Special Issue "Cannabidiol: Advances in Therapeutic Applications and Future Perspectives"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: 31 March 2022.

Special Issue Editors

Dr. Maurizio Bifulco
E-Mail Website
Guest Editor
Department of Molecular Medicine and Medical Biotechnology, University of Naples ‘Federico II’, Via S. Pansini 5, Naples, Italy
Interests: experimental medicine; pharmacology; endocannabinoid system; mevalonate pathway; statins; glioblastoma
Dr. Simona Pisanti
E-Mail Website
Guest Editor
Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, Via S. Allende 84081, Baronissi (SA), Italy
Interests: biochemistry; molecular biology; experimental medicine; pharmacology; endocannabinoid system; mevalonate pathway; innate immunity; angiogenesis; cancer

Special Issue Information

Dear Colleagues,

Cannabidiol (CBD) is one of the main natural cannabinoids found in Cannabis sativa. Due to the lack of psychotropic effects associated with Δ9THC and its good safety profile, CBD is the most interesting cannabinoid from a pharmacological point of view. Beneficial therapeutic effects have been reported in patients with inflammatory, neurodegenerative, and autoimmune diseases as well as in those with epilepsy and cancer. The use of CBD-based products in the form of high-concentration oil, powder and extract is permitted under current regulations. There is no evidence of its use for recreational purposes, nor have any health and safety problems been identified in relation to its consumption (WHO, 2018). In light of previous studies conducted, more and more countries have or are changing their rules on cannabis regulation to consider CBD as a medicinal product as well as a food supplement. Currently, the first CBD-based drug, GW Pharmaceuticals' Epidiolex®, has been approved in both the US and Europe for the treatment of some severe forms of epilepsy. Others such as Echo Pharmaceuticals' Arvisol® are in the advanced clinical development stage.

This Special Issue aims to provide readers with the most recent advances in this field. Authors are invited to submit relevant original articles, reviews or short communications for inclusion.

Dr. Maurizio Bifulco
Dr. Simona Pisanti
Guest Editors

Manuscript Submission Information

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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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • cannabis
  • cannabidiol
  • experimental medicine
  • pharmacology
  • biochemistry
  • natural products
  • inflammatory diseases
  • autoimmune diseases
  • cancer
  • epilepsy
  • neurodegenerative diseases

Related Special Issues

Published Papers (9 papers)

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Research

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Article
Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels
Pharmaceuticals 2021, 14(10), 964; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100964 - 24 Sep 2021
Viewed by 430
Abstract
Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis [...] Read more.
Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis (OA). The present study focuses on cannabidiol (CBD), a non-psychoactive constituent of cannabis, targeting over 60 distinct molecular targets as a potential treatment for OA, a degenerative joint disease leading to chronic pain with a neuropathic component. We successfully identified molecular targets of CBD that were relevant in the context of OA treatment with both beneficial and detrimental effects. Our findings were confirmed by in vivo and molecular studies. A key role of PPARγ in mediating the therapeutic potential of CBD was revealed, whereas upregulation of multiple transient receptor potential channels demasked CBD-induced heat hyperalgesia. Our findings pave the way for novel CBD-based therapy with improved therapeutic potential but also encourage the use of bioinformatic tools to predict the mechanism of action of CBD in different conditions. We have also created an accessible web tool for analogous analysis of CBD pharmacology in the context of any disease of interest and made it publicly available. Full article
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Article
Cannabidiol Application Increases Cutaneous Aquaporin-3 and Exerts a Skin Moisturizing Effect
Pharmaceuticals 2021, 14(9), 879; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090879 - 30 Aug 2021
Viewed by 933
Abstract
Cannabidiol (CBD) is a major nonpsychotropic component of Cannabis sativa with various pharmacological activities. In this study, we investigated the skin moisturizing effect of CBD and its mechanism. A 1% CBD solution was applied daily to skin of HR-1 hairless (Seven-week-old, male) for [...] Read more.
Cannabidiol (CBD) is a major nonpsychotropic component of Cannabis sativa with various pharmacological activities. In this study, we investigated the skin moisturizing effect of CBD and its mechanism. A 1% CBD solution was applied daily to skin of HR-1 hairless (Seven-week-old, male) for 14 days. The dermal water content in CBD-treated mice was significantly increased compared to that in the control group. Furthermore, no inflammatory reaction in the skin and no obvious skin disorders were observed. The mRNA expression levels of loricrin, filaggrin, collagen, hyaluronic acid degrading enzyme, hyaluronic acid synthase, ceramide degrading enzyme, and ceramide synthase in the skin were not affected by the application of CBD. However, only aquaporin-3 (AQP3), a member of the aquaporin family, showed significantly higher levels in the CBD-treated group than in the control group at both the mRNA and protein levels. It was revealed that CBD has a moisturizing effect on the skin. In addition, it is possible that increased expression of AQP3, which plays an important role in skin water retention, is a contributor to the mechanism. CBD is expected to be developed in the future as a cosmetic material with a unique mechanism. Full article
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Article
Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice
Pharmaceuticals 2021, 14(9), 863; https://doi.org/10.3390/ph14090863 - 28 Aug 2021
Viewed by 592
Abstract
Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic [...] Read more.
Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy. Full article
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Article
3-Hydroxypropane-1,2-Diyl Dipalmitoleate—A Natural Compound with Dual Roles (CB1 Agonist/FAAH1 Blocker) in Inhibiting Ovarian Cancer Cell Line
Pharmaceuticals 2021, 14(3), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030255 - 12 Mar 2021
Viewed by 644
Abstract
Though it was once known that upregulated Cannabinoid Receptor (CB1) and downregulated Fatty Acid Amide Hydrolase (FAAH1) are associated with tumour aggressiveness and metastasis, it is now clear that upregulated CB1 levels more than a certain point cause accumulation of ceramide and directs [...] Read more.
Though it was once known that upregulated Cannabinoid Receptor (CB1) and downregulated Fatty Acid Amide Hydrolase (FAAH1) are associated with tumour aggressiveness and metastasis, it is now clear that upregulated CB1 levels more than a certain point cause accumulation of ceramide and directs cells to apoptosis. Hence, CB1 analogues/FAAH1 blockers are explored widely as anticancer drugs. There are reports on CB1-agonists and FAAH1-blockers separately, however, dual activities along with ovarian cancer-specific links are not established for any natural compound. With this setting, we describe for the first time the isolation of 3-hydroxypropane-1,2-diyl dipalmitoleate (564.48 Da) from a marine snail, Conus inscriptus, which binds to both CB1 and FAAH1 (glide energies: −70.61 and −30.52 kcal/mol, respectively). MD simulations indicate stable compound–target interaction for a minimum of 50 nanoseconds with relative invariabilities in Rg. The compound inhibited ovarian cancer cell line, PA1 at 1.7 μM. Structural and chemical interpretation of the compound (C2) was done using FT-IR, GC-MS, ESI-MS, 1H and 13C-NMR (1 and 2D). Furthermore, a probable route for gram-scale synthesis of C2 is hinted herein. With the available preliminary data, molecular mechanisms involving dual roles for this potent molecule must be elucidated to understand the possibilities of usage as an anticancer drug. Full article
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Article
Comparison of Five Oral Cannabidiol Preparations in Adult Humans: Pharmacokinetics, Body Composition, and Heart Rate Variability
Pharmaceuticals 2021, 14(1), 35; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010035 - 06 Jan 2021
Cited by 2 | Viewed by 3730
Abstract
Data supporting the physiological effects of cannabidiol (CBD) ingestion in humans are conflicting. Differences between CBD preparations and bioavailability may contribute to these discrepancies. Further, an influence of body composition on CBD bioavailability is feasible, but currently undocumented. The aims of this study [...] Read more.
Data supporting the physiological effects of cannabidiol (CBD) ingestion in humans are conflicting. Differences between CBD preparations and bioavailability may contribute to these discrepancies. Further, an influence of body composition on CBD bioavailability is feasible, but currently undocumented. The aims of this study were to: (1) compare the pharmacokinetics of five oral CBD preparations over 4 h; (2) examine the relationship between body composition and CBD pharmacokinetics; and, (3) explore the influence of CBD on heart rate variability. In total, five preparations of CBD, standardized to 30 mg, were orally administered to 15 healthy men and women (21–62 years) in a randomized, crossover design. Prior to and 60 min following CBD ingestion, heart rate variability was determined. Body composition was assessed using dual energy X-ray absorptiometry. Peak circulating CBD concentration, time to peak concentration, and area under the curve was superior in a preparation comprising 5% CBD concentration liquid. Fat free mass was a significant predictor (R2 = 0.365, p = 0.017) of time to peak concentration for this preparation. Several heart rate variability parameters, including peak frequency of the high frequency band, were favorably, but modestly modified following CBD ingestion. These data confirm an influence of CBD preparation and body composition on CBD bioavailability, and suggest that acute CBD ingestion may have a modest influence on autonomic regulation of heart rate. Full article
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Article
Topical Administration of Cannabidiol: Influence of Vehicle-Related Aspects on Skin Permeation Process
Pharmaceuticals 2020, 13(11), 337; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110337 - 23 Oct 2020
Cited by 8 | Viewed by 1963
Abstract
Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from Cannabis sativa which, given its claimed beneficial properties and therapeutic potential, has lately aroused considerable attention from the scientific community. Starting from the little literature evidence, the main purpose of this study was to investigate [...] Read more.
Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from Cannabis sativa which, given its claimed beneficial properties and therapeutic potential, has lately aroused considerable attention from the scientific community. Starting from the little literature evidence, the main purpose of this study was to investigate the topical administration of CBD, with particular focus on the influence of vehicle-related aspects on the skin permeation process. This could provide useful information for the design of suitable drug delivery systems which could be used in developing topical medicines and cosmetics. In vitro human skin permeation studies were conducted using modified Franz diffusion cells to compare the performance of four solutions and two semisolid formulations. The Hildebrand solubility parameter was used to better understand the thermodynamic aspects implied in the partitioning process of the cannabinoid compound into the skin. It was interestingly found that a hydrophilic gel, mostly consisting of propylene glycol (79%, w/w), can be an optimal choice for the topical administration of CBD. Moreover, the feasibility of the preparation of CBD-loaded (trans)dermal patches, made with new printing technology, was also demonstrated. Full article
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Review

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Review
The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases
Pharmaceuticals 2021, 14(9), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090936 - 17 Sep 2021
Viewed by 675
Abstract
In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling [...] Read more.
In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system. Full article
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Review
Clinical Evidence of Magistral Preparations Based on Medicinal Cannabis
Pharmaceuticals 2021, 14(2), 78; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020078 - 21 Jan 2021
Cited by 1 | Viewed by 1002
Abstract
Cannabis has been widely used as a medicinal plant for millennia; however, studies related to its main components were first conducted in 1960. Subsequently, laboratories have produced new components and structures related to its active biological properties. Countries that have approved the medicinal [...] Read more.
Cannabis has been widely used as a medicinal plant for millennia; however, studies related to its main components were first conducted in 1960. Subsequently, laboratories have produced new components and structures related to its active biological properties. Countries that have approved the medicinal use of cannabis impose regulations that govern its clinical and scientific use. One means of administering medicinal cannabis is via a magistral preparation that must have a medical prescription and be prepared in an establishment that meets quality standards to ensure the quantities of its main components, such as tetrahydrocannabinol (THC) and cannabidiol (CBD). Furthermore, suppliers must have a clear indication of its use in the patient before prescription. This review shows the published evidence regarding the clinical use of medicinal cannabis magistral preparations in the management of post-chemotherapy nausea and vomiting, neuropathic pain in multiple sclerosis, and anorexia and cachexia in patients with HIV. Full article
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Review
Towards Better Delivery of Cannabidiol (CBD)
Pharmaceuticals 2020, 13(9), 219; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090219 - 28 Aug 2020
Cited by 16 | Viewed by 5085
Abstract
Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits [...] Read more.
Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits the likelihood of an expensive, full development programme in anything other than orphan indications. Potential avenues to overcome these issues with CBD include self-emulsifying drug delivery systems, improved crystal formulations and other solid-state delivery formulations, which are mostly in the pre-clinical or early clinical stages of development. This review identifies issues compromising current delivery of solid-state CBD, and how advanced pharmaceutical development strategies can enable CBD to realise the full potential as a successful therapeutic agent. Full article
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