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Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 103561

Special Issue Editors

Prof. Dr. Barbara Malinowska

E-Mail Website
Guest Editor
Department of Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland
Interests: cannabinoid; cannabidiol; endocannabinoid system; presynaptic receptors; histamine; serotonin; 5-hydroxytryptamine; atypical β-adrenoceptors
Prof. Dr. Eberhard Schlicker

E-Mail Website
Guest Editor
Department of Pharmacology, University of Bonn, Bonn, Germany
Interests: cannabinoid; cannabidiol; endocannabinoid system; presynaptic receptors; histamine; serotonin; 5-hydroxytryptamine; atypical β-adrenoceptors
Prof. Dr. Roger G Pertwee

E-Mail
Guest Editor
School of Medicine, Medical Sciences and Nutrition. Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
Interests: Plant cannabinoids; phytocannabinoids; synthetic cannabinoids; endogenous cannabinoids; endocannabinoids; cannabinoid pharmacology; therapeutic potential of cannabinoids

Special Issue Information

Dear Colleagues,

The hemp plant Cannabis sativa L. contains hundreds of constituents and dozens of cannabinoids. The first of the two major cannabinoids is Δ9-tetrahydrocannabinol, which is psychoactive and has a marked effect on the endocannabinoid system (e.g. on cannabinoid receptors). The second major cannabinoid, cannabidiol, is not psychoactive and has less pronounced effects on the endocannabinoid system; among others it possesses a marked direct anti-oxidant, an anti-apoptotic and an anti-inflammatory effect. This Special Issue will focus upon cannabidiol (and not include other cannabinoids or mixtures of cannabinoids), all the more since such an issue is missing.

Cannabidiol has recently been licensed both in the United States and in Europe for the treatment of the Dravet and Lennox-Gastaut syndromes, rare forms of childhood-onset epilepsies. The Guest Editors will ask a re-known epileptologist to prepare a review about the anticonvulsant properties of this compound and to highlight his own experience. The compound is also being considered for the treatment of other disorders although its molecular mechanisms and biological effects have not yet been fully elucidated. We are inviting colleagues interested in all aspects of cannabidiol to contribute to this Special Issue by submitting original papers, short communications or reviews.

Prof. Dr. Barbara Malinowska
Prof. Dr. Eberhard Schlicker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cannabidiol
  • Anti-oxidant effect
  • Anti-apoptotic effect
  • Anti-inflammatory effect
  • Anticonvulsant effect
  • Cardiovascular diseases
  • Neurological diseases
  • Immune response
  • Cancer

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 463 KiB  
Editorial
The 90th Birthday of Professor Raphael Mechoulam, a Top Cannabinoid Scientist and Pioneer
by Roger G. Pertwee
Int. J. Mol. Sci. 2020, 21(20), 7653; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207653 - 16 Oct 2020
Viewed by 2042
Abstract
n/a Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)

Research

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19 pages, 1903 KiB  
Article
Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats
by Olga Sadowska, Marta Baranowska-Kuczko, Anna Gromotowicz-Popławska, Michał Biernacki, Aleksandra Kicman, Barbara Malinowska, Irena Kasacka, Anna Krzyżewska and Hanna Kozłowska
Int. J. Mol. Sci. 2020, 21(19), 7077; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197077 - 25 Sep 2020
Cited by 28 | Viewed by 4230
Abstract
Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension [...] Read more.
Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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Review

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18 pages, 1214 KiB  
Review
Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action
by Marcin Ożarowski, Tomasz M. Karpiński, Aleksandra Zielińska, Eliana B. Souto and Karolina Wielgus
Int. J. Mol. Sci. 2021, 22(9), 4294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094294 - 21 Apr 2021
Cited by 30 | Viewed by 11063
Abstract
As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments [...] Read more.
As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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16 pages, 719 KiB  
Review
Cannabidiol and Other Cannabinoids in Demyelinating Diseases
by Carmen Navarrete, Adela García-Martín, Alain Rolland, Jim DeMesa and Eduardo Muñoz
Int. J. Mol. Sci. 2021, 22(6), 2992; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062992 - 15 Mar 2021
Cited by 9 | Viewed by 6513
Abstract
A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple [...] Read more.
A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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42 pages, 2567 KiB  
Review
Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19
by Barbara Malinowska, Marta Baranowska-Kuczko, Aleksandra Kicman and Eberhard Schlicker
Int. J. Mol. Sci. 2021, 22(4), 1986; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041986 - 17 Feb 2021
Cited by 35 | Viewed by 8889
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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14 pages, 334 KiB  
Review
Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research
by Philippe A. Melas, Maria Scherma, Walter Fratta, Carlo Cifani and Paola Fadda
Int. J. Mol. Sci. 2021, 22(4), 1863; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041863 - 13 Feb 2021
Cited by 55 | Viewed by 13498
Abstract
Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. [...] Read more.
Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
14 pages, 790 KiB  
Review
Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals
by Ewa Galaj and Zheng-Xiong Xi
Int. J. Mol. Sci. 2021, 22(1), 134; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010134 - 24 Dec 2020
Cited by 25 | Viewed by 7736
Abstract
Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment [...] Read more.
Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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21 pages, 2474 KiB  
Review
Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action
by Jakub Mlost, Marta Bryk and Katarzyna Starowicz
Int. J. Mol. Sci. 2020, 21(22), 8870; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228870 - 23 Nov 2020
Cited by 127 | Viewed by 25693
Abstract
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not [...] Read more.
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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49 pages, 2470 KiB  
Review
The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease
by Aleksandra Kicman and Marek Toczek
Int. J. Mol. Sci. 2020, 21(18), 6740; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186740 - 14 Sep 2020
Cited by 55 | Viewed by 22383
Abstract
Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we [...] Read more.
Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases. Full article
(This article belongs to the Special Issue Cannabidiol: New Vistas of Its Molecular Mechanisms, Biological Effects and Therapeutic Application)
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