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Cannabinol modulates the endocannabinoid system and shows TRPV1-mediated anti-inflammatory properties in human keratinocytes

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“Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide-inflamed human keratinocytes (HaCaT cells).

CBN was found to increase the expression of cannabinoid receptor 1 (CB1) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2-arachidonoylglicerol (2-AG), by increasing the activities of N-acyl phosphatidylethanolamines-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH)-the biosynthetic and degradative enzyme of AEA-and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2-AG.

CBN also affected keratinocyte inflammation by reducing the release of pro-inflammatory interleukin (IL)-8, IL-12, and IL-31 and increasing the release of anti-inflammatory IL-10. Of note, the release of IL-31 was mediated by TRPV1. Finally, the mitogen-activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS-directed drugs.

Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti-inflammatory effects-remarkably via TRPV1-in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes.”

https://pubmed.ncbi.nlm.nih.gov/39275884/

“Taken together, our data suggest that CBN may hold true therapeutic potential to treat different human skin diseases. Such a biological activity of CBN occurs through engagement of selected elements of the endocannabinoid system—in particular TRPV1—a finding that paves the way to the development of distinct formulations of cannabis extracts for selected therapeutic applications.”

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.2122

Design, Synthesis, and Characterization of Novel Cannabidiol-Based Derivatives with Potent Antioxidant Activities

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“In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia.

In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD’s framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39273525/

https://www.mdpi.com/1422-0067/25/17/9579

Changes in health-related quality of life over the first three months of medical marijuana use

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“Background: The psychosocial impact of medical marijuana use is not yet known. This study evaluated short-term changes in health-related quality of life (HRQoL) over the first three months of medical marijuana use.

Methods: This prospective, observational, longitudinal study followed adults newly recommended for medical marijuana by a physician for any of the more than 20 qualifying medical conditions in Pennsylvania. Participants (N = 438) provided their clinical status and demographic information, and completed semi-structured interviews prior to medical marijuana initiation (baseline) and at three months. HRQoL was assessed by the Short Form-36 (SF-36). Paired-samples t-tests evaluated changes in HRQoL over time.

Results: Participants (M age = 46.4 years [15.6]; 66.4% female) were mostly commonly referred for medical marijuana to treat anxiety disorders (61.9%) or severe chronic or intractable pain (53.6%). Participants reported rapid and significant improvements in all of the domains of HRQoL from baseline to three months after initiating medical marijuana use (physical functioning, role limitations due to physical health problems, emotional well-being, role limitations due to emotional problems, bodily pain, social functioning, energy/fatigue and general health, P < .001 for all). Age was negatively predictive of level of improvement over time for the physical functioning (P < .0001), role limitations due to physical health problems (P < .001), and pain (P < .0001) domains after controlling for baseline, with older participants displaying less improvement than younger participants.

Conclusions: Gains were observed in all HRQoL domains assessed after three months of medical marijuana use. In several domains, age was a significant predictor of degree of improvement.”

https://pubmed.ncbi.nlm.nih.gov/39256884/

“In conclusion, the use of medical marijuana for three months was associated with improvements in physical, social, emotional and pain-related HRQoL. Ongoing surveillance of HRQoL in individuals with physical and mental health conditions can help to treat the “whole person” and to capture any collateral impact of selected therapeutic approaches as treatment initiates and progresses. Results from this study can help patients, their caregivers, and their providers to make more informed and evidence-based decisions on whether to incorporate medical marijuana into their treatment regimens.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00245-9

The neurobehavioural effects of cannabidiol in alcohol use disorder: Study protocol for a double-blind, randomised, cross over, placebo-controlled trial

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“Current treatments for alcohol use disorders (AUD) have limited efficacy. Recently, Cannabidiol (CBD) has been examined in a multitude of clinical settings. Preclinical and clinical results suggest that CBD might be particularly well suited for the treatment of AUD and may reduce alcohol cue and stress-induced craving and alcohol seeking. This study aims to investigate this new pharmacotherapy with a particular focus on neurobiological and physiological indicators of craving.

Methods: In this double-blind, within-subject, randomised, placebo-controlled, cross-over study, non-treatment seekers will be randomly allocated to three days of four 200 mg CBD gel capsules (800 mg/day) or placebo, with an 18-day washout period. Cognitive, clinical, and neuroimaging assessments will be completed during these three days. The CBD and placebo assessments will be compared.

The primary outcomes are i) BOLD signal as a proxy for regional activity during a cue reactivity and a fear response task measured with functional magnetic resonance imaging (fMRI), ii) heart rate variability and skin conductance levels as a proxy for psychophysiological responses to alcohol stimuli. The secondary outcomes are: i) neurometabolite levels (γ-Aminobutyric acid, ethanol, glutathione, and glutamate + glutamine (combined signal)) using magnetic resonance spectroscopy (MRS); ii) functional connectivity using resting state fMRI (rsfMRI); iii) executive functioning task results; iv) clinical outcomes such as craving, anxiety, and sleep. 

Discussion: This study will improve the understanding of the mechanisms of action of CBD and provide early signals of efficacy regarding the therapeutic potential of CBD in the treatment of alcohol use disorder.”

https://pubmed.ncbi.nlm.nih.gov/39252861/

“CBD could reduce alcohol craving and seeking due to moderating responses to alcohol and stress cues, normalising dysregulated neurobiological systems and/or improving relevant clinical characteristics that lead to relapse such as sleep and mood disturbances. Compared to other medications used for the management of addiction, CBD has been demonstrated to be particularly safe with less severe side effects and few contraindications which may lead to better treatment adherence. CBD may also offer potential protection from alcohol-related liver and brain damage due to anti-inflammatory and antioxidant properties. “

https://www.sciencedirect.com/science/article/pii/S2451865424000887?via%3Dihub

Targeting dysfunctional endocannabinoid signaling in a mouse model of Gulf War illness

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“Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs.

We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain.

Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia.

Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation.

Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology.”

https://pubmed.ncbi.nlm.nih.gov/39241906/

“A mouse model for Gulf War Illness (GWI) displays deficits in brain anandamide.

Normalization of endocannabinoid signaling may offer a therapeutic strategy for GWI.”

https://www.sciencedirect.com/science/article/pii/S0028390824003113?via%3Dihub

“FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis”

https://pubmed.ncbi.nlm.nih.gov/39169440/

“CBD formulation improves energetic homeostasis in dermal fibroblasts from Gulf War Illness patients.  Our data provide new evidence that will validate the potential of cannabinoids as a therapeutic strategy to mitigate energy imbalance that may contribute to detrimental symptomatology (i.e., chronic fatigue, brain fog, cognitive dysfunction, etc.) in GWI patients.”

https://pubmed.ncbi.nlm.nih.gov/35560565/

Cannabidiol suppresses silica-induced pulmonary inflammation and fibrosis through regulating NLRP3/TGF-β1/Smad2/3 pathway

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“Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis.

In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining.

The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis.

Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 μg/mL) to induce cell damage, then CBD (10 μM, 20 μM) and PFD (100 μM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells.

Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-β1/Smad2/3 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/39244899/

“CBD ameliorates silica-induced pulmonary inflammation and fibrosis.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576924016096?via%3Dihub

“Silica compounds are found throughout the environment in rocks, sand, clay, soil, air, and water. Silica is used in many commercial products, such as bricks, glass and ceramics, plaster, granite, concrete, cleansers, skin care products, and talcum powder. Some forms of amorphous silica are used as food additives, food wrappings, toothpaste and cosmetics. The general population is exposed to silica through air, certain types of indoor dust (such as from concrete), food, water, soil, and some consumer products. The exposure of greatest concern is through air.”

https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsDetails.aspx?faqid=1492&toxid=290#:~:text=Silica%20is%20used%20in%20many,food%20wrappings%2C%20toothpaste%20and%20cosmetics.

Pharmacology of Non-Psychoactive Phytocannabinoids and Their Potential for Treatment of Cardiometabolic Disease

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“The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/39235486/

https://link.springer.com/chapter/10.1007/164_2024_731

Cannabis sativa L. essential oil: chemical characterisation and antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius

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“Cannabis sativa L. essential oil has attracted the interest of the scientific community thanks to its numerous biological activities. Several studies have evaluated EOs as alternative therapeutic approaches to limit the use of antibiotics; the present study aimed to evaluate the in vitro inhibitory and bactericidal activity of the essential oils obtained from the leaves and inflorescences of two hemp genotypes against twenty-one multidrug-resistant, methicillin-resistant Staphylococcus pseudintermedius strains isolated from canine clinical samples.

Both EOs were mainly represented by sesquiterpene hydrocarbons, with a prevalence of β-caryophyllene and α-humulene. However, different relative amounts of phytocannabinoids were also detected. Microbiological results evidenced better outcomes for the EO characterised by the highest content of phytocannabinoids, which in turn showed no differences among the tested strains. Nevertheless, both the EOs showed better inhibitory and bactericidal activities than their main constituent, β-caryophyllene, tested individually, highlighting the presence of synergistic effects among the EO compounds.”

https://pubmed.ncbi.nlm.nih.gov/39229937/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2398733

Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models

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“Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death.

Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions.

Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD’s beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients.

Taken together, our results provide the first evidence for CBD as a potential treatment for LS.”

https://pubmed.ncbi.nlm.nih.gov/39231983/

“Here we report that daily CBD administration significantly extends lifespan and improves clinical signs in mouse models of two distinct LS phenotypic presentations, identifying downstream targets for the beneficial effects of CBD and paving the way for novel therapeutic avenues for LS.”

“CBD prolongs lifespan and improves fitness in Ndufs4-deficient mice”

https://www.nature.com/articles/s41467-024-51884-8


Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro

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“Aims: Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation.

Key methods: CD3/CD28 and lipopolysaccharide activated peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 6) were treated with phytocannabinoid compounds and terpenes in vitro. Flow cytometry was used to determine regulatory T cell (Treg) and T helper 17 (Th17) cell responses to treatments. Cell pellets were harvested for qRT-PCR gene expression analysis of cytokines, cell activation markers, and inflammation-related receptors. Cell culture supernatants were analysed by ELISA to quantify IL-6, TNF-α and IL-10 secretion.

Main findings: In an initial screen of 20 μM cannabinoids and terpenes which were coded to blind investigators, cannabigerol (GL4a), caryophyllene oxide (GL5a) and gamma-terpinene (GL6a) significantly reduced cytotoxicity and gene expression levels of IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC and NFKΒ1. Tetrahydrocannabinol (GL7a) suppression of T cell activation was associated with downregulation of RORC and NFKΒ1 gene expression and reduced IL-6 (p < 0.0001) and IL10 (p < 0.01) secretion. Cannabidiol (GL1b) significantly suppressed activation of Tregs (p < 0.05) and Th17 cells (p < 0.05) in a follow-on in vitro dose-response study. IL-6 (p < 0.01) and IL-10 (p < 0.01) secretion was significantly reduced with 50 μM cannabidiol.

Significance: The study provides the first evidence that cannabidiol and tetrahydrocannabinol suppress extracellular expression of both anti- and pro-inflammatory cytokines in an in vitro PBMC model of inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39208564/

https://www.sciencedirect.com/science/article/pii/S0014480024000431?via%3Dihub