Efficacy of Exogenous Cannabinoids in Pre-Clinical Models of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

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“Background: Exogenous cannabinoids are considered promising therapeutic candidates for inflammatory bowel disease (IBD). However, robust pre-clinical evidence supporting its efficacy remains limited. This systematic review and meta-analysis aimed to evaluate the therapeutic effects of exogenous cannabinoids in animal models of IBD.

Methods: Controlled experimental studies involving animal models of IBD that evaluated the effects of exogenous cannabinoids compared to untreated models were included. Four databases (PubMed, Embase, Web of Science, and the Cochrane Library) were searched up to August 26, 2025. Two independent reviewers conducted study selection, data extraction, and the risk-of-bias assessment. The risk-of-bias assessment was performed using the Systematic Review Center for Laboratory Animal Experimentation tool. Meta-analyses were performed using standardized mean differences (SMDs) and random-effects models. The study was registered in INPLASY (INPLASY202540009).

Results: Twenty-seven pre-clinical studies involving 408 animals were included. Compared with controls, exogenous cannabinoids significantly reduced disease activity index (SMD = -3.43; 95% confidence interval [CI]: -4.98 to -1.89; I2 = 83%) and histopathological score (SMD = -4.46; 95% CI: -6.37 to -2.54; I2 = 84%). It also decreased levels of myeloperoxidase (MPO), TNF-α, IL-6, and IL-1β. However, substantial heterogeneity was noted across several outcomes.

Interpretation: Exogenous cannabinoids show beneficial effects in pre-clinical IBD models, likely through anti-inflammatory, antioxidant, and barrier-enhancing mechanisms. These findings provide a supportive foundation for future translational research. Nevertheless, the overall certainty of the evidence is limited by unclear randomization, lack of blinding, high heterogeneity, and small sample sizes. Although some clinical trials have already begun exploring its therapeutic potential, further rigorous and standardized animal studies are needed to clarify mechanisms, optimize dosing, and reinforce the translational pathway.”

https://pubmed.ncbi.nlm.nih.gov/41804536

Therapeutic relevance of an EU-GMP certified Cannabis sativa L. strain in a dual in vivo model of cognitive impairment and chronic neuropathic pain

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“Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and frequently co-occurs with chronic pain. Worldwide, over 55 million people are affected by AD, with nearly half experiencing persistent pain. Chronic pain has been linked to accelerated memory deterioration and an increased risk of dementia, but the interplay between these conditions remains poorly understood. Existing therapies for AD and chronic pain are limited in efficacy, highlighting the need for interventions targeting multiple pathological pathways. The endocannabinoid system, which is altered in both AD and chronic pain, represents a potential therapeutic target, though its role in AD patients with comorbid pain remains unexplored.

Methods: The study evaluated the effects of an EU-GMP certified Cannabis sativa L. strain (5 mg/kg, Cannabixir® Medium Flos) on neurobiological alterations in a rat model designed to explore mechanistic interactions between scopolamine-induced transient cognitive impairment and chronic neuropathic pain induced by unilateral sciatic nerve ligation. Treatment outcomes were assessed through nociceptive tests, clinical monitoring and tissue analyses to examine cognitive and pain-related effects.

Results: Cannabixir® Medium Flos induced robust, time-dependent analgesia in thermal nociceptive tests, with the combination of the Cannabis sativa L. strain, donepezil and tramadol producing significantly longer response latencies than tramadol alone. Mechanical sensitivity was minimally affected across treatments. Immunohistochemical analyses revealed that Cannabixir® Medium Flos, either alone or in combination with donepezil or tramadol, produced the most pronounced neuroprotective effects, reducing astrocytic (GFAP) and microglial (Iba1) activation, lowering Caspase-3 and IL-6 expression, and preserving both hippocampal neuronal integrity as well as peripheral nerve structure.

Conclusion: These findings indicate that Cannabixir® Medium Flos, particularly when combined with donepezil and tramadol, provides superior analgesic and neuroprotective effects compared to tramadol alone. Its multi-target action – alleviating thermal nociception, reducing neuroinflammation, limiting apoptosis and preserving neuronal and peripheral nerve integrity-supports its potential as an adjunct therapy in managing dementia with comorbid chronic neuropathic pain. Future studies should explore the molecular mechanisms underlying these effects and assess long-term safety and efficacy across diverse models of neurodegeneration and chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41800101

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1761426/full

Therapeutic Potential of Cannabinoids in Attenuating Amiodarone-Induced Pulmonary Fibrosis: An in vivo Experimental Study in Wistar Rats

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“Introduction: Amiodarone (AMIO) is one of the most prescribed antiarrhythmic medications and is commonly used to treat atrial and ventricular fibrillations. A notable adverse effect of AMIO is pulmonary fibrosis. Cannabinoid (O-2545) has been shown to exert antioxidant, anti-inflammatory, and antifibrotic effects in both in vivo and in vitro experimental models. The present study aimed to investigate whether cannabinoid (O-2545) may attenuate amiodarone-induced pulmonary fibrosis in male Wistar rats.

Methods: A regimen of 50 mg/kg AMIO was administered via oral gavage daily for 10 consecutive days to induce acute pulmonary fibrosis. The experiment included 24 Wistar rats assigned to four groups. The control group received daily subcutaneous injections of normal saline for the same time period. The AMIO group received a daily oral gavage of AMIO (50 mg/kg) for 10 days. Concurrently, the O-2545 group received daily oral doses of cannabinoid. The combined treatment group received both AMIO and cannabinoid orally each day for 10 days.

Results: High-dose AMIO (50 mg/kg) administration resulted in a significant elevation of oxidative stress, followed by a decrease in antioxidant function, an increase in inflammatory cytokines, fibrosis markers, and apoptosis. Pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and adenosine (Adens), apoptotic markers tumor protein p53 (p53) and caspase 3 protein (caspase-3), oxidative stress malondialdehyde (MDA), fibrosis indicator hydroxyproline (HYDROX), and histone deacetylase (HDAC) activity, accompanied by a marked reduction in the antioxidant glutathione (GSH), compared to the control group. Histopathological examination of pulmonary tissues revealed that O-2545 significantly mitigated AMIO-induced pulmonary fibrosis.

In conclusion, the results showed that cannabinoid (O-2545) may offer significant therapeutic potential in mitigating pulmonary toxicity induced by AMIO in rats.

Purpose: This study investigates the possible protective therapeutic effects of (O-2545) on AMIO-induced pulmonary fibrosis in Wistar rats.”

https://pubmed.ncbi.nlm.nih.gov/41804454

https://www.dovepress.com/therapeutic-potential-of-cannabinoids-in-attenuating-amiodarone-induce-peer-reviewed-fulltext-article-DDDT

Peripheral Cannabinoid Receptor Activation Attenuates Frostbite-Induced Chronic Pain via Modulation of TRP Channels, Neuroinflammation, and Autophagy

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“Frostbite injury is a debilitating cold injury encountered in extreme high-altitude and subzero environments, frequently resulting in persistent chronic pain even after tissue healing. Using our previously validated frostbite-induced chronic pain model, we further investigated the contribution of neuroimmune, excitatory mechanisms and evaluated the therapeutic efficacy of peripheral cannabinoid receptor activation.

Frostbite produced significant mechanical allodynia, mechanical hyperalgesia, and cold hypersensitivity, along with increased spontaneous nocifensive behaviors.

Local peripheral administration of CB13, a peripherally acting CB1/CB2 receptor dual agonist, dose-dependently attenuated both mechanical and cold allodynia without impairing locomotor activity, indicating a lack of central nervous system side effects.

At the molecular level, frostbite induced marked peripheral and spinal sensitization, demonstrated by elevated expression of TRPV1, TRPA1, TRPV4, and TRPM8 channels, increased levels of pro-inflammatory cytokines, and enhanced c-Fos expression as an indicator of heightened neuronal activation in pain-relevant regions. These alterations were accompanied by pronounced microglial activation and upregulation of the NLRP3 inflammasome.

CB13 treatment significantly reversed these pathological changes and concurrently restored Beclin-1-associated autophagy signaling, suggesting engagement of both neuroimmune resolution and intracellular homeostasis pathways. Notably, frostbite injury was associated with marked oxidative and nitrosative stress in the sciatic nerve, as evidenced by reduced glutathione depletion and elevated lipid peroxidation and nitrite levels, which were significantly normalized by CB13 treatment.

Collectively, these findings demonstrate that peripheral cannabinoid receptor activation effectively inhibit frostbite induced chronic pain through modulation of nociceptive, neuroinflammatory, redox, and cellular stress pathways.

This work highlights peripherally selective cannabinoid receptor agonists as promising, safer therapeutic strategies for chronic pain associated with cold injuries.”

https://pubmed.ncbi.nlm.nih.gov/41802611

“This study demonstrates that peripheral cannabinoid receptor activation via CB13 effectively alleviates frostbite-induced chronic pain by targeting multiple pathological mechanisms, including nociceptor hyperexcitability, spinal neuronal activation, neuroinflammation, inflammasome signaling, oxidative stress, and impaired autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584926001565?via%3Dihub

Driving by frequent cannabis users ‘the morning after’ last use of smoked cannabis: an observational driving simulator study

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“It is well-established that cannabis can affect driving in the hours after cannabis use, but the exact duration of these effects, and relationship with delta-9-tetrahydrocannabinol (THC) concentrations in blood and oral fluid, remains to be determined.

Methods

Frequent (≥ 4 times a week) users of smoked cannabis drove a simulator the morning after (12-15 hours) last use of smoked cannabis; a control group of non-cannabis users matched for age and sex was also included. Concentrations of THC, cannabidiol (CBD) and metabolites were measured in oral fluid and blood at the time of the drive.

Results

In total, 65 participants (mean age 30 years; 33 males) in each group completed all study procedures. Participants were generally well-matched (age, sex, driving experience, amount of driving per year/week, hours of sleep) but differed in racial breakdown and years of education. Under both standard and dual task (distacted) conditions, standard deviation of lateral position (SDLP) was higher in the control group (standard: 0.305 meters; dual task: 0.272 meters; n=65) compared to the cannabis group (standard: 0.28 meters; dual task: 0.256 meters; n=65); these differences were small (Cohen’s d -0.389 (standard) and -0.359 (dual task)) and were not significant after correction for multiple comparisons. Measures of speed and following distance were not impacted. Neither blood nor oral fluid THC, CBD or metabolites was significantly correlated with any measure of driving after correction for multiple comparisons; mean concentrations of blood THC was above 2 ng/mL. After correction for multiple comparisons, trends between driving and concentrations of the psychoactive metabolite 11-hydroxy-THC (11-OH-THC) were found. Participants who smoked cannabis the night before reported higher levels of subjective intoxication, and more willingness to drive before the drive, that was not significant after correction for multiple comparisons.

Conclusions

The regular cannabis use group showed no significant impairment in driving performance 12-15 hours after last cannabis use the night before, compared to the control group. Blood and oral fluid THC concentrations may not be an accurate correlate of driving behavior. Large-scale studies are needed to determine whether less frequent users are impaired the morning after last use, and whether the present findings also extend to different routes of administration.”

https://link.springer.com/article/10.1186/s42238-026-00416-w

The effect of hemp product consumption on blood fatty acid profiles and cardiovascular disease risk factors: results of a randomized, double-blind, crossover clinical trial

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“Hemp seeds are high in polyunsaturated fatty acids (PUFAs) including gamma linolenic acid (GLA), stearidonic acid (SDA), alpha linolenic acid (ALA) and linoleic acid (LA). To date, limited evidence is available on hemp product consumption and particularly hemp seeds and oil in humans and its relation to cardiometabolic risk factors.

The objective of present study was to examine the effects of hemp product consumption versus similar controls on circulating fatty acid profiles and cardiovascular disease (CVD) risk factors.

A randomized, double-blinded, crossover trial with 30 normoglycemic adults (18-65 years) within a BMI range of 25-35 kg m-2 were included. Participants consumed both hemp products and controlled products over the course of 4 weeks each. As expected, ALA (18:3 n-3), GLA (18:3 n-6) and dihomo-γ-linolenic acid (DGLA, 20:3 n-6) were elevated after the hemp treatment than controls. Similarly, ALA, DGLA as well as eicosapentaenoic acid (EPA) levels were elevated after the hemp treatment than controls. No differences in serum lipid levels, glucose and insulin concentrations, blood pressure, or body composition were observed between treatments.

Overall, consumption of hemp products modulated plasma and RBC fatty acids levels in a way which reflected the fatty acids these products are enriched in, without showing differences in major cardiometabolic risk factors. The present study demonstrated the human fatty acids profile response to consuming hemp products, novel functional foods rich in polyunsaturated fatty acids.”

https://pubmed.ncbi.nlm.nih.gov/41782552

“Overall, the present study showed that 4-week consumption of hulled hempseed and hemp oil in overweight individuals increased ALA, GLA, DGLA and EPA relative percentages in plasma and RBC respectively, demonstrating effective incorporation of hemp-derived polyunsaturated fatty acids into long-term lipid pools. These changes occurred without adverse effects on lipid metabolism, vascular function, and/or body composition.

Collectively, these findings support the metabolic safety of hemp products and highlight their potential utility as dietary sources of polyunsaturated fatty acids for improving circulating fatty acid profiles.”

https://pubs.rsc.org/en/content/articlelanding/2026/fo/d5fo04672f

Hemp-Derived Extracellular Vesicles: A Novel Frontier in Nanomedicine and Therapeutics

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“While mammalian-derived extracellular vesicles (EVs) face significant challenges in clinical translation due to scalability, cost, and safety, plant-derived EVs (PDEVs) have emerged as a promising alternative.

This review focuses on EVs derived from hemp (Cannabis sativa L.), or HEVs, a particularly compelling source that combines the general benefits of PDEVs, such as improved safety and scalability, with a unique, inherent therapeutic cargo.

HEVs are naturally enriched with a potent mix of cannabinoids, terpenes, and flavonoids, which may enhance therapeutic outcomes through synergistic interactions-a phenomenon known as the ‘entourage effect.’

Preclinical studies already demonstrate their potential, showing significant anti-cancer effects against aggressive tumors like glioblastoma, along with neuroprotective and anti-inflammatory properties.

However, the critical challenge hindering their clinical application is the lack of standardized, GMP (Good Manufacturing Practice)-compliant manufacturing protocols to address the inherent biochemical variability of the source material.

Overcoming these obstacles will be vital to unlocking the potential of HEVs as a novel, scalable frontier in nanomedicine.”

https://pubmed.ncbi.nlm.nih.gov/41787227

https://link.springer.com/article/10.1007/s40259-026-00766-0

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”

Bioactivity and Regenerative Potential of Cannabidiol in Human Dental Pulp Stem Cells: A Scoping Review of In Vitro Studies

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“Introduction: Cannabidiol (CBD), a nonpsychoactive compound derived from Cannabis sativa, has shown potential to influence cellular processes that are important for dental tissue repair. The aim of this scoping review was to map in vitro studies evaluating the influence of CBD on the osteogenic/odontogenic differentiation of human dental pulp stem cells (hDPSCs) in order to contribute to a better understanding of its therapeutic potential.

Methods: The review followed the Arksey and O’Malley framework, supported by the JBI Manual and PRISMA-ScR guidelines. The protocol was registered on OSF (osf.io/zfhca/). Comprehensive searches were conducted from January to June 2025 in PubMed, EMBASE, BVS, Scopus, Web of Science, ScienceDirect, and SciELO. Only studies published in English were included.

Results: Thirty articles were identified, and three in vitro studies met the eligibility criteria. At low concentrations (0.1-5 μM), CBD improved hDPSC viability, proliferation, migration, and differentiation. CBD also activated the mitogen-activated protein kinase (MAPK) and wingless-related integration site/beta-catenin signaling (WNT/β-catenin) pathways and increased the expression of odontogenic markers such as Sialophosphoprotein (DSPP), Runt-related transcription Factor 2 (RUNX2), and osteocalcin.

Conclusion: CBD shows promise as a bioactive molecule in regenerative endodontics, supporting mineralization, regulating inflammatory mediators, and promoting critical cellular activities in hDPSCs. Nevertheless, the available evidence is limited and further preclinical and clinical studies are essential to develop therapeutic protocols and assess long-term safety.

These preliminary findings indicate CBD as a novel candidate for regenerative strategies in endodontics.”

https://pubmed.ncbi.nlm.nih.gov/41767216