“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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).”
“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.”
“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.”
“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.”
“Classical cisplatin-based chemotherapeutic drugs are widely used in clinical practice. In recent years, novel platinum-based antitumor drugs have focused on replacing classical cisplatin-like Pt(II) complexes with relatively inert Pt(IV) prodrugs to overcome drug resistance and reduce toxic side effects.
Based on the excellent physiological and pharmacological activities of cannabidiol (CBD), this study designed and synthesized novel Pt(IV) prodrugs W1-W6, which are axial conjugates of cisplatin with CBD and specific active small molecules.
These prodrugs demonstrated more significant antitumor activity against tested tumor cell lines. Among them, the multifunctional Pt(IV) prodrug W5, conjugated with CBD and the PDK inhibitor DCA, exhibited excellent activity against both platinum-sensitive and cisplatin-resistant tumor strains.
The IC50 value of W5 for the A549R tumor strain was 8.53 ± 0.76 μM, significantly higher than that of the cisplatin group and 3.64 times the activity of CBD alone, demonstrating strong synergistic antitumor activity and potential to overcome cisplatin resistance. W5 is reduced by GSH in A549R cells, releasing CBD and Pt(II). Pt(II) binds to DNA, inducing damage and inhibiting repair, while CBD activates pro-apoptotic proteins, leading to mitochondrial dysfunction. Simultaneously, W5 reduces the levels of ROS scavengers, triggering endoplasmic reticulum dysfunction. These three mechanisms synergistically promote tumor cell apoptosis and overcome drug resistance.
This design integrates multiple mechanisms through axial functionalization, breaking through the limitation of traditional platinum drugs targeting DNA alone, and achieves synergistic effects by regulating metabolism and intervening in the immune microenvironment.”
“Cannabidiol (CBD) is another high-content non-psychoactive component in cannabis extracts, possessing functions such as antitumor, antiepileptic, anticonvulsant, anxiolytic, and anti-inflammatory properties [[12], [13], [14]]. Research indicates that cannabidiol, as a hydrophobic molecule, can easily cross the blood-brain barrier to reach brain tumor sites [15], enhancing interactions with the endocannabinoid system (ECS) to alleviate pain and promote immune cell regulation [16], thereby increasing the expression of complexes that help the immune system recognize cancer.”
“Objective: This descriptive, real-world, multicenter study aimed to evaluate the efficacy, safety, and tolerability of purified cannabidiol (CBD) as an add-on therapy in children with treatment-resistant developmental and epileptic encephalopathies (DEE).
Methods: Children aged 0.5 to 16 years who met the International League against Epilepsy (ILAE) criteria for drug-resistant DEE and were treated with purified CBD at 10 different centers between March 2021 and December 2024 were included.
Results: A total of 551 patients were enrolled. The mean age at CBD initiation was 8.5 years (SD 5 years; range 0.5-18). Median follow-up duration was 22 months (range 13-32). Etiologies were structural in 249 (45 %), genetic in 160 (28.8 %), immune-mediated in five (0.9 %), infectious in three (0.5 %), and unknown in 134 (24.3 %). After 12-32 months of follow-up, 279 patients (50.6 %) had a > 50 % reduction in seizure frequency, including 78 (14.2 %) who became seizure-free. A reduction of < 50 % was observed in 106 (19.1 %), and 34 (6.2 %) experienced no change. Adverse events occurred in 32.7 %, mostly mild and transient, improving with dose adjustments. At the last visit, 389 patients (70.6 %) continued CBD, with 173 (31.4 %) maintaining a > 50 % reduction in seizures and 56 (10.2 %) remaining seizure-free.
Conclusions: This study supports the use of purified CBD as an effective, safe, and well-tolerated treatment option for children with drug-resistant DEEs of diverse etiologies.”
“Purpose: Cystic echinococcosis is a parasitic zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. Albendazole (ABZ) is the drug of choice, although its efficacy is variable. The present research aimed to assess the in vitro and in vivo efficacy of a full-spectrum extract of Cannabis sativa inflorescences against E. granulosus sensu stricto (s.s.).
Methods: Protoscoleces and cysts were incubated in vitro with the C. sativa extract, achieving final CBD concentrations of 1, 5, 10, and 50 µg/ml. Viability was evaluated periodically. Structural and ultrastructural alterations were also recorded. For the clinical efficacy study, female CF-1 mice were infected. Six months later, mice were divided into groups (n = 10): (a) water control; (b) ABZ; (c) C. sativa extract, and (d) ABZ + C. sativa extract. Treatments were administered every 24 h for 30 days. The efficacy of the treatments was evaluated according to the weight of the cysts collected and the ultrastructural alterations observed.
Results: The C. sativa extract caused a significant decrease in the viability of protoscoleces and cysts in vitro. The greatest effect was observed with 50 µg/ml, which generated the reduction in protoscoleces viability to 0% between 6 and 24 h post-incubation (pi) and the collapse of 92 ± 13% of the cysts after 24 h pi. All the in vivo treatments reduced the weight of the cysts and caused ultrastructural alterations, especially the combination of ABZ + C. sativa extract.
Conclusion: We demonstrated the in vitro and in vivo efficacy of a full-spectrum extract of C. sativa inflorescences against E. granulosus s.s.”
“Echinococcus granulosus sensu stricto (s.s.) refers to a specific species within the Echinococcus granulosus complex, a group of tapeworms that cause cystic echinococcosis (CE) in humans and other animals. This species, also known as the “sheep strain,” is the most prevalent cause of human CE globally.”
“Cystic echinococcosis in cattle and sheep caused by Echinococcus granulosus sensu stricto genotypes G1 and G3 in the USA”
“Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder caused by oxidative stress and dysregulation of lipid metabolism. The endocannabinoid system (ECS), particularly the type 1 cannabinoid (CB1) receptor, plays a crucial role in NAFLD progression. Cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), along with terpenes, such as beta-myrcene and d-limonene, have shown potential therapeutic effects on liver health, particularly in reducing oxidative stress and modulating lipid metabolism.
This study aimed to analyse the effects of five cannabis oils (COs), each with different CBD:THC ratios and terpenes content, on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor expression in an experimental model of NAFLD induced by a sucrose-rich diet (SRD) in Wistar rats for 3 weeks.
Methods: Male Wistar rats were fed either a: (1) reference diet (RD; standard commercial laboratory diet) or a: (2) sucrose-rich diet (SRD) for 3 weeks. 3 to 7 SRD + CO as following: (3) SRD + THC; (4) SRD + CBD; (5) SRD + CBD:THC 1:1; (6) SRD + CBD:THC 2:1; and (7) SRD + CBD:THC 3:1. The COs were administered orally at a dose of 1.5 mg total cannabinoids/kg body weight daily. The cannabinoid and terpenes content of all COs used in the study was determined. The terpenes found in COs were beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, (-)-guaiol, (-)-alpha-bisabolol. During the experimental period, body weight, food intake and blood pressure were measured. Serum glucose, triglyceride, total cholesterol, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) levels were evaluated. Liver tissue histology, NAFLD activity score (NAS), triglyceride and cholesterol content, lipogenic enzyme activities, enzyme related to mitochondrial fatty acid oxidation, reactive oxygen species (ROS), thiobarbituric acid reactive substance (TBARS), and antioxidant enzyme activities were also evaluated. The CB1 receptor expression was also determined.
Results: The results showed that SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and oxidative stress. This was accompanied by upregulation of liver CB1 receptor expression. CBD-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO and CBD:THC 3:1 ratio CO showed antihypertensive properties. THC-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO showed the greatest beneficial effects against hepatic steatosis and liver damage. All COs exhibited antioxidant effects in liver tissue. This was associated with normal liver CB1 receptor expression.
Conclusions: This study demonstrated that COs, particularly THC-rich CO, CBD:THC ratio 1:1 CO, CBD:THC ratio 2:1 CO and terpenes, can effectively reduce dyslipidemia, liver damage and hepatic steatosis in SRD-induced NAFLD. COs with a higher proportion of CBD in their composition showed antihypertensive properties. All the COs exhibited antioxidant properties. These findings suggest that COs, especially those with CBD:THC ratios of 1:1 and 2:1 and terpenes, may represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver disease.”
“This study demonstrated that COs, particularly THC-rich formulations, and those with CBD:THC ratios of 1:1 and 2:1, effectively reduced dyslipidemia, hepatic steatosis, and liver damage in SRD-induced NAFLD. All COs exhibited significant antioxidant properties, which contributed to the attenuation of oxidative stress. Notably, oils containing CBD also displayed antihypertensive effects, likely due to their vasodilatory properties. The modulation of CB1 receptor is closely linked to the improvement in hepatic steatosis and oxidative stress. These results underscore the synergistic role of cannabinoids and terpenes in targeting key mechanisms involved in NAFLD pathophysiology.”
“These findings suggest that COs, especially those with balanced CBD: THC ratios (1:1 and 2:1) and with meaningful terpenes content, represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver diseases.”
