Monthly Archives: October 2024

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders

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“For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times.

The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson’s disease, epilepsy, Alzheimer’s disease, and other Neurological disorders.

Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2.

While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively.

As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.”

https://pubmed.ncbi.nlm.nih.gov/39410886/

https://www.eurekaselect.com/article/143747

Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder

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“Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers.

The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics.

This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD.”

https://pubmed.ncbi.nlm.nih.gov/39409097/

https://www.mdpi.com/1422-0067/25/19/10768

Interplay between cannabinoids and the neuroimmune system in migraine

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“Migraine is a common and complex neurological disorder that has a high impact on quality of life. Recent advances with drugs that target the neuropeptide calcitonin gene-related peptide (CGRP) have helped, but treatment options remain insufficient. CGRP is released from trigeminal sensory fibers and contributes to peripheral sensitization, perhaps in part due to actions on immune cells in the trigeminovascular system.

In this review, we will discuss the potential of cannabinoid targeting of immune cells as an innovative therapeutic target for migraine treatment. We will cover endogenous endocannabinoids, plant-derived phytocannabinoids and synthetically derived cannabinoids.

The focus will be on six types of immune cells known to express multiple cannabinoid receptors: macrophages, monocytes, mast cells, dendritic cells, B cells, and T cells. These cells also contain receptors for CGRP and as such, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Unfortunately, to date most studies on cannabinoids and immune cells have relied on cell cultures and only a single preclinical study has tested cannabinoid actions on immune cells in a migraine model. Encouragingly, in that study a synthetically created stable chiral analog of an endocannabinoid reduced meningeal mast cell degranulation. Likewise, clinical trials evaluating the safety and efficacy of cannabinoid-based therapies for migraine patients have been limited but are encouraging.

Thus, the field is at its infancy and there are significant gaps in our understanding of the impact of cannabinoids on immune cells in migraine. Future research exploring the interactions between cannabinoids and immune cells could lead to more targeted and effective migraine treatments.”

https://pubmed.ncbi.nlm.nih.gov/39407099/

“Overall, the intersection of cannabinoids and immune cells presents a promising but under-investigated strategy for innovative migraine treatments. Indeed, a major limitation in the current landscape of cannabinoid research for migraine is the limited number of published studies and clinical trials. This can partly be attributed to the schedule 1 classification of cannabis products in the US and the illegalization of cannabis world-wide. In the future, this problem should improve as recent legal changes have led to the (re)legalization of cannabis for medical purposes, and the consumption of cannabis products has increased.”

https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-024-01883-3

The Modulatory Effects and Therapeutic Potential of Cannabidiol in the Gut

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“Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that exists in the Cannabis sativa plant.

CBD has been found to act on various receptors, including both cannabinoid and non-cannabinoid receptors. In addition, CBD has antioxidant effects that are independent of receptors. CBD has demonstrated modulatory effects at different organ systems, such as the central nervous system, immune system, and the gastrointestinal system. Due to its broad effects within the body and its safety profile, CBD has become a topic of therapeutic interest.

This literature review summarizes previous research findings with regard to the effect of CBD on the gastrointestinal (GI) system, including its effects at the molecular, cellular, organ, and whole-body levels. Both pre-clinical animal studies and human clinical trials are reviewed.

The results of the studies included in this literature review suggest that CBD has significant impact on intestinal permeability, the microbiome, immune cells and cytokines. As a result, CBD has been shown to have therapeutic potential for GI disorders such as inflammatory bowel disease (IBD).

Furthermore, through interactions with the gut, CBD may also be helpful in the treatment of disorders outside the GI system, such as non-alcoholic liver disease, postmenopausal disorders, epilepsy, and multiple sclerosis. In the future, more mechanistic studies are warranted to elucidate the detailed mechanisms of action of CBD in the gut. In addition, more well-designed clinical trials are needed to explore the full therapeutic potential of CBD on and through the gut.”

https://pubmed.ncbi.nlm.nih.gov/39404382/

“CBD has exhibited modulatory effects on both the intestinal barrier permeability and the gut microbiome. In addition, CBD has displayed therapeutic potential for the treatment of GI disorders such as IBD. Furthermore, CBD may produce therapeutic effects on diseases outside the GI system by regulating gut–liver, gut–bone, and gut–brain axes.”

https://www.mdpi.com/2073-4409/13/19/1618

Cannabiorcol as a novel inhibitor of the p38/MSK-1/NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis

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“Background: The bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear.

Methods: In silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1β and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol’s effects on OA and its fundamental mechanisms.

Results: Cannabiorcol inhibits the expression of IL-1β-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa β (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats.

Conclusion: Cannabiorcol inhibits IL-1β-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.”

https://pubmed.ncbi.nlm.nih.gov/39405610/

“Phytocannabinoids are naturally occurring compounds found in Cannabis sativa that are being investigated as potential therapeutic agents for various diseases. Our findings offer new perspectives on cannabiorcol’s therapeutic potential for OA treatment. Our study demonstrates the potential therapeutic effects of cannabiorcol in OA by inhibiting MMP expression and attenuating inflammatory pathways such as NF-κB and p38 MAPK. Hence, cannabiorcol may represent a promising candidate for further investigation and development of OA treatments.”

https://www.sciencedirect.com/science/article/pii/S0944711324007980?via%3Dihub

Exploring the Potential of Synthetic Cannabinoids: Modulation of Biological Activity of Normal and Cancerous Human Colon Epithelial Cells

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“Colorectal cancer (CRC) is a global problem. Oncology currently practices conventional methods of treating this carcinoma, including surgery, chemotherapy, and radiotherapy. Unfortunately, their efficacy is low; hence, the exploration of new therapies is critical.

Recently, many efforts have focused on developing safe and effective anticancer compounds. Some of them include cannabinoids.

In the present study, we obtained cannabinoids, such as cannabidiol (CBD), abnormal cannabigerol (abn-CBG), cannabichromene (CBC), and cannabicitran (CBT), by chemical synthesis and performed the biological evaluation of their activity on colon cancer cells. In this study, we analyzed the effects of selected cannabinoids on the lifespan and metabolic activity of normal colonic epithelial cells and cancer colon cells.

This study demonstrated that cannabinoids can induce apoptosis in cancer cells by modulating mitochondrial dehydrogenase activity and cellular membrane integrity. The tested cannabinoids also influenced cell cycle progression. We also investigated the antioxidant activity of cannabinoids and established a relationship between the type of cannabinoid and nitric oxide (NO) production in normal and cancerous colon cells.

To conclude, it seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research aimed at their use in alternative or combined therapies for human colon cancer.”

https://pubmed.ncbi.nlm.nih.gov/39404380/

“It seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research, aimed at their use in alternative or combined therapies for human colon cancer.”

https://www.mdpi.com/2073-4409/13/19/1616

Prenatal Cannabis Use and Offspring Attention Deficit Hyperactivity Disorder and Disruptive Behavior Disorders: A Retrospective Cohort Study

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“Objective: To examine whether maternal cannabis use during early pregnancy is associated with offspring attention deficit hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD).

Methods: We conducted a population-based retrospective birth cohort study of children (N = 141,570) born between 2011 and 2018 to pregnant individuals (N = 117,130) in Kaiser Permanente Northern California universally screened for any prenatal cannabis use at the entrance to prenatal care (at ∼8-10 wk gestation). Prenatal cannabis use was defined as (1) self-reported use and/or a positive toxicology test, (2) self-reported use, (3) a positive toxicology test, and (4) self-reported use frequency. Cox proportional hazards regression models adjusting for maternal characteristics (sociodemographics, other substance use and substance use disorders, prenatal care initiation, comorbidities) examined associations between prenatal cannabis use and offspring ADHD and DBD diagnosed by age 11 years.

Results: The sample of pregnant individuals was 27.2% Asian/Pacific Islander, 5.7% Black, 24.5% Hispanic, and 38.8% non-Hispanic White, with a mean (SD) age of 30.9 (5.2) years; 4.6% screened positive for any cannabis use (0.4% daily, 0.5% weekly, 1.1% monthly or less, 2.7% unknown frequency); 3.92% had a positive toxicology test and 1.8% self-reported use; 7.7% of offspring had ADHD and 6.8% had DBD. Maternal prenatal cannabis use was not associated with ADHD (adjusted hazard ratio [aHR]: 0.84, 95% CI, 0.70-1.01), and there was an inverse association with DBD (aHR: 0.83, 95% CI, 0.71-0.97), which remained when cannabis was defined by toxicology testing but not by self-report. Frequency of use was not associated with outcomes.

Conclusion: Maternal prenatal cannabis use was not associated with an increased risk of offspring ADHD or DBD.”

https://pubmed.ncbi.nlm.nih.gov/39400201/

https://journals.lww.com/jrnldbp/abstract/9900/prenatal_cannabis_use_and_offspring_attention.212.aspx

Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-κB pathways in mice

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“Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice.

Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7th to the 14th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7th to the 14th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed.

Findings/results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants.

Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.”

https://pubmed.ncbi.nlm.nih.gov/39399730/

“This study confirmed that CBD attenuates As-induced nephrotoxicity in mice. CBD led to the strengthening of antioxidant defense, reduction of lipid peroxidation, inflammation and expression of proteins of NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3. The dose of 10 mg/kg of CBD showed better results than 5, and 2.5 mg/kg. Finally, the findings of the present study provide evidence that CBD may serve as a potential therapeutic agent for the prevention and treatment of arsenic-induced nephrotoxicity. “

https://journals.lww.com/rips/fulltext/2024/19040/cannabidiol_attenuates_arsenic_induced.8.aspx

Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors

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“Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear.

Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG).

Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD.

These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/39396064/

https://www.nature.com/articles/s41380-024-02789-x

Prevalence and Effect of Cannabinoids in Pain Management for Hand Pathologies

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“Background: Cannabinoids are a diverse group of compounds under investigation for various medical purposes, including analgesia. Given the evolving landscape of cannabinoid use, we aimed to analyze their prevalence and effect in pain management among urban orthopedic hand patients.

Methods: An electronic survey was administered to 122 new patients presenting to the orthopedic hand clinic of a major urban academic hospital. Demographic data, numerical rating scale pain scores, cannabinoid usage, and other concomitant pain regimens were recorded.

Results: Approximately half of the new patients were dissatisfied with current pain management for their hand pathology. Prescription (Rx) and over-the-counter (OTC) pain medications were used by 58% (71/122) of patients, while cannabinoids were used by 15% (18/122) of patients. Compared with pre-usage pain scores, both cannabinoids and Rx/OTC medications induced significant reductions in pain associated with patients’ hand pathologies (Cannabinoid: Δ4.4, P = .002; Rx/OTC: Δ3.0, P < .001). Cannabinoids induced a larger analgesic effect, but this difference was not statistically or clinically significant (P = .06). Subjectively, cannabinoid users either preferred their cannabinoid over Rx/OTC medications or liked both equally. Opioid use was higher among cannabinoid users (22.2% vs 12.5%), although this was not statistically significant (P = .28).

Conclusion: Approximately 15% of new urban hand patients use cannabinoids for pain control, and these compounds have similar analgesic efficacy in hand pathologies as Rx/OTC medications. Cannabinoids are equally liked or preferred relative to traditional medications in this cohort, and they may play an important role in pain management for hand patients.”

https://pubmed.ncbi.nlm.nih.gov/39392237/

https://journals.sagepub.com/doi/10.1177/15589447241284275