Cannabis sativa L. roots extract modulates gastrointestinal motility and ameliorates ethanol-induced gastric ulcers in animal models

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“Introduction: Cannabis sativa L. roots are traditionally used to manage gastrointestinal (GI) disorders; however, experimental pharmacological evidence supporting these uses remains limited. This study investigated the chemical profile, safety, and GI-related pharmacological effects of an ethanolic extract of C. sativa roots (CEECs).

Methods: Chemical characterization was performed by spectrophotometric determination of total triterpenes and HPLC profiling. Safety and pharmacological effects were assessed through acute oral toxicity testing, antibacterial assays, and in vivo murine models of gastric emptying, diarrhea, and ethanol-induced gastric ulcer.

Results: CEECs showed a total triterpene content of 67.64 ± 5.39 μg LE·mg-1, and HPLC analysis detected p-coumaric acid and N-trans-feruloyltyramine. In vivo, CEECs significantly delayed gastric emptying at 50 mg·kg-1 (P = 0.0033) and reduced fecal output in the castor oil-induced diarrhea model at 50 (P < 0.001) and 100 mg·kg-1 (P = 0.0233), with no effect in the magnesium sulfate-induced model. CEECs also significantly reduced ethanol-induced gastric mucosal injury at 50 mg·kg-1 (P = 0.0484) and 100 mg·kg-1 (P = 0.0164). No signs of acute toxicity were observed at 2000 mg·kg-1. Antibacterial activity against Staphylococcus aureus strains was weak under the tested conditions.

Discussion: These findings provide experimental support for the traditional use of C. sativa roots in GI disorders and indicate their potential as a non-psychoactive source of bioactive constituents.”

https://pubmed.ncbi.nlm.nih.gov/41693782

“Overall, this study provides experimental support for the traditional use of cannabis roots in the management of diarrhea and gastric discomfort.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1743428/full

Altered endocannabinoid system gene expression in inflammatory bowel disease mucosa: New perspectives in inflammatory bowel disease management

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“Background: Inflammatory bowel disease (IBD) is a broad classification including various chronic inflammatory gastrointestinal conditions that comprises two main disorders: Crohn’s disease (CD) and ulcerative colitis (UC). The key components of the endocannabinoid system (ECS) are highly expressed within the gastrointestinal tract, playing a crucial role in maintaining homeostasis and providing protection against intestinal inflammation.

Aim: To investigate possible impairment of the genes belonging to ECS by analyzing their expression levels in IBD patients and controls.

Methods: The paired biopsies of endoscopically inflamed (IM) and noninflamed (NIM) colonic mucosa from 30 IBD-diagnosed patients (17 UC and 13 CD), and the colonic mucosa from 17 non-IBD controls, were collected and analyzed. The messenger RNA expression level of cannabinoid receptor (CNR) 1, CNR 2, diacylglycerol lipase alpha, diacylglycerol lipase beta, fatty acid amide hydrolase (FAAH), G protein-coupled receptor (GPR) 18, GPR55, monoglyceride lipase, peroxisome proliferator-activated receptor gamma (PPARG), and transient receptor potential cation channel, subfamily V, member 1 (TRPV1) was determined by quantitative polymerase chain reaction.

Results: Six out of the 10 investigated genes were found to be dysregulated in at least one comparison. Specifically, in IBD patients, FAAH, PPARG, and TRPV1 were significantly downregulated in IM compared to NIM (FAAH, P = 0.012; PPARG, P = 0.001; TRPV1, P = 0.032) and in IM compared to controls (FAAH, P < 0.001; PPARG, P < 0.001; TRPV1, P = 0.002). An opposite trend was reported for CNR2 and GPR55, which showed an upregulation in IM compared to NIM (CNR2, P = 0.005; GPR55, P = 0.001).

Conclusion: We found a significant impairment of the ECS in IBD patients. Further analyses on larger cohorts are needed for a better understanding of the potential of cannabinoids in managing IBD.”

https://pubmed.ncbi.nlm.nih.gov/41700170

“The role of ECS in gastrointestinal physiology and the exact involvement of this system in IBD are still under investigation. Given this, our preliminary findings of the impairment of analyzed ECS genes in the IBD mucosa may serve as a basis for more in-depth research in larger cohorts to better understand the potential of cannabinoids in the management of IBD. After the introduction of artificial intelligence in the multi-omics drug delivery pipeline, future therapeutic targets should emerge, allowing for an even more personalized approach to IBD patients.”

https://www.wjgnet.com/1948-5190/full/v18/i2/113576.htm?appgw_azwaf_jsc=pjmb6U0PmJ8Jhw6KK0wkG7dIIANmqb_h-_TRqMyZe5S0n2nN12xjj6IEXzXltFiMGkrPy5gdVTqeL9FpqEwxg2IRdQtlxGphrdrCTC-8UB5iTS-53eOUekwL8V6ddoD3rUPUEsVlA14gjfLy8jmezIuYPV2vjfZ-Qoy-hEGym4pY7k9iS4yH7a1n8E6oEldBMV5stbazp3UctrqNhXMRb1bGo8NvE8b14zuvRdlvOI8MhNFNMTV-JysZCgnImMJg1XC1kSYNzlziNr4LuxGaowrDxyFS9KaRq_rQ_cNEf6ip8MXlhXSmgIWPhdPyy1s0xQclW9zOboCaV9pRBR83KQ

Cannabidiol Protects the Heart from Ischemia-Reperfusion Injury Through SIRT-1/PGC-1α Activation and NF-κB Modulation: Experimental Insights

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“Myocardial ischemia-reperfusion (I/R) injury remains a major cause of acute cardiac dysfunction and is characterized by oxidative stress, inflammation, and apoptosis.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been reported to exert cardioprotective effects; however, its potential association with mitochondrial biogenesis-related signaling pathways remains incompletely understood.

This study aimed to evaluate the cardioprotective potential of CBD in a rat myocardial I/R model and to investigate its possible association with SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling.

Forty rats were randomly assigned to four groups: sham, I/R, prophylactic CBD, and therapeutic CBD. Myocardial ischemia was induced by ligating the left anterior descending coronary artery for 30 min followed by 30 min of reperfusion. Heart and aortic tissues were evaluated histopathologically, immunohistochemically, biochemically, and genetically to assess oxidative stress, inflammation, and mitochondrial biogenesis-related markers. The I/R group exhibited marked myocardial injury characterized by hyperemia, edema, hemorrhage, and inflammatory infiltration, accompanied by elevated vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), and NF-κB levels. Conversely, SIRT-1, PGC-1α, and B-cell lymphoma 2 (Bcl-2) expression significantly declined, alongside increased total oxidant status and oxidative stress index.

Prophylactic CBD treatment notably restored myocardial architecture, suppressed inflammatory and apoptotic responses, and enhanced mitochondrial biogenesis. Therapeutic CBD administration also provided partial protection.

CBD confers robust cardioprotection against myocardial I/R injury by activating the SIRT-1/PGC-1α axis, promoting mitochondrial biogenesis, and attenuating oxidative, inflammatory, and apoptotic pathways.

These findings indicated that confers significant cardioprotection against myocardial IR injury and that this protective effect is associated with modulation of SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling. Further mechanistic studies are warranted to establish definitive causal relationships.”

https://pubmed.ncbi.nlm.nih.gov/41696987

https://journals.lww.com/cardiovascularpharm/abstract/9900/cannabidiol_protects_the_heart_from.534.aspx

Highly purified cannabidiol (CBD) in CDKL5 deficiency disorder (CDD): Open-label prospective study

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“Objective: CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy characterized by frequent drug-resistant seizures, cerebral visual impairment, motor dysfunction, and sleep and gastrointestinal disturbances. Preliminary evidence suggests that highly purified cannabidiol (CBD) may reduce seizure frequency, but data on its effects on comorbidities are lacking. This study aimed to evaluate the efficacy and safety of CBD in individuals with CDD.

Methods: We conducted a prospective, open-label, single-center study including patients with CDD aged >1 year. Outcomes included motor seizure frequency, caregiver- and clinician-rated Clinical Global Impression (CGI), and changes in sleep, motor abilities, and EEG at 3, 6, and 12 months. CBD plasma levels were measured with High-Performance Liquid chromatography-Mass Spectrometry (HPLC-MS).

Results: Eight of nine patients (all females; median age 10 years, range 1-24) completed the study, with a retention rate at 12 months of 8/9 (89%). One discontinued at 6 months due to a skin rash. A > 50% seizure reduction was observed in 8/9 patients at 3 months, 6/9 at 6 months, and 1/8 at 12 months. Seven patients showed some degree of vigilance improvements, three in motor performance, and two in sleep and constipation. All caregivers reported at least minimal overall improvement (CGI score 3) at 3 months, and three reported marked improvement (CGI score 2), with a peak at 3 months. Five patients showed adverse events during the trial, but none were considered serious. The median CBD dose at all time-points was 15.6 mg/kg/day (IQR 10.0-18.9) corresponding to a plasma dose of 69.9 ng/mL (IQR 29.8-114.6) and the median concentration/dose ratio was 4.7 (IQR 2.7-6.8).

Significance: The safety and efficacy of highly purified CBD in CDD were consistent with previous reports in the literature, with possible benefits beyond seizure control. Further studies are warranted to assess non-seizure outcomes and compare long-term efficacy across treatment options.

Plain language summary: We studied nine girls with CDKL5 deficiency disorder who had frequent, hard-to-treat seizures. They received cannabidiol for up to 1 year, added to their usual medicines. Most children had fewer seizures in the first months of treatment. Some families also noticed better alertness, eye contact, movement, sleep, or constipation. Side effects were usually mild and manageable. Although seizure frequency often returned to baseline by the end of the study, most families chose to continue cannabidiol. Because this was a small study without a placebo group, these results are preliminary, and larger controlled trials are needed.”

https://pubmed.ncbi.nlm.nih.gov/41677102

“In this exploratory prospective open-label trial, we suggest that CBD may be an effective and relatively safe therapeutic option in patients with CDD, which warrants further investigation through randomized controlled trials. CBD may be associated with effects not only on seizures but also on awareness, sleep, and motor functions.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.70213

Cannabinoids and the autophagy-related signaling in brain Tumors: From mechanistic insights to therapeutic Frontiers in glioblastoma

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“Glioblastoma multiforme (GBM) is a very aggressive primary brain tumor in adults, characterized by extensive infiltration, therapeutic resistance, and a dismal prognosis, with an average life of roughly 14 months. Despite advances in oncology, therapeutic progress for GBM has been limited, prompting intensive efforts to discover novel interventions.

Cannabinoids, beyond their established role as antiemetics during chemotherapy and radiotherapy, have emerged as potential cytotoxic agents against neoplastic cells.

Recent studies demonstrate that GBM harbors alterations in the endocannabinoid system, including changes in cannabinoid metabolism and receptor (CB1R, CB2R) expression. Engagement of these receptors by cannabinoids can suppress proliferation, invasion, and induce morphological changes in GBM cells, also activating intrinsic autophagy pathways.

Autophagy, a process central to cellular degradation and recycling, exerts dual roles in tumor survival and apoptosis, critically modulated by cannabinoids in glioblastoma. Preclinical work in cell lines and animal models suggests that both cannabinoids and pharmacologic modulators of autophagy reduce GBM proliferation and enhance responsiveness to chemotherapeutics. Early clinical studies indicate favorable safety profiles and potential survival benefits.

This review synthesizes the molecular mechanisms and signaling pathways underlying cannabinoid-induced autophagy and anticancer activity, and summarizes the current preclinical and clinical research on cannabinoid-based therapies for GBM.”

https://pubmed.ncbi.nlm.nih.gov/41679657

“This review demonstrates that cannabinoids, an emerging class of potential antitumor agents, promote autophagy in cancer cells and enhance the cytotoxic effects of these compounds. The study demonstrated that THC facilitates autophagy and apoptosis in diverse cancer cell types, whereas nontransformed astrocytes display resistance to cannabinoid-induced cytotoxicity. “

https://www.sciencedirect.com/science/article/abs/pii/S0006295226001127?via%3Dihub


Pharmacokinetic studies and synergistic antitumor effects of cannabichromene and cannabidiol in drug-resistant breast cancers

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“Triple-negative breast cancer (TNBC) is highly aggressive with limited treatment options, and resistance to doxorubicin (DOX) further compromises outcomes.

Cannabinoids such as cannabichromene (CBC) and cannabidiol (CBD) possess anticancer properties, but their combined effects in resistant TNBC remain unexplored. This study evaluated the antitumor efficacy of a CBC + CBD combination against DOX-resistant (DOX-RT) TNBC using in vitro, in vivo, and pharmacokinetic models.

Cytotoxicity was assessed in DOX-RT MDA-MB-231 cells using 2D and 3D assays, with synergy confirmed by combination index (CI) analysis. Cell cycle and invasion assays were performed. Xenograft studies were conducted in BALB/c nude mice bearing DOX-RT tumors treated intraperitoneally with CBC (10 mg/kg), CBD (20 mg/kg), or CBC + CBD. Pharmacokinetics were evaluated in rats, complemented by GastroPlus™ simulations.

CBC + CBD synergistically inhibited cell growth induced G0/G1 arrest, and reduced invasiveness by ~ 55% in a Transwell Matrigel invasion assay. In xenografts, combination therapy reduced tumor volume by two-folds compared to single treatments and fourfolds versus control. Western blotting revealed downregulation of MEK/ERK, PI3K/AKT/mTOR, Cyclin D1, CDK6, SOD2, and NF-κB. Pharmacokinetic studies showed co-administration increased Cmax and AUC without altering Tmax, supported by simulations predicting enhanced jejunal absorption. CBC + CBD co-therapy demonstrates synergistic efficacy against resistant TNBC by inhibiting oncogenic pathways and enhancing systemic exposure.

This first study of its kind highlights CBC + CBD as a promising strategy to overcome DOX resistance in TNBC.”

https://pubmed.ncbi.nlm.nih.gov/41670942

https://link.springer.com/article/10.1007/s13346-026-02057-1

Activation of Cannabinoid Receptor 1 Enhances Wound Healing by Promoting the Proliferative Phase

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“The mechanisms underlying wound healing mediated by cannabinoid receptor 1 (CB1)-known for its neuromodulatory functions-remain incompletely understood. Therefore, we investigated the impact of activating CB1 using specific agonists, both in vitro and in vivo, with a focus on wound healing.

In the in vitro study, fibroblasts were isolated and cultured from the dermis of human skin and treated with a CB1 agonist, 2-arachidonyl glyceryl ether (2-AGE). In the in vivo study, a mouse acute wound model was created using a skin biopsy punch and treated with the CB1 agonist arachidonoyl 2′-chloroethylamide (ACEA).

The in vitro study revealed that 2-AGE increased cell proliferation and differentiation, upregulated the expression of alpha-smooth muscle actin (α-SMA), N-cadherin, and vimentin, and enhanced cell migration as well as the synthesis of type I and III collagen and fibronectin in normal human dermal fibroblasts. The CB1 antagonist AM251 abolished 2-AGE-induced expression of α-SMA, type I collagen, and fibronectin. In vivo, ACEA treatment accelerated wound closure, increased expression of α-SMA, type I collagen, and fibronectin, and ultimately increased epidermal and dermal thickness.

Overall, these findings suggest that the activation of CB1 promotes wound healing and provides evidence for the therapeutic potential of CB1 agonists in wound treatment.”

https://pubmed.ncbi.nlm.nih.gov/41683598

“Recent research has highlighted the role of the endocannabinoid system (ECS) in skin physiology and repair.”

“Clinical evidence indicates that the topical application of Cannabis-Based Medicines (TCBMs) facilitates tissue repair and promotes complete wound closure in previously refractory wounds.”

“In conclusion, our findings support the hypothesis that CB1 receptor activation facilitates wound healing through both cellular and molecular mechanisms.”

“Thus, these findings strongly support the therapeutic potential of targeting specific agonists as a viable strategy to accelerate the proliferative or contractile phases and thereby enhance the rate of wound healing.”

https://www.mdpi.com/1422-0067/27/3/1171


Role of Endocannabinoid System Perturbation in Organophosphate-Mediated Metabolic Impairment and Neuroinflammation

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“Organophosphates have been used for decades as pesticides, insecticides and herbicides, both in agricultural and industrial settings. However, their toxic effects on multiple body systems limit their safety. The clinical presentation of organophosphate toxicity varies depending on the route and duration of exposure. Although most research is focused on their cholinergic toxicity, emerging evidence points to their crucial contribution to metabolic dysfunction, including Type 2 diabetes and neuroinflammation.

Beyond acetylcholinesterase inhibition, recent research highlights the potential role of organophosphates in disrupting endocannabinoid signalling, particularly by affecting endogenous ligands that modulate G protein-coupled receptors. This dysregulation may contribute to organophosphate-induced metabolic disturbances and inflammation.

This review aims to explore how chronic subtoxic exposure to organophosphates contributes to metabolic syndrome and neuroinflammation through disruption of insulin and endocannabinoid signalling. It highlights the role of the endocannabinoid system in mediating these effects and evaluates its potential as a therapeutic target in organophosphate-induced toxicity.”

https://pubmed.ncbi.nlm.nih.gov/41668464

Plain language summary

“Organophosphates (OPs), commonly used as pesticides, have been shown to adversely affect both metabolism and brain health by disrupting the endocannabinoid system (ECS), a critical regulatory network involved in inflammation, energy balance, and neural function. Chronic, low‐dose exposure to OPs can alter ECS enzymes and signalling pathways, contributing to insulin resistance, obesity and neuroinflammation. These metabolic disturbances may play a key role in the development of neurodegenerative outcomes associated with OP toxicity. This review aims to examine the interplay between OPs exposure and ECS disruption, emphasizing the ECS role in pathogenesis and its potential as a therapeutic target.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.70198

Anti-inflammatory and analgesic potential of minor cannabinoids in vivo

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“The cannabis plant produces many bioactive compounds, including the major cannabinoids THC and CBD, and many lesser studied “minor” phytocannabinoids including cannabinol (CBN), cannabichromene (CBC), cannabicyclol (CBL), and cannabigerol (CBG). These compounds are touted for various ailments, including pain, inflammation, and anxiety, but experimental data on their effects are lacking, especially that of CBL, which has yet to be assessed in vivo.

Methods

To assess in vivo activity, adult male and female C57BL/6J mice were administered each compound and tested repeatedly in the tetrad battery. The potential analgesic effects in chronic pain states were assessed using the lipopolysaccharide (LPS)-induced hindpaw inflammatory pain and chronic constriction injury (CCI) neuropathic pain paradigms. Lastly, to address common psychological comorbidities of pain, CBN, CBL, and CBG were assessed in the tail suspension and marble burying tests.

Results

Cannabinol (≥ 25 mg/kg) induced classic cannabinoid effects, including acute antinociception. These effects were differentially and partially blocked by selective antagonism of CB1, adenosine A2A, or TRPV1 receptors. CBL (≥ 50 mg/kg) induced hypothermia that was fully blocked by A2A antagonism but had no apparent CB1-mediated activity. LPS-induced edema and paw proinflammatory cytokine levels were reduced by either CBN or CBL (100 mg/kg). CCI-induced cold allodynia was attenuated by either CBN (≥ 50 mg/kg) or CBL (100 mg/kg), but only at high doses that also induce catalepsy and hypothermia. None of these minor cannabinoids displayed anxiolytic- or antidepressant-like activity without concomitant locomotor effects.

Conclusions

Together, these findings suggest that CBN produces anti-inflammatory effects via cannabinoid receptor-dependent and -independent pathways, whereas CBL acts primarily through CB receptor-independent mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41680865

https://link.springer.com/article/10.1186/s42238-025-00384-7

Cannabidiol modulates exosomal miRNA networks to enhance Imatinib mesylate response in chronic myelogenous leukemia

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“Background/objectives: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease driven by the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKIs) such as Imatinib mesylate have dramatically improved patient outcomes, yet resistance remains a major obstacle to long-term efficacy. Exosomes, as carriers of bioactive molecules including miRNAs, are increasingly recognized as mediators of drug resistance. CBD has demonstrated antiproliferative and pro-apoptotic effects in several cancer models, but its potential to modulate Imatinib sensitivity or resistance in CML remains unclear. This study aimed to investigate exosomal miRNA signatures associated with Imatinib sensitivity and resistance in the context of treatment with Cannabidiol (CBD), Imatinib mesylate (IM), and their combination.

Methods: Following treatment with CBD, IM, and CBD+IM, exosomal miRNA profiles in Imatinib-sensitive (K-562S) and Imatinib-resistant (K-562 R) cell lines were analyzed. Gene Ontology (GO) enrichment and semantic clustering was performed.

Results: CBD activated tumor-suppressive and apoptosis-related miRNAs in K-562S cells, whereas K-562 R cells showed a dual response involving oncogenic miRNAs and metabolic regulators. IM induced suppressive cascades in K-562S but caused loss of canonical tumor suppressors in K-562 R. CBD+IM produced synergistic amplification of apoptotic and differentiation-related pathways in sensitive cells, while resistant cells showed partial restoration of apoptosis but persistent loss of tumor suppressors. HMGB1-associated miRNAs were identified, of which suppressed were miR-615-5p, miR-4435, let-7 g-3p, and the miR-548 family, alongside upregulated miR-3191-3p and miR-33a-5p.

Conclusions: Circulating miRNAs are valuable biomarkers for TKI resistance in CML. Targeting HMGB1-associated miRNAs, together with combined CBD and IM treatment, may help re-establish apoptotic regulation and overcome resistance mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41657764

https://www.sciencedirect.com/science/article/pii/S2699940426000020?via%3Dihub