Cannabis sativa CBD Extract Exhibits Synergy with Broad-Spectrum Antibiotics against Salmonella enterica subsp. Enterica serovar typhimurium

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“New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections.

The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species, it is important to examine potential interactions between CBD and common therapeutics such as broad-spectrum antibiotics.

In this study it is demonstrated that CBD-antibiotic (combination of CBD and antibiotic) co-therapy can effectively fight Salmonella typhimurium (S. typhimurium) via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics (ampicillin, kanamycin, and polymyxin B) for potential CBD-antibiotic co-therapy. In this study, it is revealed that S. typhimurium growth is inhibited at very low dosages of CBD-antibiotic.

This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating S. typhimurium.”

https://pubmed.ncbi.nlm.nih.gov/36557613/

“The decrease in antibiotic development over the 21st century has exacerbated the need for new antibacterial agents as well as new methodologies designed to retain the efficacy of current antibiotics. CBD extract from C. sativa has been presented as a promising antibacterial agent with in vitro efficacy against several relevant bacterial pathogens including Staphylococcus aureus, Streptococcus pneumoniae, Salmonella spp. Clostridium difficile, Neisseria spp., Moraxella catarrhalis, and Legionella pneumophila. This antibacterial activity achieved through membrane disruption of both Gram-positive and Gram-negative bacterial species presents CBD as a unique and particularly effective class of antibacterial agents.”

https://www.mdpi.com/2076-2607/10/12/2360

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

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“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.”

https://pubmed.ncbi.nlm.nih.gov/36555519/

“We have shown that the mode of action of CBD against S. mutans is multifactorial and attributed to: inhibition of bacterial growth and subsequently hindrance of biofilm formation, diminished biofilm metabolic activity and prevention of bacterial recovery within the biofilms following CBD treatment. Some of these effects can be attributed to the membrane hyperpolarization caused by CBD. The combined anti-bacterial and anti-metabolic effects of CBD contribute to the prevention in pH drop with implications for being a potential adjuvant drug in protecting against dental caries.”

https://www.mdpi.com/1422-0067/23/24/15878

Cannabidiol and Its Combinations with Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Activation of NF-κB Signaling in Vulvar Squamous Cell Carcinoma

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“Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with a relatively good prognosis. However, the prognosis remains poor for elderly patients and those with a significant depth of tumor invasion; thus, novel treatment modalities are needed.

The aim of this study was to analyze the impact of cannabidiol (CBD) and its combination with NSAIDs, diclofenac (DIC) and ibuprofen (IBU) on VSCC cells. In this regard, the MTT test was applied for cytotoxicity analysis. Moreover, the influence of CBD, DIC and IBU, as well as their combinations, on apoptosis and cell cycle distribution were analyzed by flow cytometry. The mechanisms of action of the analyzed compounds, including their impact on NF-κB signaling, p53 and COX-2 expression were evaluated using Western blot.

This study shows that CBD and its combinations with NSAIDs are cytotoxic to A431 cells, but they also reduce, in a dose-dependent manner, the viability of immortalized keratinocyte HaCaT cells, and human umbilical vein cell line, EA.hy926. Moreover, the compounds and their combinations induced apoptosis, diminished the NF-κB signaling activation and reduced COX-2 expression.

We conclude that CBD and its combination with DIC or IBU are promising candidates for the adjuvant treatment of high-risk VSCC patients.”

https://pubmed.ncbi.nlm.nih.gov/36557911/

“The results of our study regarding the use of a CDB and NSAIDs, as well as the combi-treatment of CBD together with NSAIDs, provide the foundation for a new approach to therapy of VSCC.”

https://www.mdpi.com/1420-3049/27/24/8779

Phytocannabinoids Act Synergistically with Non-Steroidal Anti-Inflammatory Drugs Reducing Inflammation in 2D and 3D In Vitro Models

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“Lung inflammation is associated with elevated pro-inflammatory cytokines and chemokines. Treatment with FCBD:std (standard mix of cannabidiol [CBD], cannabigerol [CBG] and tetrahydrocannabivarin [THCV]) leads to a marked reduction in the inflammation of alveolar epithelial cells, but not in macrophages.

In the present study, the combined anti-inflammatory effect of FCBD:std with two corticosteroids (dexamethasone and budesonide) and two non-steroidal anti-inflammatory drugs (NSAID; ibuprofen and diclofenac), was examined. Enzyme-linked immunosorbent assay (ELISA) was used to determine protein levels. Gene expression was determined by quantitative real-time PCR. Inhibition of cyclo-oxygenase (COX) activity was determined in vitro.

FCBD:std and diclofenac act synergistically, reducing IL-8 levels in macrophages and lung epithelial cells. FCBD:std plus diclofenac also reduced IL-6, IL-8 and CCL2 expression levels in co-cultures of macrophages and lung epithelial cells, in 2D and 3D models. Treatment by FCBD:std and/or NSAID reduced COX-1 and COX-2 gene expression but not their enzymatic activity. FCBD:std and diclofenac exhibit synergistic anti-inflammatory effects on macrophages and lung epithelial cells, yet this combined activity needs to be examined in pre-clinical studies and clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36559009/

“We have shown that FCBD:std and diclofenac have synergistic anti-inflammatory effects on macrophages and lung epithelial cells, which involve the reduction of COX and CCL2 gene expression and IL levels. FCBD:std, when combined with diclofenac, can have considerably increased anti-inflammatory activity by several fold, suggesting that in an effective cannabis-diclofenac combined treatment, the level of NSAIDs may be reduced without compromising anti-inflammatory effectivity.”

https://www.mdpi.com/1424-8247/15/12/1559

Cannabinoids in Late Life Parkinson’s Disease and Dementia: Biological Pathways and Clinical Challenges

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“The use of cannabinoids as therapeutic drugs has increased among aging populations recently. Age-related changes in the endogenous cannabinoid system could influence the effects of therapies that target the cannabinoid system. At the preclinical level, cannabidiol (CBD) induces anti-amyloidogenic, antioxidative, anti-apoptotic, anti-inflammatory, and neuroprotective effects. These findings suggest a potential therapeutic role of cannabinoids to neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer.

Emerging evidence suggests that CBD and tetrahydrocannabinol have neuroprotective therapeutic-like effects on dementias. In clinical practice, cannabinoids are being used off-label to relieve symptoms of PD and AD. In fact, patients are using cannabis compounds for the treatment of tremor, non-motor symptoms, anxiety, and sleep assistance in PD, and managing responsive behaviors of dementia such as agitation. However, strong evidence from clinical trials is scarce for most indications.

Some clinicians consider cannabinoids an alternative for older adults bearing Parkinson’s disease and Alzheimer’s dementia with a poor response to first-line treatments. In our concept and experience, cannabinoids should never be considered a first-line treatment but could be regarded as an adjuvant therapy in specific situations commonly seen in clinical practice. To mitigate the risk of adverse events, the traditional dogma of geriatric medicine, starting with a low dose and proceeding with a slow titration regime, should also be employed with cannabinoids. In this review, we aimed to address preclinical evidence of cannabinoids in neurodegenerative disorders such as PD and AD and discuss potential off-label use of cannabinoids in clinical practice of these disorders.”

https://pubmed.ncbi.nlm.nih.gov/36552056/

“Cannabinoids constitute a promising pharmacological approach to treatment of neuropsychiatric disorders in late life.

Overall, cannabinoids compounds are well tolerated and appear to be safer than most psychotropic medication, but given the vulnerability of patients with dementia, they require appropriate monitoring by the clinician.”

https://www.mdpi.com/2076-3425/12/12/1596

Cannabinoid Compounds as a Pharmacotherapeutic Option for the Treatment of Non-Cancer Skin Diseases

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“The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin’s immune response.

In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/36552866/

“Based on the current publications, it can be summarised that cannabinoid compounds have great potential in the treatment of skin diseases, both as topical applications and as systemic medications.”

https://www.mdpi.com/2073-4409/11/24/4102

Real-Time Monitoring of the Cytotoxic and Antimetastatic Properties of Cannabidiol in Human Oral Squamous Cell Carcinoma Cells Using Electric Cell-Substrate Impedance Sensing

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“Cannabidiol (CBD) is an active natural compound that is extracted from Cannabis sativa. Previous studies show that CBD is a nonpsychotropic compound with significant anticancer effects.

This study determines its cytotoxic effect on oral cancer cells and OEC-M1 cells and compares the outcomes with a chemotherapeutic drug, cisplatin. This study has investigated the effect of CBD on the viability, apoptosis, morphology, and migration of OEC-M1 cells. Electric cell-substrate impedance sensing (ECIS) is used to measure the change in cell impedance for cells that are treated with a series concentration of CBD for 24 h.

AlamarBlue and annexin V/7-AAD staining assays show that CBD has a cytotoxic effect on cell viability and induces cell apoptosis. ECIS analysis shows that CBD decreases the overall resistance and morphological parameters at 4 kHz in a concentration-dependent manner. There is a significant reduction in the wound-healing recovery rate for cells that are treated with 30 μM CBD.

This study demonstrates that ECIS can be used for in vitro screening of new chemotherapy and is more sensitive, functional, and comprehensive than traditional biochemical assays. CBD also increases cytotoxicity on cell survival and the migration of oral cancer cells, so it may be a therapeutic drug for oral cancer.”

https://pubmed.ncbi.nlm.nih.gov/36555480/

“In conclusion, this study determines the effect of CBD on OEC-M1 cells. The cytotoxicity results show that CBD at higher concentrations (100 μM) increases cytotoxicity and is more likely to lead to the apoptosis of cancer cells more than cisplatin at the same concentration. ECIS is used to determine the effect of the drug on the adhesion, spread, and migration of cells.

The results show that there is a linear, concentration-dependent decrease in OEC-M1 cells that are treated with CBD. Treatment with CBD at low concentrations (30 μM) completely inhibits cell migration and micromotion without affecting cell viability and apoptosis.

In comparison with cisplatin, this study shows that CBD has a greater ability to inhibit metastasis and trigger apoptosis. It might work successfully as a treatment for oral cancer.

We can also screen drugs more efficiently and rapidly by using the Var32 analysis method in combination with ECIS. ECIS provides a more precise measurement of experimental data and prevents operator errors by its real-time monitoring. It is promising for possible uses in new drug screening, and it might promote the development of oral cancer treatments and other medical applications.”

https://www.mdpi.com/1422-0067/23/24/15842

Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction

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“Cannabis contains over 500 distinct compounds, which include cannabinoids, terpenoids, and flavonoids. However, very few of these compounds have been studied for their beneficial effects. There is an emerging concept that the constituents of the cannabis plant may work in concert to achieve better therapeutic benefits. This study is aimed at determining if the combination of a minor cannabinoid (cannabidiol, CBD) and a terpene (beta-caryophyllene, BCP) works in concert and if this has any therapeutic value. We used an inflammatory pain model (formalin) in mice to test for any functionality of CBD and BCP in combination. First, we determined the analgesic effect of CBD and BCP individually by establishing dose-response studies. Second, we tested the analgesic effect of fixed-ratio combinations and monitored any adverse effects. Finally, we determined the effect of this combination on inflammation. The combination of CBD and BCP produces a synergistic analgesic effect. This effect was without the cannabinoid receptor-1 side effects. The analgesic effect of CBD and BCP in combination involves an inflammatory mechanism. The combination of these two constituents of the cannabis plant, CBD and BCP, works in concert to produce a therapeutic effect with safety profiles through an inflammatory mechanism.”

https://pubmed.ncbi.nlm.nih.gov/36555111/

“In summary, the present data support the concept that cannabinoids and terpenes work synergistically with therapeutical value. In particular, the CBD and BCP in combination produce a synergistic analgesic effect without CB1-associated side effects. Finally, scientific investigation of the interactive effects of CBD and BCP on a therapeutic target has not been undertaken. Therefore, our present data set the stage for future studies on the therapeutic value of this combination in other diseases and testing other terpenes in combination with other cannabinoids or terpenes.”

https://www.mdpi.com/1422-0067/23/24/15470

Therapeutic Effects of Cannabinoids and Their Applications in COVID-19 Treatment

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“Cannabis sativa is one of the first medicinal plants used by humans. Its medical use remains controversial because it is a psychotropic drug whose use has been banned. Recently, however, some countries have approved its use, including for recreational and medical purposes, and have allowed the scientific study of its compounds. Cannabis is characterized by the production of special types of natural products called phytocannabinoids that are synthesized exclusively by this genus. Phytocannabinoids and endocannabinoids are chemically different, but both pharmacologically modulate CB1, CB2, GRP55, GRP119 and TRPV1 receptor activities, involving activities such as memory, sleep, mood, appetite and motor regulation, pain sensation, neuroinflammation, neurogenesis and apoptosis. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids with greater pharmacological potential, including anti-inflammatory, neuroprotective and anticonvulsant activities. Cannabidiol is showing promising results for the treatment of COVID-19, due to its capability of acting on the unleashed cytokine storm, on the proteins necessary for both virus entry and replication and on the neurological consequences of patients who have been infected by the virus. Here, we summarize the latest knowledge regarding the advantages of using cannabinoids in the treatment of COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/36556483/

“Cannabinoids, especially CBD, appear to be promising in the treatment of COVID-19, as an adjuvant of current antiviral drugs, reducing lung inflammation by decreasing chemokines and cytokines secreted by the cells of the immune system or mediating in the CNS reducing morbidity as fear, anxiety, stress, sleep disorders. However, more research and clinical studies are necessary, especially to establish the effects of their long-term use. In any case, many countries are allowing the use of medical cannabis and this plant, which has been used since ancient times, could be a natural therapeutic alternative for COVID-19 infected patients, but there is still a long way to go for its acceptance and use in routine clinical practice.”

https://www.mdpi.com/2075-1729/12/12/2117

Analysis and Identification of Bioactive Compounds of Cannabinoids in Silico for Inhibition of SARS-CoV-2 and SARS-CoV

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“Despite the approval of multiple vaccinations in different countries, the majority of the world’s population remains unvaccinated due to discrepancies in vaccine distribution and limited production capacity. The SARS-CoV-2 RBD-ACE2 complex (receptor binding domain that binds to ACE2) could be a suitable target for the development of a vaccine or an inhibitor. Various natural products have been used against SARS-CoV-2. Here, we docked 42 active cannabinoids to the active site of the SARS-CoV-2 and SARS-CoV complex of RBD-ACE2. To ensure the flexibility and stability of the complex produced after docking, the top three ligand molecules with the best overall binding energies were further analyzed through molecular dynamic simulation (MDS). Then, we used the webserver Swissadme program and binding free energy to calculate and estimate the MMPBSA and ADME characteristics. Our results showed that luteolin, CBGVA, and CBNA were the top three molecules that interact with the SARS-CoV-2 RBD-ACE2 complex, while luteolin, stigmasterol, and CBNA had the strongest contact with that SARS-CoV. Our findings show that luteolin may be a potential inhibitor of infections caused by coronavirus-like pathogens such as COVID-19, although further in vivo and in vitro research is required.”

https://pubmed.ncbi.nlm.nih.gov/36551156/

“Viral entry was crucial to the invasion of the host cell. In a recent investigation, luteolin and CBNA were found to have antiviral properties against SARS-CoV-2 and SARS-CoV. It can be concluded that luteolin and CBNA not only restrict virus entry by blocking the RBD-ACE2 complex, which was previously thought to be responsible for membrane fusion but also modulates the immune system, as other cannabinoids such as CBD have demonstrated. The top three bioactive substances were strongly associated with the main viral entrance sites, according to our research, indicating that they could be used as a potential inhibitor against severe acute respiratory syndrome. Thus, luteolin and CBNA can be a potential inhibitor to avoid COVID-19 or severe acute respiratory syndrome, although their inhibitory effects in vivo and in vitro need to be investigated further.”

https://www.mdpi.com/2218-273X/12/12/1729