Buds and Bugs: A Fascinating Tale of Gut Microbiota and Cannabis in the Fight against Cancer

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“Emerging research has revealed a complex bidirectional interaction between the gut microbiome and cannabis. Preclinical studies have demonstrated that the gut microbiota can significantly influence the pharmacological effects of cannabinoids.

One notable finding is the ability of the gut microbiota to metabolise cannabinoids, including Δ9-tetrahydrocannabinol (THC). This metabolic transformation can alter the potency and duration of cannabinoid effects, potentially impacting their efficacy in cancer treatment. Additionally, the capacity of gut microbiota to activate cannabinoid receptors through the production of secondary bile acids underscores its role in directly influencing the pharmacological activity of cannabinoids.

While the literature reveals promising avenues for leveraging the gut microbiome-cannabis axis in cancer therapy, several critical considerations must be accounted for. Firstly, the variability in gut microbiota composition among individuals presents a challenge in developing universal treatment strategies. The diversity in gut microbiota may lead to variations in cannabinoid metabolism and treatment responses, emphasising the need for personalised medicine approaches.

The growing interest in understanding how the gut microbiome and cannabis may impact cancer has created a demand for up-to-date, comprehensive reviews to inform researchers and healthcare practitioners. This review provides a timely and invaluable resource by synthesizing the most recent research findings and spotlighting emerging trends. A thorough examination of the literature on the interplay between the gut microbiome and cannabis, specifically focusing on their potential implications for cancer, is presented in this review to devise innovative and effective therapeutic strategies for managing cancer.”

https://pubmed.ncbi.nlm.nih.gov/38255944/

https://www.mdpi.com/1422-0067/25/2/872

Cannabidiol Combination Enhances Photodynamic Therapy Effects on MCF-7 Breast Cancer Cells

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“Cannabis sativa is a well-known plant for its psychoactive effects; however, its many derivatives, such as Cannabidiol (CBD), contain several therapeutic applications. Tetrahydrocannabinol (THC) is the main cannabis derivative responsible for psychoactive properties, while CBD is non-psychotropic. For this reason, CBD has been more exploited in the last decade.

CBD has been connected to multiple anticancer properties, and when combined with photodynamic therapy (PDT), it is possible to eradicate tumors more effectively. In this study, CBD was utilized to treat MCF-7 breast cancer cells, followed by in vitro PDT combination therapy. Conventional breast cancer treatment modalities such as chemotherapy, radiotherapy, etc. have been reported for inducing a number of undesirable side effects, recurrence of the disease, and low quality of life.

In this study, cells were exposed to varying concentrations of CBD (i.e., 1.25, 2.5, 5, 10, and 20 μg/mL) and incubated 12 and 24 h after treatment. The optimal doses were then used in combination therapy. Morphology and biochemical assays, including lactate dehydrogenase (LDH) for membrane integrity, adenosine triphosphate (ATP) for viability, and trypan blue exclusion assay for viability, were used to examine cellular responses after treatments. The optimal concentration was then utilized in Hypericin-Gold nanoparticles mediated PDT combination.

The results revealed that, in a dose-dependent manner, conventional morphological characteristics of cell death, such as vacuolization, blebbing, and floating were observed in treated cells. The biochemical responses demonstrated an increase in LDH, a decrease in ATP, and a reduction in viability. This study demonstrated that CBD induces cell death in MCF-7 breast cancer cells cultured in vitro. The immunofluorescence results of combination therapy indicated that cell death occurred via apoptosis.

In conclusion, this study proposes that the CBD and PDT combination therapy is effective in killing MCF-7 breast cancer cells in vitro by induction of apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/38247877/

https://www.mdpi.com/2073-4409/13/2/187

Current cannabis use and pain management among US cancer patients

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“Background: National studies reporting the prevalence of cannabis use have focused on individuals with a history of cancer without distinction by their treatment status, which can impact symptom burden. While pain is a primary motivation to use cannabis in cancer, the magnitude of its association with cannabis use remains understudied.

Methods: We examined cannabis use and pain management among 5523 respondents of the Behavioral Risk Factor Surveillance System with a cancer history. Survey-weighted prevalence proportions of respondents’ cannabis use are reported, stratified on cancer treatment status. Regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer-related pain and cannabis use.

Results: Cannabis use was slightly more prevalent in those undergoing active treatment relative to those who were not undergoing active treatment (9.3% vs. 6.2%; P=0.05). Those under active treatment were more likely to use cannabis medicinally (71.6% vs. 50.0%; P=0.03). Relative to those without cancer-related pain, persons with pain under medical control (OR 2.1, 95% CI, 1.4-3.2) or uncontrolled pain were twice as likely to use cannabis (OR 2.0, 95% CI, 1.1-3.5).

Conclusions: Use of cannabis among cancer patients may be related to their treatment and is positively associated with cancer-related pain. Future research should investigate the associations of cannabis use, symptom burden, and treatment regimens across the treatment spectrum to facilitate interventions.”

https://pubmed.ncbi.nlm.nih.gov/38236449/

https://link.springer.com/article/10.1007/s00520-024-08321-9

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial

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“Background: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects.

Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.

Methods: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.

Discussion: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.”

https://pubmed.ncbi.nlm.nih.gov/38225549/

“Phytocannabinoids occur naturally in cannabis plants and have been used medicinally for centuries for a variety of purposes . Δ9-tetrahydrocannabinol (THC) is the major psychoactive constituent in cannabis, and cannabidiol (CBD) the major non-psychoactive constituent.

In vivo studies have found that the administration of CBD and THC reduced tumour growth in animal models of glioma.

Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray of a complex botanical mixture containing THC and CBD as the principal cannabinoids, with additional cannabinoid constituents and non-cannabinoid components.”

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11792-4

“Sativex is a standardized medication containing 2.5 mg/actuation CBD and 2.7 mg/ actuation THC.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836266/

Cannabinoids in Treating Chemotherapy-Induced Nausea and Vomiting, Cancer-Associated Pain, and Tumor Growth

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“Cannabis has been used as an herbal remedy for thousands of years, and recent research indicates promising new uses in medicine. So far, some studies have shown cannabinoids to be safe in helping mitigate some cancer-associated complications, including chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor growth.

Researchers have been particularly interested in the potential uses of cannabinoids in treating cancer due to their ability to regulate cancer-related cell cycle pathways, prompting many beneficial effects, such as tumor growth prevention, cell cycle obstruction, and cell death.

Cannabinoids have been found to affect tumors of the brain, prostate, colon and rectum, breast, uterus, cervix, thyroid, skin, pancreas, and lymph. However, the full potential of cannabinoids is yet to be understood.

This review discusses current knowledge on the promising applications of cannabinoids in treating three different side effects of cancer-chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor development.

The findings suggest that cannabinoids can be used to address some side effects of cancer and to limit the growth of tumors, though a lack of supporting clinical trials presents a challenge for use on actual patients. An additional challenge will be examining whether any of the over one hundred naturally occurring cannabinoids or dozens of synthetic compounds also exhibit useful clinical properties.

Currently, clinical trials are underway; however, no regulatory agencies have approved cannabinoid use for any cancer symptoms beyond antinausea.”

https://pubmed.ncbi.nlm.nih.gov/38203245/

https://www.mdpi.com/1422-0067/25/1/74

Cannabinoids in the treatment of cancer anorexia and cachexia: Where have we been, where are we going?

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“Cachexia-anorexia cancer syndrome remains an unmet clinical need with a dearth of treatment and no standard of care.

Acting through the endocannabinoid system, cannabinoids are one potential cancer cachexia treatment.

Herein, the potential mechanisms for cannabinoids for cancer cachexia are discussed as are previous and ongoing clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/38197037/

https://linkinghub.elsevier.com/retrieve/pii/S2347562523001105

Awareness and interest in cannabis use for cancer management among cancer survivors

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“Background: We examined the awareness, interest, and information sources relating to cannabis use for cancer management (including management of cancer symptoms and treatment-related side effects) and determined factors associated with cancer survivors’ awareness and interest in learning about cannabis use for cancer management.

Methods: This was a cross-sectional study of adult cancer survivors (N = 1886) receiving treatment at a comprehensive cancer center. Weighted prevalence and multivariable logistic regression analyses were conducted.

Results: Among cancer survivors, 88% were aware and 60% were interested in learning about cannabis use for cancer management. Common sources of information to learn about cannabis use for cancer management were cancer doctors/nurses (82%), other patients with cancer (27%), websites/blogs (26%), marijuana stores (20%), and family/friends (18%). The odds of being aware of cannabis use for cancer management was lower among male compared to female survivors (adjusted odds ratio [AOR]: 0.61; 95% confidence interval [CI]: 0.41-0.90), non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 0.36; 95% CI: 0.21-0.62), and survivors who do not support the legalization of cannabis for medical use compared to those who do (AOR: 0.10; 95% CI: 0.04-0.23). On the other hand, the odds of being interested in cannabis use for cancer management was higher among non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 1.65; 95% CI: 1.04-2.62), and among cancer survivors actively undergoing cancer treatment compared to patients on non-active treatment (AOR: 2.25; 95% CI: 1.74-2.91).

Conclusion: Awareness of cannabis use for cancer management is high within the cancer survivor population. Results indicated health care providers are leading information source and should receive continued medical education on cannabis-specific guidelines. Similarly, tailored educational interventions are needed to guide survivors on the benefits and risks of cannabis use for cancer management.”

https://pubmed.ncbi.nlm.nih.gov/38180296/

“In conclusion, most cancer survivors are aware of and interested in cannabis use for medical management. “

https://onlinelibrary.wiley.com/doi/10.1002/cam4.6902

Cannabigerolic Acid (CBGA) Inhibits the TRPM7 Ion Channel Through its Kinase Domain

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“Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. Previous work has demonstrated that the main cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) can have some beneficial effects on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. While CBD and THC represent the two major plant cannabinoids, some hemp varieties with enzymatic deficiencies produce mainly cannabigerolic acid (CBGA). We recently reported that CBGA has a potent inhibitory effect on both Store-Operated Calcium Entry (SOCE) via inhibition of Calcium Release-Activated Calcium (CRAC) channels as well as currents carried by the channel-kinase TRPM7. Importantly, CBGA prevented kidney damage and suppressed mRNA expression of inflammatory cytokines through inhibition of these mechanisms in an acute nephropathic mouse model. In the present study, we investigate the most common major and minor cannabinoids to determine their potential efficacy on TRPM7 channel function. We find that approximately half of the tested cannabinoids suppress TRPM7 currents to some degree, with CBGA having the strongest inhibitory effect on TRPM7. We determined that the CBGA-mediated inhibition of TRPM7 requires a functional kinase domain, is sensitized by both intracellular Mg⋅ATP and free Mg2+ and reduced by increases in intracellular Ca2+. Finally, we demonstrate that CBGA inhibits native TRPM7 channels in a B lymphocyte cell line. In conclusion, we demonstrate that CBGA is the most potent cannabinoid in suppressing TRPM7 activity and possesses therapeutic potential for diseases in which TRPM7 is known to play an important role such as cancer, stroke, and kidney disease.”

https://pubmed.ncbi.nlm.nih.gov/38162115/

https://academic.oup.com/function/article/5/1/zqad069/7462310?login=false

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds

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“The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target.

Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2.

Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support.

In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.”

https://pubmed.ncbi.nlm.nih.gov/38136172/

https://www.mdpi.com/2076-3921/12/12/2052

Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells

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“Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB1 receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.”

https://pubmed.ncbi.nlm.nih.gov/38100640/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.1152