Monthly Archives: September 2024

Effect of Topical Hemp (Cannabis sativa L.) Seed Oil on Knee Osteoarthritis: A Randomized Double-Blind Controlled Trial

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“Purpose, and design: Knee osteoarthritis (OA) is one of the most common and debilitating diseases, especially in the elderly. Hemp seed oil is a plant product that has been used as a food or drug since ancient times because of its anti-inflammatory and analgesic properties.

Methods: A double-blind, active, placebo-controlled trial was done to assess the efficacy of hemp seed oil on knee OA. Ninety patients were randomly allocated to three groups; hemp seed oil, diclofenac gel, and placebo via a blocked randomization method, and were asked to apply the topical treatment daily for 2 months. The study participant underwent assessments before, and four and 8 weeks after the intervention. Evaluation included measurements of the heel-to-thigh distance, utilization of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and application of visual analog scale (VAS). Data analysis was performed using SPSS.24 and the significance level was considered as p < .05.

Results: All parameters, except heel-to-thigh distance, improved significantly in the hemp seed oil group compared to placebo group. Improvements in VAS and WOMAC parameters were not different comparing the hemp seed oil and diclofenac gel groups. Heel-to-thigh distance decreased significantly within all groups during the study. There were no significant differences in improvements in heel-to-thigh distance comparing the three groups.

Conclusion, and clinical implications: Hemp seed oil led to greater improvements in VAS pain score and WOMAC parameters, but not knee flexion range, compared to placebo. There were no differences in measured outcomes comparing hemp seed oil and diclofenac gel.”

https://pubmed.ncbi.nlm.nih.gov/39256070/

https://www.painmanagementnursing.org/article/S1524-9042(24)00229-7/fulltext

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

Alcohol Activates Cannabinoid Receptor 1 and 2 in a Model of Pathogen Induced Pulmonary Inflammation

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“Alcohol use disorder (AUD) is defined as patterns of alcohol misuse and affects over 30 million people in the US. AUD is a systemic disease with the epidemiology of acute lung injury and excessive alcohol use established in the literature. However, the distinct mechanisms by which alcohol induces the risk of pulmonary inflammation are less clear.

A compelling body of evidence shows that cannabinoid receptors (CB1R and CB2R) play a relevant role in AUD. For this study, we investigated the role of CBR signaling in pulmonary immune activation.

Using a human macrophage cell line, we evaluated the expression of CBR1 and CBR2 after cells were exposed to EtOH, +/- cannabinoid agonists and antagonists by flow cytometry. We also evaluated the expression of cannabinoid receptors from the lungs of adolescent mice exposed to acute binge EtOH +/- cannabinoid agonists and antagonists at both resting state and after microbial challenge via western blot, rt-PCR, cytokine analysis, and histology.

Our results suggest that EtOH exposure modulates the expression of CBR1 and CBR2. Second, EtOH may contribute to the release of DAMPs and other proinflammatory cytokines, Finally, microbial challenge induces pulmonary inflammation in acute binge EtOH-exposed mice, and this observed immune activation may be CBR-dependent.

We have shown that adolescent binge drinking primes the lung to subsequent microbial infection in adulthood and this response can be mitigated with cannabinoid antagonists. These novel findings may provide a framework for developing potential novel therapeutics in AUD research.”

https://pubmed.ncbi.nlm.nih.gov/39251147/

  • “Acute binge alcohol modulates the levels of cannabinoid receptor expression in the lung.
  • •Microbial challenge induces pulmonary inflammation in mice previously exposed to binge alcohol
  • •Excessive alcohol paired with microbial challenge contributes to the release of proinflammatory cytokines in the lung
  • •Cannabinoid receptor antagonists block alcohol-induced pulmonary inflammation”

https://www.sciencedirect.com/science/article/abs/pii/S0378427424010981?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/

The Endocannabinoid System in Alzheimer’s Disease: A Network Meta-Analysis

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“The findings concerning the association between endocannabinoid system (ECS) and Alzheimer’s disease (AD) exhibited inconsistencies when examining the expression levels of endocannabinoids. This study aimed to provide a comprehensive summary of the studies regarding alterations of the ECS in AD.

Six databases were thoroughly searched for literature to select relevant studies investigating the ECS in AD, including changes in cannabinoid receptors (CB1R and CB2R), endocannabinoids (2-AG and AEA), and their associated enzymes (FAAH and MAGL). Traditional meta-analysis evaluated the expression levels of the ECS in AD, and the results showed no significant differences in ECS components between healthy controls and AD patients. However, subgroup analysis revealed significantly lower expression levels of CB1R in AD than in controls, particularly in studies using western blot (SMD = -0.88, p < 0.01) and in studies testing CB1R of frontal cortex (SMD = -1.09, p < 0.01). For studies using HPLC, the subgroup analysis indicated significantly higher 2-AG levels in AD than in controls (SMD = 0.46, p = 0.02). Network meta-analysis examined the rank of ECS alterations in AD compared to controls, and the findings revealed that 2-AG and MAGL exhibited the largest increase and CB1R showed the largest decrease relative to the control group.

Based on the findings of traditional meta-analysis and network meta-analysis, we proposed that AD patients may present decreased expression levels of CB1R and increased expression levels of 2-AG and its degrading enzyme MAGL.

Our results may contribute to the growing body of research supporting the therapeutic potential of ECS modulation in the management of AD.”

https://pubmed.ncbi.nlm.nih.gov/39245959/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25380

Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression

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“Background: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.

Methods: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.

Results: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.

Conclusions: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39245706/

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-024-03213-5

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.

Neuromolecular and behavioral effects of Cannabidiol on depressive-associated behaviors and neuropathic pain conditions in mice

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“Background and aims: Neuropathic pain (NP) has a high incidence in the general population, is closely related to anxiety disorders, and has a negative impact on the quality of life. Cannabidiol (CBD), as a natural product, has been extensively studied for its potential therapeutic effects on symptoms such as pain and depression (DP). However, the mechanism of CBD in improving NP with depression is not fully understood.

Methods: First, we used bioinformatics tools to deeply mine the intersection genes associated with NP, DP, and CBD. Secondly, the core targets were screened by Protein-protein interaction network, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, molecular docking and molecular dynamics simulation. Next, the effects of CBD intervention on pain and depressive behaviors in the spinal nerve ligation (SNL) mouse model were evaluated using behavioral tests, and dose-response curves were plotted. After the optimal intervention dose was determined, the core targets were verified by Western blot (WB) and Quantitative Polymerase Chain Reaction (qPCR). Finally, we investigated the potential mechanism of CBD by Nissl staining, Immunofluorescence (IF) and Transmission Electron Microscopy (TEM).

Results: A total of five core genes of CBD most associated with NP and DP were screened by bioinformatics analysis, including PTGS2, GPR55, SOD1, CYP1A2 and NQO1. Behavioral test results showed that CBD by intraperitoneal administration 5mg/kg can significantly improve the pain behavior and depressive state of SNL mice. WB, qPCR, IF, and TEM experiments further confirmed the regulatory effects of CBD on key molecules.

Conclusion: In this study, we found five targets of CBD in the treatment of NP with DP. These findings provide further theoretical and experimental basis for CBD as a potential therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39245142/

“We identified five core genes associated with comorbid NP and DP targeted by CBD. CBD intervention can improve NP and depressive-associated behavior in mice.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003228?via%3Dihub


Effects of Cannabidiol on Bone Quality in Ovariectomized Rats

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“The incidence of osteoporosis and related fractures increases significantly with age, impacting public health and associated costs. Postmenopausal osteoporosis results from increased bone resorption due to decreased estrogen levels.

The endocannabinoid system, especially cannabidiol (CBD), has shown therapeutic potential in modulating bone formation. This study investigated the effects of administration of CBD in rats after the onset of with ovariectomy-induced osteopenia (OVX).

Forty-eight female Sprague‒Dawley rats were divided into four groups (n = 12): OVX + CBD, SHAM + CBD, OVX + vehicle, and SHAM + vehicle. CBD was administered intraperitoneally for 3 weeks. After euthanasia, the bone quality, mechanical properties, and bone microarchitecture of the femurs and lumbar vertebrae were assessed by microcomputed tomography (micro-CT), bone densitometry, mechanical tests, and histological and immunohistochemical analyses.

CBD treatment improved the bone mineral density (BMD) of the lumbar vertebrae and increased the BV/TV% and Tb.N in the femoral neck. There were also improvements in the mechanical properties, such as the maximum force and stiffness of the femurs and vertebrae. CBD significantly increased the bone matrix in osteopenic femurs and vertebrae, Although did not significantly influence the expression of RANKL and OPG, in ovariectomized animals, there was an increase in osteoblasts and a decrease in osteoclasts.

Determining the optimal timing for CBD use in relation to postovariectomy bone loss remains a crucial issue. Understanding when and how CBD can be most effective in preventing or treating bone loss is essential to emphasize the importance of early diagnosis and treatment of osteoporosis. However, further studies are needed to explore in more detail the efficacy and safety of CBD in the treatment of postmenopausal osteoporosis.”

https://pubmed.ncbi.nlm.nih.gov/39245783/

https://link.springer.com/article/10.1007/s00223-024-01281-6

Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex

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“Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB1 receptors (CB1Rs). The action of CB1R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood.

In this study, we demonstrated that, at low doses, the CB1R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST).

This effect is CB1R dependent because it was blocked by the CB1R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB1R-dependent mechanism.

Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB1R-independent mechanism. The CB1R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB1R-dependent antidepressant-like effect in the FST.

These results demonstrate that CB1R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.”

“These results establish that low doses of a CB1R agonist elicit potent antidepressant-like behavior and enhance 5-HT neurotransmission, mediated by CB1R activation in the mPFCv. Conversely, high doses nullify antidepressant-like behavior and markedly attenuate 5-HT neurotransmission, an effect that appears to be instigated by a non-CB1R mechanism.”

https://pubmed.ncbi.nlm.nih.gov/17959812/