Unravelling a novel role for cannabidivarin in the modulation of subventricular zone postnatal neurogenesis

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“Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis.

Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5′-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation.

Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.”

https://pubmed.ncbi.nlm.nih.gov/37802277/

“These findings suggest the potential of CBDV as a novel therapeutic target for neural stem cell repair strategies.”

https://www.sciencedirect.com/science/article/abs/pii/S0014299923005915?via%3Dihub

Cannabidiol Antiproliferative Effect in Triple-Negative Breast Cancer MDA-MB-231 Cells Is Modulated by Its Physical State and by IGF-1

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“Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has been discussed for its safety and efficacy in cancer treatments. For this reason, we have inquired into its use on triple-negative human breast cancer. Analyzing the biological effects of CBD on MDA-MB-231, we have demonstrated that both CBD dosage and serum concentrations in the culture medium influence its outcomes; furthermore, light scattering studies demonstrated that serum impacts the CBD aggregation state by acting as a surfactant agent. Pharmacological studies on CBD in combination with chemotherapeutic agents reveal that CBD possesses a protective action against the cytotoxic effect exerted by cisplatin on MDA-MB-231 grown in standard conditions. Furthermore, in a low serum condition (0.5%), starting from a threshold concentration (5 µM), CBD forms aggregates, exerts cytostatic antiproliferative outcomes, and promotes cell cycle arrest activating autophagy. At doses above the threshold, CBD exerts a highly cytotoxic effect inducing bubbling cell death. Finally, IGF-1 and EGF antagonize the antiproliferative effect of CBD protecting cells from harmful consequences of CBD aggregates. In conclusion, CBD effect is strongly associated with the physical state and concentration that reaches the treated cells, parameters not taken into account in most of the research papers.”

https://pubmed.ncbi.nlm.nih.gov/35806150/

“Among the various biological properties of phytocannabinoids, their ability to induce antiproliferative effects in different human cancer cells raises the scientific interest in their therapeutic potential in the field of oncology.”

https://www.mdpi.com/1422-0067/23/13/7145

Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3 is mediated by apoptotic cell death, NFκB activation, increased oxidative stress, and lower reduced glutathione status

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“Prostate cancer is the second most frequent cancer diagnosed in men in the world today. Almost all prostate cancers are adenocarcinomas and develop from gland cells. We used the PC3 prostate cancer cell line, which is well studied and derived from a bone metastasis of a grade IV prostatic adenocarcinoma.

Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, is a cannabinoid with anti-tumor properties but its effects on prostate cancer cells are not studied in detail.

Here, we found cannabidiol decreased prostate cancer cell (PC3) viability up to 37.25% and induced apoptotic cell death in a time and dose-dependent manner. We found that CBD activated the caspases 3/7 pathways and increased DNA fragmentation. Furthermore, we observed an increase of pro-apoptotic genes Bax, an increased level of reactive oxygen species, lower reduced glutathione level, and altered mitochondrial potential in response to CBD treatment leading to lower cellular ATP.

Overall, our results suggest that CBD may be effective against prostate cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/37796968/

“In summary, we have demonstrated CBD as a potential therapeutic molecule in the treatment of prostate cancer based on its properties of anti-proliferative effect on PC3 cancer cells by promoting intrinsic apoptotic pathway via mitochondrial and NFkB activation followed by intracellular ROS generation and reducing cellular redox status of glutathione.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0286758

Effects of the Acute and Chronic Administration of Cannabidiol on Cognition in Humans and Animals: A Systematic Review

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“Introduction: The effects of cannabidiol (CBD) on cognition has been investigated in recent years to determine the therapeutic potential of this cannabinoid for a broad gamut of medical conditions, including neuropsychiatric disorders. The aim of the present study was to perform a systematic review of studies that analyzed the effects of the acute and chronic administration of CBD on cognition in humans and animals both to assess the cognitive safety of CBD and to determine a beneficial potential of CBD on cognition. 

Methods: The PubMed, Web of Science, PsycINFO, and Scopus databases were searched in December of 2022 for relevant articles using the following combinations of keywords: (“cannabidiol” OR “CBD”) AND (“cognition” OR “processing cognitive” OR “memory” OR “language” OR “attention” OR “executive function” OR “social cognition” OR “perceptual motor ability” OR “processing speed”). 

Results: Fifty-nine articles were included in the present review (36 preclinical and 23 clinical trials). CBD seems not to have any negative effect on cognitive processing in rats. The clinical trials confirmed these findings in humans. One study found that repeated dosing with CBD may improve cognitive in people who use cannabis heavily but not individuals with neuropsychiatric disorders. Considering the context of neuropsychiatric disorders in animal models, CBD seems to reverse the harm caused by the experimental paradigms, such that the performance of these animals becomes similar to that of control animals. 

Conclusions: The results demonstrate that the chronic and acute administration of CBD seems not to impair cognition in humans without neuropsychiatric disorders. In addition, preclinical studies report promising results regarding the effects of CBD on the cognitive processing of animals. Future double-blind, placebo-controlled, randomized clinical trials with larger, less selective samples, with standardized tests, and using different doses of CBD in outpatients are of particular interest to elucidate the cognitive effects of CBD.”

https://pubmed.ncbi.nlm.nih.gov/37792394/

https://www.liebertpub.com/doi/10.1089/can.2023.0086

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality

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“The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as “very poor” or “poor.” The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [-0.96, -0.05], p = .025) and overall sleep disturbance (95% CI [-2.59, -0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue.”

https://pubmed.ncbi.nlm.nih.gov/37796540/

“Cannabinol (CBN), a partial agonist at cannabinoid receptor Type 1 (CB1) that is formed through the oxidation of delta-9-tetrahydrocannabinol (THC), has both alone and in combination with cannabidiol (CBD) garnered increased attention as a potential pharmacological intervention for sleep difficulties.”

https://psycnet.apa.org/fulltext/2024-14146-001.html

Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype

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“Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief.

Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment.

In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.”

https://pubmed.ncbi.nlm.nih.gov/35011388/

“Cannabinoids have been used for centuries in several therapeutic applications. Regarding cancer, the use of cannabinoids has already been approved in several countries for the relief of chemotherapy-associated effects, but their clinical potential is greater than initially thought, and their clinical interest has been rising in recent years. Pre-clinical studies have demonstrated that cannabinoids exert important antitumor properties in the main breast cancer subtypes, particularly in TNBC, where different phytocannabinoids and synthetic cannabinoids have shown interesting therapeutic actions.”

“Thus, it is strongly believed that Cannabis, being an important natural source of many cannabinoids, may be a potential therapeutic option for the treatment or modulation of different physiological processes and, even, pathological conditions, such as cancer.”

https://www.mdpi.com/1420-3049/27/1/156

“Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.”

https://www.sciencedirect.com/science/article/pii/S0305737212001399

Cannabis Use Patterns among Patients with Early-Stage Breast Cancer in a Large Multicenter Cohort from a State with Legalized Adult Non-Medical Cannabis

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“Purpose/objective(s): Cannabis use among patients with cancer is an area of great interest given its widespread acceptance despite the lack of supporting clinical data. The absence of data limits the understanding of potential clinical benefits of cannabis and the ability of providers to deliver evidence-based recommendations for patient care. We explored cannabis use patterns in patients with early-stage breast cancer in a large multicenter cohort in a state with legalized adult non-medical cannabis.

Materials/methods: Initial questions about cannabis use history and frequency were introduced in Michigan Radiation Oncology Quality Consortium (MROQC) breast cancer patient surveys on 2/1/2020 for female patients receiving radiation after lumpectomy for non-metastatic breast cancer. Expanded questions were introduced on 6/28/2022 to assess mode of administration, active ingredient, and reason for use. Summary statistics were generated. A multivariable model using logistic regression identified patient characteristics associated with cannabis use.

Results: Among 3948 eligible patients, 2738 (69.35%) completed survey questions, and 2462/2738 (89.9%) completed the initial question on cannabis use. Among those, 364/2462 (14.8%) noted cannabis use in the last 30 days, 588 (23.9%) noted remote use (>30 days ago), 1462 (59.4%) reported never having used cannabis, 44 (1.8%) preferred not to answer cannabis use questions, and 4 (0.4%) did not provide use history. Younger age [age <50 vs 60-70, OR 2.5 (95% CI 1.65, 3.79) p<0.001)], Hispanic ethnicity [OR 2.20 (95% CI 1.06, 4.56) p = 0.03], history of smoking [OR 2.56 (95% CI 1.88, 3.48) p<0.001], current smoking [OR 4.70 (95% CI 3.22, 6.86) p<0.001)], and prior chemotherapy [OR 1.40 (95% CI 1.00, 1.96) p = 0.05] predicted recent cannabis use in a multivariable model. Of the 364 patients endorsing cannabis use in the last 30 days, 89 (24.5%), 72 (19.8%), 29 (8.0%), 66 (18.1%), 30 (8.2%), and 78 (21.4%) reported using cannabis 1-2 days, 3-5 days, 6-9 days, 10-19 days, 20-29 days, and all 30 days, respectively. The most common modes of administration among 76 individuals who responded to the expanded questionnaire to date were oral (39.4%), smoking (30.3%), and topical (10.5%). The products used contained tetrahydrocannabinol (THC; 26.3%), cannabidiol (CBD; 19.7%), balanced levels of THC and CBD (19.7%), or active ingredients that were unknown to the patient (34.2%). Patients frequently endorsed cannabis use for insomnia, anxiety, and pain.

Conclusion: Many patients with early-stage breast cancer are using cannabis. Younger age, Hispanic ethnicity, smoking, and chemotherapy history are predictors of cannabis use. Patients are often unaware of the active ingredients in the products that they use, suggesting an important role for patient education and a need to equip providers to advise patients in their care.”

https://pubmed.ncbi.nlm.nih.gov/37786222/

https://www.redjournal.org/article/S0360-3016(23)05292-6/fulltext

Stigma-related barriers to medical cannabis as harm reduction for substance use disorder: Obstacles and opportunities for improvement

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“Emerging evidence on substituting cannabis for more harmful drugs has led to cannabis becoming a novel harm-reduction strategy for combating the current drug poisoning crisis. However, the authorization of medical cannabis as part of a harm-reduction approach and recovery strategy has significant implementation barriers rooted in longstanding stigma towards cannabis. Through a multi-discipline collaboration of Canadian clinicians and academic researchers, we highlighted stigma barriers and opportunities to address these barriers to elicit improved delivery of medical cannabis as a harm-reduction therapy within existing therapeutic frameworks. Evidence from existing literature and real-world experiences converged on three key themes related to stigma barriers: (1) Lack of medical cannabis education within the healthcare community, (2) lack of consensus and coordination among harm-reduction services and (3) access to medical cannabis. We highlight potential solutions to these issues, including improved healthcare education, better coordination between care teams and suggestions for improving access. Through this discussion, we hope to contribute to reducing the stigma around using medical cannabis as a harm-reduction strategy for individuals with a substance use disorder and consider new perspectives in policy development surrounding recovery services.”

https://pubmed.ncbi.nlm.nih.gov/37767954/

https://onlinelibrary.wiley.com/doi/10.1111/inm.13231

An Individual’s Lived Experiences of Taking Cannabis-Based Medicinal Products (CBMPs) to Treat Anxiety

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“This report documents the case of a patient (the author) participating in a clinical trial of medical cannabis (Cannabis sativa L.)-the Sapphire Access Scheme, run by the Sapphire Medical Clinic as part of the UK Medical Cannabis Registry-to explore the impacts of cannabis-based medicinal products (CBMPs) on anxiety. For most of my life, I have experienced often very serious bouts of poor mental health arising, in part, from childhood abuse, and have been diagnosed with several mental health conditions which constitute disabilities. I have received various conventional treatments and multiple alternative therapies. However, none of these have enabled me to consistently manage my conditions long-term, and I often suffer relapses. As part of the Sapphire Access Scheme, I complete regular quantitative questionnaires regarding the impacts of the CBMPs on my anxiety and have also obtained the clinic’s permission to qualitatively document and write up the impacts of CBMPs on my mental health. Here, I present a preliminary autoethnographic exploration of my lived experiences of CBMP use over the first four months of the trial, which show that even within such a short space of time, CBMPs have had a positive impact on treating what had previously been treatment-refractive chronic anxiety.”

https://pubmed.ncbi.nlm.nih.gov/37754635/

https://www.mdpi.com/1660-4601/20/18/6776

Cannabidiol attenuates inflammatory impairment of intestinal cells expanding biomaterial-based therapeutic approaches

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“Cannabis-based biomaterials have the potential to deliver anti-inflammatory therapeutics specifically to desired cells, tissues, and organs, enhancing drug delivery and the effectiveness of anti-inflammatory treatment while minimizing toxicity. As a major component of Cannabis, Cannabidiol (CBD) has gained major attention in recent years because of its potential therapeutic properties, e.g., for restoring a disturbed barrier resulting from inflammatory conditions. The aim of this study was to test the hypothesis that CBD has beneficial effects under normal and inflammatory conditions in the established non-transformed intestinal epithelial cell model IPEC-J2. CBD induced a significant increase in transepithelial electrical resistance (TER) values and a decrease in the paracellular permeability of [³H]-D-Mannitol, indicating a strengthening effect on the barrier. Under inflammatory conditions induced by tumor necrosis factor alpha (TNFα), CBD stabilized the TER and mitigated the increase in paracellular permeability. Additionally, CBD prevented the barrier-disrupting effects of TNFα on the distribution and localization of sealing TJ proteins. CBD also affected the expression of TNF receptors. These findings demonstrate the potential of CBD as a component of Cannabis-based biomaterials used in the development of novel therapeutic approaches against inflammatory pathogenesis.”

https://pubmed.ncbi.nlm.nih.gov/37779918/

“Overall, these findings suggest that CBD will be a promising component in biomaterial-based therapeutic approaches for the treatment of inflammatory pathomechanisms.”

https://www.sciencedirect.com/science/article/pii/S2590006423002685?via%3Dihub