Author Archives: David Worrell

Transient CB2R modulation durably restricts breast cancer plasticity by stabilizing a luminal like cell identity

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New breast cancer research suggests that brief modulation of cannabinoid receptor 2 (CB2R), including with THC, may have lasting effects on tumor cell behavior. Researchers found reduced self-renewal, invasiveness, and tumor-initiating capacity, along with greater tamoxifen sensitivity and a durable shift toward a more stable luminal-like cell identity.

“Cancer cell plasticity enables therapy resistance and metastasis by allowing transitions between stem-like and differentiated states. Differentiation-based strategies aim to stabilize tumor cell identity, yet pharmacological approaches that induce durable lineage restriction remain limited.

Here, we show that transient modulation of cannabinoid receptor 2 (CB2R) durably restricts breast cancer cell plasticity by stabilizing a luminal-like cell state. Using patient-derived and murine tumor organoids, we demonstrate that brief, low-dose CB2R modulation reduces self-renewal, invasiveness and tumor-initiating capacity, while enhancing tamoxifen sensitivity and limiting the emergence of resistant phenotypes.

These effects persist under pro-dedifferentiation conditions, including TGFβ exposure, stromal co-culture, immune signaling and mechanical stress, and are maintained in vivo following orthotopic transplantation. RNA sequencing reveals a progressive transition from an early plastic state toward a stabilized luminal-like identity, supported by CUT&Tag profiling that uncovers chromatin remodeling associated with this stabilization.

Together, our findings redefine CB2R as a regulator of tumor cell state and establish transient CB2R modulation as a strategy to durably constrain breast cancer plasticity through differentiation-based therapy.”

https://www.nature.com/articles/s42003-026-10837-1

“Low-dose THC keeps breast cancer cells in tumor models from reverting to an aggressive state”

https://medicalxpress.com/news/2026-09-dose-thc-breast-cancer-cells.html

Trimetallic MgO-ZnO-BaO Nanoparticles Catalyzed Biodiesel Production Using Industrially Cultivated Cannabis sativa L. Oil: RSM Optimization and Assessment of Fuel Properties

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Industrial hemp continues to demonstrate value far beyond traditional agricultural uses. In this study, researchers combined hemp seed oil with a trimetallic nanoparticle catalyst and process optimization technology to produce biodiesel at a 92% yield, with fuel characteristics comparable to established ASTM standards—highlighting Cannabis sativa as a potential renewable feedstock for advanced biofuel production.

“Biodiesel synthesis by utilizing nonedible species of oil-bearing seeds is a viable, eco-friendly, and pragmatic approach to combating fossil fuel shortages and environmental pollution.

Therefore, in the present research work, hemp oil was extracted in good yield (29.9%) utilizing industrial hemp ( Cannabis sativa L.) seeds cultivated in a greenhouse at PCSIR-Lahore, Pakistan, using hydroponic technology (Crop 2022).

For maximum biodiesel production, a ternary metal (MgO-ZnO-BaO NPs) nanocatalyst was designed and thoroughly characterized by PXRD, SEM, EDX, and FTIR analysis. Afterward, the nanocatalyst-assisted transesterification of hemp oil was carried out. The transesterification reaction of hemp oil was optimized by response surface methodology based on central composite design (CCD-RSM). A quadratic polynomial equation was employed to predict the optimal yields, while analysis of variance (ANOVA) identified the statistically significant factors influencing the process.

The maximum yield of biodiesel (92%) was obtained by adjusting the methanol to hemp oil molar ratio (6:1), temperature at 65°C, MgO-ZnO-BaO NPs dosage of 2.5 g, and a reaction time of 3 h with a constant stirring rate of 750 rpm. The hemp-oil-based biodiesel was characterized by FTIR and GC-MS analysis. Fuel characteristics of biodiesel were determined according to ASTM D 6751, which were comparable to literature and ASTM standards.

The findings of this comprehensive study proved the credibility of hemp seed oil as a feasible nonfood, nonconventional feedstock for producing high-quality biodiesel.”

https://pubmed.ncbi.nlm.nih.gov/40739776

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jemt.70051

Benefits of cannabis in treating lower urinary tract symptoms: A scoping review

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Cannabis-based therapies may offer another approach to managing lower urinary tract symptoms such as urinary urgency, frequency, and incontinence. A 2026 scoping review found encouraging evidence that THC, CBD, and combined cannabinoid formulations can improve several urinary symptoms and quality-of-life measures, with the most consistent evidence found among patients with multiple sclerosis.

“Introduction: Anticholinergics and β3-agonists remain the mainstay for bladder dysfunction but are limited by side effects and poor adherence. Cannabinoids are a potential alternative given receptor distribution in bladder control pathways. Early studies suggested that cannabis may demonstrate benefits in overactive bladder (OAB) and lower urinary tract symptoms (LUTS), but findings are limited by small sample sizes and cross-sectionality. This review investigates the therapeutic utility of cannabis and its impact on LUTS.

Methods: This scoping review was conducted following Cochrane and PRISMA guidelines. Eligible studies included adults with OAB symptoms due to neurogenic disease, benign prostatic hyperplasia (BPH), or cystitis, treated with cannabis vs. placebo, no treatment, or active therapies. Outcomes included urinary function and quality of life. Databases searched included MEDLINE, EMBASE, and CENTRAL. Non-English studies were excluded.

Results: From 998 abstracts, 31 full-text articles were reviewed and 12 were included. Studies showed consistent evidence on the effectiveness of cannabis-based therapies for managing LUTS, particularly in patients with multiple sclerosis (MS). Cannabis interventions, including THC, CBD, and combined formulations, showed some improvements in incontinence episodes, frequency, and quality-of-life measures. Mild adverse effects, including dizziness and dry mouth, were common (2-18%) and sometimes led to treatment discontinuation. Nine of 12 studies were done on MS populations, and only three studies were randomized controlled trials.

Conclusions: Evidence for the benefits of cannabis in treating LUTS is limited and largely observational. While preliminary findings are encouraging, randomized trials focusing on patient-centered outcomes are needed to clarify its role in clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/42678682

https://cuaj.ca/index.php/journal/article/view/9478

Effects of delta-9 tetrahydrocannabinol and cannabidiol on cognitive outcomes following acute use of cannabis for chronic pain

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In a study of 183 adults using edible cannabis for chronic low back pain, researchers found no significant acute changes in executive function, episodic memory, or processing speed after cannabis use. Participants using CBD-dominant products performed better on working memory than those using CBD + THC one hour after use, while the CBD group also showed more stable verbal-learning scores than participants using THC or mixed CBD/THC products. The findings add useful evidence to the discussion of how different cannabinoid profiles may affect cognition when cannabis is used for chronic pain.

“Rationale: An estimated two-thirds of medical cannabis users in the United States are motivated by chronic pain, but clinical guidance remains guarded as to whether the potential benefit of cannabinoids for pain outweighs potential risks, such as effects on cognition.

Objectives: In a study where participants experienced benefits of cannabinoids for pain and tension, we evaluated cannabis effects on executive function, processing speed, memory, and verbal learning following acute use for chronic, non-specific low back pain.

Methods: Participants were in one of three self-selected edible cannabis groups: a) CBD-dominant, b) THC-dominant, or c) a mixed ratio of CBD to THC and completed a battery of cognitive tasks at pre-use, 1 h post-use use, and 2 h post-use.

Results: Among 183 participants (56.8% female; Mage = 45.6), those in the group using CBD outperformed participants using CBD + THC 1 h post use in working memory and produced more stable scores in verbal learning after use than participants using THC or CBD + THC. Additionally, while older age was associated with better working memory in the CBD group before use, that relationship was progressively attenuated over the subsequent timepoints. There were no significant effects of cannabis use on cognition in the domains of executive function, episodic memory, or processing speed.

Conclusions: Given the ubiquity of cannabis use for chronic pain and the ongoing call for more data, this study is relevant for informing clinical guidance on whether, and how, cannabis could be used in this context. In particular, understanding the acute impact on cognition from cannabis is critical, as cognitive functioning directly affects patients’ daily lives and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/42678518

“In summary, these findings support CBD’s potential to preserve cognitive performance in the context of chronic pain, contrasting with the more variable effects of THC across cognitive domains. The observed influence of age, particularly among those using CBD, suggests that both cannabinoid composition and individual factors shape cognitive outcomes following acute cannabinoid use.”

https://link.springer.com/article/10.1007/s00213-026-07157-x

Cannabidiolic acid causes a defect in tail retraction of migrating MDA-MB-231 cells: possible involvements of Rho-associated protein kinases inhibition and accumulation of vinculin at the rear of migrating cells

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A new study adds mechanistic detail to earlier evidence that cannabidiolic acid (CBDA) can interfere with the migration of highly aggressive MDA-MB-231 breast cancer cells. Researchers found that CBDA inhibited Rho-associated kinases (ROCKs), impaired tail retraction, altered cell shape and caused vinculin to accumulate at the trailing edge—revealing another way this cannabis-derived compound may disrupt cellular behavior involved in cancer spread.

“We previously reported that cannabidiolic acid (CBDA), a major cannabinoid constituent of the fiber-type cannabis plant, abrogates the migration of highly aggressive human breast cancer MDA-MB-231 cells and activates the small GTPase RhoA by inhibiting protein kinase A. However, the mechanism(s) mediating RhoA signaling, which decreases cell migration, have not yet been comprehensively elucidated.

RhoA is an upstream mediator of Rho-associated kinases (ROCKs), diaphanous-related formins (DIAPHs), the RhoA-ROCK pathway (tail retraction) and the RhoA-DIAPH pathway (lamellipodia formation).

Herein, we identified CBDA as an inhibitor of ROCKs (at approximately 25 μM), which markedly elongated the cell body of MDA-MB-231 cells, similar to Y-27632, an established ROCK inhibitor.

CBDA stimulated lamellipodia formation at the leading edge, whereas NSC23766 (an established Rac1 inhibitor) completely blocked this elongated morphology. Biochemical analyses, including time-lapse imaging and confocal laser scanning microscopy, revealed that, compared to Y-27632, CBDA can induce impaired tail retraction coupled with unidirectional elongation of the cell body, upregulate the mRNA expression of DIAPHs and accumulate vinculin, an adhesion protein, at the trailing edge without affecting its expression.

These results indicate the potential of CBDA as a new candidate for the synthesis of ROCK inhibitors, which can evoke the directed elongation of MDA-MB-231 cells.”

https://pubmed.ncbi.nlm.nih.gov/42186359

https://academic.oup.com/jb/article-abstract/180/2/143/8693860?redirectedFrom=fulltext

The role of cannabidiol treatment in reducing HER2 expression and inducing ER stress-mediated apoptosis in HER2-positive breast cancer

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Researchers examining cannabidiol (CBD) in HER2-positive breast cancer cells found that CBD significantly reduced HER2 gene expression while activating endoplasmic reticulum (ER) stress pathways, decreasing cell viability, and increasing apoptosis. The findings identify another potential molecular mechanism behind CBD’s previously observed anticancer activity in breast cancer and suggest that CBD warrants further investigation both alone and in combination with HER2-targeted therapy.

“Cannabidiol (CBD) has attracted attention as a potential anticancer agent due to its observed efficacy, particularly in breast cancer. However, the exact molecular pathway through which it exerts its anticancer effects remains unknown. The present study aimed to investigate the effects of CBD on the HER2 receptor, endoplasmic reticulum (ER) stress signaling pathway, and apoptosis in HER2-positive breast cancer cells, as well as to examine the effect of trastuzumab (TZB), used in treatment, on the ER stress signaling pathway.

Methods

For this purpose, SKBR3 cells were treated with CBD at three different concentrations (9.38, 18.75, and 37.5 µM), TZB at 62.5 µg/mL, and two combinations of TZB and CBD (18.75 µM CBD + 62.5 µg/mL TZB and 37.5 µM CBD + 62.5 µg/mL TZB). Cell proliferation was assessed using real-time cell analysis, while expression levels of ER stress-associated genes were measured by qPCR. Apoptosis was analyzed by Annexin V/PI flow cytometry.

Results

Findings revealed that CBD, TZB, or their combination were associated with reduced cell proliferation, significant activation of ER stress pathways, and increased apoptosis, while CBD was associated with marked downregulation of HER2 gene expression. Treatment with 9.38 µM CBD, 18.75 µM CBD, 37.5 µM CBD, 62.5 µg/mL TZB, 18.75 µM CBD + 62.5 µg/mL TZB, and 37.5 µM CBD + 62.5 µg/mL TZB significantly increased GRP78, PERK, IRE1, ATF6, eIF2A, ATF4, CHOP, and XBP1s gene expression levels, and significantly decreased HER2 gene expression at all doses except 62.5 µg/mL TZB. All doses significantly increased the total number of apoptotic cells and were associated with significantly reduced cell viability.

Conclusions

The present findings demonstrated that both TZB and CBD are associated with activation of the ER stress response and induction of apoptosis in HER2-positive breast cancer cells, and that CBD is associated with downregulation of HER2 receptor gene expression. Collectively, our results indicate that CBD may have potential as an adjunct or alternative strategy in HER2-positive breast cancer, although further in vivo studies are required to evaluate the efficacy and safety of its combination with low-dose TZB.”

https://link.springer.com/article/10.1186/s12906-026-05523-y

Next-generation hybrid nanosystems for cannabidiol: From molecular challenges to site-specific preclinical applications

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CBD’s therapeutic potential is constrained by a fundamental delivery problem: it dissolves poorly in water, undergoes extensive first-pass metabolism, and typically has low oral bioavailability. Researchers are now developing hybrid nanosystems designed to protect CBD, improve its stability and absorption, control its release, and potentially deliver it directly to specific sites in the body.

“Cannabidiol (CBD) is a monoterpene phenolic compound extracted mainly from Cannabis sativa, which is produced in high amounts compared to other plants. The compound is regarded as a promising therapeutic agent with anti-inflammatory, analgesic, and neuroprotective effects for biomedical use. Furthermore, important advances have been obtained in dermatological and anticancer effects.

Nowadays, the major challenges to the development of new medicine based on CBD arise from its unfavorable physicochemical properties that include reduced solubility in aqueous media (∼0.01 mg/mL), significant degradation due to first-pass metabolism, very low oral bioavailability (typically 6-20%), and an adverse pharmacokinetic profile. Seeking to overcome these disadvantages, recent studies have focused on employing delivery systems, including liposomes, polymeric nanoplatforms, and inorganic nanoparticles, which have attracted considerable attention for their excellent biocompatibility, high encapsulation capacity, and controlled-release properties.

Although conventional single-nanoplatforms offer advantages such as a large number of potential applications, they also have serious drawbacks, including burst drug release and short-term instability. Therefore, with respect to systems that will possess improved properties, hybrid nanoparticle systems have emerged as a second-generation class of systems capable of encapsulating CBD and potentially providing characteristics not available from single-nanoparticle systems. These include higher load efficiencies and stability, controlled and targeted delivery profiles, lower levels of premature drug release and greater enhancement of bioavailability. They are further able to provide site-specific delivery (i.e., transdermal, oral, or CNS-targeted).

The aim of this review is to provide readers with a simple summary of the most recent information found within the literature concerning CBD-loaded hybrid nanoparticle systems. It also discusses current preclinical evidence, translational challenges, and future perspectives for the clinical development of these systems.”

https://pubmed.ncbi.nlm.nih.gov/42659806

“Cannabidiol (CBD) constitutes one of the most promising therapeutic agents against different human diseases, mainly related to pathological conditions related to chronic inflammation, oxidative stress, and neurological dysregulation and degeneration, with relevant clinical results in epilepsy, autism, and pain management.”

“In summary, hybrid nanosystems have tremendous potential to transition cannabidiol delivery from traditional formulations to functional therapeutic platforms that deliver controlled release at the desired site of action while enhancing therapeutic performance.”

https://www.sciencedirect.com/science/article/pii/S0753332226009133?via%3Dihub

Cannabinoid efficacy for pain: dose, chronicity and route

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Cannabinoid pain relief depends on more than whether THC or CBD is used. Dose, route of administration, treatment duration and the type of pain can all influence whether a cannabis-based therapy provides meaningful analgesia or produces unwanted effects. This review examines those variables across preclinical and clinical research, while also considering the independent and combined roles of cannabis-derived terpenes.

“Cannabis-based therapies are widely used for chronic pain, yet their mechanisms and therapeutic windows remain incompletely defined. This review synthesizes preclinical and clinical evidence on how dose, route of administration, treatment duration, and chemical composition shape analgesic efficacy and adverse-effect liability for Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and select cannabis-derived terpenes.

Across rodent pain models, acute THC reliably produces antinociception, but its therapeutic window is narrow because analgesic doses overlap with CB1 receptor-mediated side effects such as sedation, hypothermia, hyperphagia, and motor impairment. Repeated THC exposure leads to tolerance and dependence.

In contrast, CBD shows limited acute efficacy in naïve and inflammatory models but demonstrates more consistent benefit with repeated dosing in neuropathic and chemotherapy-induced pain, often without cannabimimetic adverse effects.

Terpenes such as linalool, β-caryophyllene, myrcene, limonene, α-terpineol, and α-bisabolol exhibit independent antinociceptive and anti-inflammatory properties and are thought to pharmacologically interact with cannabinoids in a dose-, ratio-, and route-dependent “entourage” effect that either enhance or constrain therapeutic benefit.

This review also focuses on integrating machine learning-based behavioral phenotyping of rodents to refine cannabinoid analgesia preclinical research. Computer vision pose-estimation and unsupervised clustering approaches enable high-resolution quantification of spontaneous and evoked natural behaviors, allowing the analytical dissociation of true analgesia from sedation, ataxia, or reduced exploration. By coupling these behavioral pipelines with pharmacokinetic and circuit-level analyses, emerging frameworks will define therapeutic windows with greater precision and improve the translational relevance of cannabinoid-based pain therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/42661783

“Cannabinoid-based therapeutics are among the most widely used treatments for pain indications, with nearly one-third of adults with chronic pain using Cannabis for pain management.”

“Taken together, the studies reviewed here demonstrate that the analgesic efficacy of THC, CBD, and Cannabis-derived terepenes is dependent on dose, route of administration, treatment chronicity, and chemical composition.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2026.1888863/full

Brain cannabinoid CB1 receptor signaling modulates reward responses and inhibitory control in humans

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Researchers using PET and fMRI brain imaging found that natural differences in cannabinoid CB1 receptor availability are associated with how strongly the brain responds to anticipated food rewards and how it engages inhibitory-control systems. The findings provide new human evidence connecting the endocannabinoid system with appetite-related behavior and suggest CB1 signaling as a potential therapeutic target for eating disorders and appetite regulation.

“The central endocannabinoid system, particularly the in vivo cannabinoid type 1 (CB1) receptor signaling, presents a promising target for treating eating disorders. However, its precise role in appetite control remains unclear.

This study aimed to determine how CB1 receptor signaling contributes to key aspects of appetite regulation, specifically anticipatory food reward responses and inhibitory control.

Forty-one healthy male participants underwent [18F]FMPEP-d2 positron emission tomography (PET) to quantify CB1 receptor availability. Functional magnetic resonance imaging (fMRI) was used to assess anticipatory neural responses to food cues, while inhibitory control was measured using a go/nogo task.

Data show that individuals with higher CB1 receptor availability exhibited stronger anticipatory reward-related neural responses and reduced activation during inhibitory control. Therefore, CB1 receptor signaling plays a distinct role in modulating reward and inhibitory processes related to feeding behavior.

The findings suggest that the CB1 receptor may serve as a therapeutic target for regulating appetite.”

https://pubmed.ncbi.nlm.nih.gov/42662580

“Brain cannabinoid CB1 receptor availability modulates reward responses and inhibitory control, key neural mechanisms involved in appetite regulation. The findings suggest that individuals with elevated CB1 receptor availability may require increased engagement of inhibitory control mechanisms to counteract reward-driven responses triggered by external cues, as opposed to enhanced internal satiety signals.

These insights have potential implications for developing therapeutic strategies targeting the endogenous cannabinoid system to address obesity epidemic.”

https://direct.mit.edu/imag/article/doi/10.1162/IMAG.a.1344/138067/Brain-cannabinoid-CB1-receptor-signaling-modulates

Quality by Design-Driven Formulation Development of Cannabidiol Orally Disintegrating Tablets

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Orally disintegrating tablets may offer a more convenient way to deliver cannabidiol, particularly for people who have difficulty swallowing conventional pills. In this study, researchers used a Quality by Design approach to optimize a CBD tablet formulation for rapid disintegration, dose consistency, and reliable pharmaceutical performance.

“The development of cannabidiol (CBD) orally disintegrating tablets (ODTs) is effective in treating anxiety in a patient-friendly manner. The application of Quality by Design (QbD) enhances the efficiency and robustness of the pharmaceutical development of CBD ODTs.

The objective of this work was to develop a formulation for CBD ODTs using a QbD-driven approach. Quality target product profile, critical quality attributes, and an initial risk assessment were identified and evaluated. Subsequently, a Box-Behnken design was employed to analyze the effects of varied compression force, the quantity of microcrystalline cellulose, and the quantity of croscarmellose sodium to create a design space and control space.

Results indicated that the design and control spaces produced tablets with hardness ranging from 4 to 6 kg-force, a disintegration time (DT) ≤ 30 s, and a friability ≤ 1%. All formulations contained 4% CBD (or 10 mg per tablet). The optimal formulation consisted of 35% microcrystalline cellulose and 1% croscarmellose sodium and was compressed at 1400 pounds per square inch.

This formulation exhibited a hardness of approximately 5 kg-force, a DT of 13-15 s, and a friability of approximately 0.3%. Verification data confirmed the accuracy of the predictions made by computer software. The content uniformity and assay determined using validated high-performance liquid chromatography ranged between 90% and 100%. CBD was released from the CBD ODT in 1% sodium lauryl sulfate solution, with approximately 76% dissolved within 3 h in the dissolution study.

In conclusion, the QbD-driven approach successfully facilitated the formulation development of CBD ODTs with the desired properties for the treatment of anxiety in a patient-friendly manner.”

https://pubmed.ncbi.nlm.nih.gov/42662497

“The present study demonstrates the successful development of CBD ODTs using the QbD approach, which has proven effective in enhancing both the efficiency and robustness of the formulation process.

Overall, this study demonstrates the successful implementation of a QbD-driven strategy for laboratory-scale formulation development and optimization of CBD ODTs.

The findings contribute to pharmaceutical development efforts involving cannabinoid-based formulations and may provide useful guidance for future studies related to scale-up, stability evaluation, and in vivo performance.

https://onlinelibrary.wiley.com/doi/10.1155/sci5/3553253