Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging

Posted on by
Reply
pubmed logo

“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.

Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.

Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.

Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.

While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40770774/

“Targeting the ECS could be a promising strategy for developing therapies aimed at promoting healthy aging and longevity.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00313-8

Single oral administration of dronabinol increases ocular blood flow in patients with glaucoma

Posted on by
Reply
pubmed logo

“Purpose: Glaucoma is a leading cause of irreversible blindness globally, primarily driven by elevated intraocular pressure (IOP). Still, some patients progress despite significant IOP lowering, potentially due to impaired ocular blood flow. This study aimed to evaluate the effects of dronabinol, a synthetic tetrahydrocannabinol derivative, on ocular blood flow in primary open-angle glaucoma (POAG) patients.

Methods: This randomized, double-masked, placebo-controlled, cross-over study included 23 patients with treated POAG (mean age 68 ± 7 years). All participants received dronabinol (11 patients received 5 mg and 12 received 10 mg in a randomized fashion) on one study day and placebo on the other study day. The primary outcome was optic nerve head blood flow (ONHBF) measured by laser speckle flowgraphy. Mean blur rate was determined for the large vessel area (MV), the tissue area (MT) and the total ONH area (MA). Secondary outcomes included vessel densities assessed by optical coherence tomography angiography, IOP, and blood pressure.

Results: Administration of 10 mg dronabinol significantly increased ONHBF (MA: 10.8 ± 20.6%, p = 0.018, MV: 12.0 ± 24.8%, p = 0.042, and MT: 11.0 ± 22.6%, p = 0.022, each vs. placebo) up to 4 h post-administration without affecting IOP or mean arterial pressure (p > 0.548 each). Additionally, a significant increase in vessel density in the superficial vascular plexus was found after administration of 10 mg dronabinol (6.7 ± 14.7%, p = 0.040 vs. 5 mg).

Conclusion: This pilot study demonstrates that systemic dronabinol enhances ONHBF in glaucoma patients, suggesting its potential as adjunct therapy for glaucoma by targeting vascular dysfunction. Further longitudinal studies are needed to explore its long-term impact on disease progression and visual field preservation.”

https://pubmed.ncbi.nlm.nih.gov/40772417/

“Tetrahydrocannabinol (THC) has long been considered a treatment option for glaucoma, mainly because of its IOP-lowering properties. In addition, THC may also increase ocular blood flow, at least in healthy subjects. Recent data from our laboratory confirm that even low doses of THC, which neither affect IOP nor induce systemic psychoactive side effects, can increase ocular blood flow considerably.”

“In summary, our study demonstrates that administration of 10 mg dronabinol leads to a significant increase in ocular blood flow in patients with glaucoma. The effect seems to be dose-dependent, as a single administration of 5 mg had no effect on ocular blood flow. These findings highlight the potential role of dronabinol in improving ocular perfusion in glaucoma patients but also underscore the importance of considering age and disease-related factors when assessing cannabinoid-mediated vascular effects. Further investigations with larger sample sizes, longer study durations, and multiple applications instead of single intake are warranted to evaluate the potential clinical benefits of this therapeutic approach.”

https://onlinelibrary.wiley.com/doi/10.1111/aos.17573

Cannabidiol Suppresses EMT in Pancreatic Cancer via Inhibition of MALAT1 lncRNA and PI3K/Akt/mTOR Signaling Pathway

Posted on by
Reply
pubmed logo

“Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive metastasis and poor response to chemotherapy, largely driven by epithelial-mesenchymal transition (EMT) and chemokine signaling.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown anticancer potential, yet its mechanisms in EMT regulation remain underexplored in PDAC.

In this study, we demonstrate that CBD significantly suppresses the expression of CXCR4/CXCR7 and matrix metalloproteinases (MMP-2/9), leading to reduced migration and invasion of MIA PaCa-2, PANC-1, and AsPC-1 cells. Moreover, CBD reversed CXCL12-induced EMT by downregulating mesenchymal markers and restoring epithelial markers. Mechanistically, CBD inhibited the expression of the long non-coding RNA MALAT1, a known EMT regulator, and antagonized its pro-invasive effects. Overexpression of MALAT1 activated the PI3K/Akt/mTOR pathway and enhanced EMT-related protein expression, all of which were effectively reversed by CBD. Furthermore, the combination of CBD and gemcitabine exhibited synergistic inhibition of MALAT1, EMT markers, and PI3K/Akt/mTOR signaling without inducing cytotoxicity, suggesting a therapeutic advantage.

Collectively, these findings reveal a novel mechanism through which CBD impedes PDAC metastasis and underscore its promise as a complementary agent in chemotherapy regimens.”

https://pubmed.ncbi.nlm.nih.gov/40767250/

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has garnered considerable interest in oncology for its anti-inflammatory, pro-apoptotic, and anti-metastatic properties.”

“CBD has garnered increasing interest in oncology due to its multifaceted anticancer properties.”

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/iub.70042

Neural Signatures of Cannabis Use: Reversing Cognitive Aging via Whole-Brain Functional Network Connectivity

Posted on by
Reply
pubmed logo

“Given the growing trend toward permissive societal attitudes and the legalization of cannabis, coupled with an increasing recognition of its therapeutic potential, there has been a notable rise in cannabis consumption among older adults.

Cognitive aging, one of the most prevalent concerns in this demographic, intersects with cannabis use, which shares several neural correlates. However, the precise impact of cannabis on the aging brain and cognitive function remains poorly understood.

In this study, we leveraged large-scale data from the UK Biobank, which includes over 25,000 participants, to conduct a comprehensive examination of the relationships between cannabis use, normative aging, and cognitive function. Our focus was on how these factors correlate with brain functional network connectivity (FNC), aiming to elucidate the interactive effects underlying brain neuroimaging patterns.

Our findings reveal that cannabis usage and healthy aging are associated with overlapping brain network configurations, particularly within the FNC between subcortical and sensorimotor regions, as well as between subcortical and cerebellar areas, albeit with significantly reversed effects.

Notably, cannabis users exhibited superior performance across multiple cognitive domains, and interestingly, the effects of cannabis and cognition are presented concurrently across a range of brain systems.

In conclusion, our study offers valuable insights into the potential influence of cannabis on brain aging and cognitive performance. The results suggest that cannabis users display brain network characteristics typically associated with younger brains, along with enhanced cognitive abilities, highlighting a potential modulatory role for cannabinoids and endocannabinoids in neurodegenerative processes, as explained through neural dedifferentiation and compensation theories.”

https://pubmed.ncbi.nlm.nih.gov/40766216/

https://www.researchsquare.com/article/rs-6977015/v1

Cannabidiol exerts anti-inflammatory effects but maintains T effector memory cell differentiation: A Single-Cell Study in Humans

Posted on by
Reply
pubmed logo

“Cannabidiol is widely available and often used for pain management.

Individuals with kidney disease or renal allografts have limited analgesia options. We conducted a Phase 1 human study to compare the peripheral immune cell distribution before (pre-cannabidiol) and after exposure to cannabidiol at steady state (post-cannabidiol).

This ex vivo study included specimens from 23 participants who received oral cannabidiol (up to 5 mg/kg twice daily) for 11 days. Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus. Pharmacodynamic responses were assessed via CellTiter-Glo® proliferation, scRNA-seq, cytokine assays, and flow cytometry. Steady-state plasma concentrations of CBD were quantified via tandem mass spectrometry.

We identified an increased proportion of T effector memory (TEM) cells post-cannabidiol (22% increase, P-value of 3.2 x 10 -32 ), which correlated with CBD plasma concentrations ( Pearson Corr= 0.77, P-value < 0.01 ). Post-cannabidiol cytokine assays revealed elevated proinflammatory IL-6 protein levels and anti-inflammatory IL-10 levels ( adjusted P-values < 0.0001 ). Cannabidiol reduced overall T and B lymphocyte proliferation with additive immunosuppressive effects to tacrolimus. In flow cytometry, the proportion of TEM and TEMRA increased post-cannabidiol with tacrolimus ( P-values < 0.05 ).

Cannabidiol exhibits mixed immunomodulatory effects with pro- and anti-inflammatory signals. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations.”

https://pubmed.ncbi.nlm.nih.gov/40766582/

https://www.biorxiv.org/content/10.1101/2025.07.30.667742v1

Cannabidiol reduces synaptic strength and neuronal firing in layer V pyramidal neurons of the human cortex with drug-resistant epilepsy

Posted on by
Reply
pubmed logo

“The use of cannabidiol (CBD) as an alternative pharmacological approach for the symptomatic management of epilepsy has gained attention due to its potential efficacy, particularly in drug-resistant cases of epilepsy.

Although multiple studies have described that CBD reduces neuronal hyperexcitability, the mechanistic basis of CBD remains a topic of ongoing research. In this study, we provide an electrophysiological portrayal of CBD’s effects on the glutamatergic transmission and intrinsic excitability of layer V pyramidal neurons of the human neocortex resected from drug-resistant epilepsy patients.

The perfusion of CBD transiently depressed the field excitatory potential amplitude elicited in layer I/II and recorded in layer V without altering the paired-pulse ratio, suggesting a postsynaptic locus of action for CBD. Cortical slices perfused with 4-aminopyridine exhibited an increased number of spontaneous synaptic events that were abolished in the presence of CBD.

At the cellular level, whole-cell patch-clamp recordings showed that CBD decreased the excitability of layer V pyramidal neurons, as evidenced by changes in the somatic input resistance, the membrane time constant, the hyperpolarization-induced “sag” conductance, the rheobase current needed to elicit an action potential, and the firing discharge in response to depolarizing current steps.

Consistent with the last observation, CBD decreased the amplitude of the TTX-sensitive inward currents without altering the kinetics of the macroscopic outwardly directed currents. CBD washout restored the passive and active electrophysiological properties of pyramidal neurons.

Collectively, these experiments demonstrate that CBD decreases the neuronal excitability of human cortical neurons from patients with drug-resistant epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/40766754/

“Within this framework, cannabidiol (CBD), a non-euphoric compound derived from the Cannabis plant, is a drug approved by multiple regulatory agencies for treating drug-resistant seizures associated with epileptic encephalopathies, such as tuberous sclerosis complex and the Dravet and Lennox–Gastaut syndromes.”

“Although our findings may be considered modest, they provide direct evidence of CBD’s modulatory actions on the electrophysiological parameters underlying the neuronal hyperexcitability associated with epilepsy. More importantly, our results reinforce clinical observations reporting CBD’s positive effects in treating patients with DRE.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1627465/full

Transient CB2 receptor activation triggers irreversible luminal differentiation via chromatin remodeling in breast cancer

Posted on by
Reply
bioRxiv

“Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists—either phytogenic or synthetic—induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress.

Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones.

Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.”

https://www.biorxiv.org/content/10.1101/2025.07.29.667375v2

CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

Posted on by
Reply
pubmed logo

“Tumor adaptability relies on the ability of cancer cells to dedifferentiate and acquire stem-like features, fueling therapeutic resistance and metastasis. Differentiation therapy aims to reprogram tumor cells into more mature, less aggressive states to counteract this plasticity.

Here, we identify cannabinoid receptor 2 (CB2R) as a novel therapeutic target that promotes sustained differentiation in breast cancer. Using tumor-derived organoids from both mouse models and patient biopsies, we show that brief, low-dose exposure to phytogenic or synthetic CB2R ligands induces a basal-to-luminal switch, suppresses stemness, and reduces invasiveness and self-renewal. These phenotypic changes are associated with decreased tumor initiation and aggressiveness in vivo .

Transcriptomic profiling reveals that CB2R activation initiates transient chromatin remodeling and epigenetic reprogramming, resulting in a stably differentiated state. Importantly, CB2R-driven differentiation sensitizes tumor cells to tamoxifen, enabling lower therapeutic doses with improved efficacy-supporting the principles of adaptive therapy aimed at long-term disease control.

Our findings position CB2R modulation as a promising non-cytotoxic strategy to restrict cancer plasticity and enhance the effectiveness of existing breast cancer treatments.”

https://pubmed.ncbi.nlm.nih.gov/40766353/

Treatment of malignant diseases with phytocannabinoids: promising observations in animal models and patients

Posted on by
Reply

“Amazingly, almost 50 years after the first demonstration of anticancer effects of cannabinoids in vitro and in vivo, well-designed clinical trials that definitively prove tumour-inhibiting effects in man are still missing. Whereas a large number of preclinical studies exist that describe tumour-inhibiting effects of cannabinoids, alone or in combination, but also in the form of medical cannabis or natural extracts in vitro, the number of in vivo studies is still limited. Even more limited are well-documented experiences in man. Most animal studies and experience with cannabinoids in man concern brain tumours.

This review summarises the effects of phytocannabinoids in brain, breast, colorectal, head and neck, haematological, liver, lung, pancreatic, ovarian, prostate, and skin cancers in animal models and, if available, in patients.

The large majority of animal studies demonstrate tumour-inhibiting effects of cannabinoids, thus confirming in vitro data. Experiences in cancer patients are almost exclusively limited to individual case reports and case series without a control group. Many questions are currently unanswered such as the role of pure cannabinoids compared to combinations, cannabinoids as the eventual sole cancer therapy, optimal dosages, or duration of treatment. Pure cannabidiol (CBD) seems to be superior to pure delta-9-tetrahydrocannabinol (THC) in experimental settings. The role of medical cannabis or extracts is less clear as they vary in their phytochemical composition.

In conclusion, cannabis/cannabinoids may slow the progression of tumours. However, the hope that cannabinoids could eventually cure cancer as often spread in social media, is, at present, wishful thinking. Above all, well-designed clinical trials paired with long-term follow-up of cancer patients are needed.”

“Cytotoxic effects of cannabinoids have been known since the very first series of in vitro and animal experiments by Munson et al. in 1975, almost 50 years ago, performed at the request of the National Institute on Drug Abuse (US). Since then, an overwhelming number of preclinical experiments have demonstrated the potential benefit of cannabinoids for treating malignant diseases.”

“In conclusion, although the number of studies in various animal cancer models as well as articles on therapeutic experience with cannabinoids in cancer patients is still very limited, the large majority describes impressing tumour-inhibiting effects warranting further research.”

https://www.explorationpub.com/Journals/em/Article/1001182

Cannabidiol as a therapeutic agent for rosacea through simultaneous inhibition of multiple inflammatory pathways

Posted on by
Reply
pubmed logo

“Rosacea is a chronic inflammatory skin disorder characterized by facial erythema, papules, pustules, and telangiectasia, affecting approximately 5.5% of the global population. Current treatments, primarily topical and oral antibiotics and anti-inflammatories, often show limited efficacy and may cause undesirable side effects, prompting the need for alternative therapies.

Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has shown promise as a therapeutic agent for rosacea due to its anti-inflammatory, antioxidant, and anti-apoptotic properties. CBD interacts with the endocannabinoid system, which plays a crucial role in cutaneous homeostasis.

This study evaluated the efficacy of CBD, both alone and in combination with metronidazole (MET), in reducing inflammation and modulating immune responses in a rosacea-like mouse model.

Our results demonstrated that both CBD and MET significantly inhibited redness, epidermal thickness, and mast cell infiltration, with their combination being more effective. Mechanistic analyses revealed that the therapeutic effect of CBD is associated with the suppression of key inflammatory regulators in the MAPK signaling pathway, particularly the ERK, JNK, and p38 pathways. CBD treatment also led to a significant reduction in proinflammatory cytokines and chemokines, indicating immune modulation.

These findings suggest that CBD, especially in combination with MET, may represent a novel therapeutic option for rosacea and offer a scientific basis for its clinical application in managing inflammatory skin conditions.”

https://pubmed.ncbi.nlm.nih.gov/40754776/