Category Archives: Liver Disease

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

Cannabis Oil Prevents Early Hepatic Fibrosis, Inflammation, and Endothelial Dysfunction in a Sucrose-Rich Diet-Induced MASLD Model: Role of Cannabinoid Receptors

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“Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern globally, often associated with excessive sugar intake and metabolic dysregulation. In this study, we explored early hepatic alterations induced by a short-term sucrose-rich diet (SRD) and evaluated the preventive effects of a full-spectrum cannabis oil (CO) with a CBD:THC ratio of 2:1.

Methods: Male Wistar rats were assigned to three groups: reference diet, SRD, and SRD plus CO (SRD + CO). CO was administered daily to the SRD + CO group from the onset of SRD exposure and throughout the 3-week experimental period. Liver fibrosis was assessed through hydroxyproline content, total collagen, TGF-β, and CB1R expression. Endothelial dysfunction was evaluated by measuring nitric oxide (NO) levels, endothelial nitric oxide synthase, myeloperoxidase, and VCAM-1 expression. Inflammatory responses were analyzed through hepatic expression of IL-10, TNF-α, PAI-1, MCP-1, F4/80, and CB2R. Transmission electron microscopy was performed on liver tissue to evaluate ultrastructural alterations.

Results: SRD induced significant hepatic fibrosis, endothelial dysfunction, and inflammation. Ultrastructural analysis revealed nuclear alterations, including chromatin condensation, reduced mitochondrial number, intracellular lipid accumulation, increased glycogen deposits, and stromal changes characterized by perisinusoidal and periportal fibrosis with inflammatory cell infiltration. CO administration attenuated these pathological features and was accompanied by modulation of cannabinoid receptor expression.

Conclusion: These findings highlight the preventive effects of CBD- and THC-containing CO against early liver alterations associated with MASLD.”

https://pubmed.ncbi.nlm.nih.gov/42367574

“Phytocannabinoids, such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with the ECS and various other signaling pathways, providing antioxidant, anti-inflammatory, and antifibrotic properties. Full-spectrum cannabis extracts, which combine phytocannabinoids like CBD and THC, have emerged as therapeutic candidates in preclinical studies for the treatment of liver disorders associated with metabolic dysfunction. Previous studies conducted by our group have demonstrated hepatoprotective and antioxidant effects following the administration of full-spectrum COs in rats fed an SRD for 3 weeks.”

“The present study was designed to evaluate the preventive effects of daily CO administration during the early stages of SRD-induced MASLD.”

“Daily CO administration prevented these alterations and the SRD-induced increase in cannabinoid receptor protein levels.”

“These findings position ECS modulation – particularly through phytocannabinoid combinations – as a promising multi-target strategy capable of mitigating the earliest pathogenesis processes underlying MASLD.”

https://karger.com/mca/article/9/1/163/950066/Cannabis-Oil-Prevents-Early-Hepatic-Fibrosis

Acute Effects of Cannabinoid Combination Therapies in a Western Diet-Induced Murine Model of Metabolic Liver Disease

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“Pharmacological treatment of metabolic-dysfunction-associated steatohepatitis remains challenging due to its complex pathophysiology. The endocannabinoidome (eCB) has emerged as a promising therapeutic target given its central role in energy homeostasis and its pharmacological tractability. Western-style diets high in fat and sugar exacerbate metabolic liver disease, highlighting the need for effective interventions.

Here, we investigated the therapeutic potential of cannabinoid combinations targeting the eCB-liver axis in a Western diet-induced model of metabolic dysfunction.

Two weeks of treatment reduced body weight, improved glycaemic control, and ameliorated liver pathology. These effects were accompanied by decreased liver weight, improved liver enzyme profiles, and reduced histological features of steatosis and injury.

Overall, these findings suggest that modulation of the eCB system can induce acute improvements in metabolic and hepatic parameters under conditions of diet-induced metabolic stress. These results support further investigation into the eCB system as a therapeutic target, particularly to elucidate underlying mechanisms and longer-term effects.”

https://pubmed.ncbi.nlm.nih.gov/42278403

“To our knowledge, this is the first study to investigate the therapeutic effects of combination cannabinoid treatment in a mouse model of metabolic liver disease.

Targeting the endocannabinoid system, even acute treatment markedly improved metabolic parameters, including significant weight loss, reduced fasting blood glucose, and improved liver condition.

The triple cannabinoid combination produced the most pronounced effects, improving markers of hepatic injury and inflammation.

Mechanistically, modulation of the LPI/GPR55 and GPR119/incretin axes highlights the therapeutic potential of targeting the gut–liver axis using small-molecule agonists and endogenous bioactive lipids.”

https://www.mdpi.com/1422-0067/27/11/4872

Immunohistochemical analysis and distribution of lymphocytes and Kupffer cells in the liver of rats with long-term experimental use of hemp seed oil

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“Objective: Aim: To conduct histological and immunohistochemical analysis and distribution of lymphocytes and Kupffer cells in the liver of rats with long-term experimental use of hemp seed oil (HSO).

Patients and methods: Materials and Methods: 26 sexually mature male rats (180-230 g, 5-7 months old) were divided into three groups: experimental (n=14, 0.5 ml/kg/day HSO orally for 10 weeks), control (n=6, 0.1 ml/kg/day HSO orally for 10 weeks), and intact (n=6). Histological and immunohistochemical (CD3, CD20, CD56, CD68) studies, alongside quantitative analysis of lymphocyte and macrophage distribution in hepatic lobules, were performed. Statistical significance was assessed using Mann-Whitney and Pearson tests, with p<0.05 considered significant.

Results: Results: After 10 weeks of 0.5 ml/kg/day HSO, 71.43% of experimental rats developed mild fatty liver disease (Kleiner grade S1 steatosis), a significant difference from the control group (p<0.0001). No histological inflammation or necrotic changes in hepatocytes were observed. Small numbers of CD3 lymphocytes were present in portal tracts, without extending into or damaging the adjacent parenchyma. CD20 and NK resident lymphocytes were sparse. Aggregates of CD68-positive Kupffer cells were most common near liver lobule triads. The average number of Kupffer cells (5.79±0.06 per 0.01 mm2) in the experimental group significantly (p<0.001) exceeded the control by 1.49 times, suggesting hyperplasia of specialized macrophages and their increased role in liver immune function.

Conclusion: Conclusions: Ten weeks of experimental use indicates that hemp seed oil is safe to consume at a dose of 0.5 ml/kg/day.”

https://pubmed.ncbi.nlm.nih.gov/42048501

Cannabidiol as a Modulator of the Gut-Liver Axis: Clinical and Pharmacological Insights into Hepatic and Metabolic Disorder Therapies

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“A non-intoxicating substance produced from Cannabis sativa, cannabidiol (CBD) has shown promise as a treatment for metabolic and hepatic diseases, primarily due to its capacity to alter the gut-liver axis.

A vital bidirectional communication pathway, the gut-liver axis is where substances produced from the liver affect gut homeostasis and gut-derived microbial products and metabolites influence liver health. Conditions including alcoholic liver disease (ALD), metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD) are mostly caused by dysregulation of this axis.

According to preclinical research, CBD has hepatopro-tective benefits via improving the integrity of the gut barrier, decreasing intestinal permea-bility, altering the gut microbiota, and suppressing inflammatory signaling pathways such NF-κB and NLRP3 inflammasome activation. Furthermore, CBD improves insulin sensitivi-ty and lowers hepatic steatosis via modifying lipid and glucose metabolism via the PPARγ and CB1/CB2 receptor pathways. Its antioxidant qualities also help to lessen cellular dam-age and oxidative stress in hepatic tissues.

Despite these encouraging results, there is still inconsistency in the clinical data because of variations in dosage, formulation, administra-tion method, and patient-specific variables including liver function and microbiota makeup. Furthermore, broad therapeutic usage is restricted by issues with hepatic metabolism, pos-sible drug-drug interactions, and regulatory obstacles.

This review highlights information gaps, critically assesses the available preclinical and clinical evidence, and investigates the mechanisms underlying CBD’s impact on the gut-liver axis. Additionally, it identifies po-tential avenues for future optimization of CBD-based therapies targeting liver and metabol-ic illnesses through personalized medicine, sophisticated delivery methods, and standard-ized clinical trial procedures.”

https://pubmed.ncbi.nlm.nih.gov/41935387

https://www.eurekaselect.com/article/154488


Cannabis oil modulates liver alterations and endocannabinoid system changes in a female rat model of diet-induced MASLD

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“Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to alterations in liver lipid metabolism, oxidative stress, fibrosis, and dysregulation of the endocannabinoid system (ECS). Although increasing evidence supports a role for cannabinoids in metabolic disorders, most preclinical studies have been conducted in male models, leaving female-specific responses largely unexplored.

Methods: This study evaluated the effects of oral administration of a full-spectrum cannabis oil (CBD:THC 2:1) on MASLD-related alterations and ECS regulation in female Wistar rats fed a sucrose-rich diet (SRD). Rats were assigned to reference diet (RD), SRD, or SRD plus cannabis oil (1 mg/kg/day) for 3 weeks.

Results: SRD-fed rats developed liver steatosis and increased NAFLD activity score (NAS), accompanied by enhanced de novo lipogenesis, reduced mitochondrial fatty acid oxidation, increased oxidative stress, early fibrotic changes, and ECS overactivation. Cannabis oil administration improved liver lipid metabolism, reduced NAS and fibrosis markers, attenuated lipid peroxidation and oxidative stress, increased NrF2 and decreased NF-κB p65 expression, and normalized hepatic CB1 expression and circulating endocannabinoid levels.

Discussion: These findings demonstrate that full-spectrum cannabis oil is associated with improved MASLD-related outcomes and modulation of ECS tone in a female-specific model of diet-induced metabolic liver disease.”

https://pubmed.ncbi.nlm.nih.gov/41883411

“For millions of years, medicinal plants have been employed in the treatment and handling of liver diseases”

 “Our results indicate that cannabis oil with this particular CBD:THC ratio may serve as a natural nutraceutical to help prevent metabolic disorders linked to hepatic steatosis, oxidative stress, liver fibrosis, and MASLD.”

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2026.1770150/full

Cannabidiol and cannabigerol ameliorate steatotic liver disease via phosphocreatine buffering and lysosomal restoration

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“Background and purpose: Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive phytocannabinoids with emerging therapeutic potential in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the molecular mechanisms underlying their beneficial effects remain incompletely understood. In this study, we assessed the metabolomic and lipidomic impact of CBD and CBG in a mouse model of diet-induced obesity and MASLD.

Experimental approach: Male C57Bl/6 mice fed on a high-fat diet for 14 weeks were treated for 4 weeks with daily intraperitoneal CBD, CBG or vehicle. Assessments included body composition, indirect calorimetry, glucose tolerance, serum biochemistry and VLDL-triglyceride profiling. Hepatic mechanisms were examined by metabolomics, lipidomics, creatine kinase activity, cathepsin activity-based probes and gene/protein expression, with a choline-deficient diet cohort to test phospholipid-dependence of CBG.

Key results: CBD or CBG treatment improved glycaemic control, reduced hepatic triglycerides and normalised serum lipids, without affecting energy expenditure. Metabolomics revealed increased hepatic phosphocreatine and creatine with enhanced creatine kinase activity, indicating phosphocreatine-based energy buffering independent of fatty acid oxidation changes. Lipidomics showed reduced triglycerides and ceramides, with increased phospholipids and lysobisphosphatidic acids, correlating with restored hepatic cathepsin activity and improved lysosomal lipid degradation. CBG was ineffective in choline-deficient MASLD, indicating phospholipid pathway dependence.

Conclusions and implications: These findings identify a novel, endocannabinoid system-independent mechanism by which CBD and CBG enhance hepatic energy buffering and lysosomal function, contributing to improved liver lipid handling and supporting phytocannabinoids as promising MASLD therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/41785476

Cannabidiolic acid as a modulator of lipid metabolism in the liver of rats with metabolic-associated steatotic liver disease

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“This study investigated the effects of cannabidiolic acid (CBDA) on hepatic lipid metabolism in a rat model of metabolic dysfunction-associated steatotic liver disease (MASLD), addressing the need for natural therapeutic compounds targeting lipid metabolism disorders.

Male Wistar rats were fed a standard diet or a high-fat diet (HFD) for 8 weeks. During the last 14 days, half of the rats received CBDA intragastrically (0.1 mg/kg BW). The hepatic lipid fractions were analyzed via gas-liquid chromatography, and protein expression was assessed via Western blotting and immunohistochemistry. Compared with the control diet, the HFD significantly increased the expression of fatty acid transporters CD36, FATP5, and FABPpm and elevated the levels of free fatty acids (FFAs), triacylglycerols, diacylglycerols, and phospholipids compared with controls.

CBDA treatment in HFD-fed rats significantly decreased CD36, FABPpm, and FATP5 expression as well as total diacylglycerol and phospholipid concentrations. CBDA also decreased the saturated fatty acid content in the FFA and phospholipid fractions while increasing omega-3 polyunsaturated fatty acids in the diacylglycerol and triacylglycerol fractions.

CBDA ameliorated HFD-induced hepatic steatosis by modulating fatty acid transporter expression, reducing harmful lipid accumulation and improving fatty acid composition.

These findings suggest the potential of CBDA as a therapeutic agent for MASLD through the targeting of multiple dysregulated pathways in hepatic lipid metabolism, potentially limiting disease progression.”

https://pubmed.ncbi.nlm.nih.gov/41792203

https://www.nature.com/articles/s41598-026-41130-0

“Cannabidiolic acid (CBDA) is a non-psychoactive cannabinoid found in raw, fiber-type hemp and cannabis plants”

Therapeutic potential of cannabidiol supplementation in mitigating lipid precursors of inflammation in hepatic steatosis progression

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“Background: This study investigated the effects of cannabidiol (CBD) on early-stage inflammation, a key factor in the progression of liver diseases from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH) and irreversible cirrhosis. The study focused on CBD’s influence on the pro-inflammatory n-6 and anti-inflammatory n-3 pathways, on arachidonic acid (AA) levels as an early marker of inflammation, and the expression of enzymes involved in AA metabolism, as well as inflammatory cytokines and chemokines.

Methods: Forty male Wistar rats were randomly divided into four groups: control (C)-fed a standard diet and treated with cannabidiol vehicle for the last 14 days, control + cannabidiol (C + CBD) – fed a standard diet and treated with CBD for the last 14 days, high-fat diet (HFD) – fed a high-fat diet and treated with cannabidiol vehicle for the last 14 days, high-fat diet + cannabidiol (HFD + CBD)-fed a high-fat diet and treated with cannabidiol for the last 14 days. At the end of the treatment period, all the rats were fasted for 24 h, anesthetized, and sacrificed. Gas-liquid chromatography was used to measure n-6 and n-3 pathway polyunsaturated fatty acids (PUFAs) activities and AA levels in lipid fractions in the liver. The Multiplex immunoassay assessed cytokine and chemokine content in liver tissue, while Western Blot analyzed the expression of selected enzymes.

Results: Initial findings indicated CBD’s potential in reducing inflammation and its therapeutic efficacy in preventing MASH development induced by HFD. The results indicated that supplementing with CBD led to a decrease in the n-6 PUFA pathway, known for its pro-inflammatory effects, and an increase in the anti-inflammatory n-3 PUFA pathway. These changes were simultaneous with lower levels of arachidonic acid, which is crucial for the formation of inflammatory mediators. CBD influenced the expression of enzymes like COX-1 and COX-2 involved in AA metabolism and reduced the levels of pro-inflammatory cytokines.

Conclusions: Our observations confirmed that CBD, which affects early indicators of inflammation, has the potential to become a new and safe, promising supportive drug for hepatic inflammation and steatosis treatment.”

https://pubmed.ncbi.nlm.nih.gov/41742322

https://link.springer.com/article/10.1186/s42238-026-00413-z

Pharmacological, Molecular Mechanisms, and Therapeutic Potential of β-Caryophyllene and β-Caryophyllene-Rich Plants in Liver Diseases

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“β-caryophyllene, a bicyclic sesquiterpene widely abundant in various plant essential oils, has garnered growing attention for its potential biological effects and therapeutic benefits in liver diseases. This review systematically evaluates preclinical evidence on the pharmacological properties of BCP with emphasis on its hepatoprotective effects primarily through its anti-inflammatory, antioxidant, antifibrotic, and immunomodulatory actions.

BCP is classified as a dietary cannabinoid due to its ability to activate cannabinoid type 2 receptors in the endocannabinoid system and thereby influence key cellular signaling pathways involved in lipid metabolism and tissue remodeling. Emerging studies also highlight BCP interaction with PPAR nuclear receptor and AMPK signaling, further corroborating its role in regulating lipid homeostasis.

In the present review, we compile, summarize, and critically analyze findings from in vitro and in vivo studies on nonalcoholic fatty liver disease, recently termed as metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease, and liver fibrosis, highlighting the pharmacological and molecular mechanisms underlying therapeutic effects. These studies consistently demonstrate a reduction in hepatic steatosis, collagen deposition, and hepatocellular markers reflecting a broad spectrum of hepatoprotective effects.

Taken together, the pharmacological properties and mechanistic insights place BCP as a promising natural compound with nutraceutical, phytopharmaceutical, or dietary supplement applications for liver diseases. Despite the robust preclinical evidence, clinical validation remains scarce. Therefore, regulatory toxicology and efficacy studies are needed to establish the therapeutic potential of BCP in liver diseases and its integration as a nutraceutical or phytopharmaceutical in the clinical usage.”

https://pubmed.ncbi.nlm.nih.gov/41489519

“BCP is one of the important constituents in Cannabis with an abundance of 35%. In addition to its presence in Cannabis, BCP is largely present in numerous edible plants.”

“In conclusion, BCP represents a promising therapeutic avenue for managing liver diseases due to its ability to modulate multiple interrelated molecular and cellular pathways.”

“With continued research, BCP has the potential to evolve from a natural product with hepatoprotective properties to an effective adjunct or alternative in liver disease therapy, offering new hope for patients and advancing the field of liver health management.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202502436R