Author Archives: David

Protective Action of Cannabidiol on Tiamulin Toxicity in Humans-In Vitro Study

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“The growing awareness and need to protect public health, including food safety, require a thorough study of the mechanism of action of veterinary drugs in consumers to reduce their negative impact on humans. Inappropriate use of veterinary drugs in animal husbandry, such as tiamulin, leads to the appearance of residues in edible animal tissues.

The use of natural substances of plant origin, extracted from hemp (Cannabis sativa L.), such as cannabidiol (CBD), is one of the solutions to minimize the negative effects of tiamulin.

This study aimed to determine the effect of CBD on the cytotoxicity of tiamulin in humans.

The cytotoxic activity of tiamulin and the effect of its mixtures with CBD were tested after 72 h exposure to three human cell lines: SH-SY5Y, HepG2 and HEK-293. Cytotoxic concentrations (IC50) of the tested drug and in combination with CBD were assessed using five biochemical endpoints: mitochondrial and lysosomal activity, proliferation, cell membrane integrity and effects on DNA synthesis. Oxidative stress, cell death and cellular morphology were also assessed. The nature of the interaction between the veterinary drug and CBD was assessed using the combination index. The long-term effect of tiamulin inhibited lysosomal (SH-SY5SY) and mitochondrial (HepG2) activity and DNA synthesis (HEK-293). IC50 values for tiamulin ranged from 2.1 to >200 µg/mL (SH-SY5SY), 13.9 to 39.5 µg/mL (HepG2) and 8.5 to 76.9 µg/mL (HEK-293). IC50 values for the drug/CBD mixtures were higher.

Reduced levels of oxidative stress, apoptosis and changes in cell morphology were demonstrated after exposure to the mixtures. Interactions between the veterinary drug and CBD showed a concentration-dependent nature of tiamulin in cell culture, ranging from antagonistic (low concentrations) to synergistic effects at high drug concentrations.

The increased risk to human health associated with the presence of the veterinary drug in food products and the protective nature of CBD use underline the importance of these studies in food toxicology and require further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39769305/

https://www.mdpi.com/1422-0067/25/24/13542

Cannabichromene as a Novel Inhibitor of Th2 Cytokine and JAK/STAT Pathway Activation in Atopic Dermatitis Models

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“Cannabichromene (CBC) is one of the main cannabinoids found in the cannabis plant, and although less well known than tetrahydrocannabinol (THC) and cannabidiol (CBD), it is gaining attention for its potential therapeutic benefits.

To date, CBC’s known mechanisms of action include anti-inflammatory, analgesic, antidepressant, antimicrobial, neuroprotective, and anti-acne effects through TRP channel activation and the inhibition of inflammatory pathways, suggesting that it may have therapeutic potential in the treatment of inflammatory skin diseases, such as atopic dermatitis (AD), but its exact mechanism of action remains unclear. Therefore, in this study, we investigated the effects of CBC on Th2 cytokines along with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in AD pathogenesis. We used a 2,4-Dinitrochlorobenzene (DNCB)-induced BALB/c mouse model to topically administer CBC (0.1 mg/kg or 1 mg/kg).

The results showed that skin lesion severity, ear thickness, epithelial thickness of dorsal and ear skin, and mast cell infiltration were significantly reduced in the 0.1 mg/kg CBC-treated group compared with the DNCB-treated group (p < 0.001). In addition, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed a significant decrease in the mRNA expression of Th2 cytokines (TSLP, IL-4, IL-13) and inflammatory mediators (IFN-γ, IL-1β, IL-6, IL-17, IL-18, and IL-33) (p < 0.05). Western blot analysis also revealed a significant decrease in JAK1, JAK2, STAT1, STAT2, STAT3, and STAT6 protein expression (p < 0.05).

These results suggest that CBC is a promising candidate for the treatment of AD and demonstrates the potential to alleviate AD symptoms by suppressing the Th2 immune response.”

https://pubmed.ncbi.nlm.nih.gov/39769302/

https://www.mdpi.com/1422-0067/25/24/13539

Exploring Natural Analgesics for Chronic Pain Management: Cannabinoids and Other Phytoconstituents

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“Chronic pain lasting more than three months or persisting after normal healing is a significant global health issue. In a healthcare system, it is crucial to ensure proper chronic pain management. Traditional pharmacological and non-pharmacological pain management techniques may not fully meet the requirements of physicians regarding effectiveness and safety. Therefore, researchers are exploring natural analgesics.

Plant-based phytoconstituents show promise in relieving chronic pain associated with various diseases.

This study aims to review the latest advances in discovering natural bioactive compounds that can help alleviate chronic pain. It discusses the pathways of chronic pain and a multifactorial treatment strategy. It also organizes data on using plant- derived substances, such as cannabinoids, terpenoids, phenolics, and crude extracts. Additionally, it delves into the pharmacodynamics of cannabinoids, including their route of administration and elimination.

The review presents the results of 22 clinical trials on various cannabinoids for pain relief. It is important to note that opioids and other alkaloids from plants are not covered in this article due to their primary use in controlling acute rather than chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/39779559/

https://www.eurekaselect.com/article/145464

Synergistic Pain-Reducing Effects of Bixa orellana (Chronic® and Chronic In®) and Cannabidiol-Rich Cannabis sativa Extracts in Experimental Pain Models

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“Background: The present study aimed to evaluate the potential synergy between pharmaceutical formulations containing Bixa orellana L. (granulated-CHR OR and injectable nanodispersion-CHR IN) in conjunction with a cannabidiol (CBD)-rich extract of Cannabis sativa L. (CSE) on experimental pain models in Wistar rats. 

Methods: Chemical analysis was performed using gas chromatography (GC-MS). The pain tests employed were acetic acid-induced writhing (injection i.p. of 0.9% acetic acid), formalin (solution 1%), hot plate (55 ± 0.5 °C), and cold-water tail withdrawal tests. 

Results: Chemical analyses by chromatography confirmed that the oil from B. orellana is rich in δ-tocotrienol (72.0 ± 1.0%), while the oil from Cannabis sativa highlighted the presence of cannabidiol (CBD). The results from the experimental pain tests indicated that the combined administration of formulations containing Bixa orellana and C. sativa, such as the granulated CHR OR (400 mg/kg, orally) with CSE (40 mg/kg, orally) or the nanodispersion CHR IN (10 mg/kg, intramuscularly) with CSE (40 mg/kg, orally), demonstrated significant results (p < 0.001) in pain reduction. Although the formulations containing Bixa orellana extract showed statistical significance in the tests when used in isolation, their effects were inferior compared to the combined use with CSE or the isolated use of CSE. These findings suggest that combining formulations containing extracts of these plant species may represent a viable therapeutic option, considering the synergistic action in reducing pain under the experimental conditions employed. 

Conclusions: these results imply that combining the phytocomplexes present in B. orellana and C. sativa may be a promising approach for pain treatment.”

https://pubmed.ncbi.nlm.nih.gov/39770552/

https://www.mdpi.com/1424-8247/17/12/1710

Hemp Extract (Extractum Cannabis) in the Treatment of Gastrointestinal Distress and Dyspepsia: Historical Insights from Barcelona, Spain

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“This study explores the trajectory of interest in and use of Extractum Cannabis (hemp extract, i.e., extract of Cannabis sativa L.) for the symptomatic treatment of minor gastrointestinal distress and dyspepsia in nineteenth- and early twentieth-century Barcelona (Catalonia, Spain) prior to 1939, through a review of primary sources.

The objective of this paper is to present a historical pharmaceutical and applied review of the medical use of the hemp genus (Cannabis L.) prior to its prohibition, thereby contributing to its recognition as a medicinal product.

The information provided demonstrates evidence of the medicinal use of cannabis within the historical context studied. The interactions between this legacy medical use and the contemporary body of pharmacological and toxicological knowledge (on hemp, its constituents, and the endocannabinoid system in gastrointestinal and stomach disorders) are discussed, providing new possible clinical perspectives.

Within its limitations-including the scope, limited accessibility to, and varying quality of archives-this research contributes to a more granular understanding of the historical embeddedness of psychoactive hemp medicines in northeastern Spain, suggesting that medical and pharmaceutical traditions could play a role in informing contemporary approaches to “medical marijuana”.”

https://pubmed.ncbi.nlm.nih.gov/39770428/

https://www.mdpi.com/1424-8247/17/12/1585

An In Vitro Evaluation of Industrial Hemp Extracts Against the Phytopathogenic Bacteria Erwinia carotovora, Pseudomonas syringae pv. tomato, and Pseudomonas syringae pv. tabaci

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“Pests and diseases have caused significant problems since the domestication of crops, resulting in economic loss and hunger. To overcome these problems, synthetic pesticides were developed to control pests; however, there are significant detrimental side effects of synthetic pesticides on the environment and human health. There is an urgent need to develop safer and more sustainable pesticides.

Industrial hemp is a reservoir of compounds that could potentially replace some synthetic bactericides, fungicides, and insecticides.

We determined the efficacy of industrial hemp extracts against Pseudomonas syringae pv. tabaci (PSTA), Pseudomonas syringae pv. tomato (PSTO), and Erwinia carotovora (EC).

The study revealed a minimum inhibitory concentration (MIC) of 2.05 mg/mL and a non-inhibitory concentration (NIC) of 1.2 mg/mL for PSTA, an MIC of 5.7 mg/mL and NIC of 0.66 mg/mL for PSTO, and an MIC of 12.04 mg/mL and NIC of 5.4 mg/mL for EC. Time-kill assays indicated the regrowth of E. carotovora at 4 × MIC after 15 h and P. syringae pv. tomato at 2 × MIC after 20 h; however, P. syringae pv. tabaci had no regrowth. The susceptibility of test bacteria to hemp extract can be ordered from the most susceptible to the least susceptible, as follows: P. syringae pv. tabaci > P. syringae pv. tomato > E. carotovora.

Overall, the data indicate hemp extract is a potential source of sustainable and safe biopesticides against these major plant pathogens.”

https://pubmed.ncbi.nlm.nih.gov/39769990/

“The data show the susceptibility of the test bacteria to hemp extract, ordered from the most susceptible to the least susceptible, as follows: P. syringae pv. tabaci > P. syringae pv. tomato > E. carotovora.

This study indicates that hemp extract is effective in controlling E. carotovora, P. syringae pv. tabaci, and P. syringae pv. tomato. However, the hemp extract is more effective against both Pseudomonas spp. than E. carotovora. The difference could be due to their difference in cell wall structure, resistance mechanisms, and metabolic pathways.

More studies are needed to determine how hemp extract causes stress to bacteria such as interference with quorum sensing, biofilm formation, and oxidative stress. Moreover, to ensure sustainable agricultural practices that are safe and affordable for low-income farmers, synergistic effect studies are needed between hemp compounds in the extract and, more importantly, between hemp extracts and other plant extracts.”

https://www.mdpi.com/1420-3049/29/24/5902

The Anticancer Activity of Cannabinol (CBN) and Cannabigerol (CBG) on Acute Myeloid Leukemia Cells

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“Several cannabis plant-derived compounds, especially cannabinoids, exhibit therapeutic potential in numerous diseases and conditions.

In particular, THC and CBD impart palliative, antiemetic, as well as anticancer effects.

The antitumor effects include inhibition of cancerous cell growth and metastasis and induction of cell death, all mediated by cannabinoid interaction with the endocannabinoid system (ECS). However, the exact molecular mechanisms are still poorly understood. In addition, their effects on leukemia have scarcely been investigated.

The current work aimed to assess the antileukemic effects of CBN and CBG on an acute monocytic leukemia cell line, the THP-1. THP-1 cell viability, morphology and cell cycle analyses were performed to determine potential cytotoxic, antiproliferative, and apoptotic effects of CBN and CBG. Western blotting was carried out to measure the expression of the proapoptotic p53.

Both CBN and CBG inhibited cell growth and induced THP-1 cell apoptosis and cell cycle arrest in a dose- and time-dependent manner. CBN and CBG illustrated different dosage effects on THP-1 cells in the MTT assay (CBN > 40 μΜ, CBG > 1 μM) and flow cytometry (CBN > 5 μM, CBG > 40 μM), highlighting the cannabinoids’ antileukemic activity.

Our study hints at a direct correlation between p53 expression and CBG or CBN doses exceeding 50 μM, suggesting potential activation of p53-associated signaling pathways underlying these effects.

Taken together, CBG and CBN exhibited suppressive, cell death-inducing effects on leukemia cells. However, further in-depth research will be needed to explore the molecular mechanisms driving the anticancer effects of CBN and CBG in the leukemia setting.”

https://pubmed.ncbi.nlm.nih.gov/39770061/

https://www.mdpi.com/1420-3049/29/24/5970

Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor

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“Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability.

Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signaling.

Activation of the 5-HT2A intracellular signaling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket.

Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.”

https://pubmed.ncbi.nlm.nih.gov/39761844/

“Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.”

https://www.sciencedirect.com/science/article/abs/pii/S0898656825000014?via%3Dihub

“Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer’s disease psychosis: A systematic review and meta-analysis. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.”

https://pubmed.ncbi.nlm.nih.gov/37166012/

Cannabinoid receptor ligands modulate fibrosis and inflammation in idiopathic pulmonary fibrosis: a preliminary study

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“Background/aim: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes.

Materials and methods: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-β1, IL-8, and TNF-α inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA.

Results: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,212-2 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-β1 and TNF-α release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBR-mediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3.

Conclusion: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.”

https://pubmed.ncbi.nlm.nih.gov/39758842/

https://journals.tubitak.gov.tr/biology/vol48/iss6/4/

Three new α-glucosidase inhibitors from aqueous extract of Cannabis sativa leaves: isolation, characterisation, and kinetic study

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“α-Glucosidase inhibitory assay-guided isolation of the aqueous extract from Cannabis sativa leaves afforded three new compounds named cannabisaldehyde (8), cannacone A (9), and canniprene C (10), along with eight previously known compounds (1–7, 11). The structures of new compounds were determined through extensive analysis of various spectroscopic data. Of isolated compounds, cannacone A (9) demonstrated most potent inhibition against maltase and sucrase with IC50 values of 80.0 and 82.9 μM, respectively. Cannacone A (9) inhibited both maltase and sucrase by competitive mechanism.”

https://pubmed.ncbi.nlm.nih.gov/39756038/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2448841

“Alpha-glucosidase inhibitors (AGIs) are used to treat type 2 diabetes and to prevent or delay the development of type 2 diabetes in people at risk.”

“Alpha-glucosidase inhibitors are antihyperglycemic agents that lower blood glucose by delaying the digestion and absorption of complex carbohydrates.”