Genotoxic assessment of a Cannabis sativa L. extract

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“Context: As a naturally occurring terpenoid found in Cannabis sativa L. (Cannabaceae), cannabidiol (CBD) has gained public and industry interest for the purposes of personal well-being as a foodstuff and pharmaceutical. Despite a number of publications on CBD toxicology, many have significant limitations, especially those relating to genotoxicity. These include poor characterization of the CBD extract and/or lack rigor in conforming to accepted regulatory guidelines and best practice. A number of regulatory agencies have highlighted these issues and requested additional genotoxicity data to help ensure the safe use of CBD.

Objective: To provide insights into the genotoxicity of a CBD isolate and its lipid carrier.

Materials and methods: We have conducted an in vitro mammalian cell micronucleus (OECD 487) and a bacterial reverse mutagenicity assay (Ames test) (OECD 471) in a CBD isolate (97% > CBD) with its carrier.

Results: The samples tested were non-mutagenic, as determined in the Ames test. The in vitro micronucleus assay conducted was negative for genotoxicity, with no statistically significant increases in the incidences of micronucleated cells observed at any dose compared to negative controls.

Conclusions: These studies confirm that this CBD rich isolate in combination with its carrier, are unlikely to post any genotoxic hazard at exposure levels expected in foods.”

https://pubmed.ncbi.nlm.nih.gov/40326262/

“In summary, the potential genotoxicity of the CBD test substance was assessed using a mammalian cell micronucleus test and Ames test. These tests respectively assess chromosomal damage and base changes, or frameshift mutations in the genome. Application of these assays to the CBD test substance did not produce any evidence of genotoxic effects, findings that are consistent with other studies.”

https://www.tandfonline.com/doi/full/10.1080/13880209.2025.2499075

Cannabis use is associated with less peripheral inflammation but similar insulin sensitivity as non-use in healthy adults

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“Objective: This study tested whether cannabis affects inflammation and insulin sensitivity and if this varied based on THC:CBD ratios. Participants who currently used cannabis were assigned to use one of three cannabis flower products ad libitum for four weeks and compared to non-using participants.

Methods: Healthy participants 21 to 40 years old without diabetes were included. Participants had to engage in ≥ weekly cannabis use for ≥ one year (cannabis use groups) or no cannabis use in the past year (cannabis non-use group). Participants who used cannabis purchased and used a THC-dominant (23% THC, 0% CBD), THC+CBD (10% THC, 8% CBD), or CBD-dominant product (20% CBD, 1% THC). Peripheral inflammation was assessed with several cytokines (TNF-α, IL-1β, IL-4, IL-6, IL-12, IFNG, IL10) and one chemokine (MCP-1). Insulin sensitivity was assessed via the Matsuda Index.

Results: Models were intent-to-treat and utilized maximum likelihood estimation. Cannabis use was associated with lower peripheral inflammation (p<.001) than non-use. THC:CBD ratio of products used over four weeks did not change peripheral inflammation levels nor affect insulin sensitivity compared to non-use.

Conclusions: Habitual cannabis use (vs. non-use) is associated with lower peripheral inflammation with no difference in insulin sensitivity in metabolically healthy, young people.”

https://pubmed.ncbi.nlm.nih.gov/40324550/

https://www.amjmed.com/article/S0002-9343(25)00281-5/abstract

Cannabis use is associated with a lower likelihood of presence of HIV drug resistance mutations in a retrospective cohort of adults with HIV

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“Objectives: A significant clinical concern in the era of Pre-Exposure Prophylaxis (PrEP) is the increased incidence of HIV Anti-Retroviral Drug Resistance Mutations (ARV-DRM). Previous research has indicated that there is an association between substance use and failed viral suppression, which can lead to ARV-DRM. The goal of this retrospective study was to investigate whether substance use as determined by at least one positive urinalysis screen is associated with increased/decreased odds of having a ARV-DRM.

Methods: This study used firth logistic regression analyses of data retrieved from the National NeuroAIDS Tissue Consortium Data Coordinating Center to examine the relationship between substance use and ARV-DRM. The dataset analyzed 614 participants with the following criteria: HIV+ status, at least one paired plasma and cerebrospinal fluid (CSF) viral load measurement, at least one urinalysis of substance use, at least 18 years of age, and analysis of DRM in CSF/Plasma.

Results: Cannabis use was a significant predictor of ARV-DRM and was associated with a lower odds of having ARV-DRM (odds ratio=0.189), after accounting for demographic variables and the interaction between polysubstance use and cannabis use. A significant negative relationship was observed between a cannabis positive test and high viremia (>1,000 copies/mL) but not between a cannabis positive test and CSF Escape (viral load CSF>viral load plasma).

Conclusions: The above results may suggest an immunomodulatory role for cannabis that impacts the propensity for ARV-DRM. These findings could incentivize future research to further investigate effects of cannabis use on the development of HIV ARV-DRM.”

https://pubmed.ncbi.nlm.nih.gov/40313366/

“We have found that cannabis use is significantly associated with a decreased likelihood of HIV ARV-DRM and suggest that cannabis use may be a protective factor against the development of anti-retroviral drug resistance mutations. “

https://www.degruyterbrill.com/document/doi/10.1515/nipt-2024-0010/html

Cannabidiol potentiates p53-driven autophagic cell death in non-small cell lung cancer following DNA damage: a novel synergistic approach beyond canonical pathways

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“The search for more effective and safer cancer therapies has led to an increasing interest in combination treatments that use well-established agents.

Here we explore the potential of cannabidiol (CBD), a compound derived from cannabis, to enhance the anticancer effects of etoposide in non-small cell lung cancer (NSCLC). Although CBD is primarily used to manage childhood epilepsy, its broader therapeutic applications are being actively investigated, particularly in oncology.

Our results revealed that, among various tested chemotherapeutic drugs, etoposide showed the most significant reduction in NSCLC cell viability when combined with CBD.

To understand this synergistic effect, we conducted extensive transcriptomic and proteomic profiling, which showed that the combination of CBD and etoposide upregulated genes associated with autophagic cell death while downregulating key oncogenes known to drive tumor progression. This dual effect on cell death and oncogene suppression was mediated by inactivation of the PI3K-AKT-mTOR signaling pathway, a crucial regulator of cell growth and survival, and was found to be dependent on the p53 status.

Interestingly, our analysis revealed that this combination therapy did not rely on traditional cannabinoid receptors or transient receptor potential cation channels, indicating that CBD exerts its anticancer effects through novel, noncanonical mechanisms.

The findings suggest that the combination of CBD with etoposide could represent a groundbreaking approach to NSCLC treatment, particularly in cases where conventional therapies fail. By inducing autophagic cell death and inhibiting oncogenic pathways, this therapeutic strategy offers a promising new avenue for enhancing treatment efficacy in NSCLC, especially in tumors with p53 function.”

https://pubmed.ncbi.nlm.nih.gov/40307570/

“In conclusion, the combination of CBD and etoposide presents a compelling therapeutic strategy for NSCLC, leveraging mechanisms of autophagy, apoptosis and oncogene suppression. These findings not only provide a strong rationale for further exploration in preclinical and clinical settings but also suggest the potential to address key challenges in NSCLC treatment, such as drug resistance and the limitations of existing therapies. Furthermore, this combination therapy holds particular promise for patients with p53 mutations or those who have developed resistance to EGFR inhibitors (for example, osimertinib) or ALK-targeted drugs (for example, alectinib), providing a promising alternative approach for improving the outcomes of patients with NSCLC.”

https://www.nature.com/articles/s12276-025-01444-x

“Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple.”

“Cannabidiol (CBD) is a cannabinoid found in the Cannabis sativa plant.”

Cost-Effectiveness of Medical Cannabis Versus Opioids for Chronic Noncancer Pain

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“Background: Chronic noncancer pain (CNCP) affects one in five adults and is commonly managed with long-term opioid therapy. Concerns regarding rare but catastrophic harms associated with opioids, including overdose and death, have generated interest in alternatives including cannabis; however, the comparative cost-effectiveness of these management options is uncertain. 

Methods: We used findings from a network meta-analysis of 90 randomized trials to develop a 1-year microsimulation model to compare costs and quality-adjusted life years (QALY) between oral medical cannabis and opioids for CNCP. We used a publicly funded health care payer perspective for our analyses and obtained cost and utility data from publicly available sources. All costs are reported in 2023 Canadian dollars. All analyses were probabilistic, and we conducted sensitivity and scenario analyses to assess robustness. 

Results: Total mean annual cost per patient was $1,980 for oral medical cannabis and $1,851 for opioids, a difference of $129 (95% confidence interval [CI]: -$723 to $525). Mean QALYs were 0.582 for both oral medical cannabis and opioids (95% CI: -0.007 to 0.015). Cost-effectiveness acceptability curves showed that oral medical cannabis was cost-effective in 31% of iterations at willingness-to-pay thresholds up to $50,000/QALY gained.

Use of opioids is associated with nonfatal and fatal overdose, whereas medical cannabis is not. 

Discussion: Our findings suggest that medical cannabis as an alternative to opioids for chronic pain may confer similar, but modest, benefits to patients, and reduce the risk of opioid overdose without substantially increasing costs.”

https://pubmed.ncbi.nlm.nih.gov/40304409/

https://www.liebertpub.com/doi/10.1089/can.2024.0120

Adjunctive use of cannabidiol in pediatric drug-resistant epilepsy: A retrospective multicenter analysis

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“Background: Epilepsy affects approximately 70 million people globally, with one-third experiencing drug-resistant epilepsy (DRE). Cannabidiol (CBD) has shown promise in reducing seizure frequency for specific epilepsy syndromes, though data for broader etiologies remain limited. The goal of the study is to evaluate the effectiveness of CBD as an adjunct treatment in the reduction of seizure frequency in DRE patients of various etiologies.

Methods: We conducted a retrospective chart review of patients with refractory epilepsy who received a CBD as an adjunct treatment at two tertiary care centers. Seizure frequency at the start of CBD treatment and at a minimum follow-up of 3 months was recorded. Epilepsy diagnosis was categorized into five groups: Focal/Multifocal Epilepsy, Primary Generalized Epilepsy, Lennox-Gastaut Syndrome, Dravet Syndrome, and Other Developmental and Epileptic Encephalopathies.

Results: Among all patients, 49 % achieved a ≤ 25 % reduction in seizures, while 5 % had a 26-50 % reduction, 21 % reached a 51-75 % reduction, 20 % experienced a 76-99 % reduction, and 5 % achieved near seizure freedom. There was a significant reduction in median seizure frequency from 30 at baseline to 8 post-treatment (p = 0.000). Significant reductions in seizure frequency were also observed within each diagnostic category.

Discussion: CBD has proven to be an effective adjunctive treatment for medically refractory epilepsy, showing significant efficacy across various epilepsy etiologies and genetic backgrounds. Its ability to reduce seizure frequency and the burden of anti-seizure medications (ASMs), especially in syndromes that are traditionally difficult to manage, highlights its value as an additional therapeutic option.”

https://pubmed.ncbi.nlm.nih.gov/40288063/

https://www.epilepsybehavior.com/article/S1525-5050(25)00165-9/abstract

Cannabidiol in Drug-Resistant Epilepsy (DRE) in Children: A Retrospective Study

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“Objectives: To describe the effectiveness and tolerability of cannabidiol (CBD) in children with drug-resistant epilepsy (DRE).

Methods: Records of children with DRE who received CBD for at least six months were reviewed. Reduction in seizure frequency [complete (> 90%), partial (30-90%), no response (< 30%)], parent reported adverse effects and discontinuation of CBD, if any, were noted.

Results: Records of 50 children with DRE (Lennox-Gastaut syndrome 32, Dravet syndrome 4, and Tuberous sclerosis complex 2), mean (SD) age 7.8 (4.3) years were reviewed. Complete, partial, and no response to CBD was seen in 10, 18 and 14 children; 8 became seizure-free. Eight children discontinued treatment due to lack of efficacy (n = 4), by increased adverse effects (n = 3) and aggravation of seizures (n = 1). Adverse effects were noted in 22 (44%), none required hospitalization.

Conclusion: Cannabidiol is a useful and safe add-on drug in children with DRE.”

https://pubmed.ncbi.nlm.nih.gov/40261499/

https://link.springer.com/article/10.1007/s13312-025-00075-9

Unlocking the Antidiabetic Potential of CBD: In Vivo Preclinical Studies

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“Background/Objectives: Diabetes mellitus is a growing global health concern, driving the exploration of new therapies like cannabidiol (CBD), which shows potential in improving insulin sensitivity and glycemic control, though its effects on glucose metabolism remain unclear. This study evaluates CBD’s dose-dependent effects on glycemia, insulin, and hepatic carbohydrate metabolism in diabetic rats. 

Methods: The Oral Glucose Tolerance Test (OGTT) was performed in healthy rats to compare intragastric vs. intraperitoneal CBD (0.5, 5, 50 mg/kg). Diabetic rats were treated with intragastric CBD (25, 50, 100 mg/kg) or metformin (70 mg/kg) for 8 days. Blood glucose, insulin, lipid profiles, and key carbohydrate-metabolizing enzymes were analyzed. 

Results: In the OGTT, intragastric CBD reduced glycemic AUC, with 50 mg/kg showing the strongest effect, while intraperitoneal CBD had no impact. In diabetic rats, metformin and 25 mg/kg CBD lowered blood glucose, but only CBD increased insulin. The 50 mg/kg dose caused the greatest glucose reduction and moderate insulin rise, while 100 mg/kg had no effect. At 25 mg/kg, CBD inhibited glucose-6-phosphatase and increased glucose-6-phosphate. The 50 mg/kg dose further suppressed gluconeogenic enzymes, reduced glycogen phosphorylase and liver glucose, and enhanced glucose-6-phosphate, showing the strongest metabolic effects. The 100 mg/kg dose increased hexokinase but had weaker metabolic effects. Metformin improved glucose utilization and glycogen storage. CBD at 25 and 50 mg/kg reduced triacylglycerols and increased HDL, while 100 mg/kg had no effect. 

Conclusions: This study provides strong evidence of CBD’s antidiabetic potential, especially at 50 mg/kg, particularly through its modulation of glucose metabolism and tendency to regulate insulin levels.”

https://pubmed.ncbi.nlm.nih.gov/40283884/

https://www.mdpi.com/1424-8247/18/4/446

Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease

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“Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. 

Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including “cannabinoids”, “endocannabinoid system”, “endocannabinoidome”, “inflammatory bowel disease”, and “extraintestinal manifestations” were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. 

Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. 

Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40283915/

“Extraintestinal manifestations of IBD pose a significant and diverse array of clinical challenges, significantly impacting patients’ lives and healthcare utilization. While conventional therapies primarily target gut inflammation, the endocannabinoidome emerges as a promising and versatile target for managing inflammatory, metabolic, and extraintestinal complications of IBD. Preliminary evidence highlights its therapeutic potential, but further research is essential to optimize clinical applications and ensure safety.”

https://www.mdpi.com/1424-8247/18/4/478

The Role of Endocannabinoids in Physiological Processes and Disease Pathology: A Comprehensive Review

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“The endocannabinoid system is a complex communication system involved in maintaining homeostasis in various physiological processes, including metabolism, immune response, pain modulation, and neuroprotection. Endocannabinoids, mainly anandamide and 2-arachidonoylglycerol, are natural ligands of the cannabinoid receptors CB1 and CB2, which are widely distributed throughout the central nervous system and peripheral tissues. Their biosynthesis, degradation, and interaction with other signaling pathways play crucial roles in both health and disease. This article provides a comprehensive overview of the physiological and pathological roles of endocannabinoids, discusses their potential as therapeutic targets, and highlights recent advances in endocannabinoid-based treatments.”

https://pubmed.ncbi.nlm.nih.gov/40283681/

https://www.mdpi.com/2077-0383/14/8/2851

“The endocannabinoid system plays a crucial role in maintaining physiological balance and regulating functions such as pain perception, immune response, metabolism, and neurological processes . Due to the multifaceted biological actions of the components of the ECS, researchers are seeking agonists/antagonists of cannabinoid receptors or other kinds of compounds with potential applications in targeted pharmacotherapy aimed at the endocannabinoid system. Although plant-derived cannabinoids have long been used in medicine, there are increasing attempts to use synthetic compounds as ligands for cannabinoid receptors or modulators of enzymes involved in endocannabinoid metabolism. Rimonabant, a selective CB1 receptor antagonist, was registered in Europe for the treatment of obesity from 2006 to 2008, particularly in patients with type 2 diabetes or metabolic syndrome. However, the European Medicines Agency determined that the risks of using the drug outweighed its benefits due to the serious psychiatric side effects, including depression and suicidal thoughts. Several novel drugs targeting ECS are under investigation. Notable examples include endocannabinoid reuptake inhibitors (eCBRIs) such as SYT-510 (currently under development), which are designed to treat anxiety, mood, and traumatic stress disorders, and AM404, an active metabolite of paracetamol, which inhibits AEA uptake. The other group consists of inhibitors of enzymes degrading AEA (fatty acid amide hydrolase—FAAH) and 2-AG (monoacyloglycerol lipase—MAGL) being explored for their potential in treating anxiety and pain. Drugs that modulate ECS hold promise for a variety of therapeutic applications, including glucose metabolism, obesity, neuroprotection, psychiatric disorders, pain management, and inflammation control, also in the context of chronic diseases. Further studies are needed to fully understand the complexities of this system and develop safe, effective treatments.”