Cannabidiol- and Celecoxib-Loaded Liposomes as a Strategy to Modulate Redox and Inflammatory Signaling in High-Grade Glioma: A Preliminary In Vivo Study

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“Inflammation contributes to the rapid progression of high-grade gliomas, indicating that anti-inflammatory strategies targeting NF-κB signaling may offer therapeutic benefit.

Cannabidiol (CBD) and celecoxib (CELE) are hydrophobic pharmacological agents whose formulation in lipid carriers may support their combined biological evaluation.

In this proof-of-concept study, we investigated liposomal formulations containing CBD, CELE, or both compounds in U-87 MG high-grade glioma cells and in a subcutaneous xenograft model.

We assessed cytotoxicity, apoptosis, oxidative stress, Nrf2-dependent responses, NF-κB-centered inflammatory networks, tumor cell invasive properties, and Wnt/β-catenin pathway activity. The nanoformulations induced reactive oxygen species generation by 1.8-fold, which was accompanied by Nrf2 activation. Cationic formulations loaded with the compounds produced more pronounced pro-apoptotic effects (up to 39%) than POPC liposomes, although both types reduced the nuclear translocation of the NF-κB p65 subunit.

The CBD + CELE-containing formulation showed a trend toward reduced tumor progression in mice. It is important to note that the in vitro and in vivo nanoformulations were physicochemically related, but not identical, and the in vivo experiment should be interpreted as a preliminary assessment after intratumoral administration.

Overall, cationic liposomes co-loaded with CBD + CELE represent a promising platform for further optimization aimed at coordinated modulation of inflammatory, oxidative, and proliferative pathways in glioma. However, additional studies, including tissue distribution, release kinetics, and efficacy in orthotopic glioma models, are needed to fully verify their translational potential.”

https://pubmed.ncbi.nlm.nih.gov/42511566

“In summary, this study shows that liposomal formulations containing CBD and CELE, particularly DOTAP:POPC formulations prepared with both compounds, modulate apoptosis, cell cycle distribution, oxidative stress, Nrf2/NF-κB/Wnt-related pathways, and glioma-associated inflammatory mediators in U-87 MG-based models. In the subcutaneous xenograft model, intratumoral administration of the CBD + CELE-containing formulation was associated with a trend toward reduced tumor progression and modulation of selected tumor-associated proteins.”

https://www.mdpi.com/1422-0067/27/14/6220

Cannabidiol selectively attenuates lipotoxic immunometabolic inflammation in human macrophages

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“The role of saturated fatty acid-induced immunometabolic stress in macrophage dysfunction during metabolic disease remains incompletely understood, particularly the interplay between inflammatory signaling and intracellular lipid handling.

We employed a tightly controlled palmitic acid (PA)-based lipotoxicity model in PMA-differentiated U937-derived human macrophage-like cells to investigate how lipid excess reshapes inflammatory responses and to evaluate the modulatory effects of cannabidiol (CBD).

PA exposure induced a metabolically stressed yet viable macrophage phenotype, characterized by a broad cytokine remodeling profile. This included induction of classical proinflammatory cytokines such as interleukin (IL)-6, together with activation of inflammasome-associated cytokines IL-1β and IL-18 and additional immunoregulatory mediators, while tumor necrosis factor alpha (TNF-α) contributed to the overall inflammatory profile in a multivariate analysis. These changes were accompanied by a significant, time-dependent storage of intracellular triglycerides (TG) consistent with lipid overload and altered lipid handling.

CBD co-treatment did not compromise cell viability but selectively attenuated PA-induced inflammatory response in a cytokine-dependent manner, with the most significant reduction observed at higher concentrations. In parallel, CBD significantly reduced intracellular TG accumulation under lipotoxic conditions.

Collectively, these findings define a lipotoxicity-associated macrophage phenotype driven by saturated fatty acids and identify CBD as a context-dependent modulator of immunometabolic inflammation.

This work provides a controlled experimental framework to study lipid-driven inflammatory dysfunction and supports the potential of CBD as a targeted strategy to modulate metabolic inflammation without broadly suppressing immune function.”

https://pubmed.ncbi.nlm.nih.gov/42534637

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential regulator of inflammatory and metabolic processes. Unlike traditional anti-inflammatory drugs, CBD exerts context-dependent immunomodulatory effects across multiple experimental systems, encompassing both immune and metabolic cells.”

“Overall, this work supports CBD as a context-dependent modulator of immunometabolism response in PMA-differentiated U937-derived macrophages and provides a controlled experimental framework for studying lipid-driven inflammatory dysfunction in U937-derived macrophages.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1873494/full

Cannabidiol Attenuates Seizure Progression and Recognition Memory Deficit Induced by Hippocampal HCN1 Knockdown in the Kindling Model of Epilepsy in Male Rats

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“Epilepsy is a neurological disorder characterized by excessive neuronal firing, frequently originating in the hippocampus. Hyperpolarization-activated cyclic nucleotide-gated channel-1 (HCN1) regulates neuronal excitability and resting membrane potential, yet its role in seizure progression remains unclear.

Cannabidiol (CBD), an effective anticonvulsant, may exert part of its effects through HCN1.

This study investigated the contribution of HCN1 to seizure progression, synaptic plasticity, and CBD-mediated neuroprotection.

Rats were implanted with stimulation electrodes in the perforant path (PP) and recording electrodes with a guide cannula in the dentate gyrus (DG). One week later, lentiviral shRNA-HCN1 was injected into the DG, followed by PP electrical kindling. CBD (100 ng/2 μL) was administered every other day in shRNA-HCN1-treated or non-manipulated animals. Seizure severity was assessed using Racine’s scale. Synaptic transmission, paired-pulse plasticity, and long-term potentiation (LTP) were evaluated by extracellular field recordings, HCN1 function by whole-cell patch-clamp recordings of Ih (Hyperpolarization-activated current), HCN1 expression by RT-qPCR, and recognition memory using the novel object recognition (NOR) test.

Kindling reduced HCN1 mRNA expression, which was further decreased by shRNA-HCN1. HCN1 knockdown accelerated seizure progression, prolonged after-discharge duration, increased spike activity, reduced the sag ratio, and impaired synaptic transmission, paired-pulse plasticity, LTP, and object recognition memory in fully kindled rats.

CBD significantly attenuated these electrophysiological and recognition memory deficits, although its protective effects were partially reduced following HCN1 knockdown.

These findings indicate that HCN1 contributes to seizure progression and hippocampal dysfunction, while CBD exerts anticonvulsant and neuroprotective effects through both HCN1-dependent and HCN1-independent mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/42532179

“CBD attenuates seizure severity and rescues recognition memory deficits.”

“This study provides direct experimental evidence that hippocampal HCN1 channels play a vital protective role against seizure progression and recognition memory disturbance in the kindling model. Furthermore, we found that the functional involvement of these channels in the DG is an essential and novel mechanism underlying the anticonvulsant and neuroprotective effects of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390826002893?via%3Dihub

Cannabis-Based Nanolipid Formulations for Pain Management

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“Medicinal cannabis has gained increasing attention from both the scientific community and clinical practice, due to the therapeutic potential of its major phytocannabinoids, particularly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), for pain management.

This review compiled and analyzed the available evidence regarding the antinociceptive effects of nanoencapsulated cannabinoids compared to free compounds. The published works have explored some pharmaceutical formulations and administration routes on different acute, chronic and neuropathic pain experimental models.

The findings indicated that cannabinoids exhibited promising analgesic effects, while nanoencapsulation could enhance its stability and bioavailability.

Despite these advances, the number of reports investigating nanostructured cannabinoid-based systems remains limited, with a predominance of preclinical research. A recurrent lack of structural information and quality control data for such works was also noted. Furthermore, there were not identified any research regarding the nanoencapsulation of full-spectrum cannabis oils or whole cannabis extracts, highlighting a significant gap in the current literature.

Overall, nanoencapsulation emerges as a versatile strategy to overcome the intrinsic limitations of cannabinoids and expand its clinical applicability for pain treatment. Nevertheless, further efforts are required to determine standardized methodologies, facilitating the translation of preclinical findings into clinical practice, in order to provide stable, safe, effective and more accessible cannabinoid-based therapies.”

https://pubmed.ncbi.nlm.nih.gov/42514922

“Overall, advances in the nanoencapsulation of cannabinoids and other cannabis-derived products can significantly contribute to the development of stable, safe, effective and cost-effective pain therapies, particularly for chronic and neuropathic pain conditions.”

https://www.mdpi.com/1999-4923/18/7/844


Lower Pain Intensity Is Associated with the Use of Recreational Edible Cannabis Products Containing Delta-9-Tetrahydrocannabinol: A Secondary Analysis in Adults Self-Managing Their Chronic Low Back Pain

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“Background/Objectives: Current literature regarding the efficacy of cannabis to reduce chronic pain intensity is mixed. Despite growing accessibility throughout the U.S., it is still unclear if the naturalistic use of recreational cannabis edible products is associated with decreases in pain intensity on days of use or longitudinally, and if these associations are dependent on the doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being consumed. 

Methods: The trial (NCT03522324) from which these data were pulled was pre-registered in April 2018. Participants (N = 243; 56% female; mean age = 46 ± 12 years) with self-reported chronic low-back pain selected a recreational edible cannabis product to use exclusively, ad libitum, for 14 days. Labeled THC and CBD potency were used to determine product group: CBD-dominant (n = 97), THC + CBD (n = 112), or THC-dominant (n = 34). Participants completed daily surveys indicating current pain intensity (PROMIS; 0-10 scale), use or non-use of their product, and cannabinoid dose (THC and CBD). 

Results: Linear mixed effects showed a significant use × group interaction (p = 0.002), indicating that pain intensity was significantly lower on days of use in THC-dominant (b = -0.66, 95% CI [-0.94,-0.37]) and THC + CBD (b = -0.41, 95% CI [-0.57,-0.25]) groups compared to days when cannabis was not used. A significant group × time interaction (p = 0.02) indicated that pain intensity significantly decreased from day 1 to day 14 in those using THC + CBD products (b = -0.05, 95% CI [-0.07,-0.03]), with 36.6% of participants in the THC + CBD group experiencing ≥30% reduction in pain intensity from day 1 to day 14. Increasing doses of THC (b = -0.02, 95% CI [-0.04, -0.01]), not CBD (b = 0.003, 95% CI [-0.03, 0.01]), were associated with significantly lower pain intensity on days following product use, with increasing doses of CBD diminishing the impact of THC dose (b = 0.02, 95% CI [0.01, 0.04]). 

Conclusions: These findings indicate a complex relationship between THC, CBD, and pain intensity associated with the naturalistic use of recreational cannabis edible products. Lower daily pain intensity was associated with the use of products containing THC; however, dose models indicate that this association may be attenuated at higher doses of CBD. Additionally, only products containing relatively equal amounts of THC and CBD were associated with lower pain intensity after 14 days of observation.”

https://pubmed.ncbi.nlm.nih.gov/42512114

“Daily data collected over 14 days of naturalistic cannabis use demonstrated that reductions in participants’ current pain intensity were associated with the use of cannabis edible products, but only in products that contained THC. More frequent use of these products in the previous 24 h was associated with improved reductions in pain intensity.”

https://www.mdpi.com/2227-9059/14/7/1642


A Comparative Analysis of the Action Mechanisms of Cannabidiol, Cannabigerol, and Cannabinol in Human Cholangiocarcinoma Cell Lines

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“Background: Chemoresistance remains a major obstacle in managing cholangiocarcinoma (CCA). The cannabis plant contains several phytocannabinoids, including cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN), which exhibit anticancer properties. However, to the best of our knowledge, their effects on CCA have not been previously investigated. This study aimed to explore the molecular mechanisms underlying the anticancer effects of CBD, CBG, and CBN in CCA cells. 

Methods: KKU-100 and KKU-452 cells were treated with varying concentrations of CBD, CBG, and CBN for 24 and 48 h. Cytotoxicity was assessed using the MTT assay, and half maximal inhibitory concentration (IC50) values were calculated. KKU 452 cells were further analyzed for apoptosis, mitochondrial membrane potential (MMP), and Ki67 expression using flow cytometry. Proteomics profiling was performed to compare the effect of these cannabinoids with those of gefitinib and cisplatin. 

Results: Monotherapy with CBD, CBG, or CBN induced dose-dependent cytotoxicity at 24 and 48 h with lower IC50 values than those of cisplatin and comparable efficacy to that of gefitinib. At low doses, CBD, CBG, and CBN induced early apoptosis, while higher doses triggered late apoptosis. MMP loss increased by 2.5-, 4.9-, and 1.7-fold, respectively, after 6 h. Ki67, highly expressed in KKU-452 cells (Ki67-positive ratio = 3.16 ± 0.16), was significantly reduced after the cannabinoid treatment, with Ki67-positive ratios of 0.38 ± 0.22, 0.38 ± 0.13, and 0.32 ± 0.23 for CBD, CBG, and CBN, respectively. Proteomics analysis identified 2781 proteins affected by CBD, CBG, CBN, cisplatin, and gefitinib. All three cannabinoids downregulated key upstream regulatory proteins (LARP1, TFEB, and BCR). Similar patterns of LARP1 and TFEB downregulation were also observed with cisplatin and gefitinib. CBN showed the closest similarity to cisplatin, followed by gefitinib, by targeting CDK4/6 and PCGEM1 proteins. CBD and CBG exhibited the greatest similarity to each other, also influencing MASTL expression. 

Conclusions: CBD, CBG, and CBN exhibit potential anticancer activity in CCA by suppressing proliferation, reducing Ki67 expression, and inducing apoptosis through MMP disruption. The identification of shared molecular targets, including LARP1 and TFEB, provides new mechanistic insight and supports the potential development of cannabinoid-based therapeutic strategies for cholangiocarcinoma.”

https://pubmed.ncbi.nlm.nih.gov/42513130

“CBD, CBG, and CBN exhibited significant anti-cholangiocarcinoma activity by reducing cell viability, suppressing proliferation, decreasing nuclear Ki67 expression, disrupting mitochondrial membrane potential, and inducing apoptosis in KKU-452 cells.”

https://www.mdpi.com/1420-3049/31/14/2446


Cannabidiol-Dominant Cannabis sativa L. Inflorescence Extract Ameliorates Atopic Dermatitis by Modulating NLRP3 Inflammasome and JAK1/STAT6 Signaling in DNCB-Induced Mice

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“Background/objectives: Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring sustainable therapeutic alternatives. Cannabis sativa L. is a valuable industrial crop rich in bioactive secondary metabolites; its potential as a standardized functional ingredient for promoting skin health has not yet been fully investigated. This study aimed to evaluate the therapeutic effects of a chemically characterized C. sativa inflorescence ethanol extract (CSE) on AD.

Methods: To evaluate the efficacy of CSE, phytochemical profiling was performed using UPLC, and its underlying molecular mechanisms were investigated in a DNCB-induced mouse model.

Results: UPLC analysis was employed to establish the phytochemical profile, identifying 15 cannabinoids and quantifying 8 major components. CBDA was the most abundant component, with a content of 261.79 mg/g in the extract. In a DNCB-induced mouse model, CSE significantly reduced mast cell infiltration and serum IgE levels while downregulating Th2-associated cytokines. At the molecular level, CSE inhibited the activation of the MAPK, NLRP3 inflammasome, and JAK1/STAT6 signaling pathways. Crucially, CSE treatment substantially increased the expression of skin barrier proteins, such as filaggrin and involucrin, thereby enhancing skin hydration.

Conclusions: These findings suggest CSE as a high-value functional ingredient capable of ameliorating AD by modulating multi-target immune responses. This study provides a robust scientific basis for utilizing standardized C. sativa inflorescence as a potent functional ingredient or a nutraceutical agent for the management of chronic skin inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/42514451

“In conclusion, this study provides a comprehensive scientific basis for the use of CSE by demonstrating its multi-target modulation of inflammatory pathways, specifically the MAPK/NLRP3 and JAK1/STAT6 pathways. These results indicate that CSE is a promising candidate for the management of AD. Despite the recognized limitations, such as the need for comparative studies with isolated compounds, our findings suggest that CSE possesses substantial potential as a valuable nutraceutical and cosmeceutical resource. Ultimately, CSE represents a high-value material with significant prospects for both therapeutic and industrial applications.”

https://www.mdpi.com/2072-6643/18/14/2382

Nabiximols in Multiple Sclerosis: Beyond Spasticity-An Exploratory Systematic Review and Meta-Analysis of Symptomatic Outcomes

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“Background/Objectives: Nabiximols, a standardized extract of Cannabis sativa, has been approved as an add-on therapy for patients with moderate to severe spasticity associated with multiple sclerosis (MS). Moreover, current Italian treatment algorithms suggest that cannabis-based therapies may have further relevance in the management of MS. The aim of our systematic review and meta-analysis was to assess the effectiveness of nabiximols in relieving symptoms other than spasticity in adult MS patients. 

Methods: A systematic search was conducted in Web of Science, MEDLINE (via PubMed), Cochrane CENTRAL and Embase on September 10, 2025. Study selection was performed according to the predefined PROSPERO protocol (CRD42022329952). Data were combined into a common denominator and examined using a random-effects model with meta-regression expressed as mean difference (MD) and a 95% confidence interval (CI). Risk of bias was assessed using the Cochrane risk of bias instrument (RoB2) and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. 

Results: Of the 49 eligible articles, 25 were included in the statistical analysis (2949 patients). Significant improvements in spasm quality (MD = -16.87; 95% CI = (-29.75)-(-3.99)), bladder function (MD = -16.38; 95% CI = (-22.18)-(-10.58)), sleep disruption (MD = -15.75; 95% CI = (-22.02)-(-9.49)) and gait function (timed walk MD(s) = -5.31; 95% CI(s) = (-9.88)-(-0.74)) were observed. Time-dependency was not significant. The subject global impression of change (SGIC) improved significantly after the first month (odds ratio (OR) = 1.69; 95% CI = (1.30)-(2.18)). 

Conclusion: Beyond spasticity, nabiximols may represent a signal of benefit for bladder function, sleep disruption, spasm quality, and gait function in MS, in line with the “spasticity-plus” concept. However, the evidence certainty was low to very low, and these findings should be considered exploratory.”

https://pubmed.ncbi.nlm.nih.gov/42506315

“Nabiximols is a well-characterized extract of Cannabis sativa (27 mg/mL tetrahydrocannabinol (THC) and 25 mg/mL cannabidiol (CBD)) that acts on the cannabinoid system. It is effective in treatment-resistant MS-related spasticity and may also improve several associated symptoms. Moreover, nabiximols has shown encouraging results in the treatment of various symptoms such as pain, gait function, sleep disruption, bladder function, fatigue, and tremors.”

https://www.mdpi.com/2076-3271/14/3/346


Preclinical antitumor evaluation of a tetrahydrocannabinol and cannabidiol (1:6) cannabis extract in an MCF-7 xenograft model of estrogen receptor-positive breast cancer

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“Background and aim: Breast cancer remains one of the leading causes of cancer-related mortality worldwide, despite advances in surgery, chemotherapy, endocrine therapy, and targeted treatments. Cannabinoids derived from Cannabis sativa, particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), have demonstrated anticancer properties in several experimental models; however, in vivo evidence in estrogen receptor (ER)-positive breast cancer remains limited. This study aimed to evaluate the antitumor effects of a THC:CBD (1:6) cannabis extract in a Michigan Cancer Foundation-7 breast cancer cell line (MCF-7) xenograft mouse model of ER-positive breast cancer.

Materials and methods: Female BALB/c nude mice bearing MCF-7 xenograft tumors were randomly assigned into five groups (n = 5/group): negative control (sesame oil), positive control treated with 5-fluorouracil (5-FU; 20 mg/kg), and three treatment groups receiving oral THC:CBD (1:6) extract at doses of 2, 10, or 20 mg/kg body weight for 30 consecutive days. Tumor growth was monitored throughout the experiment. Histopathological examination and immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) expression were performed to evaluate apoptosis-related morphology and tumor cell proliferation. Hematological and biochemical parameters were assessed to determine systemic safety.

Results: Cannabinoid-treated groups exhibited significant suppression of tumor growth compared with the negative control group. Tumor volume reduction was observed in all treatment groups, with the greatest reduction detected in the high-dose THC:CBD group. Histopathological evaluation revealed increased numbers of tumor cells exhibiting morphological features consistent with apoptosis in cannabinoid-treated mice. Immunohistochemical analysis demonstrated significantly lower PCNA expression scores in all THC:CBD-treated groups compared with both negative and positive controls, indicating reduced tumor cell proliferation. Hematological parameters remained within normal physiological ranges in cannabinoid-treated animals. However, elevated alanine aminotransferase and aspartate aminotransferase levels were observed in the high-dose group, suggesting potential dose-related hepatic stress.

Conclusion: The THC:CBD (1:6) cannabis extract demonstrated significant antitumor activity in an MCF-7 xenograft model by suppressing tumor progression primarily through inhibition of tumor cell proliferation, with supportive apoptosis-related histological features. These findings provide novel in vivo evidence supporting the potential of cannabinoid-based formulations as adjunctive therapeutic approaches for ER-positive breast cancer.”

https://pubmed.ncbi.nlm.nih.gov/42494695

“In conclusion, the present study demonstrated that the THC:CBD (1:6) whole-cannabis extract exerted significant antitumor activity in an MCF-7 xenograft model of ER-positive breast cancer. Treatment with the cannabinoid extract resulted in marked suppression of tumor growth, significant reduction in tumor volume, decreased PCNA expression, and increased numbers of tumor cells exhibiting apoptosis-related morphological features.

Among the tested doses, the high-dose THC:CBD group showed the greatest reduction in tumor volume, indicating a strong antiproliferative effect of the cannabinoid formulation.”

“Overall, despite the inherent limitations of xenograft models, the present findings indicate that the THC:CBD (1:6) cannabis extract possesses promising antiproliferative and antitumor properties in ER-positive breast cancer. These results provide a foundation for future mechanistic and translational studies exploring cannabinoids as potential adjunctive agents in breast cancer therapy.”

https://veterinaryworld.org/Vol.19/June-2026/17.php

Phytochemistry, bioactivity, and medicinal use of Cannabis sativa roots: a comprehensive review

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“Background: Cannabis sativa is among the earliest domesticated plants and has been widely utilized for nutritional, industrial, and medicinal purposes. While its aerial parts, particularly the leaves and inflorescences, have been extensively studied due to their recreational and therapeutic applications, the roots remain comparatively neglected, despite their long-standing use in traditional medicine for treating wounds, burns, and inflammation.

Aim: This review aims to summarize the current knowledge on the phytochemical composition and biological activities of C. sativa roots, with emphasis on their pharmacological potential. RESULTS: The roots of C. sativa contain a diverse spectrum of secondary metabolites, including phytosterols, alkaloids, terpenes, and phenolic compounds. These bioactive constituents have been reported to exert antioxidant, anti-inflammatory, and antimicrobial activities. In vivo studies further demonstrate nociceptive and antispasmodic effects, with no evidence of cytotoxicity.

Conclusion: C. sativa roots represent an underexplored pharmacognostic resource with significant potential for the discovery of novel bioactive compounds. Their chemical diversity and biological activities provide a strong rationale for renewed scientific attention, supporting future research into this underestimated part of a species of growing medical and economic relevance.”

https://pubmed.ncbi.nlm.nih.gov/42477783

https://link.springer.com/article/10.1186/s42238-026-00470-4