Category Archives: Uncategorized

Cannabigerol Exerts In Vivo and In Vitro Anti-Inflammatory Effects via Inhibition of the MAPK and NF-κB Pathways

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“Cannabis sativa L. has a long history of use and contains more than 80 cannabinoids. However, although cannabigerol (CBG), which acts as a biosynthetic precursor of its most abundant phytocannabinoids, has anti-inflammatory effects, the exact mechanism of action remains underexplored.

In this study, we explored the anti-inflammatory potential of CBG to assess its potential for therapeutic and industrial applications.

CBG was extracted from the cannabis cultivar ‘Pink Pepper’ In vitro assays were performed via RAW 264.7 mouse macrophages stimulated with lipopolysaccharide, and in vivo efficacy was evaluated through a carrageenan-induced paw edema mouse model to confirm the activity of CBG in acute inflammation.

Nitric oxide production, mRNA, and protein expression of inflammatory mediators were suppressed by CBG treatment in a process downregulated through the MAPK and NF-κB pathways. Although paw edema was not statistically significantly reduced, oral administration of CBG suppressed the expression of COX-2, iNOS, TNF-α, IL-1β, and IL-6 in the carrageenan-induced mouse model.

CBG has been demonstrated to exert significant anti-inflammatory effects via modulation of key inflammatory mediators and signaling pathways in both in vivo and in vitro models.

Our findings further support the potential of CBG as a bioactive compound for further anti-inflammatory research.”

https://pubmed.ncbi.nlm.nih.gov/41423277

https://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.2509.09034

Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

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“Ethnopharmacological relevance: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.

Objective: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.

Methods: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD’s protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.”

https://pubmed.ncbi.nlm.nih.gov/41419044

“The natural plant extract cannabidiol (CBD) attenuates acute liver injury.”

“Cannabis sativa L. (family Cannabaceae) is a valuable natural plant resource that has been used as a folk medicine since ancient times.”

https://www.sciencedirect.com/science/article/abs/pii/S037887412501760X?via%3Dihub

Changes in sleep quality during the 12 months following medical cannabis initiation

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“Background: Poor sleep quality is a commonly reported reason for medical cannabis (MC) use, yet evidence regarding its long-term impact on sleep remains limited. This study evaluated changes in subjective sleep quality over a 12-month period among adults initiating MC treatment in Pennsylvania and explored whether preferred route of administration and referring condition were associated with observed changes.

Methods: A total of 137 adults newly referred for MC in PA completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and at 3, 6, 9, and 12 months. Linear mixed effects models assessed changes in PSQI global and subscale scores over time. Additional models evaluated whether preferred administration route (oral vs. other) and referring condition (chronic pain, anxiety, PTSD) were associated with differences in observed outcomes.

Results: Global sleep quality scores, where higher values indicate poorer sleep quality, were significantly higher at baseline than at each follow-up point (p < .0001), with no significant differences among follow-up assessments, suggesting early and sustained improvements in self-reported sleep quality. Improvements were observed across all PSQI subscales. No significant relationships were found between sleep quality scores and either administration route or referring condition.

Conclusions: These findings suggest that MC may be associated with improvements in subjective sleep quality, though its impact did not vary as a function of administration route or primary referring condition. Additional research using objective sleep measures and controlled designs is needed to clarify MC’s role in sleep quality.”

https://pubmed.ncbi.nlm.nih.gov/41422305

https://link.springer.com/article/10.1186/s42238-025-00376-7

Letters From the Field: Challenges and Opportunities in the Development of Botanical Drugs From Cannabis

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“Cannabis and cannabis-derived products (CCDPs) have gained recognition for their therapeutic potential, driving legal and social shifts worldwide. In the United States, state-level medical cannabis programs exist alongside the federal drug development framework, which remains the gold standard for ensuring safety and efficacy.

The Food and Drug Administration (FDA) botanical drug development guidance provides a structured approval pathway for plant-derived products, including CCDPs, accounting for their unique chemical complexity. Despite this guidance, significant gaps persist in preclinical and clinical data, particularly for minor cannabinoids.

Development of botanical drugs from cannabis is further complicated by regulatory oversight from the Drug Enforcement Administration, which constrains the cultivation, handling, and distribution of cannabis and imposes logistical and security requirements during drug development.

This article discusses the unique experience of drug developers navigating the scientific and regulatory challenges inherent in advancing CCDPs toward FDA drug approval. Collaborative efforts among federally compliant drug developers, regulatory bodies, healthcare providers, academic institutions, investors, and patients/patient advocacy groups are critical to generate rigorous, reproducible evidence to support the safe and effective use of CCDPs in medical conditions where they hold the greatest therapeutic potential. Such partnerships can advance studies that elucidate cannabinoid pharmacology, optimize dosing with rigorously characterized materials via clinically relevant routes, and identify clinical outcomes that are meaningful to patients.

Advancing CCDPs through federally compliant drug development pathways will enable the translation of promising botanical therapies into safe, effective, and evidence-based treatments, ultimately informing clinical practice and benefiting patients.”

https://pubmed.ncbi.nlm.nih.gov/41421888

https://www.clinicaltherapeutics.com/article/S0149-2918(25)00407-2/abstract

Cannabinoid and cannabinoid related receptors in fibroblasts, inflammatory and endothelial cells of the equine hoof with and without laminitis: novel pharmacological target

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“Background: Evidence suggests that the endocannabinoid system (ECS) is crucial for regulating inflammation, cell proliferation and pain. The ECS is composed of cannabinoid receptors such as type 1 (CBR1), type 2 (CBR2) and GPR55, endocannabinoids and enzymes. Proteins of ECS have previously been localized in the epidermal cells of the horse hooves. Given the physio-pathological role and cellular distribution of the ECS across species, the authors hypothesized that cannabinoid receptors are expressed within the inflammatory cells, fibroblasts and endothelial cells of the equine hoof laminae, going beyond the epidermal cells.

Objectives: To preliminary analyze the gene expression of Cn1r, Cn2r and GPR55 in the hoof laminae and test the specificity of the antibody against GPR55. To characterize the distribution and expression of CBRs in the inflammatory cells and fibroblasts of the laminar junction of equine healthy hooves and with laminitis.

Animals: Animals were divided into 3 groups: healthy, acute laminitis and chronic laminitis. A total of 18 samples were collected and processed from the front limb of animals slaughtered for consumption or euthanized (6 control animals, 4 acute laminitis, 8 chronic laminitis).

Methods: Analysis of CBR1, CBR2 and GPR55 protein expression was made by fluorescence microscopy with co-localization with antibodies against the macrophages marker IBA1, the T cell marker CD3, the neutrophils marker calprotectin (MAC387), the fibroblasts marker vimentin (Clove V9) and the nerve fibers marker Substance P. Preliminary analysis was performed to evaluate gene expression (Cnr1, Cnr2, and Gpr55) using real-time PCR and to verify the specificity of the primary antibody (Gpr55) with Western Blotting (WB).

Results: The resident pool of inflammatory cells in the normal laminae and the inflammatory infiltrate cells of the affected equine laminae showed protein expression of CB2R and GPR55; no CB1R staining was seen at the inflammatory cells. Equine dermal fibroblast and endothelial cells exhibited protein expressions of CB1R, CBR2 and GPR55. Substance P positive nerve fibers were positive for CB1R.

Conclusions and clinical importance: Cannabinoid receptors are expressed in different immune cell types of the hoof laminae, pointing to the role of the ECS in modulating inflammatory outburst, tissue degeneration and pain. Our results serve as a foundation for the development of new veterinary pharmacotherapies that target the ECS during laminitis.”

https://pubmed.ncbi.nlm.nih.gov/41394912

“The present findings highlight the presence of cannabinoid receptors CB1, CB2, and GPR55 in the inflammatory cells, fibroblasts and endothelial cells of healthy and pathological hoof lamellar epithelial tissue. The modulation of CB1R, CB2R, and GPR55 signaling pathways could offer novel therapeutic approaches for managing hoof diseases.”

https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2025.1723160/full

Marijuana Legalization and Suicides Among Older Adults

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“Suicide rates among older adults have been rising over time in the United States. At the same time, more individuals have been suffering with chronic pain and illness, which are often underlying risk factors for suicide. As self-medication with marijuana has become common, we ask whether access to legal marijuana for medical and recreational purposes reduces suicides rates among older individuals. We find that suicide rates among older age groups decline following the opening of recreational marijuana dispensaries, especially among older Whites, and middle-aged White males and females with low levels of education.”

https://www.nber.org/papers/w34519

Cannabidiol promotes fine-tuning of natural killer and monocytic cells subsets as well as cytokine storm during chikungunya virus exposure in vitro: Insights for putative therapeutic interventions

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“Chikungunya virus (CHIKV) is an arbovirus that causes acute and chronic disease by strong stimulation of the immune system. It activates innate and adaptive immune cells, including monocytes, natural killer (NK) cells, and lymphocytes, as well as soluble mediators such as IL-17A, IFN-γ, IL-13, and IL-7. Despite the significant morbidity associated with CHIKV, no specific antiviral therapy is currently available.

In this context, natural compounds with immunomodulatory potential, such as cannabidiol (CBD), represent promising candidates. Here, we investigated whether CBD modulates immune responses following CHIKV stimulation. Peripheral blood mononuclear cells (PBMCs) were stimulated with inactivated CHIKV and treated with CBD. Immune cell subsets were analyzed by flow cytometry, and soluble factors were profiled by Luminex assay.

CBD treatment fine-tuned NK and monocyte subsets in vitro and attenuated key inflammatory pathways, particularly the IL-17A-IFN-γ axis, in response to CHIKV stimulation.

These findings identify CBD as a potential immunomodulatory candidate for innovative therapeutic strategies against CHIKV and other alphaviruses.”

https://pubmed.ncbi.nlm.nih.gov/41385863

“Altogether, our results show that Cannabidiol promotes fine-tuning of NK, monocytic subsets CHIKV stimuli in vitro. In addition, CBD attenuates key inflammatory pathways upon CHIKV immune recall, characterized by the IL-17A-IFN-g axis.

Overall, this study provides new insights into the immunological landscape of CHIKV-induced immunity and identifies CBD as a promising candidate for innovative immunomodulatory therapeutic strategies against the disease associated to this Alphavirus.”

“CBD could be a potential immunomodulatory agent against viral inflammation.”

“Overall, this study provides new insights into the immunological landscape of CHIKV infection and identifies CBD as a promising candidate for innovative therapeutic strategies against this disease.”

https://www.sciencedirect.com/science/article/pii/S0753332225010947?via%3Dihub


Protective Role of CBD Against Nicotine Pouch-Induced Seizure Aggravation and Alterations in Brain Glymphatic Biomarkers

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“Introduction: Nicotine pouches are rapidly increasing in popularity, yet their long-term neurological consequences remain poorly understood. Emerging evidence suggests nicotine may influence seizure susceptibility and neuroimmune signaling, while cannabidiol (CBD) has demonstrated neuroprotective and anti-inflammatory effects. This study investigated the time-dependent impact of acute versus chronic oral nicotine exposure on seizure vulnerability, neuroinflammation, and glymphatic function, and evaluated whether inhaled CBD can reverse these pathological changes.

Methods: Mice were exposed to acute or 7-day chronic nicotine pouch prior to kainic acid-induced seizures. Seizure severity was scored using the Racine scale. Neuroinflammatory markers (IL-6, HMGB1), neuronal activation markers (BDNF, c-FOS), and AQP4 expression were quantified via flow cytometry, immunofluorescence, and Western blotting. Glymphatic function was assessed using cisterna magna injection of rhodamine dextran tracers. An ex vivo IL-6 modulation assay evaluated nicotine-induced cytokine production and CBD-mediated suppression, with or without IL-6 receptor blockade.

Results: Acute nicotine transiently reduced seizure severity, whereas chronic exposure significantly exacerbated seizures, elevated IL-6, HMGB1, BDNF, and c-FOS, and markedly downregulated AQP4. CSF tracer studies confirmed impaired glymphatic influx following chronic nicotine exposure. CBD inhalation effectively reversed seizure severity restored AQP4 expression, normalized IL-6 and HMGB1 levels, and reduced c-FOS protein expression. The IL-6R blockade assay showed that nicotine induces IL-6 production in brain-derived immune cells, while CBD suppresses this response upstream of IL-6 signaling.

Conclusions: Chronic nicotine pouch exposure promotes seizure susceptibility through converging neuroimmune and glymphatic disruptions. Inhaled CBD counteracts these effects, supporting its potential as a targeted therapeutic strategy for nicotine-associated neurological risk.”

https://pubmed.ncbi.nlm.nih.gov/41384771

https://academic.oup.com/ntr/advance-article-abstract/doi/10.1093/ntr/ntaf253/8377968?redirectedFrom=fulltext&login=false

Cannabis Use and Nicotine Vaping Cessation Outcomes: A Secondary Analysis of a Randomized Clinical Trial

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“Importance: Cannabis use is prevalent among adolescents and young adults who vape nicotine. It is not known if cannabis use affects nicotine vaping cessation success.

Objective: To assess whether baseline frequency of cannabis use or cannabis use disorder (CUD) symptom severity was associated with nicotine vaping cessation in a randomized clinical trial.

Design, setting, and participants: This secondary analysis of a randomized clinical trial with youth who vaped nicotine recruited at a single site in Massachusetts from June 2022 to May 2024. The trial included 3 groups receiving 12 weeks of varenicline treatment and placebo (both double-masked, paired with counseling), as well as single-masked referral to texting-app-based nicotine vaping cessation support (enhanced usual care [EUC]). Eligible participants were aged 16 to 25 years who reported vaping nicotine regularly and did not smoke tobacco.

Exposure: Baseline cannabis use was assessed via self-reported number of days of cannabis use per week and with Cannabis Use Disorder Identification Test (CUDIT) scores.

Main outcomes and measures: Biochemically verified 7-day point prevalence nicotine vaping abstinence at week 12. Logistic regression models estimated associations between baseline cannabis use and vaping abstinence. Interaction terms were evaluated to examine whether cannabis use moderated the effect of varenicline on nicotine abstinence.

Results: Among the 261 participants randomized to nicotine vaping cessation treatment (mean [SD] age, 21.5 [2.0] years; 139 female [53%]), 28% (73 participants) reported no past-month cannabis use, 38% (100 participants) reported using cannabis more than 0 and less than 4 d/wk, and 30% (78 participants) reported using cannabis 4 to 7 d/wk. Cannabis use frequency was not significantly associated with nicotine vaping cessation (eg, 4 to 7 d/wk use vs no use: adjusted odds ratio [aOR], 1.14; 95% CI, 0.51-2.57; overall P = .20). Nor did cannabis frequency modify the effect of varenicline (eg, abstinence varenicline vs placebo or EUC among those with 4 to 7 d/wk use: aOR, 8.47; 95% CI, 2.78-28.25; vs among those with no use: aOR, 5.60; 95% CI, 1.97-17.06; overall interaction P = .32). Findings were similar for CUD symptom severity.

Conclusions and relevance: Among adolescents and young adults attempting to reduce or stop nicotine vaping, baseline cannabis use was not associated with nicotine vaping abstinence. Varenicline proved helpful for nicotine vaping cessation regardless of cannabis use, indicating that co-use of cannabis may not represent a barrier to successful nicotine vaping cessation treatment.”

https://pubmed.ncbi.nlm.nih.gov/41385228

“Findings indicate that regular cannabis or alcohol use is not expected to diminish the effectiveness of offering varenicline for nicotine vaping cessation in youth.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2842688

Design and Semisynthesis of Aminocannabinoids as Neurological Magic Shotguns

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“The design of neurological “magic shotguns” represents a modern approach toward the treatment of complex central nervous system disorders, and many natural products like cannabidiol possess distinct potential due to their unique polypharmacological profiles toward central nervous system targets.

Herein, we describe the computational design, semisynthesis, and preliminary biological screening of aminergic cannabidiol derivatives as neurological magic shotguns.

A small library of 22 aminergic cannabidiol derivatives were synthesized and evaluated through radioligand binding assays, revealing that these derivatives generally exhibit higher affinity toward serotonin, dopamine and sigma receptors than the parent compound.

Notably, compounds 8d and 8e displayed significantly improved affinity toward sigma-1 receptors (Ki = 4.8 nM and 8.3 nM, respectively). We then established the functional behavior of compound 8e in mouse primary hippocampal neurons through whole-cell patch clamp assays: exposure to compound 8e potentiates N-methyl-d-aspartate receptors, an effect that may be reversed in the presence of a selective sigma-1 receptor antagonist.

These results suggest that compound 8e behaves as an agonist of sigma-1 receptors, thereby promoting downstream potentiation of N-methyl-d-aspartate receptors.

Altogether, these findings provide preliminary evidence that aminergic cannabinoids, and potentially other derivatives of promiscuous natural products, may hold utility as neurological magic shotguns.”

https://pubmed.ncbi.nlm.nih.gov/41378694

https://pubs.acs.org/doi/10.1021/acs.jnatprod.5c01236