Targeting carbohydrate metabolism in colorectal cancer – synergy between DNA-damaging agents, cannabinoids, and intermittent serum starvation

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“Chemotherapy is a therapy of choice for many cancers. However, it is often inefficient for long-term patient survival and is usually accompanied by multiple adverse effects. The adverse effects are mainly associated with toxicity to normal cells, frequently resulting in immune system depression, nausea, loss of appetite and metabolic changes.

In this respect, the combination of chemotherapy with cannabinoids, especially non-psychoactive, such as cannabidiol, cannabinol and other minor cannabinoids, as well as terpenes, may become very useful. This is especially pertinent because the mechanisms of anticancer effects of cannabinoids on cancer cells are often different from conventional chemotherapeutics.

In addition, cannabinoids help alleviate chemotherapy-induced adverse effects, regulate sleep and appetite, and are shown to have analgesic properties. Another component for achieving potential anti-cancer synergism is regulating nutrient availability and metabolism by calorie restriction and intermittent fasting in cancer cells. As tumours require a lot of energy to grow and because glucose is constantly available, malignant cells often opt to use glucose as a primary source of ATP production through substrate-level phosphorylation (fermentation) rather than through oxidative phosphorylation. Thus, periodic depletion of cancer cells of primary fuel, glucose, could result in a strong synergy in killing cancer cells by chemo- and possibly radiotherapy when combined with cannabinoids. This commentary will discuss what is known about such combinatorial treatments, including potential mechanisms and future protocols.”

https://pubmed.ncbi.nlm.nih.gov/39534512/

https://www.oncoscience.us/article/611/text/

Case reports of identical twins with developmental and epileptic encephalopathy with STXBP1 gene mutations for whom different CBD supplementations were markedly effective

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“Cannabidiol (CBD) is a compound found specifically in the cannabis plant. Although a clinical trial for intractable epilepsy started in Japan in 2023, it is also available in the market as a dietary supplement. Herein, we report two cases of identical twins with developmental and epileptic encephalopathy with STXBP1 gene mutation who achieved seizure suppression through different regimens of CBD supplementation. The observation that different trace ingredients produced different effects in patients with identical genetic backgrounds is a crucial finding that has implications for the future regulation and clinical application of cannabinoid products.”

https://pubmed.ncbi.nlm.nih.gov/39534466/

https://www.sciencedirect.com/science/article/pii/S2589986424000777?via%3Dihub

Boosting Acetylcholine Signaling by Cannabidiol in a Murine Model of Alzheimer’s Disease

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“Alzheimer’s disease (AD) is a challenging medical issue that requires efficacious treatment options to improve long-term quality of life.

Cannabidiol (CBD) is a cannabis-derived phytocannabinoid with potential health benefits, including reports from our laboratory and others showing a therapeutic role in the pre-clinical treatment of AD; however, the mechanisms whereby CBD affects AD progression remain undefined.

Innate lymphoid cells (ILCs) are recently discovered immune cells that initiate and orchestrate inflammatory responses. ILC2, a sub-class of ILCs, is proposed to have a role in cognitive function via unknown mechanisms. In this present study, we explored whether CBD ameliorates AD symptoms via the enhancement of acetylcholine (ACh), a cholinergic neurotransmitter involved in cognition that may regulate ILC2. 5xFAD mice were chronically treated by inhalation of a formulation of broad-spectrum CBD for seven months. ACh production, ILC2s profile, brain histopathology, and long-term behavior were assessed.

Together, our studies showed that long-term inhalation of CBD improved cognitive function and reduced senile plaques in a murine AD model, effects that were associated with enhanced ACh production and altered ILC2s distribution within the CNS.

These findings indicate that inhaled CBD could offer a cost-effective, non-invasive, and effective treatment for managing AD. The beneficial effects of CBD inhalation may be linked to increased ACh production and an altered distribution of ILC2s, highlighting the need for further research in this area.”

https://pubmed.ncbi.nlm.nih.gov/39519315/

https://www.mdpi.com/1422-0067/25/21/11764

Efficiency of cannabis and cannabidiol in managing chronic pain syndromes: A comprehensive narrative review

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“Chronic pain affects up to 40% of adults, contributing to high medical expenses, the loss of productivity, reduced quality of life (QoL), and disability. Chronic pain requires detailed diagnostic assessment, treatment and rehabilitation, yet approx. 80% of patients report inadequate pain management.

As new treatment options are needed, we aimed to explore the effectiveness of medical cannabis-based products in managing chronic pain, with a particular focus on treatment patterns.

We searched the PubMed, Scopus and Web of Science databases using keywords related to cannabinoids and chronic pain syndromes. In total, 3,954 articles were identified, and 74 studies involving 12,562 patients were included. The effectiveness of cannabis-based products varied across studies.

Cannabinoids were most effective in treating chronic secondary headache and orofacial pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, and chronic neuropathic pain. Properly qualifying patients is the first crucial step in managing chronic pain, considering pain characteristics, comorbidities and other treatment options.

Treatment should start with low doses of cannabinoids, which are then increased to achieve the desired therapeutic effect while minimizing adverse effects.This narrative review revealed significant gaps in the evidence regarding precise treatment patterns, particularly for the long-term maintenance treatment needed by patients with chronic pain.

Medical cannabis can be considered an option for carefully selected patients with chronic pain syndromes when other treatment options fail to achieve an adequate response, and when the potential benefits outweigh the risks. However, there is still a need for well-designed clinical research to establish the long-term efficacy and safety of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/39499191/

“Medical cannabis can be considered an option in carefully selected patients with chronic pain syndrome for the management of chronic pain when other treatment options fail to achieve an adequate response, and when potential benefits outweigh the risks. Patients with chronic secondary headache and orofacial pain, chronic secondary visceral pain, chronic secondary musculoskeletal pain, and chronic neuropathic pain can benefit more than other groups of patients experiencing chronic pain.”

https://dmp.umw.edu.pl/en/article/2024/61/5/765/

Cannabinoids for spasticity in patients with multiple sclerosis: A systematic review and meta-analysis

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“Background: One of the most disabling symptoms of patients with multiple sclerosis (MS) is spasticity which affects their quality of life. Nowadays, cannabinoids are used for spasticity control in patients with MS, while the efficacy and safety are not clearly understood. So, we designed this systematic review and meta-analysis to assess the efficacy of cannabinoids for controlling MS-related spasticity.

Methods: PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were systematically searched by two independent researchers on 1 May 2023. They also searched gray literature (references of included studies, as well as conference abstracts).

Results: A literature search revealed 6552 records, 95 full-texts were evaluated, and finally, 31 studies remained for systematic review. Among included studies, six randomized trials were included. Nabiximols was the most commonly used medication for controlling MS-related spasticity. Mean Expanded Disability Status Scale ranged between 4.6 and 7. Most studies (17 studies) were done in Italy, followed by Germany (4 studies). The pooled standardized mean difference (SMD) of NRS (Numeric Rating Scale) (after-before) is estimated as -1.41 (95% confidence interval (CI): -1.65, -1.17) (I2 = 97%, p < 0.001). The pooled standardized mean difference (SMD) of Ashworth (after-before) is estimated as -0.39 (95% CI: -0.72, -0.06) (I2 = 69.9%, p = 0.005).

Conclusion: The results of this systematic review and meta-analysis showed that nabiximols was the most common cannabinoid which was used to control MS-related spasticity, and it was effective in controlling MS-related spasticity (significantly decreased SMD of NRS, and Ashworth after treatment).”

https://pubmed.ncbi.nlm.nih.gov/39502271/

“The results of this systematic review and meta-analysis showed that nabiximols was the most common cannabinoid which was used to control MS-related spasticity, and it was effective in controlling MS-related spasticity (significantly decreased SMD of NRS, and Ashworth after treatment).”

https://journals.sagepub.com/doi/10.1177/20552173241282379

Improved Therapeutic Efficacy of Doxorubicin Chemotherapy With Cannabidiol in 4T1 Mice Breast Cancer Model

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“Background: High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects.

Method: Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor.

Results: Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX.

Conclusions: This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone.”

https://pubmed.ncbi.nlm.nih.gov/39503169/

“This study demonstrated the potent efficacy of cannabidiol in mouse breast cancer model with high-dose chemotherapy on the antitumor, anti-metastasis and cardioprotective roles against doxorubicin. Simultaneous administration of cannabidiol with high-dose doxorubicin not only improved the antitumor and anti-metastasis efficacy, but also could reduce cardiotoxicity by decreasing MMP2 and MMP9 and improving cardiac function by decreasing iNOS. Furthermore, cannabidiol could improve antioxidant system by increasing SOD2. Eventually, these findings demonstrated cannabidiol as a potential effective agent in coadministration with doxorubicin at the same time in improving anticancer effects and reducing cardiotoxicity.”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.70395

Cannabidiol Treatment for Adult Patients with Drug-Resistant Epilepsies: A Real-World Study in a Tertiary Center

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“Background and purpose: Around 30% of patients with epilepsy show drug-resistant epilepsy (DRE). While cannabidiol has demonstrated efficacy as an adjunctive treatment in Dravet syndrome (DS), Lennox-Gastaut Syndrome (LGS), and epilepsy related to tuberous sclerosis complex (TSC), its more global effectiveness in adult patients with DRE apart from these three specific contexts needs to be clarified.

Methods: We conducted a retrospective study at the epilepsy unit of Pitié Salpêtrière Hospital. Patients initiating pharmaceutical cannabidiol treatment and followed for at least 1 year were included. Patients were categorized into “authorized” (LGS, DS, or TSC) and “off-label” groups. Cannabidiol effectiveness and tolerance were compared between groups, and characteristics of responders (patients with >50% reduction in seizure frequency) in the off-label group were examined.

Results: Ninety-one patients, followed by a median duration of 24 months, were included. A total of 35.2% of the patients were in the authorized group. No significant differences were observed in responder rates between groups (31.3% vs. 35.6%, p = 0.85) and retention rates at 1 year (75.0% vs. 74.6%, p = 0.97). Sleepiness was more commonly reported in the authorized group (50.0% vs. 22.0%, p = 0.01), with no other significant differences. Among off-label patients (n = 59), clobazam co-prescription was more prevalent in responders (71.4% vs. 28.9%, p = 0.002).

Conclusion: Our findings suggest that cannabidiol may benefit all adult patients with DRE, particularly those already receiving clobazam. Randomized controlled trials are warranted in off-label patients to validate these observational findings.”

https://pubmed.ncbi.nlm.nih.gov/39501537/

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70122

Effects of cannabidiol on AMPKα2 /HIF-1α/BNIP3/NIX signaling pathway in skeletal muscle injury

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“Cannabidiol: (CBD) is a non-psychoactive natural active ingredient from cannabis plant, which has many pharmacological effects, including neuroprotection, antiemetic, anti-inflammatory and anti-skeletal muscle injury. However, the mechanism of its effect on skeletal muscle injury still needs further research.

In order to seek a scientifically effective way to combat skeletal muscle injury during exercise, we used healthy SD rats to establish an exercise-induced skeletal muscle injury model by treadmill training, and systematically investigated the effects and mechanisms of CBD, a natural compound in the traditional Chinese medicine Cannabis sativa L., on combating skeletal muscle injury during exercise.

CBD effectively improved the fracture of skeletal muscle tissue and reduced the degree of inflammatory cell infiltration. Biochemical indexes such as CK, T, Cor, LDH, SOD, MDA, and GSH-Px in serum of rats returned to normal. Combining transcriptome and network analysis results, CBD may play a protective role in exercise-induced skeletal muscle injury through HIF-1 signaling pathway. The experimental results implied that CBD could down-regulate the expression of IL-6, NF-κB, TNF-α, Keap1, AMPKα2, HIF-1α, BNIP3 and NIX, and raised the protein expression of IL-10, Nrf2 and HO-1.

These results indicate that the protective effect of CBD on exercise-induced skeletal muscle injury may be related to the inhibition of oxidative stress and inflammation, thus inhibiting skeletal muscle injury through AMPKα2/HIF-1α/BNIP3/NIX signal pathways.”

https://pubmed.ncbi.nlm.nih.gov/39502531/

“This study preliminarily explored the protective effect of CBD on skeletal muscle in the rat model of acute exercise-induced skeletal muscle injury. The CBD intervention can reduce CK and LDH levels and increase T/COR ratio. The MDA content in the low-dose and high-dose groups of CBD was declined, while the SOD and GSH-Px content were raised. The intervention of CBD can reduce the level of oxidative stress and inflammatory response, and then reduce the expressions of AMPKα2, HIF-1α, BNIP3 and NIX, thus protecting skeletal muscle from injury. This study could provide a new potential target for the treatment of exercise-induced skeletal muscle injury. It can provide new ideas for the basic research and clinical treatment of CBD repairing skeletal muscle injury in the future.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1450513/full

Effectiveness and safety of cannabis-based products for medical use in patients with fibromyalgia syndrome: A systematic review

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“Background: There is a need to explore pharmacological options for syndrome (FMS), such as medical cannabis. The aim of this systematic review was to synthesize and analyze the available information about the effectiveness/efficacy and safety of cannabis-based products for medical use (CBPMs) and cannabis-based medicines (CBMs), in patients with FMS.

Methods: Interventional or observational studies, systematic reviews and meta-analysis regarding the effectiveness/efficacy and safety of CBPMs and CBMs in patients with FMS were retrieved from the PubMed/Medline database until April 2024. Then, the information was summarized in tables, with the type of CBPM and CBM, the method used in the study and the effective-ness/efficacy and safety outcomes.

Results: 19 publications were selected from the search or form the relevant references. Different CBPM and CBM were used across the studies. Also, different instruments for measuring the effectiveness were used. In general, the use of CBPMs and CBM showed an important improvement in pain, quality of life, and sleep habits. There were no serious adverse events.

Conclusions: The results show that CBMPs and CBMs could be effective and safe in patients with FMS; however, the evidence is limited and there is a need for high-quality clinical studies conducted with improved methodological design.”

https://pubmed.ncbi.nlm.nih.gov/39498228/

“Cannabis-based products for medicinal use (CBPMs) and cannabis-based medicines (CBMs) improve the fibromyalgia symptoms.”

https://www.sciencedirect.com/science/article/pii/S2667276624001215?via%3Dihub

Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy

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“Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson’s disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis.

Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc.

Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling.

Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.”

https://pubmed.ncbi.nlm.nih.gov/39487447/

“Cannabinoids have emerged as promising neuroprotective agents given their ability to work as pleiotropic compounds against the multiple events that affect neural cell homeostasis, integrity and survival in conditions of brain damage and neurodegeneration.”

https://behavioralandbrainfunctions.biomedcentral.com/articles/10.1186/s12993-024-00256-9