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      Cannabis and Canabidinoids on the Inflammatory Bowel Diseases: Going Beyond Misuse

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          Abstract

          Inflammatory bowel diseases (IBD) are characterized by a chronic and recurrent gastrointestinal condition, including mainly ulcerative colitis (UC) and Crohn’s disease (CD). Cannabis sativa (CS) is widely used for medicinal, recreational, and religious purposes. The most studied compound of CS is tetrahydrocannabinol (THC) and cannabidiol (CBD). Besides many relevant therapeutic roles such as anti-inflammatory and antioxidant properties, there is still much controversy about the consumption of this plant since the misuse can lead to serious health problems. Because of these reasons, the aim of this review is to investigate the effects of CS on the treatment of UC and CD. The literature search was performed in PubMed/Medline, PMC, EMBASE, and Cochrane databases. The use of CS leads to the improvement of UC and CD scores and quality of life. The medical use of CS is on the rise. Although the literature shows relevant antioxidant and anti-inflammatory effects that could improve UC and CD scores, it is still not possible to establish a treatment criterion since the studies have no standardization regarding the variety and part of the plant that is used, route of administration and doses. Therefore, we suggest caution in the use of CS in the therapeutic approach of IBD until clinical trials with standardization and a relevant number of patients are performed.

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          Most cited references56

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          Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

          Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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            Safety and side effects of cannabidiol, a Cannabis sativa constituent.

            Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.
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              An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.

              2-Arachidonoyl-glycerol (2-Ara-GI) has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-GI is accompanied by several 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2-Palm-Gl). These two esters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB1 or CB2; however, they significantly potentiate the apparent binding of 2-Ara-Gl and its apparent capacity to inhibit adenylyl cyclase. Together these esters also significantly potentiate 2-Ara-Gl inhibition of motor behavior, immobility on a ring, analgesia on a hot plate and hypothermia caused by 2-Ara-Gl in mice. 2-Lino-Gl, but not 2-Palm-GI, significantly inhibits the inactivation of 2-Ara-Gl by neuronal and basophilic cells. These data indicate that the biological activity of 2-Ara-Gl can be increased by related, endogenous 2-acyl-glycerols, which alone show no significant activity in any of the tests employed. This effect ('entourage effect') may represent a novel route for molecular regulation of endogenous cannabinoid activity.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 April 2020
                April 2020
                : 21
                : 8
                : 2940
                Affiliations
                [1 ]Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia (UNIMAR), Avenue Hygino Muzzy Filho, 1001, Marília 17525902, São Paulo, Brazil; drantonelycarvalho@ 123456hotmail.com (A.C.A.d.C.); elguiguer@ 123456gmail.com (É.L.G.); adrianocressoniaraujo@ 123456yahoo.com.br (A.C.A.); ricardogoulartmed@ 123456hotmail.com (R.d.A.G.); uriflato@ 123456gmail.com (U.A.P.F.); rogerio@ 123456fob.usp.br (R.L.B.)
                [2 ]School of Medicine, University of Marília (UNIMAR), Avenida Higino Muzzi Filho, 1001, Marília 17525902, São Paulo, Brazil; gabriela.achete@ 123456outlook.com (G.A.d.S.); Samyllavaz@ 123456outlook.com (S.V.d.M.); claudio.rubira@ 123456gmail.com (C.J.R.); pcincotto@ 123456gmail.com (P.C.d.S.B.)
                [3 ]Department of Biochemistry and Nutrition, Faculty of Food Technology of Marília, Marília 17525902, São Paulo, Brazil
                [4 ]Department of Animal Sciences, School of Veterinary Medicine, University of Marília (UNIMAR), Avenida Higino Muzzi Filho, 1001, Marília 17525902, São Paulo, Brazil
                [5 ]Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo (FOB–USP), Alameda Doutor Octávio Pinheiro Brisolla, 9-75, Bauru 17040, São Paulo, Brazil
                Author notes
                [* ]Correspondence: smbarbalho@ 123456gmail.com ; Tel.: +55-14-99655-3190
                Author information
                https://orcid.org/0000-0003-2753-7281
                https://orcid.org/0000-0002-8381-8830
                https://orcid.org/0000-0002-5881-2218
                https://orcid.org/0000-0002-5035-876X
                Article
                ijms-21-02940
                10.3390/ijms21082940
                7215817
                32331305
                fdd96e79-e797-47ca-b020-a85904d10b81
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 March 2020
                : 20 April 2020
                Categories
                Review

                Molecular biology
                inflammatory bowel disease,ulcerative colitis,crohn’s disease,cannabis,cannabidiol

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