Receptor-mediated effects of Δ9 -THC & CBD on the inflammatory response of alveolar macrophages

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“Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD) are cannabinoids found in Cannabis sativa. While research supports cannabinoids reduce inflammation, the consensus surrounding receptor(s) mediated effects has yet to be established.

Here, we investigated the receptor-mediated properties of Δ9 -THC and CBD on alveolar macrophages, an important pulmonary immune cell in direct contact with cannabinoids inhaled by cannabis smokers.

MH-S cells, a mouse alveolar macrophage cell line, were exposed to Δ9 -THC and CBD, with and without lipopolysaccharide (LPS). Outcomes included RNA-sequencing and cytokine analysis. Δ9 -THC and CBD alone did not affect the basal transcriptional response of MH-S cells.

In response to LPS, Δ9 -THC and CBD significantly reduced the expression of numerous pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, an effect that was dependent on CB2 . The anti-inflammatory effects of CBD- but not Δ9 -THC- were mediated through a reduction in signaling through NF-κB and ERK1/2.

These results suggest that CBD and Δ9 -THC have potent immunomodulatory properties in alveolar macrophages, a cell type important in immune homeostasis in the lungs. Further investigation into the effects of cannabinoids on lung immune cells could lead to the identification of therapies that may ameliorate conditions characterized by inflammation.”

https://pubmed.ncbi.nlm.nih.gov/36510483/

https://onlinelibrary.wiley.com/doi/10.1111/imcb.12614


Treatment with Cannabidiol Results in an Antioxidant and Cardioprotective Effect in Several Pathophysiologies

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“Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects.

The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects.

Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca2+. Regarding oxidative stress, O2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages.

In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.”

https://pubmed.ncbi.nlm.nih.gov/36508270/

https://www.eurekaselect.com/article/123554

The Use of Cannabidiol in Patients With Low Back Pain Caused by Lumbar Spinal Stenosis: An Observational Study

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“Spinal stenosis is a degenerative narrowing of the spinal canal with encroachment on the neural structures by surrounding bone and soft tissue. This chronic low back condition can cause restrictions in mobility, impairment of daily activities, opioid dependence, anxiety, depression, and reduced quality of life. Spinal stenosis can be treated through surgical and nonsurgical methods, but neither has proven consistently reliable.

Cannabidiol (CBD) has also been observed to have anxiolytic, anti-inflammatory, antiemetic, and antipsychotic behaviors. CBD may provide greater nonsurgical treatment options for the pain associated with spinal stenosis while minimizing the need for opioids.

An observational study was undertaken to assess the effects of CBD on patients suffering from chronic spinal stenosis.

This observational study was investigator-initiated and designed to determine the effect of hemp-derived CBD gel caps for patients with spinal stenosis related to low back pain and leg pain relative to patient outcomes, medication utilization, and quality of life outcome measures. A total of six physician visits would be required where a set of surveys would be filled out each four weeks apart.

Results The study population consisted of 48 patients. The patient population’s age ranged from 63 to 95 years and was normally distributed, with a mean age of 75 ± 7.13 years. The sex distribution was 33% male and 67% female patients. The pain was broken down between the six visits for each of the following four questions: pain right now, usual pain level during the week, best pain level during the week, and worst pain level during the week. Usual pain levels (p < 0.001) and worst pain levels (p < 0.005) demonstrated statistically significant improvement over time, while pain right now (p > 0.05) and best pain level (p > 0.05) stayed consistent throughout without statistical significance.

Conclusions This open-label, prospective, observational study found that treatment with hemp-derived CBD gel caps was associated with significant improvements in pain scores and several quality-of-life measures for patients with lumbar spinal stenosis.”

https://pubmed.ncbi.nlm.nih.gov/36507111/

“This open-label, prospective, observational study found that treatment with hemp-derived CBD gel caps was associated with significant improvements in pain scores and several quality-of-life measures for patients with lumbar spinal stenosis.”

https://www.cureus.com/articles/106551-the-use-of-cannabidiol-in-patients-with-low-back-pain-caused-by-lumbar-spinal-stenosis-an-observational-study

Cannabis sativa Cannabinoids as Functional Ingredients in Snack Foods-Historical and Developmental Aspects

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“The published health benefits of Cannabis sativa has caught the attention of health-conscious consumers and the food industry. Historically, seeds have long been utilized as a food source and currently there is an increasing number of edibles on the market that contain cannabis. Cannabinoids include the psychoactive constituent, delta-9-tetrahydrocannabinol (THC), and the non-psychoactive cannabidiol (CBD) that are both compounds of interest in Cannabis sativa.

This paper looks at the distribution of nutrients and phytocannabinoids in low-THC Cannabis sativa, the historical uses of hemp, cannabis edibles, and the possible side-effects and concerns related to cannabis edibles. Several authors have pointed out that even though the use of cannabis edibles is considered safe, it is important to mention their possible side-effects and any concerns related to its consumption that negatively influence consumer acceptance of cannabis edibles. Such risks include unintentional overdose by adults and accidental ingestion by children and adolescents resulting in serious adverse effects. Therefore, cannabis edibles should be specifically packaged and labelled to differentiate them from known similar non-cannabis edibles so that, together with tamperproof packaging, these measures reduce the appeal of these products to children.”

https://pubmed.ncbi.nlm.nih.gov/36501366/

“Cannabis sativa possesses many health-promoting qualities and so it has played an effective role as a traditional medicine to treat a variety of ailments from pain, anxiety and weight gain through to conditions such as cardiovascular disease and diabetes, as well as infectious diseases such as malaria, and cancer.

Opinion regarding cannabis edibles is changing amongst consumers and most countries around the world are shifting towards the legalization of the recreational and medicinal use of cannabis leading to a rapid increase in the global acceptance and availability of cannabis edibles. “

https://www.mdpi.com/2223-7747/11/23/3330


Antibacterial, antioxidant, and haemolytic potential of silver nanoparticles biosynthesized using roots extract of Cannabis sativa plant

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“In this study, Cannabis sativa roots extract has been employed for the biosynthesis of silver nanoparticles (AgNPs). The appearance of reddish-brown colour followed by absorption peak of AgNPs at 408 nm through UV-vis spectrophotometry suggested biosynthesis of AgNPs. The size of the particles ranged from 90-113 nm, confirmed using DLS and TEM along with zeta potential of -25.3 mV. The FTIR provided information regarding the phytochemical capping. The study was further elaborated for determining AgNPs antibacterial, antioxidant, and cellular toxicity using MIC, DPPH, MTT, and haemolytic assays, respectively. The AgNPs were significantly effective against Staphylococcus aureus (Gram-positive), as compared to that of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli (Gram-negative). AgNPs also exhibited remarkable antioxidant potential wherein 58.01 ± 0.09% free radical scavenging was observed at a concentration of 100 µg/ml. AgNPs revealed lower cytotoxicity where cell viability was observed to be 52.38 ± 0.6% at a very high concentration of 500 µg/ml in HEK 293 cells. Further, very low toxicity was seen in RBCs i.e. 6.47 ± 0.04% at a high concentration of 200 µg/ml. Thus, the current study beholds anticipation that Cannabis sativa ethanolic root extract-mediated AgNPs may play a vital role in therapeutic.”

https://pubmed.ncbi.nlm.nih.gov/36519372/

“The study demonstrates the efficient biosynthesis of silver nanoparticles using Cannabis sativa ethanolic root extract. The potency of the plant extract and phytochemically fabricated silver nanoparticles were analysed over certain parameters such as antimicrobial, antioxidant and cellular toxicity tests. The study concludes the significant effectiveness of silver nanoparticles, thus prognosticating theirs use henceforth.”

https://www.tandfonline.com/doi/full/10.1080/21691401.2022.2149543

Phytocannabinoids Stimulate Rejuvenation and Prevent Cellular Senescence in Human Dermal Fibroblasts

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“In light of the increased popularity of phytocannabinoids (pCBs) and their appearance in beauty products without rigorous research on their rejuvenation efficacy, we decided to investigate the potential role of pCBs in skin rejuvenation.

Utilizing healthy and stress-induced premature senescent (SIPS) CCD-1064Sk skin fibroblasts, the effects of pCBs on cellular viability, functional activity, metabolic function, and nuclear architecture were tested. Both delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) within the range of 0.5 µM to 2.0 µM increased cell growth in a dose-dependent manner while significantly decreasing senescence as measured by beta-galactosidase activity.

Utilizing a scratch assay, both THC and CBD (2.0 µM) significantly improved wound healing in both healthy and SIPS fibroblasts. THC and CBD altered nuclear architecture and mRNA levels of cell cycle regulators and genes involved in ECM production. Subsequently, we found ELN, Cyclin D1, PCNA, and BID protein levels altered by SIPS but ameliorated after pCBs exposure in human dermal fibroblasts.

Lastly, we compared the efficacy of THC and CBD with common anti-aging nutrient signaling regulators in replicative senescent adult human dermal fibroblasts, CCD-1135Sk.

Both THC and CBD were found to improve wound healing better than metformin, rapamycin, and triacetylresveratrol in replicative senescent CCD-1135Sk fibroblasts. Therefore, pCBs can be a valuable source of biologically active substances used in cosmetics, and more studies using clinical trials should be performed to confirm the efficacy of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/36497198/

“THC and CBD stimulated fibroblasts’ ability to close damaged wounds, while THC induced wound healing better than common nutrient signaling regulators,”

https://www.mdpi.com/2073-4409/11/23/3939

In Silico Binding Analysis of Cannabinoids with Eph Receptors for Therapeutic Use in Gliomas

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“Background: Accumulating evidence suggests overexpression of Eph receptors is associated with malignant human gliomas. Inhibiting interactions of Eph receptors with their ephrin ligands may improve clinical outcomes in glioma patients. The present study investigated the potential of cannabinoids to bind Eph receptors and block Eph/ephrin interactions.

Methods: Twelve major cannabinoids were computationally docked with ligand binding domains from six glioma-associated Eph receptors through Auto Dock Vina to measure their potential binding affinities. The molecular structures and residue interactions of the most favorable poses for each receptor binding domain were further visually examined.

Results: Cannabichromene (CBC) exhibited the most favorable binding with EphA2, EphA3, and EphB4 receptor ligand binding domains while tetrahydrocannabinol (THC) was predicted to bind favorably with EphB2 and EphB3 receptor ligand binding domains. EphA4 showed the best potential binding affinity with cannabidivarin (CBDV). Further analysis revealed that these cannabinoids bind to specific locations on Eph receptors required for Eph/ephrin interactions.

Conclusion: The findings suggest that certain cannabinoids can effectively bind to hydrophobic pockets required for ephrin binding and thereby be used to block subsequent Eph/ephrin interactions.”

https://pubmed.ncbi.nlm.nih.gov/36468933/

Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways

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“Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/36453646/

https://onlinelibrary.wiley.com/doi/10.1002/jbt.23260

Cannabidiol Protects Striatal Neurons by Attenuating Endoplasmic Reticulum Stress

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“Introduction: The aggregation of misfolded proteins in the endoplasmic reticulum (ER) is a pathological trait shared by many neurodegenerative disorders. This aggregation leads to the persistent activation of the unfolded protein response (UPR) and ultimately apoptosis as a result of ER stress. Cannabidiol (CBD) has been demonstrated to be neuroprotective in various cellular and animal models of neurodegeneration, which has been attributed to its antioxidant and anti-inflammatory properties. However, little is known about the role of CBD in the context of protein folding and ER stress. The purpose of this study was to investigate whether CBD is neuroprotective against an in vitro model of ER stress. 

Materials and Methods: Using different exposure models, mouse striatal STHdhQ7/Q7 cells were exposed to either the ER stress inducer thapsigargin (TG) and/or CBD. Cell viabilities assays were used to investigate the effect of CBD pre-treatment, co-treatment, and post-treatment on TG-induced cell death. Real-time quantitative polymerase chain reaction was used to measure changes in ER stress regulators and UPR genes such as glucose-regulated protein-78 (GRP78), mesencephalic astrocyte-derived neurotrophic factor (MANF), B cell lymphoma 2 (BCL-2), BCL-2 interacting mediator of cell death (BIM), and caspase-12. 

Results: Cell viability increased significantly when cells were pre-treated with CBD before TG exposure. An increase in the gene expression of pro-survival ER chaperone GRP78 and ER-resident neurotrophic factor MANF coincided with this effect and decreased ER-mediated pro-apoptotic markers such as BIM, and caspase-12 was observed. 

Conclusions: These data suggest that CBD pre-treatment is neuroprotective against TG-induced cell death. Understanding the role of ER stress in CBD-driven neuroprotection provides insight into the therapeutic potential of CBD and the role of ER dysfunction in neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/36454179/

https://www.liebertpub.com/doi/10.1089/can.2022.0090

Single cannabidiol administration affects anxiety-, obsessive compulsive-, object-memory, and attention-like behaviors in mice in a sex and concentration dependent manner

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Pharmacology Biochemistry and Behavior

“Rationale: The behavioral effects of cannabidiol (CBD) are understudied, but are important, given its therapeutic potential and widespread use as a natural supplement.

Objective: The objective of this study was to test whether a single injection of CBD affected anxiety-like or attention-like behavior, or memory in wildtype mice or mice with reported trait anxiety due to a targeted-gene deletion in a voltage-dependent potassium channel, Kv1.3.

Methods: Wildtype C57BL/6 J and Kv1.3-/- mice of both sexes were reared to adulthood and then administered an intraperitoneal injection of 10 or 20 mg/kg CBD. Mice were behaviorally-phenotyped using the marble-burying test, the light-dark box (LDB), short (1 h) and long-term (24 h) object memory test, the elevated-plus maze (EPM), and the object-based attention task in order to assess obsessive compulsive-, anxiety-, attention-like behaviors, and memory.

Results: We discovered that acute CBD treatment reduced marble burying in male, but not female mice. CBD was effective in lessening anxiety-like behaviors determined by the LDB test in both male and female wildtype mice, whereby the effective dose required to observe the effect in females was less. In Kv1.3-/- mice, CBD increased anxiety-like behaviors in the LDB in both sexes at the higher concentration of CBD and it similarly increased anxiety-like behavior in females in the EPM at the lower concentration of CBD. Long-term object memory was reduced in male wildtype mice at the lower concentration of CBD. Finally, ADHD- or attention-like behaviors were not altered by CBD in wildtype mice, but in Kv1.3-/- mice, females were observed to have a loss in attention while males demonstrated improved attention.

Conclusions: We conclude that administration of a single dose of CBD has immediate effects on mouse behavior that is dose, sex, and anxiety-state dependent – and that these behavioral outcomes are important to examine in parallel human trials.”

https://pubmed.ncbi.nlm.nih.gov/36455670/

https://www.sciencedirect.com/science/article/pii/S0091305722001770?via%3Dihub