Cannabis Use and Outcomes in Patients with Chronic Pancreatitis: A National Inpatient Sample Analysis

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“Background and aims: Cannabis is a commonly used recreational and medicinal substance and has been shown to have anti-inflammatory and analgesic effects. Previous studies have shown that cannabis may reduce disease severity of pancreatitis. We aim to use nationally available data to further investigate the impact of cannabis on outcomes among patients with chronic pancreatitis (CP).

Methods: Nationwide Inpatient Sample (NIS) 2016-2020 was used to identify patients with CP. Patients were stratified based on the presence of cannabis use. Data was collected regarding patient demographics, comorbidities, and Charlson Comorbidity Index (CCI). The outcomes assessed were sepsis, acute kidney injury (AKI), deep vein thrombosis (DVT), pulmonary embolism (PE), intensive care unit (ICU) admission, acute pancreatitis (AP), pancreatic cancer, total charges, and length of stay. The relationships were analyzed using multivariate logistic regression.

Results: Out of 907,790 hospitalized patients in this study; 52,360 (5.8%) were cannabis users. After adjusting for confounding factors, cannabis use was associated with decreased odds of mortality (aOR=0.47, p<0.001), DVT (aOR=0.71, p<0.001), PE (aOR=0.622, p=0.002), ICU admission (aOR=0.705, p<0.001), pancreatic cancer (aOR=0.730, p=0.021). There was no difference in odds of AKI, sepsis or AP between the two groups.

Conclusions: Our study found that cannabis use is associated with reduced disease severity and better outcomes among patients hospitalized with CP. Further studies are needed to confirm our findings and explore the role of cannabinoids in pancreatitis.”

https://pubmed.ncbi.nlm.nih.gov/40580529/

https://jgld.ro/jgld/index.php/jgld/article/view/6066

Cannabis sativa extract and fertility: Preclinical evaluation in male and female Wistar rats

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“Currently, there are reservations regarding the medicinal use of Cannabis sativa extract and its potential to impact fertility. Certain cannabinoids, such as Δ9-tetrahydrocanabinol (THC), can modulate both male and female sex hormones, potentially leading to alterations in fertilization viability.

This study aims to evaluate the effects of standardized Cannabis sativa extract (CSE) and its respective placebos on fertility and early embryonic development in Wistar rats, including both male and female subjects.

The animals were divided into 7 groups, each consisting of 20 animals, and different doses of a Cannabis sativa extract (160.32mg/mL) were administered to assess fertility outcomes. Male and female fertility assessments were conducted according to the guidelines outlined in the “Guide for the Conduct of Non-Clinical Toxicology and Pharmacological Safety Studies Required for Drug Development,” including clinical exams, biochemical analyses, macroscopic evaluations, relative organ weight measurements, sperm production, and morphology assessments, as well as morphometric and histopathological analyses of the testes.

The results indicated that none of the tested doses (0.28, 2.8, 28, or 56mg/kg/bw) significantly affected sex hormone levels in either male or female rats. Additionally, no alterations were observed in male organ morphology and sperm characteristics. In female rats, fertility was unaffected, and blastocyst implantation was not impaired across all doses, even up to 7 days post-pregnancy confirmation.

No direct toxic effects on the embryo were observed.

In conclusion, treatment with Cannabis sativa extract did not result in any significant changes in fertility or pregnancy feasibility in either male or female rats.”

https://pubmed.ncbi.nlm.nih.gov/40582628/

Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis

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“Plant-derived cannabinoids, including Δ9-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored.

This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ9-THC, and Δ9-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90).

CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS.

Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits.

In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.”

https://pubmed.ncbi.nlm.nih.gov/40580876/

“CBDA was most active as neuroprotectant than CBD, CBDV, THC and THCV in ALS mice.”

https://www.sciencedirect.com/science/article/pii/S0753332225004822?via%3Dihub

Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1

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“Background: The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.

Purpose: This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.

Results: In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca2+ overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca2+ overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.

Conclusion: METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca2+ influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.”

https://pubmed.ncbi.nlm.nih.gov/40582208/

“In summary, our results suggest that METH induced oxidative neurotoxicity by activating TRPV1-dependent Ca2+ influx, oxidative stress, and apoptosis, while CBD pretreatment inhibited METH-induced oxidative neurotoxicity by regulating TRPV1.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711325006543?via%3Dihub

Real-Time Optical Control of CB1 Receptor Signaling In Vitro with Tethered Photoswitchable (-)- trans-Δ9-Tetrahydrocannabinol Derivatives

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“Understanding the intricacies of the endocannabinoid system is hindered by the lack of tools to target specific pools of CB1 receptors (CB1Rs) across diverse neural circuits associated with mood, motor function, cognition, and other physiological processes.

Herein, we introduce the first photoswitchable, orthogonal remotely tethered cannabinoid ligand, PORTL-THC24, designed to achieve cell-specific and reversible control of CB1R signaling with high spatial and temporal resolution, thereby overcoming the limitations of conventional freely diffusible ligands.

PORTL-THC24 was selectively tethered to membrane-anchored SNAP-tags expressed in live cells, and provided reversible optical control of CB1R signaling when photoswitched by UV-A irradiation. We validated the functionality of PORTL-THC24 in live Neuro2a cells using a novel real-time cAMP imaging assay, demonstrating light-dependent and reversible modulation of endogenously expressed CB1R activity. Additionally, we demonstrated that SNAP-tethered PORTL-THC24 does not induce CB1R internalization, distinguishing it from conventional, freely diffusible agonists.

Our results establish PORTL-THC24 as a powerful tool for optical control of CB1R in a spatially restricted manner, setting the stage for dissecting CB1R function in complex settings and advancing the study of cannabinoid signaling across various physiological and pathological contexts.”

https://pubmed.ncbi.nlm.nih.gov/40586440/

https://pubs.acs.org/doi/10.1021/jacs.4c18379