Cannflavin A inhibits TLR4-induced chemokine and cytokine expression in human macrophages

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“Cannflavin A (CFL-A), a flavonoid present in the hemp plant Cannabis sativa L. (C. sativa), has anti-inflammatory and neuroprotective capacity.

Research continues to elucidate the anti-inflammatory effects of components of C. sativa, with evidence that plant-derived cannabinoids and terpenes can mediate anti-inflammatory activity by targeting toll-like receptor (TLR) signalling, the sensors of pathogen-associated molecules.

This study set out to determine if TLR-mediated inflammatory signalling is a CFL-A target using the endotoxin lipopolysaccharide (LPS) to induce TLR4 signalling in human THP-1-derived macrophages. TLR4 activation promoted the production of the chemokine CXCL10 and cytokines IL-1β and TNFα. Treatment with CFL-A dose-dependently attenuated TLR4-induced CXCL10 and IL-1β secretion, with our findings also indicating that the inhibitory effects of CFL-A on chemokine/cytokine secretion are in line with an NF-κB inhibitor.

This study highlights TLR4 signalling as a cannflavin target in macrophages.”

https://pubmed.ncbi.nlm.nih.gov/38780010/

“This study highlights TLR4-induced inflammatory signalling as a cannflavin target. TLR4 is a key player in controlling innate immune responses to infection, and targeted TLR4 immunotherapies are under investigation for chronic inflammatory disorders. This study indicates that CFL-A warrants further study to decipher its anti-inflammatory potential in terms of regulating innate immune inflammatory signalling. Our findings also suggest that the therapeutic value of components of the hemp plant C. sativa should be broadened to include cannflavins.”

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2358382

Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer’s Disease

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“Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection.

CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood-brain barrier (BBB).

CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD’s mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD.”

https://pubmed.ncbi.nlm.nih.gov/38785534/

“Preclinical studies support the potential for CBD to be used as a treatment for combatting neuroinflammation and oxidative stress in AD.”

https://www.mdpi.com/1467-3045/46/5/266

An open-label feasibility trial of transdermal cannabidiol for hand osteoarthritis

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“Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0-10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (- 1.91 ± 0.35, p < 0.0001), average pain (- 1.92 ± 0.35, p < 0.0001) and maximum pain (- 1.97 ± 0.34, p < 0.0001) (data represent mean reduction on a 0-10 NPRS scale ± standard error of the mean (SEM)). A significant increase in grip strength in the treated hand (p < 0.0001) was observed although self-reported functionality did not improve. There were significant (p < 0.005) improvements in three QoL measures: fatigue, stiffness and anxiety. CBD and its metabolites were detected at low concentrations in all urine samples. Measured reductions in pain and increases in grip strength seen during treatment reverted back towards baseline during the washout phase. In summary, pain, grip strength and QoL measures, using smartphone technology, was shown to improve over time following transdermal CBD application suggesting feasibility of this intervention in relieving osteoarthritic hand pain. Proof of efficacy, however, requires further confirmation in a placebo-controlled randomised trial.Trial registration: ANZCTR public trials registry (ACTRN12621001512819, 05/11/2021).”

https://pubmed.ncbi.nlm.nih.gov/38783008/

“The current study suggests that transdermal CBD gel may have a beneficial effect on pain and grip strength in participants with symptomatic hand OA but requires further exploration in a randomised controlled trial. This pilot study contributes towards closing this evidence gap and demonstrates that transdermal CBD may provide some promise for a safe treatment option for symptomatically active hand OA.”

https://www.nature.com/articles/s41598-024-62428-x

Cannabidiol is a behavioral modulator in BTBR mouse model of idiopathic autism

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“Introduction: The prevalence of Autism Spectrum Disorder (ASD) has drastically risen over the last two decades and is currently estimated to affect 1 in 36 children in the U.S., according to the center for disease control (CDC). This heterogenous neurodevelopmental disorder is characterized by impaired social interactions, communication deficits, and repetitive behaviors plus restricted interest. Autistic individuals also commonly present with a myriad of comorbidities, such as attention deficit hyperactivity disorder, anxiety, and seizures. To date, a pharmacological intervention for the treatment of core autistic symptoms has not been identified.

Cannabidiol (CBD), the major nonpsychoactive constituent of Cannabis sativa, is suggested to have multiple therapeutic applications, but its effect(s) on idiopathic autism is unknown. We hypothesized that CBD will effectively attenuate the autism-like behaviors and autism-associated comorbid behaviors in BTBR T+Itpr3tf/J (BTBR) mice, an established mouse model of idiopathic ASD.

Methods: Male BTBR mice were injected intraperitoneally with either vehicle, 20 mg/kg CBD or 50 mg/kg CBD daily for two weeks beginning at postnatal day 21 ± 3. On the final treatment day, a battery of behavioral assays were used to evaluate the effects of CBD on the BTBR mice, as compared to age-matched, vehicle-treated C57BL/6 J mice.

Results: High dose (50 mg/kg) CBD treatment attenuated the elevated repetitive self-grooming behavior and hyperlocomotion in BTBR mice. The social deficits exhibited by the control BTBR mice were rescued by the 20 mg/kg CBD treatment.

Discussion: Our data indicate that different doses for CBD are needed for treating specific ASD-like behaviors. Together, our results suggest that CBD may be an effective drug to ameliorate repetitive/restricted behaviors, social deficits, and autism-associated hyperactivity.”

https://pubmed.ncbi.nlm.nih.gov/38784096/

“Data from pilot studies and case reports, though, are consistent with our preclinical findings and suggest that the CBD may be effective in alleviating both core and comorbid autistic symptoms.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1359810/full

Cannabidiol and Aza-BODIPY Coencapsulation for Photodynamic Therapy Enhancement in Liver Cancer Cells

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“Photodynamic therapy (PDT) and cannabidiol (CBD) have been explored for their potential in synergistic cancer treatment. In this study, we employed CBD oil as a lipid phase, encapsulated within AZB-I@Lec-T to create lipid-based nanoparticles. Here, CBD oil does two tasks: it acts as a pyroptosis agent to destroy liver cancer cells and as a lipid phase to dissolve the photosensitizer. It was expected that this system would offer synergistic therapy between CBD and PDT better than a single use of each treatment. With a series of in vitro experiments, the nanoparticles exhibited induced apoptosis in 68% of HepG2 cells treated with AZB-I@Lec-T@CBD and near-infrared (NIR)-light irradiation, reducing expression levels of antioxidant defense system genes. Furthermore, both components worked well in a submicromolar range when combined in our formulation. These results highlight the potential for amplifying primary cellular damage with the combination of PDT and CBD encapsulation, providing a promising therapeutic approach for liver cancer treatment guidelines.”

https://pubmed.ncbi.nlm.nih.gov/38776245/

“CBD is one of the prospective therapeutic options in oncology that has been shown to reduce angiogenesis, cancer cell motility, adhesion, and invasion, as well as limit secondary metastatic cancer spread.”

“This study successfully demonstrated the potent cytotoxic synergy between photodynamic therapy (PDT) and cannabidiol (CBD) in cancer cells.

These findings underscore the potential for augmenting primary cellular damage using PDT and CBD coencapsulation, offering a promising avenue for future therapeutic strategies in cancer treatment protocols.”

https://pubs.acs.org/doi/10.1021/acsabm.4c00239

Exploring the versatile roles of the endocannabinoid system and phytocannabinoids in modulating bacterial infections

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“The endocannabinoid system (ECS), initially identified for its role in maintaining homeostasis, particularly in regulating brain function, has evolved into a complex orchestrator influencing various physiological processes beyond its original association with the nervous system. Notably, an expanding body of evidence emphasizes the ECS’s crucial involvement in regulating immune responses.

While the specific role of the ECS in bacterial infections remains under ongoing investigation, compelling indications suggest its active participation in host-pathogen interactions. Incorporating the ECS into the framework of bacterial pathogen infections introduces a layer of complexity to our understanding of its functions.

While some studies propose the potential of cannabinoids to modulate bacterial function and immune responses, the outcomes inherently hinge on the specific infection and cannabinoid under consideration. Moreover, the bidirectional relationship between the ECS and the gut microbiota underscores the intricate interplay among diverse physiological processes.

The ECS extends its influence far beyond its initial discovery, emerging as a promising therapeutic target across a spectrum of medical conditions, encompassing bacterial infections, dysbiosis, and sepsis.

This review comprehensively explores the complex roles of the ECS in the modulation of bacteria, the host’s response to bacterial infections, and the dynamics of the microbiome. Special emphasis is placed on the roles of cannabinoid receptor types 1 and 2, whose signaling intricately influences immune cell function in microbe-host interactions.”

https://pubmed.ncbi.nlm.nih.gov/38775488/

https://journals.asm.org/doi/10.1128/iai.00020-24

Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies

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“Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination and axonal loss. Cannabis, an immunomodulating agent, is known for its ability to treat MS effectively. However, due to variations in the profile of secondary metabolites, especially cannabinoids, among cannabis cultivars, the effectiveness of cannabis treatment can vary, with significant variability in the effects on different biological parameters. For screening available cultivars, cellular in vitro as well as pre-clinical in vivo assays, are required to evaluate the effectiveness of the wide range of chemical variability that exists in cannabis cultivars. This study evaluated comparatively three chemically diverse cannabis cultivars, CN2, CN4 and CN6, containing different ratios of phytocannabinoids, for their neuroinflammatory activity in MS model.

Materials and methods: In vitro experiments were performed with lipopolysaccharide (LPS)-activated BV-2 microglia and primary glial cells to evaluate the effect of different cannabis cultivars on nitric oxide (NO) and inflammatory cytokines, as well as inducible nitric oxide synthase (iNOS) protein expression. An in vivo experiment using the experimental autoimmune encephalomyelitis (EAE) MS model was conducted using Myelin oligodendrocyte glycoprotein (MOG) as the activating peptide. The cannabis extracts of the cultivars CN2, CN4, CN6 or vehicle, were intraperitoneally injected with clinical scores given based on observed symptoms over the course of study. At the end of the experiment, the mice were sacrificed, and splenocyte cytokine secretion was measured using ELISA. Lumbar sections from the spinal cord of treated MS mice were evaluated for microglia, astrocytes and CD4+ cells.

Results: Extracts of the CN2 cultivar contained tetrahydrocannabinolic acid (THCA) and tetrahydrocannabinol (THC) without cannabidiol (CBD), and a number of monoterpenes. CN4 contained cannabidiolic acid (CBDA) and tetrahydrocannabidiolic acid (THCA), with significant amounts of THC: CBD in a 1:1 ratio, as well as sesquiterpenes and some monoterpenes; and CN6 contained primarily CBDA and THCA, as well as THC and CBD in a 2:1 ratio, with some sesquiterpenes and no monoterpenes. All extracts were not cytotoxic in glial cells up to 50 µg/ml. Dose dependent inhibition of LPS-induced BV2 as well as primary microglial NO secretion confirmed the anti-inflammatory and anti-oxidative activity of the three cannabis cultivars. CN2 but not CN4 reduced both astrocytosis and microglial activation in lumbar sections of EAE mice. In contrast, CN4 but not CN2 significantly decreased the secretion of TNFα and Interferon γ (IFNγ) in primary splenocytes extracted from EAE mice.

Conclusions: While both cannabis cultivars, CN2 and CN4, significantly reduced the severity of the clinical signs throughout the course of the study, they modulated different inflammatory mediators and pathways, probably due to differences in their phytocannabinoid composition. This demonstrates the differential potential of cannabis cultivars differing in chemotype to regulate neuroinflammation and their potential to treat MS.”

https://pubmed.ncbi.nlm.nih.gov/38778343/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00232-0

The Potential of Cannabichromene (CBC) as a Therapeutic Agent

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“There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa 

The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). While the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials.

In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. 

Significance Statement Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on THC and CBD. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.”

https://pubmed.ncbi.nlm.nih.gov/38777605/

https://jpet.aspetjournals.org/content/early/2024/05/22/jpet.124.002166

[Cannabinoid Drugs in the Treatment of Psychiatric Disorders – Data from the German Federal Institute for Drugs and Medical Devices]

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“Background: Since 2017 physicians in Germany can prescribe cannabis based medicines or medical cannabis with subsequent funding by the statutory health insurance system.

Methods: Physicians prescribing cannabinoid drugs were legally required to take part in a survey conducted by the Federal Institute for Drugs and Medical Devices. This study analyses data from 16.809 case reports that were collected from 30.3.2017 to 31.12.2021.

Results: There were 5582 cases documenting the use of cannabinoid drugs in psychiatric disorders. More than half of the prescriptions were Dronabinol. 80% of the treatments concerned somatoform disorders. Most of the treatments for other psychiatric disorders also targeted pain. Doctors reported a positive effect on symptoms in at least 75% of the cases.

Discussion: Most patients with psychiatric disorders received cannabinoid drugs for pain. The evidence from randomized controlled clinical trials for the use of cannabinoid drugs in psychiatric indications is weak.”

https://pubmed.ncbi.nlm.nih.gov/38749455/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2296-1358

The Use of Cannabidiol in Treating Psychiatric Disorders: A Systematic Review

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“Cannabidiol (CBD) has been used as a pharmacological treatment for psychiatric disorders in many studies, but few of good quality at the moment. Our objective was to assess the effect of CBD in mono/add-on therapy on symptom severity in psychiatric disorders. We performed a systematic review of clinical trials and randomized controlled trials that used CBD as treatment for psychiatric disorders. PRISMA criteria have been used for methodological purposes. Two assessors individually examined the results based on title and abstract, and decided which papers warranted full read. We included studies in English that measured disease severity as primary outcome. Out of 226 studies returned from the search, 9 warranted full read. There were 4 studies using CBD in schizophrenia, 3 studies of substance use disorder and 2 studies of social anxiety. CBD has a good safety profile even in higher doses, but results are inconclusive regarding improvements in disease severity.”

https://pubmed.ncbi.nlm.nih.gov/38765233/

https://psychiatry-psychopharmacology.com/en/the-use-of-cannabidiol-in-treating-psychiatric-disorders-a-systematic-review-133107