Monthly Archives: May 2024

Cannabidiol’s cytotoxicity in pancreatic cancer is induced via an upregulation of ceramide synthase 1 and ER stress

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“Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a median 5 year-survival rate of 12%.

Cannabidiol (CBD) has been found to exhibit antineoplastic potential and may potentiate the anticancer effects of cytotoxic’s such as gemcitabine.

CBD therapy has been linked to de novo synthesis of ceramide. The sphingolipid ceramide is a potent tumour suppressor lipid with roles in apoptosis and autophagy. One of the key players involved is ceramide synthase, an enzyme with six isoforms (CerS1-CerS6), reported to have disease prognostic value. Quantitative real time PCR was used to determine mRNA expression levels of ceramide synthase isoforms, GRP78, ATF4 and CHOP. Western blotting was used to analyze protein expression of these markers and knockdown of CerS1 and GRP78 were applied via an siRNA and confirmed by the two mentioned methods. Mice with PDAC xenografts were injected via intraperitoneal method with drugs and tumours were analysed with flow cytometry and processed using H&E and IHC staining. siRNA knockdown of ceramide synthase 1 (CerS1) and analysis point to evidence of a putative CerS1 dependent pathway driven by CBD in activating endoplasmic reticulum (ER) stress target; GRP78.

Upon CBD treatment, CerS1 was upregulated and downstream this led to the GRP78/ATF4/CHOP arm of the unfolded protein response (UPR) pathway being activated. In an in vivo model of PDAC in which CerS1 was not upregulated on IHC, there was no observed improvement in survival of animals, however a reduction in tumour growth was observed in combination chemotherapy and CBD group, indicating further investigations in vivo.

These findings provide evidence of a potential ceramide induced cytotoxic mechanism of action of CBD in pancreatic ductal adenocarcinoma.”

https://pubmed.ncbi.nlm.nih.gov/38720356/

“The findings presented in this work, indicate dose-dependent and time-dependent cytotoxic effects of CBD in both human and murine pancreatic cancer cells.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00227-x

Cannabidiol alleviates carbon tetrachloride-induced liver fibrosis in mice by regulating NF-κB and PPAR-α pathways

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“Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death.

Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions.

In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses.

The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α.

In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.”

https://pubmed.ncbi.nlm.nih.gov/38711461/

“In summary, we have shown that intraperitoneal injection of CBD exerts potent anti-inflammatory and antifibrotic activities in vivo. Moreover, we found that the first time CBD efficacy in reducing CCl4-induced hepatic fibrosis by multiple mechanisms. These mechanisms may involve inhibition of NF-κB, activation of the PPAR-α pathway, and inhibition of oxidative stress. Based on these findings, CBD has the potential to be further developed as a treatment for hepatic fibrosis, especially as a combination therapy with the currently available therapies.”

https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2024.10141/full

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

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“Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+ channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+ channel (BK channel), which plays a role in the neuronal action potential’s repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.”

https://pubmed.ncbi.nlm.nih.gov/38708937/

“Taken together, our findings expand our understanding of the spectrum of ion channels directly modulated by CBD, suggesting a potential multitarget mechanism underlying its therapeutic effects. Finally, the widespread distribution and function of BK channels in human physiology and pathologies broaden the potential therapeutic uses of CBD to other conditions in which this channel is implicated.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c01274

Terpenes from Cannabis sativa induce antinociception in a mouse model of chronic neuropathic pain via activation of adenosine A2A receptors

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“Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa.

A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action.

In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain.

We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A2AR agonists.

Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.”

https://pubmed.ncbi.nlm.nih.gov/38709489/

https://journals.lww.com/pain/abstract/9900/terpenes_from_cannabis_sativa_induce.589.aspx

In silico investigation of cannabinoids from Cannabis sativa leaves as a potential anticancer drug to inhibit MAPK-ERK signaling pathway and EMT induction

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“Genes related to MAPK-ERK signaling pathways, and epithelial-mesenchymal transition induction is evolutionarily conserved and has crucial roles in the regulation of important cellular processes, including cell proliferation.

In this study, six cannabinoids from Cannabis sativa were docked with MAPK-ERK signaling pathways to identify their possible binding interactions.

The results showed that all the cannabinoids have good binding affinities with the target proteins. The best binding affinities were MEK- tetrahydrocannabinol (- 8.8 kcal/mol) and P13k-cannabinol (- 8.5 kcal/mol). The root mean square deviation was calculated and used two alternative variants (rmsd/ub and rmsd/lb) and the values of rmsd/lb fluctuated 8.6-2.0 Å and for rmsd/ub from 1.0 to 2.0 Å that suggests the cannabinoids and protein complex are accurate and cannot destroy on binding.

The study analyzed the pharmacokinetic and drug-likeness properties of six cannabinoids from C. sativa leaves using the SwissADME web tool. Lipinski’s rule of five was used to predict drug-likeness and showed that all compounds have not violated it and the total polar surface area of cannabinoids was also according to Lipinski’s rule that is benchmarked of anticancer drugs. Cannabinoids are meet the requirements of leadlikeness and synthetic accessibility values showed they can be synthesized. The molecular weight, XLOGP3, solubility (log S), and flexibility (FLEX) are according to the bioavailability radar. The bioavailability score and consensus Log Po/w fall within the acceptable range for the suitable drug. Pharmacokinetics parameters showed that cannabinoids cannot cross the blood-brain barrier, have high GI absorption as well as cannabinoids are substrates of (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) but no substrate of P-glycoprotein.

Based on these findings, the study suggests that cannabinoids are suitable drugs that could be used as effective inhibitors for target proteins involved in cancer pathways. Among the six cannabinoids, cannabinol and tetrahydrocannabinol exerted maximum binding affinities with proteins of MAPK-ERK signaling pathways, and their pharmacokinetics and drug-likeness-related profiles suggest that these cannabinoids could be superlative inhibitors in cancer treatment. Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/38716440/

“Numerous studies have been conducted on the application of cannabinoids as an anti-cancer treatment. It was found that it generally has beneficial and protective effects, preventing the growth and spread of tumors and reestablishing homeostasis. Therapeutic trials on the use of cannabinoids as an anti-cancer medication are currently being conducted, even though their therapeutic use in palliative care is well documented.

It is anticipated that the pharmacokinetic and molecular docking data of cannabinoids and the proteins related to MAPK-ERK signaling pathways will help ensure that these drugs are successfully deciphered and developed into oncological healthcare since drug repurposing is a much faster and more cost-effective process than the de novo introduction of a new drug into the clinic.”

https://link.springer.com/article/10.1007/s40203-024-00213-4

Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma

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“Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches.

In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth.

However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies.

This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α).

The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05).

These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.”

https://pubmed.ncbi.nlm.nih.gov/38713310/

https://link.springer.com/article/10.1007/s12032-024-02381-x

Therapeutic potential of cannabidiol (CBD) in the treatment of cardiovascular diseases

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“Introduction: Cannabidiol (CBD) is the primary non-psychoactive chemical derived from Cannabis Sativa, and its growing popularity is due to its potential therapeutic properties while avoiding the psychotropic effects of other phytocannabinoids, such as tetrahydrocannabinol (THC). Numerous pre-clinical studies in cellular and animal models and human clinical trials have demonstrated a positive impact of CBD on physiological and pathological processes. Recently, the FDA approved its use for the treatment of seizures, and clinical trials to test the efficacy of CBD in myocarditis and pericarditis are ongoing.

Areas covered: We herein reviewed the current literature on the reported effects of CBD in the cardiovascular system, highlighting the physiological effects and the outcomes of using CBD as a therapeutic tool in pathological conditions to address this significant global health concern.

Expert opinion: The comprehensive examination of the literature emphasizes the potential of CBD as a therapeutic option for treating cardiovascular diseases through its anti-inflammatory, vasodilatory, anti-fibrotic, and antioxidant properties in different conditions such as diabetic cardiomyopathy, myocarditis, doxorubicin-induced cardiotoxicity, and ischemia-reperfusion injury.”

https://pubmed.ncbi.nlm.nih.gov/38703078/

https://www.tandfonline.com/doi/full/10.1080/13543784.2024.2351513

The Effect of Cannabinoids on Single-level Lumbar Arthrodesis Outcomes in a Rat Model

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“Background context: The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential non-opioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue.

Purpose: We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion.

Study design: Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1ml intraperitoneal injections weekly as follows: placebo (saline), 5mg/kg THC, 5mg/kg CBD, and a combination of 5mg/kg THC and 5mg/kg CBD (Combo).

Methods: Callus tissue was harvested 2- and 8-weeks post-surgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed.

Results: μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at two weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (P>0.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points.

Conclusion: This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at two weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases.

Clinical significance: CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the post-operative setting following spinal fusions.”

https://pubmed.ncbi.nlm.nih.gov/38704096/

https://www.thespinejournalonline.com/article/S1529-9430(24)00217-1/abstract

Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans

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“There is a significant global upsurge in the number and proportion of older persons in the population. With this comes an increasing prevalence of age-related conditions which pose a major challenge to healthcare systems. The development of anti-ageing treatments may help meet this challenge by targeting the ageing process which is a common denominator to many health problems.

Cannabis-like compounds (cannabinoids) are reported to improve quality of life and general well-being in human trials, and there is increasing preclinical research highlighting that they have anti-ageing activity. Moreover, preclinical evidence suggests that endogenous cannabinoids regulate ageing processes.

Here, we review the anti-ageing effects of the cannabinoids in various model systems, including the most extensively studied nematode model, Caenorhabditis elegans.

These studies highlight that the cannabinoids lengthen healthspan and lifespan, with emerging evidence that they may also hinder the development of cellular senescence. The non-psychoactive cannabinoid cannabidiol (CBD) shows particular promise, with mechanistic studies demonstrating it may work through autophagy induction and activation of antioxidative systems. Furthermore, CBD improves healthspan parameters such as diminishing age-related behavioural dysfunction in models of both healthy and accelerated ageing. Translation into mammalian systems provides an important next step. Moreover, looking beyond CBD, future studies could probe the multitude of other cannabis constituents for their anti-ageing activity.”

https://pubmed.ncbi.nlm.nih.gov/38696056/

“Ageing is a complex and multifactorial process that occurs as a gradual accumulation of cellular damage in various tissues of the body, leading to a decline in physiological functions across all systems. One main aim of ageing research is to identify compounds that can postpone deteriorative changes linked to ageing. Finding interventions that promote healthy ageing may provide a paradigm shift in medicine, by targeting the common denominator of many diseases, that is, the ageing process. With the ongoing trend of cannabis legalisation globally, there is a demand for research that explores the impact of cannabis and cannabinoids on healthy ageing and diseases of ageing.

The current review highlights that cannabinoids, whether endogenous or exogenous, extend lifespan and healthspan in model systems.

However, more research is needed to observe whether these results translate in mammalian systems and ultimately in the clinic. The anti-ageing effects of cannabinoids have a number of different mechanisms, including the reduction of oxidative stress and the triggering of autophagy. More research is needed to further explore the anti-ageing mechanisms of the cannabinoids and to more comprehensively examine their impact on the hallmarks of ageing including cellular senescence. The development of anti-ageing agents that tone up endocannabinoid transmission could also be examined. Moreover, plant cannabinoids beyond CBD could be explored, as well as other cannabis constituents, alone and in combination. In addition, given the robust findings with CBD, chemical analogues of CBD might be developed. The current review underscores that there is much promise for the further development of cannabinoids as anti-ageing agents, to improve healthy ageing and general well-being.”

https://link.springer.com/article/10.1007/s11357-024-01162-8

Hexahydrocannabinol (HHC) and Δ9-tetrahydrocannabinol (Δ9-THC) driven activation of cannabinoid receptor 1 results in biased intracellular signaling

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“The Cannabis sativa plant has been used for centuries as a recreational drug and more recently in the treatment of patients with neurological or psychiatric disorders.

In many instances, treatment goals include relief from posttraumatic disorders, anxiety, or to support treatment of chronic pain. Ligands acting on cannabinoid receptor 1 (CB1R) are also potential targets for the treatment of other health conditions. Using an evidence-based approach, pharmacological investigation of CB1R agonists is timely, with the aim to provide chronically ill patients relief using well-defined and characterized compounds from cannabis.

Hexahydrocannabinol (HHC), currently available over the counter in many countries to adults and even children, is of great interests to policy makers, legal administrators, and healthcare regulators, as well as pharmacologists. Herein, we studied the pharmacodynamics of HHC epimers, which activate CB1R. We compared their key CB1R-mediated signaling pathway activities and compared them to the pathways activated by Δ9-tetrahydrocannabinol (Δ9-THC). We provide evidence that activation of CB1R by HHC ligands is only broadly comparable to those mediated by Δ9-THC, and that both HHC epimers have unique properties.

Together with the greater chemical stability of HHC compared to Δ9-THC, these molecules have a potential to become a part of modern medicine.”

https://pubmed.ncbi.nlm.nih.gov/38649680/

https://www.nature.com/articles/s41598-024-58845-7