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New Insight into Cannabinoid Effects 2.0

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 28274

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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

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • cannabinoids
  • endogenous cannabinoids
  • neurodegenerative diseases
  • cancer
  • pharmacology

Published Papers (10 papers)

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Research

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16 pages, 3613 KiB  
Article
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 2408
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 [...] Read more.
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)
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16 pages, 2500 KiB  
Article
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 - 02 Apr 2023
Cited by 7 | Viewed by 2962
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 [...] Read more.
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 Aβ1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ1-42 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)
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15 pages, 1764 KiB  
Article
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 2030
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 [...] Read more.
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)
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16 pages, 2021 KiB  
Article
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 3 | Viewed by 1953
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) [...] Read more.
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)
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15 pages, 2701 KiB  
Article
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 7 | Viewed by 2075
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 [...] Read more.
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)
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19 pages, 3573 KiB  
Article
Antagonization of OX1 Receptor Potentiates CB2 Receptor Function in Microglia from APPSw/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 1933
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 [...] Read more.
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 Gi and a Gq. 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)
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Review

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32 pages, 18342 KiB  
Review
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 1671
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 [...] Read more.
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)
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47 pages, 8155 KiB  
Review
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 1937
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 [...] Read more.
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)
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20 pages, 3753 KiB  
Review
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 - 02 Jun 2023
Cited by 1 | Viewed by 5581
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 [...] Read more.
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)
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24 pages, 815 KiB  
Review
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 - 04 Feb 2023
Cited by 6 | Viewed by 4570
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 [...] Read more.
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)
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