pain : official journal of the American Pain Society (2017), 18 (8), 908-922 ISSN:.This study examined whether placebo responses were predicted by a theoretical model of specific and general treatment beliefs. Using a randomized crossover, experimental design (168 healthy individuals) we assessed whether responses to a cold pressor task were influenced by 2 placebo creams described as pharmaceutical versus natural. We assessed whether placebo responses were predicted by pretreatment beliefs about the treatments (placebo) and by beliefs about the pain. The efficacy of pharmaceutical as well as natural placebos in reducing pain intensity was predicted by aspects of pain catastrophizing including feelings of helplessness (pharmaceutical: B = .03, P < .01, natural: B = .02, P < .05) and magnification of pain (pharmaceutical: B = .04, P < .05, natural: B = .05, P < .05) but also by pretreatment necessity beliefs (pharmaceutical: B = .21, P < .01, natural: B = .16, P < .05) and, for the pharmaceutical condition, by more general beliefs about personal sensitivity to pharmaceuticals (B = .14, P < .05). Treatment necessity beliefs also partially mediated the effects of helplessness on placebo responses. Treatment necessity beliefs for the pharmaceutical placebo were influenced by general pharmaceutical beliefs whereas necessity beliefs for the natural placebo were informed by general background beliefs about holistic treatments. Our findings show that treatment beliefs influence the placebo effect suggesting that they may offer an additional approach for understanding the placebo effect. PERSPECTIVE: Placebo effects contribute to responses to active analgesics. Understanding how beliefs about different types of treatment influence placebo analgesia may be useful in understanding variations in treatment response. Using the cold pressor paradigm we found that placebo analgesia was influenced by beliefs about natural remedies, pharmaceutical medicines, and about pain.
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75Trainor, G. L. Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications. In Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.; Academic Press: San Diego, CA, 2007; Vol. 42, Chapter 31, pp 489– 502.There is no corresponding record for this reference.
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76Tayo, B.; Taylor, L.; Sahebkar, F.; Morrison, G. A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment. Clin. Pharmacokinet. 2020, 59, 747– 755, DOI: 10.1007/s40262-019-00841-676https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlyntr7N&md5=eed4a2caf04a836d61680f63c79bd583A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal ImpairmentTayo, Bola; Taylor, Lesley; Sahebkar, Farhad; Morrison, GilmourClinical Pharmacokinetics (2020), 59 (6), 747-755CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Introduction: As patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment. Methods: The pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral soln. (Epidiolex in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment (n = 8/group) relative to matched subjects with normal renal function (n = 8). Blood samples were collected until 48 h post-dose and evaluated by liq. chromatog. with tandem mass spectrometry. Anal. of variance was used to compare primary pharmacokinetic parameters (max. measured plasma concn. [Cmax], oral clearance of drug from plasma [CL/F], renal clearance [CLR], area under the plasma concn.-time curve [AUC] from time zero to last measurable concn. [AUCt], and AUC from time zero to infinity [AUC∞]); descriptive anal. was used for secondary pharmacokinetic parameters (time to Cmax [tmax], terminal [elimination] half-life [t1/2], cumulative amt. excreted from time zero to the last quantifiable sample [Aelast], and fraction of the systemically available drug excreted into the urine [fe]). Results: No statistically significant differences were obsd. in Cmax, AUCt, AUC∞, or tmax values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for Cmax values ranged from 0.68 to 1.35. No differences were obsd. for other secondary parameters (Aelast and fe). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine anal. for CBD recorded no appreciable amt., and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Lab., phys. examn., vital sign, and 12-lead ECG findings were not clin. significant. Conclusion: Renal impairment had no effect on the metab. of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function.
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77Liu, X.; Wright, M.; Hop, C. E. C. A. Rational Use of Plasma Protein and Tissue Binding Data in Drug Design. J. Med. Chem. 2014, 57, 8238– 8248, DOI: 10.1021/jm500793577https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Git77M&md5=53ffbdb88ddf500a90a0eee14b0e641fRational Use of Plasma Protein and Tissue Binding Data in Drug DesignLiu, Xingrong; Wright, Matthew; Hop, Cornelis E. C. A.Journal of Medicinal Chemistry (2014), 57 (20), 8238-8248CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. It is a commonly accepted assumption that only unbound drug mols. are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compd. structure to increase in vivo unbound drug concn. In this review, theor. analyses and exptl. observations are presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concn. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concn. Instead, low intrinsic clearance leads to high in vivo unbound plasma concn., and low efflux transport activity at the blood-brain barrier leads to high unbound brain concn. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design.
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78Wheless, J. W.; Dlugos, D.; Miller, I.; Oh, D. A.; Parikh, N.; Phillips, S.; Renfroe, J. B.; Roberts, C. M.; Saeed, I.; Sparagana, S. P.; Yu, J.; Cilio, M. R. INS011-14-029 Study Investigators. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy. CNS Drugs 2019, 33, 593– 604, DOI: 10.1007/s40263-019-00624-478https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqsbrO&md5=77382c061afe9bed0c1abfd22b76f22aPharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant EpilepsyWheless, James W.; Dlugos, Dennis; Miller, Ian; Oh, D. Alexander; Parikh, Neha; Phillips, Steven; Renfroe, J. Ben; Roberts, Colin M.; Saeed, Isra; Sparagana, Steven P.; Yu, Jin; Cilio, Maria RobertaCNS Drugs (2019), 33 (6), 593-604CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral soln. in pediatric patients with treatment-resistant epilepsy. In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral soln. administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concns. of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral soln. (mean age, 7.6 years). The age compn. was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral soln. dosing, but overall exposure varied. Approx. 2-6 days of twice-daily dosing provided steady-state concns. of cannabidiol. A bidirectional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral soln. resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concns. were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral soln. compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral soln. compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral soln. was obsd. but decreased with multiple doses. Short-term administration was generally safe and well tolerated.
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79Geffrey, A. L.; Pollack, S. F.; Bruno, P. L.; Thiele, E. A. Drug-Drug Interaction between Clobazam and Cannabidiol in Children with Refractory Epilepsy. Epilepsia 2015, 56, 1246– 1251, DOI: 10.1111/epi.1306079https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yqsbbN&md5=c171eff89dbe4e84f61281a180562e51Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsyGeffrey, Alexandra L.; Pollack, Sarah F.; Bruno, Patricia L.; Thiele, Elizabeth A.Epilepsia (2015), 56 (8), 1246-1251CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P 450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demog. information was collected for each subject including age, sex, and etiol. of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB,N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. We report elevated CLB and nCLB levels in these subjects. The mean (± std. deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 wk); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 wk). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose redn. Monitoring of CLB and nCLB levels is necessary for clin. care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
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80Bergmann, K. R.; Broekhuizen, K.; Groeneveld, G. J. Clinical Trial Simulations of the Interaction between Cannabidiol and Clobazam and Effect on Drop-Seizure Frequency. Br. J. Clin. Pharmacol. 2020, 86, 380– 385, DOI: 10.1111/bcp.1415880https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtVWktbY%253D&md5=3eb64ada7f6d50e1b7fab644f7174b64Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequencyBergmann, Kirsten Riber; Broekhuizen, Karen; Groeneveld, Geert JanBritish Journal of Clinical Pharmacology (2020), 86 (2), 380-385CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clin. trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median redn. in drop-seizure frequency and a variability in the percent redn. similar to the placebo group. The results show that the effect of cannabidiol on the median redn. in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.
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81Huddart, R.; Leeder, J. S.; Altman, R. B.; Klein, T. E. PharmGKB Summary: Clobazam Pathway, Pharmacokinetics. Pharmacogenet. Genomics 2018, 28, 110– 115, DOI: 10.1097/FPC.000000000000032781https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFGgs7c%253D&md5=894998d3164b98a20be437af9d2314d2PharmGKB summary: clobazam pathway, pharmacokineticsHuddart, Rachel; Leeder, J. Steven; Altman, Russ B.; Klein, Teri E.Pharmacogenetics and Genomics (2018), 28 (4), 110-115CODEN: PGHEAI; ISSN:1744-6872. (Lippincott Williams & Wilkins)There is no expanded citation for this reference.
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82Calculation of Molecular Properties and Bioactivity Core. https://www.molinspiration.com/cgi-bin/properties (accessed Jul 4, 2020).There is no corresponding record for this reference.
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83Thorne, N.; Auld, D. S.; Inglese, J. Apparent Activity in High-Throughput Screening: Origins of Compound-Dependent Assay Interference. Curr. Opin. Chem. Biol. 2010, 14, 315– 324, DOI: 10.1016/j.cbpa.2010.03.02083https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvVWqsL8%253D&md5=4d3dd71f66ce937002874106edaff12eApparent activity in high-throughput screening: origins of compound-dependent assay interferenceThorne, Natasha; Auld, Douglas S.; Inglese, JamesCurrent Opinion in Chemical Biology (2010), 14 (3), 315-324CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)A review. Expansive compd. collections made up of structurally heterogeneous chems., the activities of which are largely undefined, present challenging problems for high-throughput screening (HTS). Foremost is differentiating whether the activity for a given compd. in an assay is directed against the targeted biol., or is the result of surreptitious compd. activity involving the assay detection system. Such compd. interference can be esp. difficult to identify if it is reproducible and concn.-dependent - characteristics generally attributed to compds. with genuine activity. While reactive chem. groups on compds. were once thought to be the primary source of compd. interference in assays used in HTS, recent work suggests that other factors, such as compd. aggregation, may play a more significant role in many assay formats. Considerable progress has been made to profile representative compd. libraries in an effort to identify chem. classes susceptible to producing compd. interference, such as compds. commonly found to inhibit the reporter enzyme firefly luciferase. Such work has also led to the development of practices that have the potential to significantly reduce compd. interference, for example, through the addn. of non-ionic detergent to assay buffer to reduce aggregation-based inhibition.
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84Elbaz, M.; Nasser, M. W.; Ravi, J.; Wani, N. A.; Ahirwar, D. K.; Zhao, H.; Oghumu, S.; Satoskar, A. R.; Shilo, K.; Carson, W. E., 3rd; Ganju, R. K. Modulation of the Tumor Microenvironment and Inhibition of EGF/EGFR Pathway: Novel Anti-Tumor Mechanisms of Cannabidiol in Breast Cancer. Mol. Oncol. 2015, 9, 906– 919, DOI: 10.1016/j.molonc.2014.12.01084https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVaktbg%253D&md5=20fc63b1ce328066e37db731b7998cbeModulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancerElbaz, Mohamad; Nasser, Mohd W.; Ravi, Janani; Wani, Nissar A.; Ahirwar, Dinesh K.; Zhao, Helong; Oghumu, Steve; Satoskar, Abhay R.; Shilo, Konstantin; Carson, Wiliam E., III; Ganju, Ramesh K.Molecular Oncology (2015), 9 (4), 906-919CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)The anti-tumor role and mechanisms of Cannabidiol (CBD), a non-psychotropic cannabinoid compd., are not well studied esp. in triple-neg. breast cancer (TNBC). In the present study, we analyzed CBD's anti-tumorigenic activity against highly aggressive breast cancer cell lines including TNBC subtype. We show here -for the first time-that CBD significantly inhibits epidermal growth factor (EGF)-induced proliferation and chemotaxis of breast cancer cells. Further studies revealed that CBD inhibits EGF-induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion. In addn., we demonstrated that CBD inhibits tumor growth and metastasis in different mouse model systems. Anal. of mol. mechanisms revealed that CBD significantly inhibits the recruitment of tumor-assocd. macrophages in primary tumor stroma and secondary lung metastases. Similarly, our in vitro studies showed a significant redn. in the no. of migrated RAW 264.7 cells towards the conditioned medium of CBD-treated cancer cells. The conditioned medium of CBD-treated cancer cells also showed lower levels of GM-CSF and CCL3 cytokines which are important for macrophage recruitment and activation. In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment. These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are assocd. with poor prognosis and low survival rates.
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85Solinas, M.; Massi, P.; Cantelmo, A. R.; Cattaneo, M. G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L. M.; Noonan, D. M.; Albini, A.; Parolaro, D. Cannabidiol Inhibits Angiogenesis by Multiple Mechanisms. Br. J. Pharmacol. 2012, 167, 1218– 1231, DOI: 10.1111/j.1476-5381.2012.02050.x85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKktL7O&md5=892900b2b76a23f2064a76465dacb9ceCannabidiol inhibits angiogenesis by multiple mechanismsSolinas, M.; Massi, P.; Cantelmo, A. R.; Cattaneo, M. G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L. M.; Noonan, D. M.; Albini, A.; Parolaro, D.British Journal of Pharmacology (2012), 167 (6), 1218-1231CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumors, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumors in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favorable pharmacol. and toxicol. profile, here, we evaluated the ability of CBD to modulate tumor angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS anal. - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were assocd. with the down-modulation of several angiogenesis-related mols. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumor and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.
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86Ohlsson, A.; Lindgren, J. E.; Andersson, S.; Agurell, S.; Gillespie, H.; Hollister, L. E. Single-Dose Kinetics of Deuterium-Labelled Cannabidiol in Man after Smoking and Intravenous Administration. Biol. Mass Spectrom. 1986, 13, 77– 83, DOI: 10.1002/bms.1200130206There is no corresponding record for this reference.
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87Samara, E.; Bialer, M.; Mechoulam, R. Pharmacokinetics of Cannabidiol in Dogs. Drug Metab. Dispos. 1988, 16, 469– 47287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXksVOkurg%253D&md5=943104b7f2f03cd8c6b88313c36d5fb6Pharmacokinetics of cannabidiol in dogsSamara, Emil; Bialer, Meir; Mechoulam, RaphaelDrug Metabolism and Disposition (1988), 16 (3), 469-72CODEN: DMDSAI; ISSN:0090-9556.Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of 2 i.v. doses (45 and 90 mg) and 1 oral dose (180 mg) to dogs. After i.v. administration, CBD was rapidly distributed, followed by a prolonged elimination. It had a terminal half-life of 9 h. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 L/h (after the 45-mg dose) and 16 L/h (after the 90-mg dose). This clearance value, after its normalization to blood clearance using math. equations, approaches the value of the hepatic blood flow; the extn. ratio in the liver was 0.74. CBD had a large vol. of distribution, ∼100 L. In the dose range of 45-90 mg, the increase in the area under the concn.-time curve was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CbD in this dose range was not dose dependent. In 3 of the 6 dogs studied, CBD could not be detected in the plasma after oral administration. In the other 3, the oral bioavailability ranged 13-19%. Thus, CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a 1st-pass effect.
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88Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Single and Multiple Dose Pharmacokinetics of THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 1135– 1147, DOI: 10.1007/s00228-012-1441-088https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVajtL8%253D&md5=7b2eef902736fa6d5b1633dc94524addA phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal sprayStott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W.European Journal of Clinical Pharmacology (2013), 69 (5), 1135-1147CODEN: EJCPAS; ISSN:0031-6970. (Springer)Purpose A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Methods Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a min. of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatog.-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Results Δ9-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concn. (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concn. (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. Conclusions The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.
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89Deiana, S.; Watanabe, A.; Yamasaki, Y.; Amada, N.; Arthur, M.; Fleming, S.; Woodcock, H.; Dorward, P.; Pigliacampo, B.; Close, S.; Platt, B.; Riedel, G. Plasma and Brain Pharmacokinetic Profile of Cannabidiol (CBD), Cannabidivarine (CBDV), Δ9-Tetrahydrocannabivarin (THCV) and Cannabigerol (CBG) in Rats and Mice Following Oral and Intraperitoneal Administration and CBD Action on Obsessive-Compulsive Behaviour. Psychopharmacology 2012, 219, 859– 873, DOI: 10.1007/s00213-011-2415-089https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVajtLw%253D&md5=48622e6b81ae35d7f7ab26165f4c43daPlasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviourDeiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Arthur, Marlene; Fleming, Shona; Woodcock, Hilary; Dorward, Patricia; Pigliacampo, Barbara; Close, Steve; Platt, Bettina; Riedel, GernotPsychopharmacology (Heidelberg, Germany) (2012), 219 (3), 859-873CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurol. and neurodegenerative disorders. Consistent with these medicinal properties, extd. cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clin. testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Objectives and methods: We here detd. pharmacokinetic profiles of the above phytocannabinoids after acute single-dose i.p. and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, i.p. and oral) was further assessed using a marble burying test in mice. Results: All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioral anomalies, led to higher brain penetration than cremophor after oral, but not i.p. exposure. In mice, cremophor-based i.p. administration always attained higher plasma and brain concns., independent of substance given. In rats, oral administration offered higher brain concns. for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ9-THCV (30 mg/kg) and CBG (120 mg/kg), for which the i.p. route was more effective. CBD inhibited obsessive-compulsive behavior in a time-dependent manner matching its pharmacokinetic profile. Conclusions: These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for detn. of drug effects under in vivo conditions.
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90Huestis, M. A. Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9-Tetrahydrocannibinol, Cannabidiol and Cannabinol. In Cannabinoids; Pertwee, R. G., Ed.; Springer: Berlin, 2005; pp 657– 690.There is no corresponding record for this reference.
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91Jiang, R.; Yamaori, S.; Takeda, S.; Yamamoto, I.; Watanabe, K. Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol by Human Liver Microsomes. Life Sci. 2011, 89, 165– 170, DOI: 10.1016/j.lfs.2011.05.01891https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVaitbo%253D&md5=47a747f9f56840ca296c1dc1382b1bbcIdentification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomesJiang, Rongrong; Yamaori, Satoshi; Takeda, Shuso; Yamamoto, Ikuo; Watanabe, KazuhitoLife Sciences (2011), 89 (5-6), 165-170CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by exptl. animals and humans. However, human hepatic enzymes responsible for the CBD metab. remain to be elucidated. In this study, we examd. in vitro metab. of CBD with human liver microsomes (HLMs) to clarify cytochrome P 450 (CYP) isoforms involved in the CBD oxidns. Oxidns. of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatog./mass spectrometry. CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1''-OH-, 2''-OH-, 3''-OH-, 4''-OH-, and 5''-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4''-OH-CBDs were the major ones as estd. from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivs. of the metabolites. 7 Of 14 recombinant human CYP enzymes examd. (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4''-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4''-hydroxylations of CBD in HLMs.
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92Ujváry, I.; Hanuš, L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016, 1, 90– 101, DOI: 10.1089/can.2015.001292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGmurg%253D&md5=b5823918b361a30b30faef84c7440dd4Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapyUjvary, Istvan; Hanus, LumirCannabis and Cannabinoid Research (2016), 1 (1), 90-101CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)A review. Cannabidiol (CBD), the main nonpsychoactive constituent of Cannabis sativa, has shown a wide range of therapeutically promising pharmacol. effects either as a sole drug or in combination with other drugs in adjunctive therapy. However, the targets involved in the therapeutic effects of CBD appear to be elusive. Furthermore, scarce information is available on the biol. activity of its human metabolites which, when formed in pharmacol. relevant concn., might contribute to or even account for the obsd. therapeutic effects. The present overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD in humans, reviews studies on the biol. activity of CBD metabolites either in vitro or in vivo, and discusses relevant drug-drug interactions. To facilitate further research in the area, the reported syntheses of CBD metabolites are also catalogued.
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93Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 2018, 32, 1053– 1067, DOI: 10.1007/s40263-018-0578-593https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVaqtLzN&md5=09e1f5ac19da1b63c1774385794de7d8A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy SubjectsTaylor, Lesley; Gidal, Barry; Blakey, Graham; Tayo, Bola; Morrison, GilmourCNS Drugs (2018), 32 (11), 1053-1067CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)This trial assessed the safety, tolerability and PK of CBD oral soln. in healthy adult volunteers, as well as the effect of food on CBD PK parameters. The study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD) [n = 6 per group]/placebo multiple dose (750 or 1500 mg CBD and food effect) (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned. Results: CBD was generally well tolerated. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to max. plasma concn. (tmax) was approx. 4-5 h. Oral clearance of CBD was high (1111-1909 L/h) and apparent vol. of distribution was large (20,963-42,849 L). CBD reached steady state after approx. 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. CBD elimination was multiphasic; the terminal elimination half-life was approx. 60 h after 750 and 1500 mg CBD twice daily; and effective half-life ests. ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, resp.; there was no effect of food on tmax or terminal half-life. Conclusion: CBD was generally well tolerated. The safety and PK profile support twice-daily administration of CBD.
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94Harvey, D. J.; Mechoulam, R. Metabolites of Cannabidiol Identified in Human Urine. Xenobiotica 1990, 20, 303– 320, DOI: 10.3109/0049825900904684994https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXktlChtbg%253D&md5=aaedfccd73632b2585f08d8de01bdd55Metabolites of cannabidiol identified in human urineHarvey, D. J.; Mechoulam, R.Xenobiotica (1990), 20 (3), 303-20CODEN: XENOBH; ISSN:0049-8254.Urine from a dystonic patient treated with cannabidiol (I) was examd. by gas chromatog.-mass spectrometry for I metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and Me ester/TMS derivs. and as the TMS derivs. of the product of lithium aluminum deuteride redn. Thirty-three metabolites were identified in addn. to unmetabolized I, and a further four metabolites were partially characterized. The major metabolic route was hydroxylation and oxidn. at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivs. of I-7-oic acid. Other metabolites, mainly acids, were formed by β-oxidn. and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was I-oic acid contg. a hydroxyethyl side-chain. Two 8,9-dihydroxy compds., presumably derived from the corresponding epoxide were identified. Also present were several cyclized cannabinoids including Δ-6- and Δ-1-tetrahydrocannabinol and cannabinol. This is the first metabolic study of I in humans, most obsd. metabolic routes were typical of those found for I and related cannabinoids in other species.
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95Watanabe, K.; Usami, N.; Osada, S.; Narimatsu, S.; Yamamoto, I.; Yoshimura, H. Cannabidiol Metabolism Revisited: Tentative Identification of Novel Decarbonylated Metabolites of Cannabidiol Formed by Human Liver Microsomes and Recombinant Cytochrome P450 3A4. Forensic Toxicol. 2019, 37, 449– 455, DOI: 10.1007/s11419-019-00467-095https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltlOisrk%253D&md5=2ebef566215818c91b0d755f1a9e933eCannabidiol metabolism revisited: tentative identification of novel decarbonylated metabolites of cannabidiol formed by human liver microsomes and recombinant cytochrome P450 3A4Watanabe, Kazuhito; Usami, Noriyuki; Osada, Shigehiro; Narimatsu, Shizuo; Yamamoto, Ikuo; Yoshimura, HidetoshiForensic Toxicology (2019), 37 (2), 449-455CODEN: FTOOAU; ISSN:1860-8965. (Springer Japan)The purpose of the present study was to identify the structures of cannabidiol (CBD) metabolites during CO formation by human liver microsomes and human recombinant cytochrome P 450 (CYP) enzymes. CBD was NADPH-dependently metabolized by human liver microsomes and human recombinant CYP enzymes. Less-polar metabolites were analyzed by gas chromatog.-mass spectrometry monitoring, and their estd. mol. ions were m/z 286, 358 and 481 after non-derivatization, trimethylsilylation and pentafluorobenzyl oxime formation, resp. We tentatively identified novel decarbonylated metabolites of CBD as keto-enol tautomers. Among eight major recombinant human CYP enzymes, only CYP3A4 catalyzed the formation of decarbonylated metabolites. CBD was biotransformed to two decarbonylated metabolites, an enol-form (cyclopentadienol structure), and a keto-form (cyclopentenone structure) by human liver microsomes and CYP3A4.
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96Harvey, D. J.; Samara, E.; Mechoulam, R. Urinary Metabolites of Cannabidiol in Dog, Rat and Man and Their Identification by Gas Chromatography-Mass Spectrometry. J. Chromatogr., Biomed. Appl. 1991, 562, 299– 322, DOI: 10.1016/0378-4347(91)80587-396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhtlGnu74%253D&md5=171a4fec2044447fb0d554283b1293deUrinary metabolites of cannabidiol in dog, rat and man and their identification by gas chromatography-mass spectrometryHarvey, D. J.; Samara, E.; Mechoulam, R.Journal of Chromatography, Biomedical Applications (1991), 562 (1-2), 299-322CODEN: JCBADL; ISSN:0378-4347.Urinary metabolites of cannabidiol (I) (CBD), a non-psychoactive cannabinoid of potential therapeutic interest, were extd. from dog, rat, and human urine, concd. by chromatog. on Sephadex LH-20 and examd. by gas chromatog.-mass spectrometry as trimethylsilyl (TMS), [2H9]TMS, Me ester-TMS and methyloxime-TMS derivs. Fragmentation of the metabolites under electron-impact gave structurally informative fragment ions; computer-generated single-ion plots of these diagnostic ions were used extensively to aid metabolite identification. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concn. in human urine, in the free state and as its glucuronide. In dog, unusual glucoside conjugates of 3 metabolites (4''- and 5''-hydroxy- and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all 3 species were mainly acids. Side-chain hydroxylated derivs. of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species, the major oxidized metabolites were the products of β-oxidn. with further hydroxylation at C-6. A related, but undefined pathway resulted in loss of 3 carbon atoms from the side-chain of CBD in man with prodn. of 2''-hydroxy-tris,nor-CBD-7-oic acid. Metab. by the epoxide-diol pathway, resulting in dihydro-diol formation from the Δ-8 double bond, gave metabolites in dog and human urine. Thus, CBD could be used as a probe of the mechanism of several types of biotransformation: particularly those related to carboxylic acid metab. as intermediates of the type not usually seen with endogenous compds. were excreted in substantial concn.
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97Wray, L.; Stott, C.; Jones, N.; Wright, S. Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model. Cannabis Cannabinoid Res. 2017, 2, 282– 287, DOI: 10.1089/can.2017.003297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslGlsL8%253D&md5=3f7a433910a828aad279d32356fefa9aCannabidiol does not convert to Δ9-tetrahydrocannabinol in an in vivo animal modelWray, Louise; Stott, Colin; Jones, Nicholas; Wright, StephenCannabis and Cannabinoid Research (2017), 2 (1), 282-287CODEN: CCRAEP; ISSN:2378-8763. (Mary Ann Liebert, Inc.)Introduction: Cannabidiol (CBD) can convert to Δ[sup]9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N = 3) in 15mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liq. chromatog. with tandem mass spectrometry anal. detd. CBD, THC, and 11-hydroxy-THC (11-OH-THC) concns. Lower limits of quantification: plasma CBD = 1 ng/mL, plasma THC and 11-OH-THC = 0.5 ng/mL, GI tract CBD = 2 ng/mL, and GI tract THC and 11-OH-THC = 1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concns. (Cmax) of CBD were obsd. between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean Cmax CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clin. studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h · ng/mL) and 5 (881 h · ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concns. reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clin. relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.
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98Palazzoli, F.; Citti, C.; Licata, M.; Vilella, A.; Manca, L.; Zoli, M.; Vandelli, M. A.; Forni, F.; Cannazza, G. Development of a Simple and Sensitive Liquid Chromatography Triple Quadrupole Mass Spectrometry (LC-MS/MS) Method for the Determination of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Its Metabolites in Rat Whole Blood after Oral Administration of a Single High Dose of CBD. J. Pharm. Biomed. Anal. 2018, 150, 25– 32, DOI: 10.1016/j.jpba.2017.11.05498https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWgsLjN&md5=96eadfaa892555f3d58190f24ab0d709Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBDPalazzoli, Federica; Citti, Cinzia; Licata, Manuela; Vilella, Antonietta; Manca, Letizia; Zoli, Michele; Vandelli, Maria Angela; Forni, Flavio; Cannazza, GiuseppeJournal of Pharmaceutical and Biomedical Analysis (2018), 150 (), 25-32CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The investigation of the possible conversion of cannabidiol (CBD) into Δ9-tetrahydrocannabinol (THC) in vivo after oral administration of CBD is reported herein since recent publications suggested a rapid conversion in simulated gastric fluid. To this end, single high dose of CBD (50 mg/kg) was administered orally to rats and their blood was collected after 3 and 6 h. A highly sensitive and selective LC-MS/MS method was developed and fully validated in compliance with the Scientific Working Group of Forensic Toxicol. (SWGTOX) std. practices for method validation in forensic toxicol. This method also involved the optimization of cannabinoids and their metabolites extn. to remove co-eluting phospholipids and increase the sensitivity of the MS detection. Neither THC nor its metabolites were detected in rat whole blood after 3 or 6 h from CBD administration. After oral administration, the amt. of CBD dissolved in olive oil was higher than that absorbed from an ethanolic soln. After oral administration, the amt. of CBD dissolved in olive oil was higher than that absorbed from an ethanolic soln.
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99Guy, G. W.; Flint, M. E. A Single Centre, Placebo-Controlled, Four Period, Crossover, Tolerability Study Assessing, Pharmacodynamic Effects, Pharmacokinetic Characteristics and Cognitive Profiles of a Single Dose of Three Formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), Plus a Two Period Tolerability Study Comparing Pharmacodynamic Effects and Pharmacokinetic Characteristics of a Single Dose of a Cannabis Based Medicine Extract Given via Two Administration Routes (GWPD9901 EXT). J. Cannabis Ther. 2004, 3, 35– 77, DOI: 10.1300/J175v03n03_03There is no corresponding record for this reference.
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100Atsmon, J.; Cherniakov, I.; Izgelov, D.; Hoffman, A.; Domb, A. J.; Deutsch, L.; Deutsch, F.; Heffetz, D.; Sacks, H. PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers. J. Pharm. Sci. 2018, 107, 1423– 1429, DOI: 10.1016/j.xphs.2017.12.020100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeitbk%253D&md5=fd9e6fa3dfb90bca10d5b0a4c2984727PTL401, a New Formulation Based on Pro-nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy VolunteersAtsmon, Jacob; Cherniakov, Irina; Izgelov, Dvora; Hoffman, Amnon; Domb, Abraham J.; Deutsch, Lisa; Deutsch, Frederic; Heffetz, Daphna; Sacks, HagitJournal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107 (5), 1423-1429CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)There is a growing clin. interest in developing and commercializing pharmaceutical-grade cannabinoid products, contg. primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metab. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed ref. oromucosal spray (Sativex). Fourteen healthy male volunteers received, on sep. treatment days, either a single dose of PTL401 or an equiv. dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma Cmax than the equiv. dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, resp.). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clin. studies with this formulation.
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101Consroe, P.; Kennedy, K.; Schram, K. Assay of Plasma Cannabidiol by Capillary Gas Chromatography/ion Trap Mass Spectroscopy Following High-Dose Repeated Daily Oral Administration in Humans. Pharmacol., Biochem. Behav. 1991, 40, 517– 522, DOI: 10.1016/0091-3057(91)90357-8101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XjsFOqsg%253D%253D&md5=d8b64eaedffa9333da04bbce7a57bb8fAssay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humansConsroe, Paul; Kennedy, Kurt; Schram, KarlPharmacology, Biochemistry and Behavior (1991), 40 (3), 517-22CODEN: PBBHAU; ISSN:0091-3057.Plasma levels of cannabidiol (CBD) were ascertained weekly in 14 Huntington's disease patients undergoing a double-blind, placebo-controlled, crossover trial of oral CBD (10 mg/kg/day = about 700 mg/day) for 6 wk. The assay procedure involved trimethylsilyl (TMS) derivatization of CBD and the internal std. delta-6-tetrahydrocannabinol (THC), capillary column gas chromatog., ion trap mass spectroscopy in pos. ion chem. ionization mode using isobutane, and calcns. of CBD levels based on peak ion intensity of the 387 M + H peak of delta-6-THC-TMS and the 459 M + H peak of CBD-2TMS. The sensitivity of the assay was about 500 pg/mL, and the precision was about 10-15%. Mean plasma levels of CBD ranged 5.9-11.2 ng/mL over the 6 wk of CBD administration. CBD levels averaged 1.5 ng/mL one week after CBD was discontinued, and were virtually undetectable thereafter. The elimination half-life of CBD was estd. to be about 2-5 days, and there were no differences between genders for half-life or CBD levels. Addnl., no plasma delta-1-THC, the major psychoactive cannabinoid of marijuana, was detected in any subject.
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102Wall, M. E.; Brine, D. R.; Perez-Reyes, M. Metabolism of Cannabinoids in Man. In The Pharmacology of Marihuana; Braude, M. C., Szara, S., Eds.; Raven Press: New York, 1976; pp 93– 113.There is no corresponding record for this reference.
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103Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Effect of Food on the Single Dose Bioavailability of the THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 825– 834, DOI: 10.1007/s00228-012-1393-4103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s%252FjvFGjsA%253D%253D&md5=dccda46c8c7793a7e244cb94f26cfee4A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal sprayStott C G; White L; Wright S; Wilbraham D; Guy G WEuropean journal of clinical pharmacology (2013), 69 (4), 825-34 ISSN:.PURPOSE: To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. METHODS: Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). RESULTS: Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. CONCLUSIONS: The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.
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104Stout, S. M.; Cimino, N. M. Exogenous Cannabinoids as Substrates, Inhibitors, and Inducers of Human Drug Metabolizing Enzymes: A Systematic Review. Drug Metab. Rev. 2014, 46 (1), 86– 95, DOI: 10.3109/03602532.2013.849268104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVylu7Y%253D&md5=0d774cda3a4fa7cc3d50413e20e241c3Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic reviewStout, Stephen M.; Cimino, Nina M.Drug Metabolism Reviews (2014), 46 (1), 86-95CODEN: DMTRAR; ISSN:0360-2532. (Informa Healthcare)A review. Exogenous cannabinoids are structurally and pharmacol. diverse compds. that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compds. to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clin. care and drug interactions. In vitro data were identified that characterize cytochrome P 450 (CYP-450) enzymes as potential significant contributors to the primary metab. of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metab. of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metab. Clin. pharmacogenetic data further support CYP2C9 as a significant contributor to THC metab., and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis ext. further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis ext. with omeprazole suggests a less significant role of CYP2C19 in CBD metab. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clin. significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metab., although the role of cannabinoids specifically in eliciting this effect is questionable.
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105Zendulka, O.; Dovrtělová, G.; Nosková, K.; Turjap, M.; Šulcová, A.; Hanuš, L.; Juřica, J. Cannabinoids and Cytochrome P450 Interactions. Curr. Drug Metab. 2016, 17, 206– 226, DOI: 10.2174/1389200217666151210142051105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVGns7c%253D&md5=8018bdfd8377dabbd8c33932e8039f55Cannabinoids and Cytochrome P450 InteractionsZendulka, Ond|ej; Dovrt|lova, Gabriela; Noskova, Kristyna; Turjap, Miroslav; Sulcova, Alexandra; Hanus, Lumir; Ju|ica, JanCurrent Drug Metabolism (2016), 17 (3), 206-226CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Objective: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P 450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. Methods: We performed a structured search of bibliog. and drug databases for peer-reviewed literature using focused review questions. Results: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metab. and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro expts. document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clin. relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.
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106Benowitz, N. L.; Nguyen, T. L.; Jones, R. T.; Herning, R. I.; Bachman, J. Metabolic and Psychophysiologic Studies of Cannabidiol-Hexobarbital Interaction. Clin. Pharmacol. Ther. 1980, 28, 115– 120, DOI: 10.1038/clpt.1980.139106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXlt1GrsL4%253D&md5=104f81a3dee4aa0f4d62c604381bbc61Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interactionBenowitz, Neal L.; Nguyen Trong Lang; Jones, Reese T.; Herning, Ronald I.; Bachman, JohnClinical Pharmacology & Therapeutics (St. Louis, MO, United States) (1980), 28 (1), 115-20CODEN: CLPTAT; ISSN:0009-9236.The administration of cannabidiol (CBD)(I) [13956-29-1] (600 mg/day orally for 5-12 days), inhibited hexobarbital (II) [50-09-9] metab. in normal subjects. Hexobarbital oral clearance was 36% lower and the apparent vol. of distribution was 35% smaller, with no change in half-life during CBD. In subjects who received i.v. and oral hexobarbital, systemic clearance was 36% lower whereas bioavailability was 10% greater during CBD. Hexobarbital increased fatigue and tremor, impaired eye-tracking performance, and altered the EEG. Hexobarbital effects were not affected by CBD. Inhibition of metab. of other drugs should be considered when large amts. of CBD are taken or when CBD is used for therapy.
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107Garberg, H. T.; Solberg, R.; Barlinn, J.; Martinez-Orgado, J.; Løberg, E.-M.; Saugstad, O. D. High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets. Neonatology 2017, 112, 143– 149, DOI: 10.1159/000471786107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ygtrvP&md5=722d7deb5e6ac02dfef48145f8ca49e0High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in PigletsGarberg, Havard T.; Solberg, Ronnaug; Barlinn, Jon; Martinez-Orgado, Jose; Loberg, Else-Marit; Saugstad, Ola DidrikNeonatology (2017), 112 (2), 143-149CODEN: NEONCC; ISSN:1661-7800. (S. Karger AG)Background: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. Objective: To assess the safety and potential neuroprotective effects of high-dose CBD. Methods: Anesthetized newborn piglets underwent global HI by ventilation with 8% O2 until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to i.v. treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for anal. Results: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant neg. correlation between the plasma concn. of CBD and hypotension during drug infusion was obsd. (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathol. score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. Conclusions: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.
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108Murphy, S. K.; Itchon-Ramos, N.; Visco, Z.; Huang, Z.; Grenier, C.; Schrott, R.; Acharya, K.; Boudreau, M.-H.; Price, T. M.; Raburn, D. J.; Corcoran, D. L.; Lucas, J. E.; Mitchell, J. T.; McClernon, F. J.; Cauley, M.; Hall, B. J.; Levin, E. D.; Kollins, S. H. Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm. Epigenetics 2018, 13, 1208– 1221, DOI: 10.1080/15592294.2018.1554521108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnlslSnsw%253D%253D&md5=53a0321ca720a68e539e5540ef28a9ecCannabinoid exposure and altered DNA methylation in rat and human spermMurphy Susan K; Visco Zachary; Huang Zhiqing; Grenier Carole; Acharya Kelly; Boudreau Marie-Helene; Price Thomas M; Raburn Douglas J; Itchon-Ramos Nilda; Mitchell John T; McClernon F Joseph; Levin Edward D; Kollins Scott H; Schrott Rose; Corcoran David L; Lucas Joseph E; Cauley Marty; Hall Brandon JEpigenetics (2018), 13 (12), 1208-1221 ISSN:.Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.
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109Reece, A. S.; Hulse, G. K. Impacts of Cannabinoid Epigenetics on Human Development: Reflections on Murphy et. al. ‘Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm Epigenetics 2018; 13: 1208-1221’. Epigenetics 2019, 14, 1041– 1056, DOI: 10.1080/15592294.2019.1633868109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzmtFaguw%253D%253D&md5=5f715a99a6ffa633e0153481e01c2db0Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. 'cannabinoid exposure and altered DNA methylation in rat and human sperm' epigenetics 2018; 13: 1208-1221Reece Albert Stuart; Hulse Gary Kenneth; Reece Albert Stuart; Hulse Gary KennethEpigenetics (2019), 14 (11), 1041-1056 ISSN:.Recent data from the Kollins lab ('Cannabinoid exposure and altered DNA methylation in rat and human sperm' Epigenetics 2018; 13: 1208-1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers. The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis. Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required.
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110Carvalho, R. K.; Santos, M. L.; Souza, M. R.; Rocha, T. L.; Guimarães, F. S.; Anselmo-Franci, J. A.; Mazaro-Costa, R. Chronic Exposure to Cannabidiol Induces Reproductive Toxicity in Male Swiss Mice. J. Appl. Toxicol. 2018, 38, 1215– 1223, DOI: 10.1002/jat.3631110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsFOmsrs%253D&md5=8a3906504e6ec3809df124c2f6920201Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss miceCarvalho, Renata K.; Santos, Monaliza L.; Souza, Maingredy R.; Rocha, Thiago L.; Guimaraes, Francisco S.; Anselmo-Franci, Janete A.; Mazaro-Costa, RenataJournal of Applied Toxicology (2018), 38 (9), 1215-1223CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)Children and adults with frequent and severe episodes of epilepsy that do not respond to std. treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reprodn. has not been fully examd. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21-day-old male Swiss mice at doses of 15 and 30 mg kg-1 daily (CBD 15 and 30 groups, resp.), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: wt. of reproductive organs, testosterone concn., spermatogenesis, histomorphometry, daily sperm prodn. and its morphol. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiol. normal range (240-1100 ng dl-1). CBD treatment induced a significant increase in the frequency of stages I-IV and V-VI of spermatogenesis, and a decrease in the frequency of stages VII-VIII and XII. A significant decrease in the no. of Sertoli cells was obsd. only in the CBD 30 group. In both CBD groups the no. of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were obsd. in the medial region of flagellum. These results indicated that chronic CBD exposure was assocd. with changes in the male reproductive system, suggesting its reproductive toxicity.
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111Ewing, L. E.; Skinner, C. M.; Quick, C. M.; Kennon-McGill, S.; McGill, M. R.; Walker, L. A.; ElSohly, M. A.; Gurley, B. J.; Koturbash, I. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. Molecules 2019, 24, 1694, DOI: 10.3390/molecules24091694111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvF2mur4%253D&md5=7765d8d50b685310fa53d7ede40ccc9dHepatotoxicity of a Cannabidiol-rich cannabis extract in the mouse modelEwing, Laura E.; Skinner, Charles M.; Quick, Charles M.; Kennon-McGill, Stefanie; McGill, Mitchell R.; Walker, Larry A.; ElSohly, Mahmoud A.; Gurley, Bill J.; Koturbash, IgorMolecules (2019), 24 (9), 1694CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-wk-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equiv. doses (MED) of the max. recommended human maintenance dose of CBD in EPIDIOLEX (20 mg/kg). In the acute study, significant increases in liver-to-body wt. (LBW) ratios, plasma ALT, AST, and total bilirubin were obsd. for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metab. pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways assocd. with lipid and xenobiotic metab. raises serious concerns about potential drug interactions as well as the safety of CBD.
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112Russo, C.; Ferk, F.; Mišík, M.; Ropek, N.; Nersesyan, A.; Mejri, D.; Holzmann, K.; Lavorgna, M.; Isidori, M.; Knasmüller, S. Low Doses of Widely Consumed Cannabinoids (Cannabidiol and Cannabidivarin) Cause DNA Damage and Chromosomal Aberrations in Human-Derived Cells. Arch. Toxicol. 2019, 93, 179– 188, DOI: 10.1007/s00204-018-2322-9112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFygtbnL&md5=05f7839670d83b5101bc85aa36344236Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cellsRusso, Chiara; Ferk, Franziska; Misik, Miroslav; Ropek, Nathalie; Nersesyan, Armen; Mejri, Doris; Holzmann, Klaus; Lavorgna, Margherita; Isidori, Marina; Knasmuller, SiegfriedArchives of Toxicology (2019), 93 (1), 179-188CODEN: ARTODN; ISSN:0340-5761. (Springer)Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amts. worldwide in cannabis exts., as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compds. induced DNA damage in single cell gel electrophoresis (SCGE) expts. in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 μM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Addnl. expts. indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compds. Our findings show that low concns. of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.
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113Devinsky, O.; Patel, A. D.; Cross, J. H.; Villanueva, V.; Wirrell, E. C.; Privitera, M.; Greenwood, S. M.; Roberts, C.; Checketts, D.; VanLandingham, K. E.; Zuberi, S. M. GWPCARE3 Study Group. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N. Engl. J. Med. 2018, 378, 1888– 1897, DOI: 10.1056/NEJMoa1714631113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVCrt7jL&md5=6789d5c955c809a35801238a217c53f6Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndromeDevinsky, Orrin; Patel, Anup D.; Cross, J. Helen; Villanueva, Vicente; Wirrell, Elaine C.; Privitera, Michael; Greenwood, Sam M.; Roberts, Claire; Checketts, Daniel; Van Landingham, Kevan E.; Zuberi, Sameer M.New England Journal of Medicine (2018), 378 (20), 1888-1897CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)We investigated efficacy, safety of cannabidiol added to regimen of conventional antiepileptic medication to treat drop seizures in patients with Lennox-Gastaut syndrome. We randomly assigned patients with Lennox-Gastaut syndrome who had two or more drop seizures per wk during 28-day baseline period to receive cannabidiol oral soln. at a dose of either 20 mg per kg of body wt. or 10 mg per kg or matching placebo, administered in 2 equally divided doses daily for 14 wk. Primary outcome was percentage change from baseline in frequency of drop seizures during the treatment period. During 28-day baseline period, median no. of drop seizures was 85 in all trial groups combined. Median percent redn. from baseline in drop-seizure frequency during treatment period was 41.9% in 20-mg cannabidiol group, 37.2% in 10-mg cannabidiol group, and 17.2% in placebo group. Most common adverse events among patients in cannabidiol groups were somnolence, decreased appetite, diarrhea. 14 Patients who received cannabidiol had elevated liver aminotransferase concns. Among children, adults with the Lennox-Gastaut syndrome, the addn. of cannabidiol at a dose of 10 mg or 20 mg per kg per day to a conventional antiepileptic regimen resulted in greater redns. in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferases.
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114Gaston, T. E.; Bebin, E. M.; Cutter, G. R.; Liu, Y.; Szaflarski, J. P. UAB CBD Program. Interactions between Cannabidiol and Commonly Used Antiepileptic Drugs. Epilepsia 2017, 58, 1586– 1592, DOI: 10.1111/epi.13852114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOit7bM&md5=5ad7017993c10c448f8d64103e2925c1Interactions between cannabidiol and commonly used antiepileptic drugsGaston, Tyler E.; Bebin, E. Martina; Cutter, Gary R.; Liu, Yuliang; Szaflarski, Jerzy P.Epilepsia (2017), 58 (9), 1586-1592CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Summary : Objective : To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. Methods : In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 wk by 5 mg/kg/day up to a max. of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was detd. that a clin. symptom or lab. result was related to a potential interaction. The Mixed Procedure was used to det. if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial anal. were plotted for mean change in serum level over time. Subanalyses were performed to det. if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Results : Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significance : Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.
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115Groeneveld, G. J.; Martin, J. H. Parasitic Pharmacology: A Plausible Mechanism of Action for Cannabidiol. Br. J. Clin. Pharmacol. 2020, 86, 189– 191, DOI: 10.1111/bcp.14028115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzlvVaisQ%253D%253D&md5=6018dd17f8ffe625275c15cc94d30080Parasitic pharmacology: A plausible mechanism of action for cannabidiolGroeneveld Geert Jan; Groeneveld Geert Jan; Martin Jennifer H; Martin Jennifer HBritish journal of clinical pharmacology (2020), 86 (2), 189-191 ISSN:.There is no expanded citation for this reference.
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116American Epilepsy Foundation. AES Position Statement on Cannabis as a Treatment for Patients with Epileptic Seizures; American Epilepsy Foundation, 2019. https://www.aesnet.org/sites/default/files/file_attach/42981132_cannabis_position_statement_updated_2.19.19.pdf (accessed Dec 19, 2019).There is no corresponding record for this reference.
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117MacKeen, D. What Are the Benefits of CBD? N. Y. Times 2019 (October 16).There is no corresponding record for this reference.
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118Popejoy, S. Is CBD for Aging a Potential Fountain of Youth? CBGenius. https://www.cbgenius.net/2019/06/18/is-cbd-for-aging-a-potential-fountain-of-youth/ (accessed Jul 4, 2020).There is no corresponding record for this reference.
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119Freeman, J. Does CBD Oil Really Help Treat Arthritis Pain? Rheumatoid Arthritis. https://www.rheumatoidarthritis.org/cbd-oil/ (accessed Jul. 4, 2020).There is no corresponding record for this reference.
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120Skrobin, N., The Fresh Toast. Cannabis: Optimal Treatment Method for Post-Concussion Syndrome Symptoms. Chicago Tribune 2019 (August 30).There is no corresponding record for this reference.
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121Johnson, J. CBD for Weight Loss: Does It Work? https://www.medicalnewstoday.com/articles/324733 (accessed Jul 4, 2020).There is no corresponding record for this reference.
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122Kubala, J.. 7 Benefits and Uses of CBD Oil (Plus Side Effects). https://www.healthline.com/nutrition/cbd-oil-benefits (accessed Jul 4, 2020).There is no corresponding record for this reference.
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123Bonaccorso, S.; Ricciardi, A.; Zangani, C.; Chiappini, S.; Schifano, F. Cannabidiol (CBD) Use in Psychiatric Disorders: A Systematic Review. NeuroToxicology 2019, 74, 282– 298, DOI: 10.1016/j.neuro.2019.08.002123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ymtbnE&md5=2efa8d86969ee9ca64d901c32ba2cc64Cannabidiol (CBD) use in psychiatric disorders: A systematic reviewBonaccorso, Stefania; Ricciardi, Angelo; Zangani, Caroline; Chiappini, Stefania; Schifano, FabrizioNeuroToxicology (2019), 74 (), 282-298CODEN: NRTXDN; ISSN:0161-813X. (Elsevier Inc.)A review. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathol. conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstr.'s screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathol. conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
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124Hiemstra, B.; Keus, F.; Wetterslev, J.; Gluud, C.; van der Horst, I. C. C. DEBATE-Statistical Analysis Plans for Observational Studies. BMC Med. Res. Methodol. 2019, 19 (1), 233, DOI: 10.1186/s12874-019-0879-5124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mfot1Gjug%253D%253D&md5=48b47e89a91f8e32771b6c74fefc41a3DEBATE-statistical analysis plans for observational studiesHiemstra Bart; Keus Frederik; Wetterslev Jorn; Gluud Christian; van der Horst Iwan C CBMC medical research methodology (2019), 19 (1), 233 ISSN:.BACKGROUND: All clinical research benefits from transparency and validity. Transparency and validity of studies may increase by prospective registration of protocols and by publication of statistical analysis plans (SAPs) before data have been accessed to discern data-driven analyses from pre-planned analyses. MAIN MESSAGE: Like clinical trials, recommendations for SAPs for observational studies increase the transparency and validity of findings. We appraised the applicability of recently developed guidelines for the content of SAPs for clinical trials to SAPs for observational studies. Of the 32 items recommended for a SAP for a clinical trial, 30 items (94%) were identically applicable to a SAP for our observational study. Power estimations and adjustments for multiplicity are equally important in observational studies and clinical trials as both types of studies usually address multiple hypotheses. Only two clinical trial items (6%) regarding issues of randomisation and definition of adherence to the intervention did not seem applicable to observational studies. We suggest to include one new item specifically applicable to observational studies to be addressed in a SAP, describing how adjustment for possible confounders will be handled in the analyses. CONCLUSION: With only few amendments, the guidelines for SAP of a clinical trial can be applied to a SAP for an observational study. We suggest SAPs should be equally required for observational studies and clinical trials to increase their transparency and validity.
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125The Skyline Agency. CBD Oil & Cannabinol Tincture Products from Medterra CBD. https://medterracbd.com/product-cbd-oil-tincture (accessed Jul 7, 2020).There is no corresponding record for this reference.
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126Moerman, D. E.; Jonas, W. B. Deconstructing the Placebo Effect and Finding the Meaning Response. Ann. Intern. Med. 2002, 136, 471– 476, DOI: 10.7326/0003-4819-136-6-200203190-00011126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387mvVyksw%253D%253D&md5=81d68eb21291815c01381bbb30a4f1d7Deconstructing the placebo effect and finding the meaning responseMoerman Daniel E; Jonas Wayne BAnnals of internal medicine (2002), 136 (6), 471-6 ISSN:.We provide a new perspective with which to understand what for a half century has been known as the "placebo effect." We argue that, as currently used, the concept includes much that has nothing to do with placebos, confusing the most interesting and important aspects of the phenomenon. We propose a new way to understand those aspects of medical care, plus a broad range of additional human experiences, by focusing on the idea of "meaning," to which people, when they are sick, often respond. We review several of the many areas in medicine in which meaning affects illness or healing and introduce the idea of the "meaning response." We suggest that use of this formulation, rather than the fixation on inert placebos, will probably lead to far greater insight into how treatment works and perhaps to real improvements in human well-being.
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127Benedetti, F. Placebo Effects: From the Neurobiological Paradigm to Translational Implications. Neuron 2014, 84, 623– 637, DOI: 10.1016/j.neuron.2014.10.023127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvV2mtrfE&md5=0cb297b6ae7d878559b8c43c36692042Placebo Effects: From the Neurobiological Paradigm to Translational ImplicationsBenedetti, FabrizioNeuron (2014), 84 (3), 623-637CODEN: NERNET; ISSN:0896-6273. (Cell Press)Today we are witnessing a new science of placebo, a complex discipline that encompasses several exptl. approaches and translational implications. Modern neurobiol. tools have been used to answer important questions in placebo research, such as the top-down modulation of sensory and motor systems as well as the influence of cognition, emotions, and learning on symptoms, diseases, and responses to treatments. What we have learned is that there is not one single placebo effect, but many. This review highlights the translational implications of this new knowledge, ranging from clin. trial design to medical practice to social and ethical issues.
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128Hopp, C. Past and Future Research at National Center for Complementary and Integrative Health with Respect to Botanicals. HerbalGram 2015, 107, 44– 51There is no corresponding record for this reference.
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129Geller, S. E.; Shulman, L. P.; van Breemen, R. B.; Banuvar, S.; Zhou, Y.; Epstein, G.; Hedayat, S.; Nikolic, D.; Krause, E. C.; Piersen, C. E.; Bolton, J. L.; Pauli, G. F.; Farnsworth, N. R. Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial. Menopause 2009, 16, 1156– 1166, DOI: 10.1097/gme.0b013e3181ace49b129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MjkslGmsw%253D%253D&md5=0c9d2bd07ee6a27ed3c4e374632a5a30Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trialGeller Stacie E; Shulman Lee P; van Breemen Richard B; Banuvar Suzanne; Zhou Ying; Epstein Geena; Hedayat Samad; Nikolic Dejan; Krause Elizabeth C; Piersen Colleen E; Bolton Judy L; Pauli Guido F; Farnsworth Norman RMenopause (New York, N.Y.) (2009), 16 (6), 1156-66 ISSN:.OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of black cohosh and red clover compared with placebo for the relief of menopausal vasomotor symptoms. METHODS: This study was a randomized, four-arm, double-blind clinical trial of standardized black cohosh, red clover, placebo, and 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA; n = 89). Primary outcome measures were reduction in vasomotor symptoms (hot flashes and night sweats) by black cohosh and red clover compared with placebo; secondary outcomes included safety evaluation, reduction of somatic symptoms, relief of sexual dysfunction, and overall improvement in quality of life. RESULTS: Reductions in number of vasomotor symptoms after a 12-month intervention were as follows: black cohosh (34%), red clover (57%), placebo (63%), and CEE/MPA (94%), with only CEE/MPA differing significantly from placebo. Black cohosh and red clover did not significantly reduce the frequency of vasomotor symptoms as compared with placebo. Secondary measures indicated that both botanicals were safe as administered. In general, there were no improvements in other menopausal symptoms. CONCLUSIONS: Compared with placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms. Safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months.
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130Sorkin, B. C.; Kuszak, A. J.; Bloss, G.; Fukagawa, N. K.; Hoffman, F. A.; Jafari, M.; Barrett, B.; Brown, P. N.; Bushman, F. D.; Casper, S. J.; Chilton, F. H.; Coffey, C. S.; Ferruzzi, M. G.; Hopp, D. C.; Kiely, M.; Lakens, D.; MacMillan, J. B.; Meltzer, D. O.; Pahor, M.; Paul, J.; Pritchett-Corning, K.; Quinney, S. K.; Rehermann, B.; Setchell, K. D. R.; Sipes, N. S.; Stephens, J. M.; Taylor, D. L.; Tiriac, H.; Walters, M. A.; Xi, D.; Zappalá, G.; Pauli, G. F. Improving Natural Product Research Translation: From Source to Clinical Trial. FASEB J. 2020, 34, 41– 65, DOI: 10.1096/fj.201902143R130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFehsL8%253D&md5=19537e9297cca959ebd3405e66fc9b1aImproving natural product research translation: From source to clinical trialSorkin, Barbara C.; Kuszak, Adam J.; Bloss, Gregory; Fukagawa, Naomi K.; Hoffman, Freddie Ann; Jafari, Mahtab; Barrett, Bruce; Brown, Paula N.; Bushman, Frederic D.; Casper, Steven J.; Chilton, Floyd H.; Coffey, Christopher S.; Ferruzzi, Mario G.; Hopp, D. Craig; Kiely, Mairead; Lakens, Daniel; MacMillan, John B.; Meltzer, David O.; Pahor, Marco; Paul, Jeffrey; Pritchett-Corning, Kathleen; Quinney, Sara K.; Rehermann, Barbara; Setchell, Kenneth D. R.; Sipes, Nisha S.; Stephens, Jacqueline M.; Taylor, D. Lansing; Tiriac, Herve; Walters, Michael A.; Xi, Dan; Zappala, Giovanna; Pauli, Guido F.FASEB Journal (2020), 34 (1), 41-65CODEN: FAJOEC; ISSN:1530-6860. (John Wiley & Sons, Inc.)While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclin. NP research is not consistently translating into actionable clin. trial (CT) outcomes. Generally considered the gold std. for assessing safety and efficacy, CTs, esp. phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a . Participants emphasized that replicability and likelihood of successful translation depend on rigor in exptl. design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clin. predictive validity; controls for exptl. artifacts, esp. for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clin. trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.
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131Brown, J. D. Cannabidiol as Prophylaxis for SARS-CoV-2 and COVID-19? Unfounded Claims versus Potential Risks of Medications during the Pandemic. Res. Social Adm. Pharm. 2020, DOI: 10.1016/j.sapharm.2020.03.020There is no corresponding record for this reference.
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Quantum-mechanical 1H NMR characterization of CBD using HiFSA, psychoactive drug screening program activity of CBD, and pharmacological methods for evaluation of CBD (PDF)
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