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Cannabidiol (CBD) is a potent inhibitor of SARS-CoV-2 infection in vitro. (A) A549 cells with ACE2 overexpression (A549-ACE2) were treated with indicated doses of CBD, KPT-9274, or URMC-099 followed by infection with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.5 for 48 hours. The cells were stained for spike protein and the

Cannabidiol (CBD) is a potent inhibitor of SARS-CoV-2 infection in vitro. (A) A549 cells with ACE2 overexpression (A549-ACE2) were treated with indicated doses of CBD, KPT-9274, or URMC-099 followed by infection with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.5 for 48 hours. The cells were stained for spike protein and the

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The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, i...

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... with an MLK inhibitor (URMC-099) previously implicated as an antiviral for HIV (12) and KPT-9274, a PAK4/NAMPT inhibitor (13) that our analysis suggested might reverse many changes in gene expression caused by SARS-CoV-2. All three inhibitors potently inhibited viral replication under non-toxic conditions with EC50s 5 ranging from 0.2-2.1 μM (Fig. 1A). CBD inhibited SARS-CoV-2 replication in Vero E6 monkey kidney epithelial cells as well ( fig. S1A). No toxicity was observed at the effective doses ( fig. S1B). We also determined that CBD suppressed replication of a related betacoronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 μM using A549 cells ...
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... a PAK4/NAMPT inhibitor (13) that our analysis suggested might reverse many changes in gene expression caused by SARS-CoV-2. All three inhibitors potently inhibited viral replication under non-toxic conditions with EC50s 5 ranging from 0.2-2.1 μM (Fig. 1A). CBD inhibited SARS-CoV-2 replication in Vero E6 monkey kidney epithelial cells as well ( fig. S1A). No toxicity was observed at the effective doses ( fig. S1B). We also determined that CBD suppressed replication of a related betacoronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 μM using A549 cells that express the MHV receptor (A549-MHVR), indicating the 10 potential for more broader viral ...
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... reverse many changes in gene expression caused by SARS-CoV-2. All three inhibitors potently inhibited viral replication under non-toxic conditions with EC50s 5 ranging from 0.2-2.1 μM (Fig. 1A). CBD inhibited SARS-CoV-2 replication in Vero E6 monkey kidney epithelial cells as well ( fig. S1A). No toxicity was observed at the effective doses ( fig. S1B). We also determined that CBD suppressed replication of a related betacoronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 μM using A549 cells that express the MHV receptor (A549-MHVR), indicating the 10 potential for more broader viral efficacy ( fig. ...
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... S1A). No toxicity was observed at the effective doses ( fig. S1B). We also determined that CBD suppressed replication of a related betacoronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 μM using A549 cells that express the MHV receptor (A549-MHVR), indicating the 10 potential for more broader viral efficacy ( fig. ...
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... A and B) and one commercial vendor that used natural materials (Supplier C). The striking congruence between the experimental 1 H NMR and the recently established quantum-mechanical HiFSA ( 1 H Iterative Full Spin Analysis) profiles observed for all materials confirmed that 1) the compounds used were indeed 20 CBD with purities of at least 97% (Fig. 1B) and 2) congeneric cannabinoids were not present at levels above 1.0% (11). Analysis of these different CBD preparations in the viral A549-ACE2 infection assay showed similar EC50s with a range from 0.6-1.8 μM likely reflecting the intrinsic biological variability of the assay (Fig. 1C). No toxicity was observed for any of the CBD ...
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... used were indeed 20 CBD with purities of at least 97% (Fig. 1B) and 2) congeneric cannabinoids were not present at levels above 1.0% (11). Analysis of these different CBD preparations in the viral A549-ACE2 infection assay showed similar EC50s with a range from 0.6-1.8 μM likely reflecting the intrinsic biological variability of the assay (Fig. 1C). No toxicity was observed for any of the CBD preparations at the doses used to inhibit viral infection ...
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... immune host responses to pathogen exposure 40 (18). SARS-CoV-2 infection suppresses the interferon signaling pathway (19) (Fig. 5A, and fig. S9). Some genes that are induced by CBD in both the absence and presence of the virus include receptors for interferons beta and gamma as well as mediators of the signaling pathway such as STATs 1 and 2 ( Fig. 5A and fig. S10). Other genes in the pathway like OAS1, an interferon-induced gene that leads to activation of RNase L and 45 RNA degradation (20), are not significantly induced by CBD unless in the presence of the virus (Fig. 5A and fig. S11). These latter results are consistent with the possibility that CBD lowers the effective viral titer ...
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... include receptors for interferons beta and gamma as well as mediators of the signaling pathway such as STATs 1 and 2 ( Fig. 5A and fig. S10). Other genes in the pathway like OAS1, an interferon-induced gene that leads to activation of RNase L and 45 RNA degradation (20), are not significantly induced by CBD unless in the presence of the virus (Fig. 5A and fig. S11). These latter results are consistent with the possibility that CBD lowers the effective viral titer sufficiently to enable normal host activation of ...

Citations

... Cannabidiol (CBD), one of the cannabinoids derived from hemp (Cannabis sativa), also became popular during the COVID-19 pandemic, not only in Japan, but across the world because CBD is a potential alternative treatment for anxiety, depression, and psychotic disorders [20]. In addition, CBD has inhibitory effects against SARS-CoV-2 infection [21] and replication [22]. However, CBD can inhibit CYP3A4 activity [23], indicating that the concomitant use of CBD and Nirmatrelvir has a risk of interaction. ...
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Some patients use dietary supplements and medicines concomitantly, with an inappropriate perception of their safety and efficacy. To clarify the perception between dietary supplement and medicine users and non-users, we conducted an internet survey. In this survey, 38.9% of participants used dietary supplements, 32.6% used prescription medicines, and 14.7% used dietary supplements and prescription medicines concomitantly. Then, we conducted a further survey on four groups, dietary supplement and prescription medicine users, dietary supplement only users, prescription medicine only users, and non-users (500 each). Dietary supplement users had favorable outcomes in terms of both the safety and efficacy of dietary supplements compared to dietary supplement non-users. This perception of dietary supplements was independent from medicine use. The awareness of the Health Food Network consumer navigation site, which provides information about dietary supplements for consumers, was the highest among dietary supplement and prescription medicine users, but it was still low (2.2%). In conclusion, consumers who use dietary supplement and prescription medicine concomitantly have favorable outcomes for their safety and efficacy and a low awareness of their interaction. There is a need to provide information, especially regarding the risk of interaction, that takes into account the consumer’s situation.
... To confirm the results of the gel electrophoresis splicing assays for XBP1 mRNA that distinguished SARS-CoV-2 infection from that of the other betacoronaviruses (Fig. 3), we further utilized the RNA-seq results to quantitatively measure XBP1 mRNA splicing by these coronaviruses. Through RNA-seq, we visualized both the unspliced and spliced XBP1 mRNA reads based on whether they contain the 26-nucleotide nonconventional intron that is removed as a result of RNase activity of IRE1a as previously described (38) (Fig. 4B and C). MERS-CoV infection resulted in significant XBP1 mRNA splicing, in contrast to no difference detected in SARS-CoV-2-infected versus mockinfected cells ( Fig. 4B and C). ...
... RNA-seq data from Gene Expression Omnibus (GEO) no. GSE147507 (37), GSE168797 (38), and GSE144882 (35) and the data presented herein were used to compare the effects of different viruses on host ER stress response. Specifically, Ingenuity Pathway Analysis (IPA) (https://digitalinsights.qiagen.com/products-overview/discovery-insights-portfolio/analysis-and ...
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SARS-CoV-2 is the third lethal respiratory coronavirus, after MERS-CoV and SARS-CoV, to emerge this century, causing millions of deaths worldwide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease.
... There is evidence, albeit limited, that cannabidiol (CBD) may have potential as an anti-SARS-CoV-2 agent [48,[67][68][69][70][71] presented concomitantly with important warnings against prescription of cannabinoid products for COVID-related symptoms at present [50,72]. For example, CBD has been suggested to be an efficient inhibitor of SARS-CoV-2 (strain 229E) replication in human lung fibroblasts (MRC-5) through enhancement of antiviral terpene efficacy [68]. ...
... As noted earlier, Breemen et al. reported that CBGA, CBDA and tetrahydrocannabinolic acid (THCA) interact with the SARS-CoV-2 S1 spike protein subunit [49]. Nguyen et al. have evidenced that CBD and 7-OH-CBD, but not others in a bank of cannabinoids tested (CBG, CBC, CBDA, CBDV, THC), inhibit SARS-CoV-2 replication in epithelial cells in a manner associated with inhibition of viral genes, including almost complete shutdown of the activity of those encoding the spike protein and nucleocapsid, reversion of viral influence on host genes and upregulation of the IFN anti-viral axis [50]. Intriguingly, the authors also report that CBD consumption by humans correlates with a highly significant reduction in SARS-CoV-2 relative to control subjects [50]. ...
... Nguyen et al. have evidenced that CBD and 7-OH-CBD, but not others in a bank of cannabinoids tested (CBG, CBC, CBDA, CBDV, THC), inhibit SARS-CoV-2 replication in epithelial cells in a manner associated with inhibition of viral genes, including almost complete shutdown of the activity of those encoding the spike protein and nucleocapsid, reversion of viral influence on host genes and upregulation of the IFN anti-viral axis [50]. Intriguingly, the authors also report that CBD consumption by humans correlates with a highly significant reduction in SARS-CoV-2 relative to control subjects [50]. Most recently, Fernandes et al. have reported that CBD enhances the anti-viral response of SARS-CoV-2-infected epithelial cells, but not uninfected cells, as determined by activation of interferon and 2 -5 -oligoadenylate synthetase (OAS) genes [103]. ...
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Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP–microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.
... Different from delta-9-tetrahydrocannabinol (THC), CBD is known as a non-psychoactive cannabinoid and seems safe under appropriate usage. CBD shows anti-inflammatory properties [47] and inhibitory effects on SARS-CoV-2 infection [48] and replication [49]. However, only two reports have been conducted on humans. ...
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COVID-19 is still the biggest issue worldwide. Many dietary supplements on the market claim to have anti-COVID-19 effects without scientific evidence. To elucidate the prevalence of dietary supplement usage for the prevention of COVID-19, we conducted an online cross-sectional questionnaire survey among Japanese adults in January 2022. The prevalence of dietary supplement use for the prevention of COVID-19 was 8.3%, and there was no gender difference. We also conducted additional research on these dietary supplement users (1000 males and 1000 females). The most popular ingredient used was vitamin C (61.0%), with vitamin D (34.9%) and probiotics (33.4%) following. Half of these participants reported using supplements for more than one year. The information sources that reportedly led them to start using dietary supplements for the prevention of COVID-19 were the Internet (44.0%), television and radio (29.9%), and family or friends (26.0%), and these information sources differed among generations. In conclusion, some of the population used vitamin/mineral supplements for the prevention of COVID-19 that might be beneficial for their health, but some used ingredients with no scientifically proven effects against the virus at this time. Therefore, information-based scientific evidence is important to prevent the inappropriate use of dietary supplements by consumers.
... Instead, we found a potential role for CBD in augmentation of the innate anti-viral host cell response to the viral genes, with evidence of a role for enhanced IFN-and ISG-induction. While this was initially unexpected, during preparation of the manuscript, data became available demonstrating that CBD inhibits the infection of cells with SARS-CoV-2, as well as replication of the virus after entry into cells, in association with augmented host-cell IFN responses [48]. Our work now shows evidence that CBD augments the anti-viral innate immune response to three distinct viral genes with apparently disparate functions, and also that CBD may prophylactically prime the innate anti-viral response of cells, allowing them to be better prepared to respond to viral infection. ...
... This finding suggests that CBD may help limit an initial infection by promoting removal of infected cells, thereby limiting the spread, and therefore also likely raising the necessary infectious titre. This is supported by evidence from users of Epidiolex®, a high-dose pharmaceutical CBD licensed in the United States for use in the treatment of rare types of epilepsy in adults and children [48]. In that study, patients prescribed high-dose CBD had a significantly lower risk of testing positive for SARS-CoV-2, even when matched by demographics, recorded diagnoses, and other medications. ...
... In that study, patients prescribed high-dose CBD had a significantly lower risk of testing positive for SARS-CoV-2, even when matched by demographics, recorded diagnoses, and other medications. In those with use of any cannabinoid in their medical record, the positivity rate for SARS-CoV-2 was over 40% lower [48]. Taken together with our findings, this suggests that CBD may provide a prophylactic effect against the risk of contracting SARS-CoV-2 and developing COVID-19 by increasing the initial apoptotic response to viral genes. ...
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Aims To study effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD). Main methods HEK293 cells transfected with plasmids expressing control vector, ORF8, ORF10, or M protein were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without CBD. Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection. Key findings Reduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1–2 μM CBD treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2′-5′-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. CBD similarly enhanced the cellular anti-viral response to Poly (I:C). Significance Our results demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of CBD. Thus, CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.
... The virus membrane consists of three integral proteins-the spike (S), the membrane (M) and the envelope (E) [19]. SARS-CoV-2 enters human cells by binding the S protein to the angiotensin converting enzyme 2 (ACE2) receptor, which is mainly expressed in lung tissue, as well as the oral and nasal mucosa, kidneys, testes and the gastrointestinal tract [17]. ...
... Excessive expression of ACE2 receptors is correlated to cytokine secretion and inflammatory response in COVID-19 patients [20]. The binding of the S protein and the ACE2 receptor leads to proteolysis of the S protein by transmembrane serine protease 2 (TMPRSS2) into two bound peptides-S1 and S2-which facilitate the viral entry into the cell by both binding to the ACE2 receptor and mediating membrane fusion [19]. In the host cell, the viral genome undergoes translation into two polypeptides, which later become cleaved by SARS-CoV-2 proteases-main (M pro ) and papain-like (PL pro ). ...
... In the host cell, the viral genome undergoes translation into two polypeptides, which later become cleaved by SARS-CoV-2 proteases-main (M pro ) and papain-like (PL pro ). The proteins produced by this process facilitate viral replication and enable the virus to spread inside the host organism [19]. ...
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The COVID-19 pandemic caused by the SARS-CoV-2 virus made it necessary to search for new options for both causal treatment and mitigation of its symptoms. Scientists and researchers around the world are constantly looking for the best therapeutic options. These difficult circumstances have also spurred the re-examination of the potential of natural substances contained in Cannabis sativa L. Cannabinoids, apart from CB1 and CB2 receptors, may act multifacetedly through a number of other receptors, such as the GPR55, TRPV1, PPARs, 5-HT1A, adenosine and glycine receptors. The complex anti-inflammatory and antiviral effects of cannabinoids have been confirmed by interactions with various signaling pathways. Considering the fact that the SARS-CoV-2 virus causes excessive immune response and triggers an inflammatory cascade, and that cannabinoids have the ability to regulate these processes, it can be assumed that they have potential to be used in the treatment of COVID-19. During the pandemic, there were many publications on the subject of COVID-19, which indicate the potential impact of cannabinoids not only on the course of the disease, but also their role in prevention. It is worth noting that the anti-inflammatory and antiviral potential are shown not only by well-known cannabinoids, such as cannabidiol (CBD), but also secondary cannabinoids, such as cannabigerolic acid (CBGA) and terpenes, emphasizing the role of all of the plant’s compounds and the entourage effect. This article presents a narrative review of the current knowledge in this area available in the PubMed, Scopus and Web of Science medical databases.
... Therefore, CBD has the potential not only to act as an antiviral agent in the early stages of infection but also to protect the host against an overactivation of the immune system in the later stages of the disease [168]. On the other hand, CBD's therapeutic properties against anxiety or depression could be applied to treat mental health conditions derived from COVID-19 [169,170]. ...
... Chronic neuroinflammation causes an increase in levels of proinflammatory cytokines, which stimulates the inflammatory cycle by increasing oxidative and nitrosative stress and the release of inflammatory mediators [173]. Glial cells are associated with neuroinflammation and the neurodegenerative process [174]; neuroinflammation is typically characterized by the activation of immunocompetent glial cells (microglia and astroglia), the release of cytokines, prostaglandins, and reactive oxygen species, the impairment of BBB integrity and resultant infiltration of peripheral immune cells [168]. Astrocytes, the type of glial cells most abundant in the mammalian CNS, are essential for brain homeostasis as they provide metabolites and growth factors to neurons, modulate neuronal transmission and excitability, support synapse formation and plasticity, regulate the extracellular balance of ions, fluid, and neurotransmitters [175,176]. ...
Article
The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established, however, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, and indirect mechanisms of inflammatory / autoimmune origin. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potential promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review we address the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a decrease in viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.
... CBD has been shown to stimulate peroxisome-proliferator activated receptors alpha and gamma (PPAR-α and PPAR-γ) to attenuate the pathways leading to proinflammatory cytokine release [70,73,75,76]. Through their actions at inflammasomes and the transient cation receptor potential channels (TRPs) these non-psychoactive cannabinoids depress the NFκB signaling pathway, decreasing the release of IL-6, IL-1β, IFN-γ and TNF-α in animal and in vitro models [77][78][79]. Thus, the interest in cannabinoids to diminish the effects of the cytokine storm as a serious manifestation of SARS-CoV-2 infection is pronounced, of late. ...
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During the COVID-19 pandemic lasting now for well more than a year, nearly 247 million cases have been diagnosed and over 5 million deaths have been recorded worldwide as of November 2021. The devastating effects of the SARS-CoV-2 virus on the immune system lead to the activation of signaling pathways involved in inflammation and the production of inflammatory cytokines. SARS-CoV-2 displays a great deal of homology with other coronaviruses, especially SARS-CoV and MERS-CoV which all display similar components which may serve as targets, namely the Spike (S) protein, the main protease (MPro) which is a chymotrypsin-like protease (CLPro) and RNA-directed RNA polymerase (RdRp). Natural constituents found in traditional herbal medicines, dietary supplements and foods demonstrate activity against SARS-CoV-2 by affecting the production of cytokines, modulating cell signaling pathways related to inflammation and even by direct interaction with targets found in the virus. This has been demonstrated by the application of fluorescence resonance energy transfer (FRET) experiments, assays of cytopathic effect (CPE) and in silico molecular docking studies that estimate binding strength. Glycyrrhizin, flavonoids such as quercetin, kaempferol and baicalein, and other polyphenols are the most common constituents found in Traditional Chinese Medicines that modulate inflammation and cell signaling pathways, and bind viral targets demonstrating valuable effects against SARS-CoV-2. However, the bioavailability of these natural products and their dependence on each other in extracts make it difficult to assess their actual utility in the treatment of COVID-19. Therefore, more can be learned through rational drug design based on natural products and from well-designed clinical trials employing specific doses of standardized combinations.
... There is a clear paucity of data from well-designed clinical trials to support the use of cannabis, CBD, or any other cannabinoid for treating sleep disorders, either anxiety, depression, other neurological complications associated with COVID-19 or patients with SUDs. However, there is a silver lining-the fact that CBD inhibits SARS-Cov-2 replication and promotes the host innate response in humans (Nguyen et al. 2021), a clear positive aspect of CBD, and as evidenced by data from the NIH's database (http:// clini caltr ials. gov; accessed July 13, 2021), several investigators are studying either the dose tolerability or the efficacy of CBD in treating anxiety or depression. ...
Article
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COVID-19 epidemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Several effective vaccines have been developed and extensive efforts are underway to develop therapeutics to treat COVID-19. Cannabis and/or its product-cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental/neurological complications and substance use disorders. However, research reviewed shows that there is insufficient data from clinical studies to support the use of cannabis or CBD for the treatment of COVID-19 associated mental health and neurological complications. Additional basic and clinical research is suggested to develop cannabis or cannabidiol for the treatment of mental health problems associated with coronavirus infection and or substance use disorders. In the meantime, it is important that the addiction physician/psychiatrist must caution while prescribing or recommending cannabis or CBD for treating such clinical indications. Graphical abstract Research shows that currently there is no clinical evidence to support the use of cannabis or any of its compounds including CBD for treating any of the neuropsychiatric complications of COVID-19. Thus, it is important that the addiction physicians/psychiatrists caution their patients from using cannabis or cannabis products for treating any such complications.
... To date, there is also very little research on the interaction of ACE2, cannabinoids, and cannabis smoke, although there is evidence that CBD decreased ACE2 expression [114], may inhibit SARS-CoV-2 replication [115] and reduced COVID-19 related inflammation [116]. Studies utilizing over 800 C. sativa strains in 3D human models of COVID-19 target tissues (oral, airway, and intestinal) noted that high CBD/low THC extracts downregulate ACE2 gene and ACE2 protein levels [114,117]. ...
Article
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Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.