Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

New Insight into Cannabinoid Effects 2.0

Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 29698

Share This Special Issue

Special Issue Editor

Dr. Timna Naftali

E-Mail Website
Guest Editor

Division of Gastroenterology and Hepatology, Meir Medical Center, Affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv 5265601, Israel
Interests: endocannabinoid; inflammatory bowel disease; cannabis use in IBD; cannabis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cannabis is the most widely used recreational drug worldwide. The cannabis plant contains as many as 100 phytocannabinoids as well as other ingredients, such as terpenes and flavonoids. Phytocannabinoids exert their effects through the endocannabinoid system (ECS), which is an endogenous system with an important role in modulating mood, memory, reward homeostasis, immune regulation, and energy balance. The best-known phytocannabinoids are Δ9-tetrahydrocannabinol (THC), which is responsible for the psychotropic effect of cannabis, and cannabidiol (CBD), which does not have a central effect but is shown to have an anti-inflammatory effect.

The use of medical cannabis is rapidly increasing, and physicians are faced with an increasing demand from patients to prescribe it. Sadly, this is not accompanied by scientifically sound evidence regarding the efficacy, if any, of cannabis treatment. Very little is known about the effect of cannabis and the significance of various cannabinoid combinations or mode of cannabis consumption. On the other hand, we cannot afford to ignore the many reports about the positive effects of cannabis. More data and evidence on how cannabinoids affect physiology and pathophysiology, as well as their therapeutic potential are urgently needed.

The open access International Journal of Molecular Sciences (IJMS) (IF 6.208, ISSN 1422-0067) is therefore planning this Special Issue entitled “New Insight into Cannabinoid Effects 2.0”. As the Guest Editor, I would like to invite you to contribute an article/review to this issue. We promise you a rapid and rigorous peer review, manuscript handling, and editorial process.

Dr. Timna Naftali
Guest Editor

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

cannabinoids
endogenous cannabinoids
neurodegenerative diseases
cancer
pharmacology

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review

16 pages, 3613 KiB

Open AccessArticle

Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study

by Ana Batinic, Davorka Sutlovic, Sendi Kuret, Franko Burcul, Nina Kalajzic, Antonela Matana, Goran Dujic, Josip Vrdoljak, Marko Kumric, Josko Bozic and Zeljko Dujic

Int. J. Mol. Sci. 2023, 24(12), 10273; https://doi.org/10.3390/ijms241210273 - 17 Jun 2023

Cited by 4 | Viewed by 2523

Abstract

The potential therapeutic benefits of cannabidiol (CBD) require further study. Here, we report a triple-blind (participant, investigator, and outcome assessor) placebo-controlled crossover study in which 62 hypertensive volunteers were randomly assigned to receive the recently developed DehydraTECH2.0 CBD formulation or a placebo. This is the first study to have been conducted using the DehydraTECH2.0 CBD formulation over a 12-week study duration. The new formulation’s long-term effects on CBD concentrations in plasma and urine, as well as its metabolites 7-hydroxy-CBD and 7-carboxy-CBD, were analyzed. The results of the plasma concentration ratio for CBD/7-OH-CBD in the third timepoint (after 5 weeks of use) were significantly higher than in the second timepoint (after 2.5 weeks of use; p = 0.043). In the same timepoints in the urine, a significantly higher concentration of 7-COOH-CBD was observed p < 0.001. Differences in CBD concentration were found between men and women. Plasma levels of CBD were still detectable 50 days after the last consumption of the CBD preparations. Significantly higher plasma CBD concentrations occurred in females compared to males, which was potentially related to greater adipose tissue. More research is needed to optimize CBD doses to consider the differential therapeutic benefits in men and women. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

16 pages, 2500 KiB

Open AccessArticle

Δ⁸-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

by Agnese Gugliandolo, Santino Blando, Stefano Salamone, Diego Caprioglio, Federica Pollastro, Emanuela Mazzon and Luigi Chiricosta

Int. J. Mol. Sci. 2023, 24(7), 6598; https://doi.org/10.3390/ijms24076598 - 2 Apr 2023

Cited by 7 | Viewed by 3104

Abstract

Alzheimer’s disease (AD) represents the most common form of dementia, characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, the accumulation of misfolded protein, ER stress and neuronal apoptosis. It is of main importance to find new therapeutic strategies because AD prevalence is increasing worldwide. Cannabinoids are arising as promising neuroprotective phytocompounds. In this study, we evaluated the neuroprotective potential of Δ⁸-THC pretreatment in an in vitro model of AD through transcriptomic analysis. We found that Δ⁸-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Aβ_1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ_1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase in Bax and the decrease in Bcl-2 both at gene and protein expression levels. Moreover, genes involved in protein folding and degradation were also deregulated. On the contrary, Δ⁸-THC pretreatment reduced ER stress and, as a consequence, neuronal apoptosis. Then, the results demonstrated that Δ⁸-THC might represent a new neuroprotective agent in AD. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

15 pages, 1764 KiB

Open AccessArticle

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology

by Martina Di Bartolomeo, Tibor Stark, Serena Di Martino, Fabio Arturo Iannotti, Jana Ruda-Kucerova, Giovanni Luca Romano, Martin Kuchar, Samuele Laudani, Petr Palivec, Fabiana Piscitelli, Carsten T. Wotjak, Claudio Bucolo, Filippo Drago, Vincenzo Di Marzo, Claudio D’Addario and Vincenzo Micale

Int. J. Mol. Sci. 2023, 24(4), 3907; https://doi.org/10.3390/ijms24043907 - 15 Feb 2023

Cited by 5 | Viewed by 2144

Abstract

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ⁹-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

16 pages, 2021 KiB

Open AccessArticle

Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression

by Uri Bright and Irit Akirav

Int. J. Mol. Sci. 2023, 24(3), 2052; https://doi.org/10.3390/ijms24032052 - 20 Jan 2023

Cited by 4 | Viewed by 2046

Abstract

Cannabidiol (CBD) is a potential antidepressant agent. We examined the association between the antidepressant effects of CBD and alterations in brain microRNAs in the unpredictable chronic mild stress (UCMS) model for depression. UCMS male rats were injected with vehicle or CBD (10 mg/kg) and tested for immobility time in the forced swim test. Alterations in miRNAs (miR16, miR124, miR135a) and genes that encode for the 5HT1a receptor, the serotonergic transporter SERT, β-catenin, and CB1 were examined. UCMS increased immobility time in a forced swim test (i.e., depressive-like behavior) and altered the expression of miRNAs and mRNA in the ventromedial prefrontal cortex (vmPFC), raphe nucleus, and nucleus accumbens. Importantly, CBD restored UCMS-induced upregulation in miR-16 and miR-135 in the vmPFC as well as the increase in immobility time. CBD also restored the UCMS-induced decrease in htr1a, the gene that encodes for the serotonergic 5HT1a receptor; using a pharmacological approach, we found that the 5HT1a receptor antagonist WAY100135 blocked the antidepressant-like effect of CBD on immobility time. Our findings suggest that the antidepressant effects of CBD in a rat model for depression are associated with alterations in miR-16 and miR-135 in the vmPFC and are mediated by the 5HT1a receptor. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

15 pages, 2701 KiB

Open AccessArticle

Anti-Bacterial Effect of Cannabidiol against the Cariogenic Streptococcus mutans Bacterium: An In Vitro Study

by Tamar Barak, Eden Sharon, Doron Steinberg, Mark Feldman, Ronit Vogt Sionov and Miriam Shalish

Int. J. Mol. Sci. 2022, 23(24), 15878; https://doi.org/10.3390/ijms232415878 - 14 Dec 2022

Cited by 8 | Viewed by 2161

Abstract

Dental caries is caused by biofilm-forming acidogenic bacteria, especially Streptococcus mutans, and is still one of the most prevalent human bacterial diseases. The potential use of cannabidiol (CBD) in anti-bacterial therapies has recently emerged. Here we have studied the anti-bacterial and anti-biofilm activity of CBD against S. mutans. We measured minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC). The bacterial growth and changes in pH values were measured in a kinetic study. The biofilm biomass was assessed by Crystal Violet staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) metabolic assay. Spinning Disk Confocal Microscopy (SDCM) was used to assess biofilm structure, bacterial viability and extracellular polysaccharide (EPS) production. CBD inhibited S. mutans planktonic growth and biofilm formation in a dose-dependent manner, with similar MIC and MBIC values (5 µg/mL). CBD prevented the bacteria-mediated reduction in pH values that correlated with bacterial growth inhibition. SDCM showed a decrease of 50-fold in live bacteria and EPS production. CBD significantly reduced the viability of preformed biofilms at 7.5 µg/mL with an 80 ± 3.1% reduction of metabolic activity. At concentrations above 20 µg/mL, there was almost no bacterial recovery in the CBD-treated preformed biofilms even 48 h after drug withdrawal. Notably, precoating of the culture plate surfaces with CBD prior to incubation with bacteria inhibited biofilm development. Additionally, CBD was found to induce membrane hyperpolarization in S. mutans. Thus, CBD affects multiple processes in S. mutans including its cariogenic properties. In conclusion, we show that CBD has a strong inhibitory effect against cariogenic bacteria, suggesting that it is a potential drug adjuvant for reducing oral pathogenic bacterial load as well as protecting against dental caries. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

19 pages, 3573 KiB

Open AccessArticle

Antagonization of OX₁ Receptor Potentiates CB₂ Receptor Function in Microglia from APP_Sw/Ind Mice Model

by Iu Raïch, Joan Biel Rebassa, Jaume Lillo, Arnau Cordomi, Rafael Rivas-Santisteban, Alejandro Lillo, Irene Reyes-Resina, Rafael Franco and Gemma Navarro

Int. J. Mol. Sci. 2022, 23(21), 12801; https://doi.org/10.3390/ijms232112801 - 24 Oct 2022

Cited by 4 | Viewed by 2020

Abstract

Microdialysis assays demonstrated a possible role of orexin in the regulation of amyloid beta peptide (Aß) levels in the hippocampal interstitial fluid in the APP transgenic model. CB₂R is overexpressed in activated microglia, showing a neuroprotective effect. These two receptors may interact, forming CB₂-OX₁-Hets and becoming a new target to combat Alzheimer’s disease. Aims: Demonstrate the potential role of CB₂-OX₁-Hets expression and function in microglia from animal models of Alzheimer’s disease. Receptor heteromer expression was detected by immunocytochemistry, bioluminescence resonance energy transfer (BRET) and proximity ligation assay (PLA) in transfected HEK-293T cells and microglia primary cultures. Quantitation of signal transduction events in a heterologous system and in microglia cells was performed using the AlphaScreen^® SureFire^® kit, western blot, the GCaMP6 calcium sensor and the Lance Ultra cAMP kit (PerkinElmer). The formation of CB₂-OX₁ receptor complexes in transfected HEK-293T cells has been demonstrated. The tetrameric complex is constituted by one CB₂R homodimer, one OX₁R homodimer and two G proteins, a G_i and a G_q. The use of TAT interfering peptides showed that the CB₂-OX₁ receptor complex interface is TM4-TM5. At the functional level it has been observed that the OX₁R antagonist, SB334867, potentiates the action induced by CB₂R agonist JWH133. This effect is observed in transfected HEK-293T cells and microglia, and it is stronger in the Alzheimer’s disease (AD) animal model APPSw/Ind where the expression of the complex assessed by the proximity ligation assay indicates an increase in the number of complexes compared to resting microglia. The CB₂-OX₁ receptor complex is overexpressed in microglia from AD animal models where OX₁R antagonists potentiate the neuroprotective actions of CB₂R activation. Taken together, these results point to OX₁R antagonists as drugs with therapeutic potential to combat AD. Data access statement: Raw data will be provided by the corresponding author upon reasonable requirement. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

Review

Jump to: Research

32 pages, 18342 KiB

Open AccessReview

Targeting the Endocannabinoid System Present in the Glioblastoma Tumour Microenvironment as a Potential Anti-Cancer Strategy

by Mendhi Henna Dasram, Pavesan Naidoo, Roderick B. Walker and Sandile M. Khamanga

Int. J. Mol. Sci. 2024, 25(3), 1371; https://doi.org/10.3390/ijms25031371 - 23 Jan 2024

Viewed by 1956

Abstract

The highly aggressive and invasive glioblastoma (GBM) tumour is the most malignant lesion among adult-type diffuse gliomas, representing the most common primary brain tumour in the neuro-oncology practice of adults. With a poor overall prognosis and strong resistance to treatment, this nervous system tumour requires new innovative treatment. GBM is a polymorphic tumour consisting of an array of stromal cells and various malignant cells contributing to tumour initiation, progression, and treatment response. Cannabinoids possess anti-cancer potencies against glioma cell lines and in animal models. To improve existing treatment, cannabinoids as functionalised ligands on nanocarriers were investigated as potential anti-cancer agents. The GBM tumour microenvironment is a multifaceted system consisting of resident or recruited immune cells, extracellular matrix components, tissue-resident cells, and soluble factors. The immune microenvironment accounts for a substantial volume of GBM tumours. The barriers to the treatment of glioblastoma with cannabinoids, such as crossing the blood–brain barrier and psychoactive and off-target side effects, can be alleviated with the use of nanocarrier drug delivery systems and functionalised ligands for improved specificity and targeting of pharmacological receptors and anti-cancer signalling pathways. This review has shown the presence of endocannabinoid receptors in the tumour microenvironment, which can be used as a potential unique target for specific drug delivery. Existing cannabinoid agents, studied previously, show anti-cancer potencies via signalling pathways associated with the hallmarks of cancer. The results of the review can be used to provide guidance in the design of future drug therapy for glioblastoma tumours. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

47 pages, 8155 KiB

Open AccessReview

Informing the Cannabis Conjecture: From Life’s Beginnings to Mitochondria, Membranes and the Electrome—A Review

by Alistair V. W. Nunn, Geoffrey W. Guy and Jimmy D. Bell

Int. J. Mol. Sci. 2023, 24(17), 13070; https://doi.org/10.3390/ijms241713070 - 22 Aug 2023

Viewed by 2043

Abstract

Before the late 1980s, ideas around how the lipophilic phytocannabinoids might be working involved membranes and bioenergetics as these disciplines were “in vogue”. However, as interest in genetics and pharmacology grew, interest in mitochondria (and membranes) waned. The discovery of the cognate receptor for tetrahydrocannabinol (THC) led to the classification of the endocannabinoid system (ECS) and the conjecture that phytocannabinoids might be “working” through this system. However, the how and the “why” they might be beneficial, especially for compounds like CBD, remains unclear. Given the centrality of membranes and mitochondria in complex organisms, and their evolutionary heritage from the beginnings of life, revisiting phytocannabinoid action in this light could be enlightening. For example, life can be described as a self-organising and replicating far from equilibrium dissipating system, which is defined by the movement of charge across a membrane. Hence the building evidence, at least in animals, that THC and CBD modulate mitochondrial function could be highly informative. In this paper, we offer a unique perspective to the question, why and how do compounds like CBD potentially work as medicines in so many different conditions? The answer, we suggest, is that they can modulate membrane fluidity in a number of ways and thus dissipation and engender homeostasis, particularly under stress. To understand this, we need to embrace origins of life theories, the role of mitochondria in plants and explanations of disease and ageing from an adaptive thermodynamic perspective, as well as quantum mechanics. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

20 pages, 3753 KiB

Open AccessReview

Cannabidiol for Oral Health: A New Promising Therapeutical Tool in Dentistry

by Luigi Bellocchio, Assunta Patano, Alessio Danilo Inchingolo, Francesco Inchingolo, Gianna Dipalma, Ciro Gargiulo Isacco, Elisabetta de Ruvo, Biagio Rapone, Antonio Mancini, Felice Lorusso, Antonio Scarano, Giuseppina Malcangi and Angelo Michele Inchingolo

Int. J. Mol. Sci. 2023, 24(11), 9693; https://doi.org/10.3390/ijms24119693 - 2 Jun 2023

Cited by 1 | Viewed by 5747

Abstract

The medical use of cannabis has a very long history. Although many substances called cannabinoids are present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and cannabinol (CBN) are the three main cannabinoids that are most present and described. CBD itself is not responsible for the psychotropic effects of cannabis, since it does not produce the typical behavioral effects associated with the consumption of this drug. CBD has recently gained growing attention in modern society and seems to be increasingly explored in dentistry. Several subjective findings suggest some therapeutic effects of CBD that are strongly supported by research evidence. However, there is a plethora of data regarding CBD’s mechanism of action and therapeutic potential, which are in many cases contradictory. We will first provide an overview of the scientific evidence on the molecular mechanism of CBD’s action. Furthermore, we will map the recent developments regarding the possible oral benefits of CBD. In summary, we will highlight CBD’s promising biological features for its application in dentistry, despite exiting patents that suggest the current compositions for oral care as the main interest of the industry. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

24 pages, 815 KiB

Open AccessReview

Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance

by Stefano Martini, Alessandra Gemma, Marco Ferrari, Marco Cosentino and Franca Marino

Int. J. Mol. Sci. 2023, 24(4), 3125; https://doi.org/10.3390/ijms24043125 - 4 Feb 2023

Cited by 6 | Viewed by 4773

Abstract

Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD’s effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases. Full article

(This article belongs to the Special Issue New Insight into Cannabinoid Effects 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

New Insight into Cannabinoid Effects 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI