CANNABINOIDS AND EPILEPSY NOVIEMBRE 2018

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1. Methods Mol Biol.

Quantification of Eight Cannabinoids Including Cannabidiol in Human Urine Via
Liquid Chromatography Tandem Mass Spectrometry.

Scheidweiler KB(1), Barnes AJ(2).

Author information: 
(1)Quest Diagnostics, Chantilly, VA, USA.
Karl.B.Scheidweiler@questdiagnostics.com.
(2)Quest Diagnostics, Chantilly, VA, USA.

Medical and recreational cannabis legalization has highlighted the importance of 
being able to identify recent cannabis use and impairment. Monitoring minor plant
cannabinoids has been proposed to assist in identifying recent cannabis use.
Additionally, cannabidiol (CBD) has been proposed for epilepsy, pain,
inflammatory disorder, anxiety, and addiction treatment; therefore, monitoring
CBD is of increasing clinical importance. However, few methods exist capable of
monitoring extensive panels of traditional cannabinoid analytes and minor
cannabinoids (including CBD). This chapter details a liquid chromatography tandem
mass spectrometry method capable of measuring Δ9-tetrahydrocannabinol (THC),
11-hydroxy-THC, 11-nor-9-carboxy-THC, cannabinol, cannabigerol,
tetrahydrocannabivarin (THCV), and its metabolite, 11-nor-9-carboxy-THCV, in
urine.


2. Arch Toxicol. 2018 Oct

Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause 
DNA damage and chromosomal aberrations in human-derived cells.

Russo C(1), Ferk F(2), Mišík M(2), Ropek N(2), Nersesyan A(2), Mejri D(2),
Holzmann K(2), Lavorgna M(1), Isidori M(1), Knasmüller S(3).

Author information: 
(1)Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche,
Università della Campania, L. Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy.
(2)Department of Internal Medicine 1, Institute of Cancer Research, Medical
University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
(3)Department of Internal Medicine 1, Institute of Cancer Research, Medical
University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
siegfried.knasmueller@meduniwien.ac.at.

Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are
consumed in increasing amounts worldwide in cannabis extracts, 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 compounds induced DNA damage in single
cell gel electrophoresis (SCGE) experiments 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. Additional
experiments indicate that these effects are caused by oxidative base damage and
that liver enzymes (S9) increase the genotoxic activity of both compounds. Our
findings show that low concentrations 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.

3. Basic Clin Pharmacol Toxicol. 2018 Oct
Interaction between warfarin and cannabis. Damkier P(1)(2), Lassen D(3), Christensen MMH(1)(2)(4), Madsen KG(5)(6), Hellfritzsch M(1)(6), Pottegård A(6). Author information: (1)Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. (2)Department of Clinical Research, University of Southern Denmark, Odense, Denmark. (3)Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. (4)Hospital Pharmacy, Hospital of South West Denmark, Esbjerg, Denmark. (5)Department of Oncology, Odense University Hospital, Odense, Denmark. (6)Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark. Delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug-drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27-year-old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9-mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol (CBD) for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increase INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis smoking. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. 4. Australas Psychiatry. 2018 Oct Survey of Australian psychiatrists' and psychiatry trainees' knowledge about and attitudes towards medicinal cannabinoids. Jacobs NI(1), Montebello M(2), Monds LA(3), Lintzeris N(4). Author information: (1)Psychiatry Trainee, South Eastern Sydney Local Health District, Kogarah, NSW, Australia. (2)Clinical Director and Senior Staff Specialist, Northern Sydney Local Health District Drug and Alcohol Services, Saint Leonards, NSW, and Conjoint Lecturer, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia. (3)Research Fellow, South Eastern Sydney Local Health District Drug and Alcohol Services, Sydney, NSW, and; Academic Fellow, Discipline of Addiction Medicine, Central Clinical School, University of Sydney, Sydney, NSW, Australia. (4)Director and Senior Staff Specialist, South Eastern Sydney Local Health District Drug and Alcohol Services, Sydney, NSW, and; Conjoint Professor, Discipline of Addiction Medicine, Central Clinical School, University of Sydney, Sydney, NSW, Australia. OBJECTIVE: To assess Australian psychiatrists' and psychiatry trainees' knowledge about and attitudes towards medicinal cannabinoids, given the recent relaxation of cannabinoid-prescribing laws in Australia. METHOD: All Australian members of the Royal Australian and New Zealand College of Psychiatrists were invited to participate in an anonymous, 64-item online questionnaire, through Royal Australian and New Zealand College of Psychiatrists' newsletters. The questionnaire ran for a 10-week period from March to May 2017. Participants were asked about their knowledge of the evidence for and against prescribing pharmaceutical-grade cannabidiol and tetrahydrocannabinol, and their concerns about prescribing medicinal cannabinoids. RESULTS: In total, 88 doctors responded to the survey, with 55 completing all items (23 psychiatrists, 32 trainees). Overall, 54% of respondents would prescribe medicinal cannabinoids if it was legal to do so. Participants believed there was evidence for the use of cannabidiol and tetrahydrocannabinol in treating childhood epilepsy, chronic pain, and nausea and vomiting. They were most concerned about medicinal cannabinoids leading to psychotic symptoms, addiction and dependence, apathy and recreational use. CONCLUSIONS: Our sample of Australian psychiatrists and trainees were aware of the main clinical indications for medicinal cannabinoids, but were poor at differentiating between the indications for cannabidiol versus tetrahydrocannabinol. Further education about medicinal cannabinoids appears necessary. 5. Front Immunol. 2018 Sep Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Crippa JA(1)(2), Guimarães FS(2)(3), Campos AC(2)(3), Zuardi AW(1)(2). Author information: (1)Department of Neurosciences and Behavior, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. (2)National Institute for Translational Medicine (INCT-TM; CNPq), São Paulo, Brazil. (3)Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. Background: Among the many cannabinoids in the cannabis plant, cannabidiol (CBD) is a compound that does not produce the typical subjective effects of marijuana. Objectives: The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry. Methods: A non-systematic search was performed for studies dealing with therapeutic applications of CBD, especially performed by Brazilian researchers. Results: CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties. In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson. Discussion: CBD is an useful and promising molecule that may help patients with a number of clinical conditions. Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.