The endocannabinoid system as a therapeutic target in intestinal fibrosis

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“Intestinal fibrosis is a common and serious complication of inflammatory bowel diseases, often leading to strictures that require endoscopic or surgical intervention.

Despite advances in anti-inflammatory therapies, effective antifibrotic treatments is currently not available. Therefore, new treatment methods for intestinal fibrosis are sought with the endocannabinoid system (ECS) as a potential therapeutic target.

Cannabinoid receptors 1 and 2 (CB1/2) are classic receptors of the ES involved in the modulation of intestinal inflammation and permeability of the mucosal barrier. Experimental evidence from liver and lung models suggests that CB1 receptor activation promotes fibrosis through enhancement of the TGF-β/Smad pathway, interaction with the renin-angiotensin system, and upregulation of profibrotic markers, such as collagen and α-SMA.

In contrast, CB2 receptor signaling appears to exert protective effects by limiting inflammation, fibroblast activation, and extracellular matrix deposition. Recent findings also suggest cross-talk between cannabinoid signaling and platelet-derived growth factor pathways, which are key drivers of myofibroblast proliferation and fibrogenesis. Although these mechanisms are well-established in hepatic, pulmonary and skin fibrosis, data from small and large intestine is scarce. However, direct evidence in intestinal fibrosis is scarce, representing a major knowledge gap.

Elucidating ECS mechanisms in the alimentary tract could enable targeted antifibrotic strategies, complement current therapies, and reduce progression to fibrostenotic disease.”

https://pubmed.ncbi.nlm.nih.gov/41111512/

“The ECS is widespread in the human body, which proves its many functions in the body. Due to its presence in the digestive system and immune cells, it can influence the modulation of inflammation and the process of fibrosis in IBD. Numerous studies, both in animal models, cell cultures and in human tissue, show that the activation or inhibition of individual elements of the ECS can affect the process of intestinal fibrosis. Hence, the ECS may be a potential target aiming at the fibrosis reduction.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1669951/full

Survival rate of patients with combined hepatocellular cholangiocarcinoma receiving medical cannabis treatment: A retrospective, cohort comparative study

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“Background: Cholangiocarcinoma (CCA) incidence in Northeastern Thailand is very high and a major cause of mortality. CCA patients typically have a poor prognosis and short-term survival rate due to late-stage diagnosis. Thailand is the first Southeast Asian country to approve medicinal cannabis treatment, especially for palliative care with advanced cancer patients.

Methods: A retrospective cohort study compared survival among 491 newly diagnosed advanced CCA patients between September 2019 and June 2021. Of these, 404 received standard palliative pain management (ST), and 87 received medicinal cannabis treatment (CT). Patients were enrolled from four tertiary hospitals and two secondary hospitals in five provinces of Northeast Thailand. Cumulative survival was calculated by the Kaplan-Meier method, and independent prognostic factors were analyzed using Cox regression.

Results: For ST patients, follow-up time was 790 person-months, with a mortality rate of 48.35/100 person-months. For CT patients, follow-up time was 476 person-months, with a mortality rate of 10.9/100 person-months. The median survival time after registration at a palliative clinic was 0.83 months (95% CI: 0.71-0.95) for ST and 5.66 months (95% CI: 1.94-9.38) for CT. Multivariate analysis showed CT was significantly associated with prolonged survival (HRadj = 0.28; 95% CI: 0.20-0.37; p < 0.001).

Conclusions: The medical cannabis increased overall survival rates among CCA patients. In this retrospective cohort, Medicinal cannabis treatment was associated with more prolonged survival among advanced CCA patients in Northeastern Thailand. While this association remained significant after multivariable adjustment, unmeasured or residual confounding factors may have influenced the observed outcomes. Although the association remained significant after adjustment, unmeasured or residual confounders may have influenced outcomes. Further prospective studies are warranted to confirm these findings and explore potential mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41113085/

https://f1000research.com/articles/11-1212/v3

Long-term use of cannabis-based medicines in two children with Tourette syndrome: a case report

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“Introduction: Cannabis-based medicine (CBM) is recommended for the treatment of tics in otherwise treatment-resistant adult patients with Tourette syndrome (TS). However, evidence in children with TS is very limited. Long-term effects of CBM in this population are unknown.

Case presentations: We present two cases of long-term follow-up over six and five years, respectively, in male adolescents with TS who were administered CBM starting at the age of eight and 12 years, respectively. In one patient CBM treatment was initiated with pure tetrahydrocannabinol (THC) and was later changed to current treatment with an oral THC-dominant cannabis extract (THC:cannabidiol (CBD)=25:<0.5) with a daily dose of 0.5-0.6 mL (corresponding to 12.5-15 mg THC/day). The other patient was from the beginning up to now medicated by his parents, who are physicians, with vaporized THC-dominant (24%) medicinal cannabis flowers with a dose of 0.2 g between once to thrice per day (corresponding to 48-144 mg THC/day). While in one patient, there was a moderate dose increase over the years, in the other patient dosages were adjusted individually depending on tic severity. In both patients, CBM treatment resulted in continued benefit with significant improvement of tics and psychiatric comorbidities without severe adverse effects. Academic performance of both adolescents was excellent. Neurocognitive assessments demonstrated average results in the domain of working memory and average to above average results in the domain of processing speed.

Conclusions: We present two cases of minors with TS who started CBM treatment at the age of eight and 12 years, respectively, and continued treatment for five to six years resulting in clinically relevant symptom improvement without any severe adverse effects or negative impact on cognitive and academic performance.”

https://pubmed.ncbi.nlm.nih.gov/41113190/

“In summary, we present two cases of minors with TS who started CBM treatment before puberty at the age of eight and 12 years, respectively, and continued treatment for five to six years resulting in sustained clinically relevant symptom improvement without severe adverse effects or negative impact on cognitive and academic performance. Although generalizability from our case reports of two single patients is limited, we suggest to take treatment with THC-containing drugs into consideration in severely affected and otherwise treatment refractory children and adolescents before thinking of surgical treatment using deep brain stimulation.”

https://doi.org/10.3389/fpsyt.2025.1647969

Anti-inflammatory effects of cannabidiol in the treatment of type 1 diabetes: A mini review

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“This study reviews the anti-inflammatory potential of cannabidiol (CBD) in the management of type 1 diabetes (T1D).

A comprehensive search was conducted across PubMed, Scopus, and ScienceDirect databases using the terms “type 1 diabetes”, “cannabidiol”, “anti-inflammatory effect”, and “CBD”. Articles published between 2005 and 2025 were screened, and studies involving animal models that examined CBD as a therapeutic intervention for T1D and reported on its anti-inflammatory effects were included. Of the 62 retrieved articles, only 6 met the predefined inclusion criteria.

Although limited in number, the available studies show promising outcomes. CBD demonstrates potential as an adjuvant therapy for T1D due to its immunomodulatory and anti-inflammatory actions. Nonetheless, further research is required to establish safe and effective clinical application protocols.”

https://pubmed.ncbi.nlm.nih.gov/41113484/

https://doi.org/10.4239/wjd.v16.i10.110041

Cannabidiol reverses depression-like behaviors by enhancing hippocampal synaptic plasticity in rats with chronic restraint stress

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“Background and aim: Major depressive disorder is a prevalent psychiatric condition associated with impaired neuroplasticity, particularly in the hippocampus. Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, their delayed onset and adverse effects highlight the need for alternative therapies. Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has shown antidepressant-like properties, but its mechanistic link to hippocampal synaptic plasticity remains unclear. This study aimed to evaluate the effects of CBD on depression-like behaviors and hippocampal neuroplasticity in rats subjected to chronic restraint stress (CRS).

Materials and methods: Sixty male Wistar rats were randomly divided into six groups: Non-stressed vehicle (NV), CRS vehicle (SV), escitalopram-treated CRS (SE, 10 mg/kg), and CBD-treated CRS at 10, 30, or 100 mg/kg (SC10, SC30, and SC100). Rats were subjected to CRS for 28 days and treated daily through intraperitoneal injection. Depression-like behaviors were assessed using the forced swim test (FST) and sucrose preference test (SPT). Locomotor activity was evaluated through the open-field test (OFT). Hippocampal dendritic spine density (Golgi-Cox staining) and long-term potentiation (LTP, electrophysiology) were measured on day 28.

Results: CRS induced behavioral despair (↑ immobility in FST) and anhedonia (↓ sucrose preference in SPT), accompanied by reduced hippocampal spine density. At all doses, CBD significantly reduced immobility, comparable to escitalopram. Notably, only CBD at 100 mg/kg and escitalopram reversed anhedonia. All CBD-treated groups showed an increase in dendritic spine density, with SC10 producing the greatest enhancement. Moreover, CBD at 100 mg/kg markedly improved hippocampal LTP at 1 h and 2 h post-stimulation, an effect not observed with escitalopram. Locomotor activity remained unaffected.

Conclusion: CBD demonstrated potent antidepressant-like effects in a CRS rat model, alleviating behavioral despair and anhedonia while enhancing hippocampal dendritic spine density and synaptic strength. These findings suggest CBD as a promising candidate for stress-related mood disorders, with mechanistic actions distinct from conventional SSRIs and potential utility in patients unresponsive to current therapies.”

https://pubmed.ncbi.nlm.nih.gov/41113223/

https://veterinaryworld.org/Vol.18/September-2025/22.php

Cannabis Laws and Opioid Use Among Commercially Insured Patients With Cancer Diagnoses

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“Importance: Pain is a prevalent cancer-related symptom, but limited research investigates whether cannabis is an effective analgesic for cancer pain.

Objective: To examine the association of medical and recreational cannabis dispensary availability on prescription opioid dispensing among commercially insured patients with cancer.

Design, setting, and participants: This cross-sectional study used synthetic control to investigate the association of cannabis dispensary openings with pain medication dispensing among patients with cancer. Data were extracted from Optum’s deidentified Clinformatics Data Mart database from January 1, 2007, to December 31, 2020. The study population included patients aged 18 to 64 years with a cancer diagnosis and at least 6 months of continuous enrollment. Associations were estimated by age, race and ethnicity, and sex. Data were analyzed between December 2024 and February 2025.

Exposures: Exposures included indicators for whether a medical or recreational cannabis dispensary was open in each state-quarter.

Main outcomes and measures: The outcome measures for opioids prescriptions were (1) the rate of patients with a prescription per 10 000 patients, (2) the quarterly mean days’ supply per prescription, and (3) the quarterly mean number of prescriptions per patient.

Results: The study included a mean (SD) of 3.05 (0.86) million patients annually across the US (mean [SD] age, 43.7 [9.6] years; mean [SD] 59.0% [0.32%] female). Medical cannabis dispensary openings were associated with significant reductions in all opioid outcomes. The rate of patients with cancer with opioid prescriptions changed by -41.07 per 10 000 (95% CI, -54.78 to -27.36 per 10 000; P < .001), the quarterly mean days’ supply by -2.54 days (95% CI, -3.16 to -1.92 days; P < .001), and the mean number of prescriptions per patient by -0.099 (95% CI, -0.121 to -0.077; P < .001). Recreational dispensary openings were also associated with reductions in opioid outcomes, though estimated treatment effects were smaller. The rate of prescriptions changed by -20.63 per 10 000 (95% CI, -35.35 to -5.91 per 10 000; P = .049), the mean daily supply by -1.09 days supplied per prescription (95% CI, -1.72 to -0.46 days; P = .04), and the mean number of prescriptions per patient by -0.097 (95% CI, -0.134 to -0.060; P = .01).

Conclusions and relevance: This study’s findings indicate cannabis may be a substitute for opioids in the management of cancer-related pain. However, further research directly observing cannabis use is needed to evaluate the efficacy of cannabis as a treatment for cancer-related pain.”

https://pubmed.ncbi.nlm.nih.gov/41105418/

“These findings indicate that medical or recreational cannabis laws may be significantly associated with reduced opioid use among patients diagnosed with cancer.”

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2840030

Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer’s disease treatment using molecular simulations and modeling

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“Alzheimer’s disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.

Based on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.

We investigated CBD’s interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.

Our results show that CBD binds to Aβ with binding free energies of -7.81 kcal/mol, -7.46 kcal/mol, and -7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ’s β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of -9.91 kcal/mol, -9.70 kcal/mol, and -9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of -8.94 kcal/mol, -8.51 kcal/mol, and -8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD’s favorable oral bioavailability and low toxicity.

These findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.”

https://pubmed.ncbi.nlm.nih.gov/41105605/

https://journals.sagepub.com/doi/10.1177/13872877251386440

Advancing cervical cancer treatment: integrating cannabinoids, combination therapies and nanotechnology

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“Background: Cervical cancer remains a major global health challenge, with the highest incidence and mortality rates observed in sub-Saharan Africa. Despite progress in prevention and treatment, the management of advanced and recurrent disease remains difficult.

Aim: This review explores the potential role of cannabinoids in cervical cancer therapy, with a focus on their integration into existing treatment strategies, combination therapies, and nanotechnology-based delivery systems.

Methods: A critical synthesis of preclinical studies and emerging therapeutic approaches was conducted, examining the anticancer properties of cannabinoids, their mechanisms of action, and their application within combination and nanotechnology-based treatment modalities.

Results: Cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) demonstrate anticancer effects by inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis. Mechanistic studies highlight their ability to promote oxidative stress, modulate key signalling pathways, and influence immune responses in cervical cancer cells. Combination therapies involving cannabinoids with chemotherapy, radiotherapy, and immunotherapy show enhanced efficacy and reduced drug resistance. Furthermore, nanotechnology-based delivery systems offer advantages including targeted drug release, improved solubility, controlled dosing, and decreased systemic toxicity.

Conclusion: Cannabinoids represent a promising adjunct in cervical cancer management. However, successful clinical translation requires optimisation of formulations, establishment of dosing protocols, and comprehensive safety evaluation. Future research should also explore biomarker-driven personalised medicine approaches. Standardisation, along with addressing regulatory and ethical challenges, will be crucial for the integration of cannabinoid-based therapies into mainstream cervical cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/41102423/

“The convergence of cannabinoids, nanotechnology, and combination therapies presents a promising frontier in cervical cancer treatment. This approach leverages the synergistic potential of cannabinoids with conventional treatments such as chemotherapy, radiotherapy, and immunotherapy, while using nanotechnology for targeted delivery. The integration of these elements could enhance treatment efficacy and minimize side effects.”

https://link.springer.com/article/10.1007/s00432-025-06323-6

Molecular targets of cannabinoids and their derivatives in epilepsy – a review with focus on CBD

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“In recent years, cannabinoids and their derivatives have been tested for efficacy in epilepsy therapy and related disorders. Many of them may help alleviate ailments associated with seizures. An in-depth study of cannabinoid derivatives and the receptors on which they operate give us a chance for more effective use of these substances in epilepsy therapy.

Many studies point to the beneficial synergy of cannabinoids with chemotherapeutics and the increase in effectiveness of the latter. As a result, both alternatives to drug treatment and support for the pharmacotherapy are being developed.

In this review, we focused on compounds such as Δ9-THC, CBDV, Δ9-THCA, Δ9-THCV, H2CBD and their receptors as well as on CBD’s actions, and the enzymes, ion channels, and transporters engaged in the fundamental causes of epileptic seizures.

Treating epilepsy and drug-resistant epilepsy are the two common medical uses of cannabinoids. We looked at approximately 150 current scientific articles from peer-reviewed journals to explore the molecular effects of cannabinoids in these applications. Our goal was to improve physician awareness of factors influencing treatment decisions and potential adverse reactions to minimize medical errors and optimize patient care.”

https://pubmed.ncbi.nlm.nih.gov/41098593/

“In conclusion, while CBD now stands as a recognized and effective treatment for specific forms of epilepsy, a deeper, integrated understanding of its comprehensive mechanisms, validated efficacy across diverse populations, and long-term safety profile remains essential. Continued collaborative efforts among scientists, clinicians, and policymakers, coupled with stringent critical appraisal of evidence, will be key to unlocking the full and safe potential of cannabinoids in epilepsy therapy.”

https://www.frontierspartnerships.org/journals/acta-biochimica-polonica/articles/10.3389/abp.2025.15251/full

The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas

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“Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their utilization.

This review synthesizes extensive knowledge regarding the role of the endocannabinoid system (ECS) in the pathogenesis of obesity, as well as its potential as a therapeutic target. A thorough evaluation of preclinical and clinical data concerning endocannabinoid ligands, cannabinoid receptors (CB1, CB2), their genetic variants, and pharmacological interventions targeting the ECS was conducted.

Literature data suggests that the overactivation of the ECS may play a role in the pathophysiology of excessive food intake, dysregulated energy balance, adiposity, and metabolic disturbances.

The pharmacological modulation of ECS components, by means of CB1 receptor antagonists/inverse agonists, CB2 receptor agonists, enzyme inhibitors, and hybrid or allosteric ligands, has demonstrated promising anti-obesity effects in animal models. However, the translation of these findings into clinical practice remains challenging due to safety concerns, particularly neuropsychiatric adverse events.

The development of novel strategies, including peripherally restricted compounds, hybrid dual-target agents, dietary modulation of endocannabinoid tone, and non-pharmacological interventions, promises to advance the field of obesity management.”

https://pubmed.ncbi.nlm.nih.gov/41096816/

“Taken together, the growing body of evidence suggests that targeting the ECS, either pharmacologically or through lifestyle interventions, may open a new chapter in the prevention and treatment of obesity.”

https://www.mdpi.com/1422-0067/26/19/9549