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-6IL-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

Sustained cannabis use does not predispose clinical hypertension: Findings from a national survey

“Cannabis is among the most used recreational and medicinal drugs in the United States. The effects of chronic use on hypertension remain poorly understood.

Our study retrospectively evaluated data collected by the National Health and Nutrition Examination Survey from 2017 to 2018. Cannabis use was measured with five metrics: (1) sustained use at any point in the past, (2) sustained use within the past year, (3) frequency of use, (4) age of first cannabis use, and (5) current use. Hypertension status was determined by individuals reporting having been diagnosed in the past. Multivariable logistic regressions were performed, controlling for age, race, and gender. A total of 4565 respondents were identified, of which 867 (19.0%) reported sustained cannabis use in the past.

Participants who reported past sustained cannabis use did not have statistically different odds of having hypertension (OR: 1.12; 95% CI: .66-1.91; p = .6). Moderate (OR: 1.08; 95% CI: .36-3.25; p = .8) and highly-frequent users (OR: 1.30; 95% CI: .56-3.03; p = .4) did not have different odds of having hypertension than infrequent users. No relationship between the age of first cannabis use and hypertension was observed. The recency of sustained cannabis use was not associated with hypertension status. Current cannabis users had similar odds of hypertension as past users (OR: 1.03; 95% CI: .59-1.79; p = .9).

The findings of this study indicate that neither past nor current cannabis use is associated with clinical hypertension.”

https://pubmed.ncbi.nlm.nih.gov/36545898/

“The findings of this study indicate that neither past nor current cannabis use are associated with the likelihood of having clinical hypertension. Among cannabis users, frequency of use was not associated with hypertension. Similarly, the age of first cannabis use was not associated with hypertension status.”

https://onlinelibrary.wiley.com/doi/10.1111/jch.14623

Inhibiting Human and Leishmania Arginases Using Cannabis sativa as a Potential Therapy for Cutaneous Leishmaniasis: A Molecular Docking Study

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“Cutaneous leishmaniasis (CL), a vector-borne parasitic disease caused by the Leishmania protozoan, is a serious public health problem in Morocco. The treatment of this disease is still based on pentavalent antimonials as the primary therapy, but these have associated side effects. Thus, the development of effective, risk-free alternative therapeutics based on natural compounds against leishmaniasis is urgent. Arginase, the key enzyme in the polyamine biosynthetic pathway, plays a critical role in leishmaniasis outcome and has emerged as a potential therapeutic target.

The objective of this study was to test Cannabis sativa‘s phytochemical components (cannabinoids and terpenoids) through molecular docking against Leishmania and human arginase enzymes.

Our results showed that delta-9-tetrahydrocannabinol (THC) possessed the best binding energies of -6.02 and -6.35 kcal/mol with active sites of Leishmania and human arginases, respectively. Delta-9-THC interacted with Leishmania arginase through various amino acids including His139 and His 154 and linked to human arginase via His 126. In addition to delta-9-THC, caryophyllene oxide and cannabidiol (CBD) also showed a good inhibition of Leishmania and human arginases, respectively.

Overall, the studied components were found to inhibit both arginases active sites via hydrogen bonds and hydrophobic interactions. These components may serve as therapeutic agents or in co-administrated therapy for leishmaniasis.”

https://pubmed.ncbi.nlm.nih.gov/36548655/

“Since CL is still a public health problem in low-income and developing countries, the discovery of an efficient, less toxic, and accessible therapy is a necessity. The present in silico study was the first to investigate C. sativa’s selected constituents as selective inhibitory agents for parasitic as well as host arginases, which play an important role in this parasitic infection pathology. Interestingly, THC showed a great inhibitory potential for both species’ enzymes and will allow a better control of leishmaniasis.”

https://www.mdpi.com/2414-6366/7/12/400

The gut microbiota in neurodegenerative diseases: revisiting possible therapeutic targets for cannabidiol

Heliyon | Journal | ScienceDirect.com by Elsevier

“Understanding the pathophysiology of Alzheimer’s disease (AD) is essential to improve the efficacy of treatments and, consequently, patients’ lives. Unfortunately, traditional therapeutic strategies have not been effective. There is therefore an urgent need to discover or develop alternative treatment strategies.

Recently, some pieces of the puzzle appear to emerge: on a hand, the gut microbiota (GM) has gained attention since intestinal dysbiosis aggravates and generates some of the pathological processes of AD; on the other hand, cannabidiol (CBD), a phytocannabinoid, attenuates intestinal inflammation and possesses neuroprotective properties.

Intestinal dysbiosis (increased population of proinflammatory bacteria) in AD increases plasma lipopolysaccharide and Aβ peptide levels, both responsible for increasing the permeability of the blood-brain barrier (BBB). A leaky BBB may facilitate the entry of peripheral inflammatory mediators into the central nervous system and ultimately aggravate neuroinflammation and neuronal death due to chronic activation of glial cells. Studies investigating the GM reported a strong relationship between intestinal dysbiosis and AD. In this review we conjecture that the GM is a promising therapeutic target for CBD in the context of AD.”

https://pubmed.ncbi.nlm.nih.gov/36544841/

https://www.cell.com/heliyon/fulltext/S2405-8440(22)03460-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844022034600%3Fshowall%3Dtrue