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

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“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

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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

Study of potential inhibition of the estrogen receptor α by cannabinoids using an in silico approach: Agonist vs antagonist mechanism

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Computers in Biology and Medicine

“Breast cancer is the main cancer type with more than 2.2 million cases in 2020, and is the principal cause of death in women; with 685000 deaths in 2020 worldwide. The estrogen receptor is involved at least in 70% of breast cancer diagnoses, and the agonist and antagonist properties of the drug in this receptor play a pivotal role in the control of this illness.

This work evaluated the agonist and antagonist mechanisms of 30 cannabinoids by employing molecular docking and dynamic simulations. Compounds with docking scores < -8 kcal/mol were analyzed by molecular dynamic simulation at 300 ns, and relevant insights are given about the protein’s structural changes, centered on the helicity in alpha-helices H3, H8, H11, and H12.

Cannabicitran was the cannabinoid that presented the best relative binding-free energy (-34.96 kcal/mol), and based on rational modification, we found a new natural-based compound with relative binding-free energy (-44.83 kcal/mol) better than the controls hydroxytamoxifen and acolbifen. Structure modifications that could increase biological activity are suggested.”

https://pubmed.ncbi.nlm.nih.gov/36543006/

https://www.sciencedirect.com/science/article/abs/pii/S0010482522011118?via%3Dihub

The Utility of Cannabis-Based Medicine in Chronic Pain Management: A Case Report

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“Chronic pain is a common diagnosis that patients may face, resulting in increased morbidity and mortality and affecting the overall quality of life.

In addition to established multidisciplinary pain management, medical cannabis may offer an approach to improving pain outcomes and functionality. This case involves a 72-year-old female patient, with chronic neck, lower back, and diffuse arthritic pain due to comorbid osteoarthritis (OA), scleroderma, and scoliosis. Medical cannabis therapy was certified based on the goals of improving pain control and simultaneously reducing the patient’s chronic opioid medication dose.

Using potential opioid alternatives, such as medical cannabis, may prove beneficial to clinicians looking to improve pain management and reduce opioid therapy in patients.”

https://pubmed.ncbi.nlm.nih.gov/36540475/

“This case indicates that cannabinoid therapy may be useful in managing chronic pain and therein reducing its detrimental impact on patients’ overall quality of life. Potential opioid alternatives, such as medical cannabis, are becoming increasingly important in pain management to improve patients’ quality of life. Additionally, this case demonstrates that medical cannabis may prove beneficial in reducing reliance on chronic opioid therapy. Clinicians should be aware of different approaches to treatment that do not include opioids.”

https://www.cureus.com/articles/113524-the-utility-of-cannabis-based-medicine-in-chronic-pain-management-a-case-report

Clinical Outcome Data of Children Treated with Cannabis Based Medicinal Products for Treatment Resistant Epilepsy – Analysis from the UK Medical Cannabis Registry

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“Background There is a paucity of high-quality evidence of the efficacy and safety of cannabis-based medicinal products in treatment of treatment-resistant epilepsy (TRE) in children.

Methods A case series of children(<18 years old) with TRE from the UK Medical Cannabis Registry was analysed. Primary outcomes were ≥50% reduction in seizure frequency, changes in the Impact of Paediatric Epilepsy Score(IPES) and incidence of adverse events.

Results Thirty-five patients were included in the analysis. Patients were prescribed during their treatment with the following-CBD isolate oils(n=19), CBD broad-spectrum oils(n=17), and CBD/Δ9-THC combination therapy(n=17). Twenty-three(65.7%) patients achieved a ≥50% reduction in seizure frequency. 94.1%(n=16) of patients treated with CBD and Δ9-THC observed a ≥50% reduction in seizure frequency compared to 31.6%(n=6) and 17.6%(n=3) of patients treated with CBD isolates and broad-spectrum CBD products respectively(p<0.001). Twenty-six(74.3%) adverse events were reported by 16 patients(45.7%). The majority of these were mild(n=12; 34.2%) and moderate(n=10; 28.6%).

Conclusions The results of this study demonstrate a positive signal of improved seizure frequency in children treated with CBMPs for TRE. Moreover, the results suggest that CBMPs are well-tolerated in the short term. The limitations mean causation cannot be determined in this open-label, case series.”

https://pubmed.ncbi.nlm.nih.gov/36539215/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2002-2119

Medicinal cannabis improves sleep in adults with insomnia: a randomised double-blind placebo-controlled crossover study

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“Insomnia or difficulty falling and or staying asleep is experienced by up to 30% of the general population.

This randomised crossover double-blind placebo-controlled 6-week trial aimed to assess the tolerability and effectiveness of the Entoura-10:15 medicinal cannabis oil on sleep in adults with insomnia. A total of 29 participants with self-reported clinical insomnia completed the crossover trial. Participants were randomly allocated to receive placebo or active oil containing 10 mg/ml tetrahydrocannabinol (THC) and 15 mg/ml cannabidiol (CBD) over 2-weeks titrated 0.2-1.5 ml/day, followed by a 1-week wash-out period before crossover. Tolerability was assessed by daily diary. Effectiveness was measured by saliva midnight melatonin levels, validated questionnaires, i.e., the Insomnia Severity Index, and the Fitbit activity/sleep wrist tracker.

Entoura-10:15 medicinal cannabis oil was generally well tolerated, and was effective in improving sleep, whereby 60% of participants no longer classified as clinical insomniacs at the end of the 2-week intervention period. Midnight melatonin levels significantly improved in the active group by 30% compared to a 20% decline in the placebo group (p = 0.035). Medicinal cannabis oil improved both time and quality of sleep, in particular light sleep increased by 21 min/night compared to placebo (p = 0.041). The quality of sleep improved overall by up to 80% in the active group (pPhase2 = 0.003), including higher daily functioning (p = 0.032). Observed effects were more pronounced in Phase 2 due to the period effect and loss of blinding.

Entoura-10:15 medicinal cannabis oil was well tolerated and effective in improving sleep in adults with insomnia.”

https://pubmed.ncbi.nlm.nih.gov/36539991/

“In summary, our short-term trial suggests Entoura 10:15 medicinal cannabis oil, containing THC:CBD 10:15 and lesser amounts of other CBs and naturally occurring terpenes, to be well tolerated and effective in significantly improving sleep quality and duration, midnight melatonin levels, quality of life, and mood within 2-weeks in adults with insomnia.”

https://onlinelibrary.wiley.com/doi/10.1111/jsr.13793

Cannabis sativa L. alleviates loperamide-induced constipation by modulating the composition of gut microbiota in mice

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“MaZiRenWan (MZRW) is the most frequently used Traditional Chinese Medicine formula to treat chronic constipation, Cannabis sativa L. is regarded as a monarch drug in MZRW. However, the targets of Cannabis sativa L. that enhance colonic motility and improve constipation symptoms remain unknown.

This study was designed to investigate the laxative effect and underlying mechanism of the water extract of Cannabis sativa L. (WECSL) using a loperamide-induced constipation mouse model.

We found that WECSL treatment significantly improved intestinal motility and water-electrolyte metabolism, decreased inflammatory responses, prevented gut barrier damage, and relieved anxiety and depression in constipated mice. WECSL also structurally remodeled the composition of the gut microbiota and altered the abundance of bacteria related to inflammation, specifically Butyricicoccus and Parasutterella. Moreover, WECSL failed to relieve constipation symptoms following intestinal flora depletion, indicating that WECSL alleviates constipation symptoms depending on the gut microbiota.

Our research provides a basis for WECSL to be further investigated in the treatment of constipation from the perspective of modern medicine.”

https://pubmed.ncbi.nlm.nih.gov/36532754/

“In conclusion, this study demonstrated that WECSL can improve constipation symptoms, reduce anxiety and depression behaviors, and inhibit intestinal inflammation. WECSL also structurally remodeled the composition of the gut microbiota, altering the abundance of bacteria related to inflammation.

Our research provides a basis for WECSL to be further investigated in the treatment of constipation from the perspective of modern medicine. Constipation may be prevented and improved by targeting these possible gut bacteria.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1033069/full


A Novel Anti-Inflammatory Formulation Comprising Celecoxib and Cannabidiol Exerts Antidepressant and Anxiolytic Effects

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“Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib’s usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. 

Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. 

Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. 

Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.”

https://pubmed.ncbi.nlm.nih.gov/36520610/

https://www.liebertpub.com/doi/10.1089/can.2022.0225