Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy

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“While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches.

The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines.

According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders.

The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements.

This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/39862927/

https://www.sciencedirect.com/science/article/abs/pii/S0163725825000117?via%3Dihub

The comparative effectiveness of medicinal cannabis for chronic pain versus prescription medication treatment

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“Reviews of the effectiveness of medicinal cannabis for chronic pain vary in their conclusions. IASP has identified that a key missing evidence in this debate is data from observational cohort studies, analyzed with comparative effectiveness methods.

In a medically supervised context to the use of marijuana for chronic pain, we identified 440 patients certified for medical marijuana by pain specialists in a single healthcare system. They were characterized by a battery of patient-reported outcomes stored electronically in the University of Pittsburgh Patient Outcomes Repository for Treatment (PORT).

At 3 months, 38.6% were responders, based on clinically meaningful improvements in pain, function, or global impression of change, and maintained this response at 6 months. In the 157 patients who were coprescribed opioids, at 6 months there was a mean 39.3% decrease in morphine milligram equivalents (P < 0.05 for the difference vs baseline).

In addition, 8114 patients treated in the same pain clinics with prescription pain medications instead (nonopioid or opioid) during the same timeframe were selected from PORT as a control group for comparison. They had a 34.9% rate of response at 3 months. Using the causal inference method of stratified modeling, logistic regression revealed an odds ratio of 2.6 in favor of medical marijuana vs medication treatment (P < 0.01). Potential harms data were not available in the PORT registry.

Medical marijuana was comparatively more effective than prescription medications for the treatment of chronic pain at 3 months, although the populations compared were slightly different.”

https://pubmed.ncbi.nlm.nih.gov/39878633/

https://journals.lww.com/pain/abstract/9900/the_comparative_effectiveness_of_medicinal.807.aspx

Cannabidiol Ameliorates Doxorubicin-Induced Myocardial Injury via Activating Hippo Pathway

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“Background: Doxorubicin (DOX) is a chemotherapeutic agent widely used for cancer treatment and has non-negligible cardiotoxicity. Some previous studies have reported that cannabidiol (CBD) has cardioprotective effects. In this study, we evaluated the protective effects of CBD against DOX-induced cardiomyocyte injury, and explored the downstream molecular mechanism.

Methods and materials: GSE193861, containing healthy myocardial tissues and myocardial tissues with DOX-induced injury, was analyzed to screen for the involved proteins and pathways. Molecular docking was performed to identify candidate drugs. After H9c2 cells were treated with DOX and CBD, their viability, oxidative stress, and apoptosis were assessed. After YAP depletion, the role of the Hippo pathway in CBD function was investigated. C57BL/6 mice were treated with DOX to establish an in vivo model, and CBD and verteporfin (VP) were used to treat the mice. Histological analyses and immunofluorescence were used to evaluate myocardial tissue injury, and apoptosis and oxidative stress of the myocardial tissues were also analyzed. Western blotting was used to investigate the regulatory effects of CBD on the Hippo and apoptosis-related pathways.

Results: Bioinformatic analysis suggested that the Hippo pathway was a crucial pathway involved in DOX-induced myocardial injury. Molecular docking showed that CBD targeted multiple regulators of the Hippo pathway. CBD showed cardioprotective effects against DOX-induced myocardial injury both in vitro and in vivo and regulated Hippo pathway activity in cardiomyocytes. After inactivation of the Hippo pathway by YAP knockdown or VP intervention, the protective effects of CBD were reversed.

Conclusion: For the first time, we revealed that CBD is likely to reduce DOX-induced myocardial injury by regulating the Hippo signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/39876987/

“Overall, this study reports that CBD alleviates DOX-induced myocardial injury by regulating the Hippo pathway.”

https://www.dovepress.com/cannabidiol-ameliorates-doxorubicin-induced-myocardial-injury-via-acti-peer-reviewed-fulltext-article-DDDT

Exploring the diversity of cannabis cannabinoid and non-cannabinoid compounds and their roles in Alzheimer’s disease: A review

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“Cannabis sativa is recognized for its chemical diversity and therapeutic potential, particularly in addressing neurodegenerative diseases such as Alzheimer’s disease (AD). Given the complexity of AD, where single-target therapies often prove inadequate, a multi-target approach utilizing cannabis-derived compounds may offer promising alternatives.

This review first highlights the chemical diversity of cannabis by categorizing its compounds into cannabinoids and non-cannabinoids. It then examines studies investigating the effects of these compounds on AD-related pathological features.

By synthesizing existing knowledge, identifying research gaps, and facilitating comparative analysis, this review aims to advance future research and understanding. It underscores cannabis’s potential as a multi-target therapeutic strategy for AD, contributing valuable insights to ongoing scientific discussions.”

https://pubmed.ncbi.nlm.nih.gov/39866750/

“Cannabis sativa exhibits rich chemical diversity, categorized into cannabinoid and non-cannabinoid compounds.”

“The plant’s therapeutic potential is particularly relevant for treating neurodegenerative diseases like AD.”

“The discovery of the endocannabinoid system underscores the importance of cannabis-derived compounds in AD research.”

“A multi-target approach with cannabis compounds may overcome the limitations of single-target therapies in AD.”

“The review synthesizes existing research, identifies gaps, and aims to improve future studies on cannabis and AD.”

https://www.ibroneuroreports.org/article/S2667-2421(24)00119-2/fulltext


Permeability of active ingredients of cannabis and possibility for further antituberculosis drug development

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“Background

Cannabis is presently legalized in several countries owing to its medicinal property. The antibacterial properties of active ingredients of cannabis have been mentioned. Their usefulness in the management of tuberculosis is very interesting.

Materials and methods 

The authors performed a bioinformatics analysis to assess the possibility of important active ingredients of cannabis.

Results 

Based on the present analysis, it can be seen that the studied active ingredients of cannabis can effectively pass through the cell wall of Mycobacterium tuberculosis, indicating the possibility of further pharmacological actions.

Conclusion 

The active ingredients of cannabis are the possible new targets for further antituberculosis drug development.”

“Cannabis is presently legalized in several countries owing to its medicinal properties[3]. The antibacterial property of active ingredients of cannabis is mentioned. Their usefulness in management of tuberculosis is very interesting. In the present study, the authors studied the permeability of active ingredients detectable in cannabis. The studied ingredients are the important main ingredients including tetrahydrocannabinol (THC) and cannabidiol (CBD)[4]. The study is a useful basic study for further antituberculosis drug search.”

“Here, it can be shown that the studied active ingredients of cannabis have the possibility to pass into the mycobacterial cell. Difference in permeability based on the size of the ingredients can be observed. Of interest, it can confirm the previous reports that the Mycobacteria can cause biotransformation of CBD[9], delta-8-THC[9], and delta-9 THC[10]. This observation can show that CHD, delta-8-THC, and delta-9 THC can be a further target for antituberculosis drug development. The three studied main active ingredients of cannabis are reported for bactericidal activity for some gram-positive bacteria.”

“The present study is a medical pharmacoinformatics study. It can confirm that the active ingredients of cannabis are the possible new targets for further antituberculosis drug development.”

https://journals.lww.com/ecdt/fulltext/2021/70030/permeability_of_active_ingredients_of_cannabis_and.3.aspx

Molecular Mechanisms Underlying Neuroinflammation Intervention with Medicinal Plants: A Critical and Narrative Review of the Current Literature

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“Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain’s immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration into the central nervous system.

Medicinal plants, with their historical use in traditional medicine, have emerged as promising candidates to mitigate neuroinflammation and offer a sustainable alternative for addressing neurodegenerative conditions in a green healthcare framework.

This review evaluates the effects of medicinal plants on neuroinflammation, emphasizing their mechanisms of action, effective dosages, and clinical implications, based on a systematic search of databases such as PubMed, SCOPUS, and Web of Science.

The key findings highlight that plants like Cleistocalyx nervosum var. paniala, Curcuma longa, 

Cannabis sativa,

and Dioscorea nipponica reduce pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), inhibit enzymes (COX-2 and iNOS), and activate antioxidant pathways, particularly Nrf2. NF-κB emerged as the primary pro-inflammatory pathway inhibited across studies. While the anti-inflammatory potential of these plants is significant, the variability in dosages and phytochemical compositions limits clinical translation.

Here, we highlight that medicinal plants are effective modulators of neuroinflammation, underscoring their therapeutic potential. Future research should focus on animal models, standardized protocols, and safety assessments, integrating advanced methodologies, such as genetic studies and nanotechnology, to enhance their applicability in neurodegenerative disease management.”

https://pubmed.ncbi.nlm.nih.gov/39861194/

“Addressing neuroinflammation to reduce disease severity and improve patient outcomes is a promising strategy against neurodegeneration. From a molecular perspective, there are several conventional drug targets for neuroinflammation, such as enzymes, receptors, and ion channels. However, the high cost of synthetic drugs presents a challenge, emphasizing the need for alternative approaches. This has heightened interest in naturally occurring medicinal plants known for their antioxidant, anti-inflammatory, and neuroprotective properties. These plants are often more cost-effective and have been safely utilized in treatments for thousands of year.”

https://www.mdpi.com/1424-8247/18/1/133

Optimization and Evaluation of Cannabis-Based Magistral Formulations: A Path to Personalized Therapy

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“Introduction: The official implementation of pharmaceutical-grade cannabis raw materials for medicinal use has permitted doctors to prescribe and pharmacists to prepare cannabis-based formulations. The objective of the pharmaceutical development and manufacturing process optimization work was to propose a suppository formulation containing doses of 25 mg and 50 mg of tetra-hydrocannabinol (∆-9-THC) as an alternative to existing inhalable or orally administered formulations. The formulation could be used for rectal or vaginal administration, thereby providing dosage control in the treatment of endometriosis and other conditions involving pain. In this study, two substrates from suppositories with standardized Cannabis extractum normatum (CEX) were used: cocoa butter and Witepsol® H15.

Materials and methods: The long-term stability of CEX was investigated over a period of up to 24 months. The concentrations of ∆-9-THC, cannabidiol (CBD), and cannabinol (CBN) were determined using an HPLC method. Furthermore, the water content of the extract, the ethanol residue, and the microbiological purity were determined. The pharmaceutical properties of CEX-incorporated suppositories, namely content uniformity, hardness, softening time, total deformation time, disintegration time, and the release profile of ∆-9-THC, CBD, and CBN, were evaluated in order to develop optimal preparation procedures for pharmacists.

Results and discussion: Following a 24-month stability study on CEX, no significant alterations in component content were observed beyond the specified requirements. The disintegration time, total deformation time, and hardness of the suppositories based on Witepsol® H15 with CEX were found to be longer and higher, respectively, than those of suppositories formulated with cocoa butter. In vitro studies demonstrated that suppositories prepared with Witepsol® H15 exhibited superior release of ∆-9-THC compared to those prepared with cocoa butter.

Conclusions: We suggest that pharmacists making prescription drugs in a pharmacy setting in the form of medical marijuana suppositories will receive a better release profile of the drug by choosing Witepsol® H15 as a substrate.”

https://pubmed.ncbi.nlm.nih.gov/39861136/

https://www.mdpi.com/1424-8247/18/1/73

Exploring the Therapeutic Potential of Cannabidiol in U87MG Cells: Effects on Autophagy and NRF2 Pathway

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“Cannabinoids include both endogenous endocannabinoids and exogenous phytocannabinoids, such as cannabidiol (CBD), and have potential as therapeutic agents in cancer treatment due to their selective anticancer activities.

CBD exhibits both antioxidant and pro-oxidant effects depending on its concentration and cell types. These properties allow CBD to influence oxidative stress responses and potentially enhance the efficacy of antitumor therapies.

In this study, we treated U87MG glioma cells with low dose (1 μM) CBD and evaluated its molecular effects.

Our findings indicate that CBD reduced cell viability by 20% (p < 0.05) through the alteration of mitochondrial membrane potential. The alteration of redox status by CBD caused an attempt to rescue mitochondrial functionality through nuclear localization of the GABP transcription factor involved in mitochondria biogenesis. Moreover, CBD treatment caused an increase in autophagic flux, as supported by the increase in Beclin-1 and the ratio of LC3-II/LC3-I. Due to mitochondria functionality alteration, pro-apoptotic proteins were induced without activating apoptotic effectors Caspase-3 or Caspase-7. The study of the transcription factor NRF2 and the ubiquitin-binding protein p62 expression revealed an increase in their levels in CBD-treated cells.

In conclusion, low-dose CBD makes U87MG cells more vulnerable to cytotoxic effects, reducing cell viability and mitochondrial dynamics while increasing autophagic flux and redox systems. This explains the mechanisms by which glioma cells respond to CBD treatment.

These findings highlight the therapeutic potential of CBD, suggesting that modulating NRF2 and autophagy pathways could represent a promising strategy for glioblastoma treatment.”

https://pubmed.ncbi.nlm.nih.gov/39857352/

“Our study demonstrates that low-dose CBD treatment (1 μM) in U87MG glioblastoma cells stimulates the autophagy process, which is essential for mitochondrial renewal, contributing to an increase in mitochondria with altered membrane potential. Moreover, CBD-treated U87MG cells present an abnormal activation of the NRF2 pathway, reducing the expression of antioxidant target genes and consequently altering mitochondrial integrity. These molecular effects suggest that CBD could have therapeutic repercussions or be useful in the development of multi-target agents acting on the NRF2 mitochondrial biogenesis–autophagy axis.”

https://www.mdpi.com/2076-3921/14/1/18

Anti-Inflammatory Effects of Cannabigerol In Vitro and In Vivo Are Mediated Through the JAK/STAT/NFκB Signaling Pathway

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“Cannabinoid compounds have potential as treatments for a variety of conditions, with cannabigerol (CBG) being known for its anti-inflammatory properties.

In this study, we investigated the effects of CBG in a cellular model of 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD).

In the cellular model, we confirmed the cytotoxicity of CBG and downregulated the expression of inflammatory markers CCL26, IL1B, IL6, and TNF (p < 0.001). In the mouse model, clinical, histological, and immunological changes were analyzed.

The results showed that CBG improved dermatitis severity score, epidermal thickness, and mast cell count and reduced inflammatory cytokines (Tslp, Il1b, Il4, Il6, Il13, Il17, Il18, Il22, and Il33) by qRT-PCR (p < 0.001). Western blot results showed modulated changes in JAK1, JAK2, TYK2, STAT1, STAT2, STAT3, p-STAT3, STAT6, and p-STAT6 (p < 0.05). Subsequently, p-IκBα, NF-κB, and p-NF-κB signaling factors were also reduced (p < 0.05), with corresponding changes in skin barrier factors.

The results of this study indicate that CBG effectively alleviates AD-like symptoms and suggest the potential of CBG as a therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39851511/

https://www.mdpi.com/2073-4409/14/2/83

Cannabidiol Modulates Neuroinflammatory and Estrogen-Related Pathways in a Sex-Specific Manner in a Chronic Stress Model of Depression

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“Evidence indicates a bidirectional link between depressive symptoms and neuroinflammation. This study evaluated chronic cannabidiol (CBD) treatment effects in male and female rats subjected to the unpredictable chronic mild stress (UCMS) model of depression.

We analyzed the gene expression related to neuroinflammation, cannabinoid signaling, estrogen receptors, and specific microRNAs in the ventromedial prefrontal cortex (vmPFC), CA1, and ventral subiculum (VS). UCMS influenced immobility in a sex-specific manner, increasing it in males and decreasing it in females, effects that were reversed by CBD.

CBD also normalized the UCMS-induced upregulation of tumor necrosis factor α (TNF-α) in the CA1 and VS in males. In both sexes, UCMS induced the upregulation of the nuclear factor kappa B subunit 1 (NF-κB1) gene in the VS, which was unaffected by CBD. Additionally, CBD reversed CB1 downregulation in the VS of males but not in the vmPFC of either sex. In males, CBD restored the UCMS-induced downregulation of VS estrogen receptor genes ERα and ERβ. UCMS also altered miR-146a-5p expression, downregulating it in females (VS) and upregulating it in males (CA1), with no CBD effect.

These findings highlight the sex-specific mechanisms of CBD’s antidepressant effect, with hippocampal neuroinflammatory and estrogenic pathways playing a key role in males.”

https://pubmed.ncbi.nlm.nih.gov/39851527/

“Cannabidiol (CBD), renowned for its anti-inflammatory and antioxidative properties, has emerged as a promising candidate for treating depression.”

https://www.mdpi.com/2073-4409/14/2/99