Cannabidiol protects mouse hippocampal neurons from neurotoxicity induced by amyloid β-peptide25-35

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“Alzheimer’s disease (AD), the most prevalent form of dementia worldwide, is a significant health concern, according to the World Health Organization (WHO). The neuropathological diagnostic criteria for AD are based on the deposition of amyloid-β peptide (Aβ) and the formation of intracellular tau protein tangles. These proteins are associated with several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, reduced neuronal viability, and cell death.

In this context, our study focuses on the potential therapeutic use of cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and anti-inflammatory effects. We aim to evaluate CBD’s neuroprotective role, particularly in protecting hippocampal neurons from Aβ25-35-induced toxicity.

Our findings indicate that CBD significantly improves cell viability and decreases levels of lipid peroxidation and oxidative stress. The results demonstrate that CBD possesses a robust potential to rescue cells from induced neurotoxicity through its antioxidant properties. Additionally, the neuroprotective effect of CBD may be associated with the modulation of the endocannabinoid system.

These findings suggest that CBD could be a promising compound for adjuvant treatments in neurodegenerative processes triggered by amyloid-β peptide.”

https://pubmed.ncbi.nlm.nih.gov/38901785/

https://www.sciencedirect.com/science/article/abs/pii/S0887233324001103?via%3Dihub

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

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“Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties.

Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, and rectal, provide flexibility in treatment delivery.

This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies.

Drawing from surveys, patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms, slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.”

https://pubmed.ncbi.nlm.nih.gov/38891938/

https://www.mdpi.com/1422-0067/25/11/5749


Anti-Cancer and Anti-Proliferative Potential of Cannabidiol: A Cellular and Molecular Perspective

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“Cannabinoids, the bioactive compounds found in Cannabis sativa, have been used for medicinal purposes for centuries, with early discoveries dating back to the BC era (BCE). However, the increased recreational use of cannabis has led to a negative perception of its medicinal and food applications, resulting in legal restrictions in many regions worldwide.

Recently, cannabinoids, notably Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have gained renewed interest in the medical field due to their anti-cancer properties. These properties include the inhibition of tumour growth and cell invasion, anti-inflammatory effects, and the induction of autophagy and apoptosis.

As a result, the use of cannabinoids to treat chemotherapy-associated side effects, like nausea, vomiting, and pain, has increased, and there have been suggestions to implement the large-scale use of cannabinoids in cancer therapy. However, these compounds’ cellular and molecular mechanisms of action still need to be fully understood.

This review explores the recent evidence of CBD’s efficacy as an anti-cancer agent, which is of interest due to its non-psychoactive properties. The current review will also provide an understanding of CBD’s common cellular and molecular mechanisms in different cancers. Studies have shown that CBD’s anti-cancer activity can be receptor-dependent (CB1, CB2, TRPV, and PPARs) or receptor-independent and can be induced through molecular mechanisms, such as ceramide biosynthesis, the induction of ER stress, and subsequent autophagy and apoptosis.

It is projected that these molecular mechanisms will form the basis for the therapeutic applications of CBD. Therefore, it is essential to understand these mechanisms for developing and optimizing pre-clinical CBD-based therapies.”

https://www.mdpi.com/1422-0067/25/11/5659

“Overall, the studies presented herein have given insights into the potential of CBD as an anti-cancer agent and a possible sustainable alternative to current treatments.”

https://pubmed.ncbi.nlm.nih.gov/38891847/

Modulation of Redox and Inflammatory Signaling in Human Skin Cells Using Phytocannabinoids Applied after UVA Irradiation: In Vitro Studies

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“UVA exposure disturbs the metabolism of skin cells, often inducing oxidative stress and inflammation. Therefore, there is a need for bioactive compounds that limit such consequences without causing undesirable side effects.

The aim of this study was to analyse in vitro the effects of the phytocannabinoids cannabigerol (CBG) and cannabidiol (CBD), which differ in terms of biological effects. Furthermore, the combined use of both compounds (CBG+CBD) has been analysed in order to increase their effectiveness in human skin fibroblasts and keratinocytes protection against UVA-induced alternation.

The results obtained indicate that the effects of CBG and CBD on the redox balance might indeed be enhanced when both phytocannabinoids are applied concurrently. Those effects include a reduction in NOX activity, ROS levels, and a modification of thioredoxin-dependent antioxidant systems. The reduction in the UVA-induced lipid peroxidation and protein modification has been confirmed through lower levels of 4-HNE-protein adducts and protein carbonyl groups as well as through the recovery of collagen expression. Modification of antioxidant signalling (Nrf2/HO-1) through the administration of CBG+CBD has been proven to be associated with reduced proinflammatory signalling (NFκB/TNFα).

Differential metabolic responses of keratinocytes and fibroblasts to the effects of the UVA and phytocannabinoids have indicated possible beneficial protective and regenerative effects of the phytocannabinoids, suggesting their possible application for the purpose of limiting the harmful impact of the UVA on skin cells.”

https://pubmed.ncbi.nlm.nih.gov/38891097/

“The results presented in this manuscript indicate that the concurrent use of the two phytocannabinoids (CBG and CBD), acting as both a protective and regenerative system, may have a beneficial effect on the redox balance in human keratinocytes and skin fibroblasts, even if they were applied after UVA irradiation. The tested phytocannabinoids also counteract proinflammatory reactions, which, consequently, contribute to the development of various pathological conditions. The obtained results suggest the combined use of CBG and CBD as a potential preventive and regenerative method for skin cells, especially those damaged by UV radiation, which may be used for the purpose of both prevention and therapy.”

https://www.mdpi.com/2073-4409/13/11/965

Minor Cannabinoids as Inhibitors of Skin Inflammation: Chemical Synthesis and Biological Evaluation

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“Despite millennia of therapeutic plant use, deliberate exploitation of Cannabis‘s diverse biomedical potential has only recently gained attention. Bioactivity studies focus mainly on cannabidiol (CBD) and tetrahydrocannabinol (THC) with limited information about the broader cannabinome’s “minor phytocannabinoids”. In this context, our research targeted the synthesis of minor cannabinoids containing a lateral chain with 3 or 4 carbon atoms, focusing on cannabigerol (CBG) and cannabichromene (CBC) analogues. Using known and innovative strategies, we achieved the synthesis of 11 C3 and C4 analogues, five of which were inhibitors of skin inflammation, with the CBG-C4 ester derivative emerging as the most potent compound.”

https://pubmed.ncbi.nlm.nih.gov/38889235/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00212

Cannabigerol and Cannabicyclol Block SARS-CoV-2 Cell Fusion

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“The search for new active substances against SARS-CoV-2 is still a central challenge after the COVID-19 pandemic. Antiviral agents to complement vaccination are an important pillar in the clinical situation.

Selected cannabinoids such as cannabigerol, cannabicyclol, cannabichromene, and cannabicitran from Cannabis sativa and synthetic homologues of cannabigerol and cannabicyclol were evaluated for effects on the cell viability of Vero cells (CC50 of cannabigerol and cannabicyclol 40 resp. 38 µM) and reduced virus entry of vesicular stomatitis pseudotyped viruses with surface-expressed SARS-CoV-2 spike protein at 20 µM. In addition to a reduction of pseudotyped virus entry, a titer reduction assay on Vero cells after preincubation of Wuhan SARS-CoV-2 significantly confirmed antiviral activity.

Investigations on the molecular targets addressed by cannabigerol and cannabicyclol indicated that both compounds are inhibitors of SARS-CoV-2 spike protein-mediated membrane fusion, as could be shown by a virus-free reporter fusion inhibition assay (EC50 for cannabigerol 5.5 µM and for cannabicyclol 10.8 µM) and by monitoring syncytia formation in Vero reporter cells. Selectivity indices were calculated as 7.4 for cannabigerol and 3.5 for cannabicyclol. Systematic semisynthetic alterations of cannabigerol and cannabicyclol indicated that the side chains of both compounds do not contribute to the observed anti-membrane fusion activity.”

https://pubmed.ncbi.nlm.nih.gov/38885660/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2320-8822

Hepatoprotective Effect of Cannabidiol on the Progression of Experimental Hepatic Cirrhosis in Rats

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“Introduction: Liver cirrhosis is a condition characterized by the gradual replacement of normal liver tissue with scar tissue, ultimately leading to liver failure. This slow and progressive disease begins with a chronic inflammatory process induced by a noxious agent. In its advanced stages, the disease lacks effective therapies. Research has demonstrated the significant involvement of the endocannabinoid system in the pathogenesis of this disease. This study evaluated the hepatoprotective effect of cannabidiol (CBD) in the progression of experimental hepatic cirrhosis induced by thioacetamide (TAA) in rats. 

Methods: A randomized experimental design was employed using Holtzman rats. Hepatic cirrhosis was induced by intraperitoneal administration of TAA at a dose of 150 mg/kg for 6 weeks, with treatment initiated additionally. The groups were as follows: Group 1: TAA + vehicle; Group 2: TAA + CBD 2 mg/kg; Group 3: TAA + CBD 9 mg/kg; Group 4: TAA + CBD 18 mg/kg; Group 5: TAA + silymarin 50 mg/kg; and Group 6: Healthy control. Serum biochemical analysis (total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and albumin) and hepatic histopathological study were performed. The Knodell histological activity index (HAI) was determined, considering periportal necrosis, intralobular degeneration, portal inflammation, fibrosis, and focal necrosis. 

Results: All groups receiving TAA exhibited an elevation in AST levels; however, only those treated with CBD at doses of 2 mg/kg and 18 mg/kg did not experience significant changes compared to their baseline values (152.8 and 135.7 IU/L, respectively). Moreover, ALT levels in animals treated with CBD showed no significant variation compared to baseline. The HAI of hepatic tissue was notably lower in animals treated with CBD at doses of 9 and 18 mg/kg, scoring 3.0 and 3.25, respectively, in contrast to the TAA + vehicle group, which recorded a score of 7.00. Animals treated with CBD at 18 mg/kg showed a reduced degree of fibrosis and necrosis compared to those receiving TAA alone (p ≤ 0.05). 

Conclusion: Our findings demonstrate that cannabidiol exerts a hepatoprotective effect in the development of experimental hepatic cirrhosis induced in rats.”

https://pubmed.ncbi.nlm.nih.gov/38885158/

https://www.liebertpub.com/doi/10.1089/can.2023.0285


Prescribed Medical Cannabis Use Among Older Individuals: Patient Characteristics and Improvements in Well-Being: Findings from T21

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“Background: Previous research has suggested that the use of cannabis-based medicinal products is increasing most rapidly among older aged individuals (65+ years). Despite this, little is known about the characteristics of older people using cannabis-based medicinal products and their effectiveness.

Objectives: We aimed to document the characteristics, outcomes and prescribing patterns of individuals aged 65+ years receiving prescribed cannabis compared to younger individuals receiving prescribed cannabis.

Methods: Data from T21, an observational study of patients seeking treatment with medicinal cannabinoids, including self-report ratings of quality of life (assessed via the EQ-5D-5L), general health (assessed via the visual analogue scale of the EQ-5D-5L), mood (assessed via the Patient Health Questionnaire-9) and sleep (assessed using four items derived from the Pittsburgh Sleep Quality Index) were available at treatment entry [n = 4228; 198 (4.7%) 65+ years] and at a 3-month follow-up [n = 2455; 98 (4.2%) = 65+ years].

Results: Relative to younger individuals, those aged over 64 years were more likely to be female (52.5% vs 47.0%; p < 0.001), more likely to report pain as their primary condition (76.3% vs 45.6%; p < 0.001) and less likely to report current daily use (20.2% vs 60.3%, p < 0.001). They received fewer cannabis-based medicinal products (mean = 1.4 vs 2.1; F(1,2199) = 32.3, p < 0.001) and were more likely to receive a prescription for a cannabidiol dominant oil (17.5% vs 5.7%; p < 0.001) and less likely to receive a prescription for delta-9-tetrahydrocannabinol dominant flower (32.5% vs 75.2%; p < 0.001). There were significant improvements across all measures of well-being (p < 0.001), but the extent of improvements in sleep were more marked in younger individuals (p < 0.001).

Conclusions: There are important differences between individuals aged 65+ years and younger individuals receiving cannabis-based medicinal products. Older aged individuals experience considerable improvement in health and well-being when prescribed cannabis-based medicinal products.”

https://pubmed.ncbi.nlm.nih.gov/38880841/

https://link.springer.com/article/10.1007/s40266-024-01123-y

Vasoactive and Antifibrotic Properties of Cannabinoids and Applications to Vasospastic/Vaso-Occlusive Disorders: A Systematic Review

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“Background: Management of vasospastic and vaso-occlusive disorders is a complex challenge, with current treatments showing varied success. Cannabinoids have demonstrated both vasodilatory and antifibrotic properties, which present potential mechanisms for therapeutic relief. No existing review examines these effects in peripheral circulation in relation to vasospastic and vaso-occlusive disorders. This study aims to investigate vasodilatory and antifibrotic properties of cannabinoids in peripheral vasculature for application in vasospastic and vaso-occlusive disorders affecting the hand.

Methods: A systematic search was conducted by 2 independent reviewers across PubMed, Cochrane, Ovid MEDLINE, and CINAHL to identify studies in accordance with the determined inclusion/exclusion criteria. Information regarding study design, medication, dosage, and hemodynamic or antifibrotic effects were extracted. Descriptive statistics were used to summarize study findings as appropriate.

Results: A total of 584 articles were identified, and 32 were selected for inclusion. Studies were grouped by effect type: hemodynamic (n = 17, 53%) and antifibrotic (n = 15, 47%). Vasodilatory effects including reduced perfusion pressure, increased functional capillary density, inhibition of vessel contraction, and increased blood flow were reported in 82% of studies. Antifibrotic effects including reduced dermal thickening, reduced collagen synthesis, and reduced fibroblast migration were reported in 100% of studies.

Conclusion: Overall, cannabinoids were found to have vasodilatory and antifibrotic effects on peripheral circulation via both endothelium-dependent and independent mechanisms. Our review suggests the applicability of cannabis-based medicines for vasospastic and vaso-occlusive disorders affecting the hand (eg, Raynaud disease, Buerger disease). Future research should aim to assess the effectiveness of cannabis-based medicines for these conditions.”

https://pubmed.ncbi.nlm.nih.gov/38857012/

https://journals.lww.com/annalsplasticsurgery/abstract/2024/06004/vasoactive_and_antifibrotic_properties_of.19.aspx

Lysosomal cholesterol accumulation in aged astrocytes impairs cholesterol delivery to neurons and can be rescued by cannabinoids

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“Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function.

This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. We found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter, which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR-33 in aged astrocytes, which targets ABCA1 and NPC1. In addition, we demonstrate that the microR-33 increase is triggered by oxidative stress, one of the hallmarks of aging. By coculture experiments, we show that cholesterol accumulation in astrocytes impairs the cholesterol delivery from astrocytes to neurons.

Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Finally, according to data demonstrating that aged astrocytes develop an A1 phenotype, we found that cholesterol buildup is also observed in reactive C3+ astrocytes.

Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in aging and inflammation.”

https://pubmed.ncbi.nlm.nih.gov/38856177/

https://onlinelibrary.wiley.com/doi/10.1002/glia.24580