Cannabidiol-Loaded Nanostructured Lipid Carriers for Nose to Brain Delivery: An Effective Therapeutic Approach against Epilepsy

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“The presence of first-pass metabolism and the obstacle of the blood-brain barrier may reduce the effectiveness of oral antiepileptic medications. Nasal drug delivery has been considered a promising selective route to the brain for drugs with low aqueous solubility in the treatment of CNS disease.

The purpose of our study was to improve the bioavailability as well as brain targetability of cannabidiol (CBD) by encapsulating it in nanostructured lipid carriers (NLCs) and delivering the formulation via the nasal route.

CBD-NLCs were effectively prepared with the appropriate particle sizes and polydispersity index for the nasal route (77.71 nm± 0.79 and 0.23 ± 0.00, respectively). These particles demonstrated a high entrapment efficiency and drug loading of 99.24% ± 0.07 and 8.73% ± 0.56 w/w, respectively. According to the FTIR, XRD, and DSC data, CBD was either in the amorphous state or distributed molecularly in the lipid matrix.

The absorption of CBD-NLCs in the nasal cavity was significantly superior to pure CBD (the rate constants were 9.02 ± 1.64 and 2.10 ± 0.25 μg/min, respectively). Compared to the intravenous administration of CBD, CBD-NLCs showed a drug targeting efficiency of 277.82% after nasal administration, indicating a more efficient brain targeting. In a rat model where seizure activity was induced by PTZ, intranasal administration of CBD-NLCs significantly prolonged seizure latency and decreased the Racine score.

All of the results suggest CBD-NLCs administered intranasally might be a promising alternative to traditional epilepsy treatments.”

https://pubmed.ncbi.nlm.nih.gov/40693913/

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c00452

Role of the Endocannabinoid System in Fibromyalgia

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“Fibromyalgia is a chronic disease marked by extensive musculoskeletal pain, persistent fatigue, and cognitive impairments. Despite its high prevalence, the underlying pathological mechanisms of fibromyalgia are still not fully elucidated.

Emerging research has identified the endocannabinoid system as an essential factor in modulating pain and other symptoms related to fibromyalgia. The endocannabinoid system plays a key role in many physiological processes such as pain perception, mood regulation, and inflammation.

This review provides a powerful analysis of the principal aspects of fibromyalgia and examines the evidence regarding the involvement of the endocannabinoid system in this condition, focusing on its influence on pain modulation. Moreover, the dysregulation of the endocannabinoid system in fibromyalgia patients will be examined, with an assessment of how variations in endocannabinoid levels and receptor activity may contribute to the clinical manifestations of the condition.

A better knowledge of this physiological system could lead to the development of novel strategies for managing fibromyalgia.”

https://pubmed.ncbi.nlm.nih.gov/40699629/

https://www.mdpi.com/1467-3045/47/4/230

Inflammatory bowel disease patients believe cannabis and cannabidiol oil relieve symptoms

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“Background: Patients with Inflammatory bowel disease (IBD) often seek alternative therapies for symptom management. This study investigates the perceptions, consumption patterns, and reported outcomes of cannabis and cannabidiol (CBD) oil use among IBD patients and controls.

Methods: A 37-question survey was administered to 139 participants (IBD patients, n = 93; control/non-IBD participants, n = 33) to assess usage frequency and beliefs regarding cannabis and CBD oil as treatment for IBD. The survey also evaluated the impact of these substances on IBD symptoms, quality of life, and opioid use.

Results: Cannabis consumption was higher in IBD patients (57, 53.8%) than controls (15, 45.5%) with both groups strongly supporting medical cannabis use (IBD; 92, 86.8% vs. controls; 29, 84.9%). Most IBD patients believed cannabis (67, 63.2%), CBD oil (60, 56.6%), corticosteroids (77, 73.3%), and biologics/immunosuppressants (85, 81.0%) had a somewhat-extremely beneficial effect in relieving IBD symptoms. Over 50% of IBD cannabis users reported relief from abdominal pain, other pain, stress, anxiety, depression, and nausea/vomiting, with Crohn’s disease patients experiencing significantly more relief than ulcerative colitis patients for certain symptoms (p < 0.05). Notably, 19.4% of IBD patients reported decreased opioid use, and 14.5% reported induced remission with cannabis or CBD oil.

Conclusions: Consumption of cannabis and CBD oil was perceived as beneficial for relieving IBD, with many reporting significant symptom relief from using these substances. The strong support of cannabis and CBD oil as medical treatments and therapeutic effects highlights the potential for cannabis and CBD oil as treatments in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40687272/

“Recent preclinical studies have suggested that cannabinoids, including CBD and THC, may reduce gastrointestinal inflammation and modulate intestinal motility. The presence of cannabinoid receptors in the gut, along with the anti-inflammatory effects of some cannabinoids, has led researchers to explore the potential for therapeutic applications of cannabis in the treatment of IBD.”

“Animal studies of the chemistry and physiology of cannabinoids have shown potential anti-inflammatory, antidiarrheal, and nociceptive-limiting effects, paralleling the growing interest in cannabis as a treatment option for IBD.

Human studies have also indicated that there may be a benefit in controlling IBD symptoms and improving quality of life. Additionally, anecdotal reports and observational studies have highlighted potential benefits in reducing disease activity and managing symptoms like abdominal pain, cramping, joint pain, and diarrhea.”

https://www.academia.edu/2994-435X/2/2/10.20935/AcadMed7773

The effects of nabiximols (Sativex®) on spasticity and non-motor symptoms in chronic spinal cord injury (SCI): a longitudinal prospective study

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“Objectives: This study aimed to evaluate the effects of Nabiximols (Sativex®) on spasticity in chronic spinal cord injury (SCI) individuals refractory to conventional therapy. Secondary objectives included assessing its impact on functional independence, neuropathic pain, sleep quality, and depression.

Setting: Institute Guttmann, a neurorehabilitation hospital in Badalona, Catalonia (Spain).

Methods: Adult participants ( >18 years) with chronic SCI ( >6 months) and moderate to severe spasticity refractory to conventional treatments were recruited. All participants underwent baseline assessments and were followed up at one and two months after initiating treatment with nabiximols oromucosal spray, with individualised dose adjustments on a weekly basis. Assessed variables included spasticity, functional independence, neuropathic pain, sleep quality, depression, quality of life, and Patient Global Impression of Improvement (PGI-I).

Results: Statistically significant improvements in spasticity were observed after one month (VAS decrease of 30%, p < 0.001; MAS decrease of 60%, p = 0.001) and two months (VAS decrease of 30%, p < 0.001; MAS decrease of 52%, p = 0.011) of treatment. A positive PGI-I was reported in 67% of participants. However, no significant changes were noted in spasms frequency, functional independence, neuropathic pain, or sleep quality. No significant differences in spasticity change or non-motor symptoms were found between participants with complete and incomplete SCI.

Conclusions: Nabiximols may effectively reduce spasticity in individuals with SCI resistant to conventional therapies. Given the significant impact of spasticity associated with SCI, it could be considered a viable add-on therapy for this population.”

https://pubmed.ncbi.nlm.nih.gov/40675989/

https://www.nature.com/articles/s41394-025-00712-2

How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1

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“Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data.”

https://pubmed.ncbi.nlm.nih.gov/40687805/

“We developed a model for predicting binding affinity and activity of cannabinoids which can be used for further drug design efforts in the design of new cannabinoid-based ligands.”

https://www.cell.com/iscience/fulltext/S2589-0042(25)00967-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004225009678%3Fshowall%3Dtrue

Integrated multi-omic profiling uncovers endocannabinoid system as a driver of nerve agent-induced cognitive dysfunction in guinea pigs

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“Soman, a highly lethal organophosphorus compound (OP), is notorious for its rapid induction of irreversible acetylcholinesterase binding through accelerated aging. Although subacute soman exposure has been specifically implicated in cognitive deficits, the molecular pathways driving these impairments remain poorly characterized, highlighting a significant research gap.

This study aims to comprehensively elucidate the effects of soman exposure on cognitive impairment by analyzing proteome and lipidome alterations in the hippocampal tissue of guinea pigs administered a sublethal dose (11 µg/kg) of soman. A molecular network based on lipidomic and proteomics data was constructed to investigate the key molecules.

The study demonstrates that subcutaneous exposure to low-dose soman for 14 consecutive days in guinea pigs impairs learning and memory. We further observed that soman exposure induces damage to both the hippocampal neurons and the mitochondrial ultrastructure in the brains of these animals.

The study revealed that subacute soman exposure significantly altered the endocannabinoid system, characterized by disrupted biosynthesis and metabolism of 2-arachidonoylglycerol (2-AG), with a significant down-regulation of 2-AG lipid metabolism pathways, as well as a significant up-regulation of cannabinoid receptor 1 (CB1R) pathways. Notably, the disruption of 2-AG biosynthesis and metabolism is primarily attributed to the upregulation of the activities of three key enzymes, DAGLα, MAGL, and ABHD6. The activation of CB1R negatively feedback-regulate the cAMP/PKA pathway which further leads to dysregulation of mitochondrial homeostasis and reduced energy metabolism. Pharmacodynamic evaluations demonstrated that reversible MAGL inhibitor and ABHD6 inhibitor effectively elevate 2-AG levels in cerebral organoid models, subsequently restoring mitochondrial energy metabolism.

This research expands the current understanding of soman’s systemic neurotoxicity, particularly its capacity to modulate endocannabinoid-mediated cognitive processes. Our results provide mechanistic insights into soman-induced cognitive deficits and associated health risks. Importantly, elevating 2-AG levels may serve as an effective strategy for preventing and treating soman-induced memory impairment.”

https://pubmed.ncbi.nlm.nih.gov/40691673/

https://link.springer.com/article/10.1007/s00204-025-04131-y

Association of Smoking Cannabis With Cardiovascular Events Among Veterans With Coronary Artery Disease

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“Background: Whether cannabis is a risk factor for cardiovascular events is unknown. We examined the association between smoking cannabis and cardiovascular events in a cohort of older veterans (66 to 68 years of age) with coronary artery disease.

Methods: The THC Cohort (Heart and Cannabis) comprised 4285 veterans (mean [SD] age, 67.5 [1.01] years; 2% female) with coronary artery disease who were born in 1950 to 1952. Participants were recruited between April 5, 2018, and March 12, 2020, interviewed about health behaviors, and then classified according to their self-reported cannabis smoking status in the previous 30 days. In a separate analysis, we classified participants according to any form of cannabis use (smoking, vaping, or edible use) versus nonuse in the past 30 days. Data on demographic, behavioral, and clinical characteristics were collected by telephone interview and from national Department of Veterans Affairs and Medicare data sources. The primary outcome included a composite of fatal and nonfatal stroke, fatal and nonfatal acute myocardial infarction, and cardiovascular death. The follow-up period for each patient extended from the date of their initial interview until the end of study (June 14, 2022). All participants were followed until they experienced an outcome or until the end of the follow-up period. Survey nonresponse weights and propensity score-based weights were used to reduce bias and confounding. Hazard ratios were estimated using cause-specific hazard models.

Results: The cohort included 1015 veterans with coronary artery disease who reported smoking cannabis in the previous 30 days and 3122 veterans who did not smoke cannabis in the previous 30 days. Mean follow-up was 3.3 years, and 563 events occurred. Compared with veterans who did not smoke cannabis, smoking cannabis (past 30 days) was not associated with the composite outcome of acute myocardial infarction, stroke, and cardiovascular death (adjusted hazard ratio, 0.87 [95% CI, 0.61-1.24]). Similarly, use of any form of cannabis (smoking, vaping, dabbing, edibles) in the past 30 days was not associated with the composite outcome.

Conclusions: In this cohort of older veterans with coronary artery disease, self-reported cannabis use was not independently associated with increased cardiovascular events over a mean of 3.3 years of follow-up.”

https://pubmed.ncbi.nlm.nih.gov/40686207/

“In this older cohort of veterans with coronary artery disease, both recent and lifetime smoking of cannabis were not associated with risk for having a CVD event, defined as heart attack, stroke, or cardiovascular death.”

“Beyond established CVD risk factors, we could not detect an association of cannabis use with CVD events, so it may not be an important contributor in this population.”

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.073193

Cannabidiol improves L-DOPA-induced dyskinesia and modulates neuroinflammation and the endocannabinoid, endovanilloid and nitrergic systems

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“Despite the widespread use of L-3,4-dihydroxyphenylalanine (L-DOPA) as the gold standard for dopamine (DA) replacement in Parkinson’s Disease (PD), its prolonged administration frequently leads to L-DOPA-induced dyskinesia (LID), a significant therapeutic challenge.

Modulating the endocannabinoid system has emerged as a promising approach for managing LID.

This study explored whether cannabidiol (CBD), a non-psychoactive compound of Cannabis sativa, and PECS-101, a fluorinated derivative of CBD, could mitigate the onset and progression of LID.

We used unilateral 6-hydroxydopamine-lesioned rats, treated with L-DOPA (10 mg kg – 1) for three weeks to induce severe abnormal involuntary movements (AIMs). Treatments were administered during the final two weeks. CBD (30 mg kg – 1) and PECS-101 (3 and 30 mg kg – 1) significantly reduced AIMs without impairing the motor benefits of L-DOPA.

The antidyskinetic effects of CBD were associated with decreased striatal Fos-B and phospho-ERK expression and were independent of lesion severity. CBD effects were prevented by antagonists of CB1 (1 mg kg – 1) and PPARγ (4 mg kg – 1) receptors. Co-administration of TRPV-1 antagonist capsazepine (5 mg kg – 1) enhanced the antidyskinetic effects of CBD. Combining the capsazepine with the neuronal nitric oxide synthase inhibitor, 7-nitroimidazole (10 mg kg – 1) enhanced these effects. CBD did not alter striatal DA levels but significantly increased the concentrations of anandamide and 2-arachidonoylglycerol in dyskinetic animals.

The antidyskinetic effects of CBD were associated with a reduction of the enhanced striatal glia and peripheral inflammation markers. These findings suggest that CBD alleviates LID by interacting with the nitrergic neurotransmission and TRPV-1, CB1, and PPARγ receptors.”

https://pubmed.ncbi.nlm.nih.gov/40684872/

“Cannabidiol (CBD), the primary non-psychotomimetic compound in Cannabis sativa, has shown promise in PD and LID treatment (Junior et al., 2020; Fernández-Ruiz et al., 2013). Its pharmacological profile includes neuroprotective, anti-inflammatory, and antioxidant properties, as well as interaction (either directly or indirectly) with several receptors associated with LID (Ibeas Bih et al., 2015; Devinsky et al., 2014). CBD also protects neurons from toxic insults by modulating glutamatergic and dopaminergic signaling (Fogaça et al., 2012; Kim et al., 2006).”

https://www.sciencedirect.com/science/article/abs/pii/S0278584625002106?via%3Dihub

Antitumor effects of cannabidiol (CBD) on osteosarcoma by targeting TNF-α/NF-κB/CCL5 signaling axis

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“Background: Osteosarcoma remains a therapeutic challenge due to its aggressive behavior and high metastatic potential, necessitating exploration of novel treatment modalities. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with emerging anticancer properties, has shown promise in preclinical cancer models. However, its mechanisms of action in osteosarcoma remain incompletely understood. This study systematically investigates the antitumor effects of CBD on osteosarcoma and elucidates its molecular targets within the TNF-α/NF-κB/CCL5 signaling axis.

Methods: The effective concentration of CBD was determined using the CCK-8 assay. Functional assays (EdU proliferation, Transwell migration/invasion, and scratch wound healing) evaluated its impact on osteosarcoma cell malignancy. A mouse xenograft model assessed in vivo efficacy. Network pharmacology and RNA-seq identified key pathways, which were validated via ELISA, qRT-PCR, and western blot. Molecular interactions were confirmed through CETSA, SPR, ITC, and molecular docking analyses targeting p65 (NF-κB subunit).

Results: CBD potently suppressed osteosarcoma cell proliferation, migration, and invasion while inhibiting xenograft tumor growth in vivo. Mechanistically, CBD disrupted the TNF-α/NF-κB/CCL5 axis by directly binding p65, thereby attenuating NF-κB-mediated transcriptional activation of CCL5. Notably, CBD abrogated a p65-CCL5 positive feedback loop that perpetuates inflammatory signaling, a novel finding linking CBD’s effects to inflammatory cascade disruption in osteosarcoma.

Conclusion: This study provides the first evidence that CBD inhibits osteosarcoma progression by targeting the TNF-α/NF-κB/CCL5 axis, disrupting a coordinated inflammatory-proliferative cascade. These findings position CBD as a promising therapeutic candidate for osteosarcoma, warranting further clinical investigation.”

https://pubmed.ncbi.nlm.nih.gov/40680332/

“CBD exhibits both efficacy and safety as an anticancer medication.”

https://www.sciencedirect.com/science/article/pii/S0944711325007056?via%3Dihub

Machine-learning of medical cannabis chemical profiles reveals analgesia beyond placebo expectations

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“Background: The efficacy of medical cannabis in alleviating pain has been demonstrated in clinical trials, yet questions remain regarding the extent to which specific chemical compounds contribute to analgesia versus expectation-based (placebo) responses. Effective blinding is notoriously difficult in cannabis trials, complicating the identification of compound-specific effects.

Methods: In a prospective study of 329 chronic pain patients (40% females; aged 48.9 ± 15.5) prescribed medical cannabis, we examined whether the chemical composition of cannabis cultivars could predict treatment outcomes. We used a Random Forest classifier with nested cross-validation to assess the predictive value of demographics, clinical features, and approximately 200 chemical compounds. Model robustness was evaluated using six additional machine learning algorithms.

Results: Here we show that incorporating chemical composition markedly improves the prediction of pain relief (AUC = 0.63 ± 0.10) compared to models using only demographic and clinical features (AUC = 0.52 ± 0.09; p < 0.001). This result is consistent across all models tested. While well-known cannabinoids such as THC and CBD provide limited predictive value, specific terpenoids, particularly α-Bisabolol and eucalyptol, emerge as key predictors of treatment response.

Conclusions: Our findings demonstrate that pain relief can be predicted from cannabis chemical profiles that are unknown to patients, providing evidence for compound-specific therapeutic effects. These results highlight the importance of considering the full range of cannabis compounds when developing more precise and effective cannabis-based therapies for pain management.”

https://pubmed.ncbi.nlm.nih.gov/40670615/

“Chronic pain affects millions of people, and many turn to medical cannabis for relief. However, scientists debate whether cannabis truly reduces pain or if patients feel better simply because they expect it to work (placebo effect). In this study, we looked at 329 people who used medical cannabis and analyzed the chemical makeup of their treatments. Using machine learning, we tested whether the specific chemicals in cannabis could predict who would get pain relief.

We found that patients’ pain improvement could be predicted from the chemical content of their cannabis, even though patients didn’t know what chemicals they were receiving. This suggests that cannabis provides real pain relief beyond just patient expectations.

These findings show that medical cannabis has genuine therapeutic effects for pain management.”

“In conclusion, to the best of our knowledge, our study provides compelling evidence that the efficacy of MC in pain relief is not merely a placebo response but is strongly influenced by its diverse chemical composition. Our findings challenge the traditional focus on THC and CBD as the primary therapeutic agents in cannabis and highlight the importance of considering the full spectrum of chemical compounds present in MC. By embracing a more comprehensive approach to understanding MC’s therapeutic potential, we can work towards developing safer, more effective, and more precisely targeted treatments for the millions of individuals suffering from chronic pain worldwide.”

https://www.nature.com/articles/s43856-025-00996-3