Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system

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“Although obesogenic high-fat/high-sugar diets impair memory function in humans and rodents, the underlying mechanisms remain elusive. Given that the brain endocannabinoid system and type-1 cannabinoid receptors (CB1Rs) control memory processes and are overactive under obesogenic conditions, we studied whether the effects of obesogenic diet consumption on memory function are dependent on this system.

Using an object recognition memory (ORM) task in male mice, we showed that CB1R activity is required for obesogenic-diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB1R, which also normalized training-induced hippocampal cellular and synaptic overactivation.

Consistently, the obesogenic diet potentiated the increase in hippocampal endocannabinoid levels and enhanced CB1R expression induced by ORM, and genetic CB1R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, the obesogenic diet enhanced the hippocampal mechanistic target of rapamycin (mTOR) pathway in a CB1R-dependent manner, and pharmacological mTOR inhibition after training rescued diet-induced ORM consolidation deficits.

Together, these results establish how an obesogenic environment can lead to hippocampal overactivation of the endocannabinoid system and the mTOR pathway to eventually impair memory consolidation. Thus, these results shed light on the mechanisms of diet-induced cognitive alterations and may pave the way for novel therapeutic strategies.”

https://pubmed.ncbi.nlm.nih.gov/41237773

“Foodomics Reveals Anti-Obesity Properties of Cannabinoids from Hemp Oil”

https://pubmed.ncbi.nlm.nih.gov/36382382

“Anti-obesity effect of unsaponifiable matter from hemp seed in 3T3-L1 adipocytes and high-fat diet-induced obese mice”

https://pubmed.ncbi.nlm.nih.gov/41047880

“Anti-Obesity diet drug from cannabis works!“

https://www.news-medical.net/news/2006/01/17/15421.aspx

A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study

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“Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored.

Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia.

ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment.

Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner.

This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.”

https://pubmed.ncbi.nlm.nih.gov/41240218

https://link.springer.com/article/10.1007/s12640-025-00770-2

Combination of CBD with minor cannabinoid CBDV suppresses CXCR4 via CB2 receptor and alleviates colitis in mice

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“Cannabis extracts, particularly those rich in cannabinoids like cannabidiol (CBD), have shown potential anti-inflammatory properties and are being examined in managing conditions involving inflammation.

One proposed mechanism is their modulation of chemokine expression and function in immune cells. C-X-C chemokine receptor type 4 (CXCR4) plays a pivotal role in immune cell trafficking and is implicated in the pathogenesis of inflammatory bowel disease (IBD).

Given emerging evidence that cannabinoids can influence chemokine signaling, we explored whether they could downregulate CXCR4 in immune cells.

In this study, we show that the combination of CBD and cannabidivarin (CBDV) at a 20:1 ratio significantly reduces CXCR4 expression in MOLT-4 cells, murine splenocytes and human peripheral blood mononuclear cells. This reduction in CXCR4 expression correlated with impaired chemotactic responses and suppressed actin polymerization, effects that were abrogated by CB2 receptor inhibition. In vivo, the CBD:CBDV combination ameliorated disease severity in a murine model of DSS-induced colitis, improving disease activity index, colon length, and histological outcomes. These therapeutic benefits were absent in CB2 knockout mice, confirming CB2 dependence.

Our findings support a CB2-mediated mechanism by which the CBD:CBDV combination downregulates CXCR4, providing a mechanistic basis for the entourage effect and highlighting the significance of CBDV as a modulator of the CBD effect.

Overall, this study implicates cannabinoid combinations as a promising therapeutic strategy for treating IBD.”

https://pubmed.ncbi.nlm.nih.gov/41237459

Insights into Thai and Foreign Hemp Seed Oil and Extracts’ GC/MS Data Re-Analysis Through Learning Algorithms and Anti-Aging Properties

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“This study successfully established a novel discriminative model that distinguishes between Thai and foreign hemp seed extracts based on gas chromatography/mass spectrometry (GC/MS) metabolic profiling combined with machine learning algorithms such as hierarchy clustering analysis (HCA), principal component analysis (PCA), and partial least square-discriminant analysis (PLS-DA).

The findings highlighted significant metabolic features, such as vitamin E, clionasterol, and linoleic acid, related with anti-aging properties via elastase inhibition.

Our biological validation experiment revealed that the individual compound at 2 mg/mL exhibited a moderate elastase inhibitory activity, 40.97 ± 1.80% inhibition (n = 3). However, a binary combination among these metabolites at 1 mg/mL of each compound demonstrated a synergistic effect against elastase activities up to 89.76 ± 1.20% inhibition (n = 3), showing 119% improvement. Molecular docking experiments aligned with biological results, showing strong binding affinities and enhanced inhibitory effects in all combinations.

This integrated approach provided insights into the bioactive compounds responsible for anti-aging effects and established a dependable framework for quality control and standardization of hemp seed-based skincare products. Additionally, the developed models enable effective discrimination between Thai and foreign strains, which is valuable for sourcing and product consistency.

Overall, this research advances our understanding of hemp seed phytochemicals and their functional potential, paving the way for optimized natural anti-aging formulations and targeted functional foods.”

https://pubmed.ncbi.nlm.nih.gov/41227709/

“Integrating hemp actives into cosmeceuticals offers sustainable and natural substitutes for conventional skincare products with a variety of advantages, such as moisturizing and anti-aging effects.”

https://www.mdpi.com/2304-8158/14/21/3739

Acute effects of cannabis on core and co-occurring features associated with autism spectrum disorder in adults

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“Pharmacological interventions that treat core and co-occurring features of autism spectrum disorder (ASD) are a persistent unmet need.

As such, use of cannabis to manage ASD features is common in the autistic community. Yet, few studies have examined the acute effects of cannabis on symptoms associated with ASD. Therefore, we measured changes in symptom ratings from before to after cannabis use in a sample of 111 self-identified autistic adults.

Anonymized archival data sourced from the Strainprint® app were analyzed. A subset of tracked information that reflected changes in core and co-occurring symptoms associated with ASD (i.e., Sensory Sensitivity, Repetitive Behaviors, Mental Control, and Negative Affect) were used to assess the impacts of cannabis on symptom severity.

Overall, symptom severity ratings were reduced by 73.09% from before to after cannabis use. More severe symptoms were associated with greater reductions in severity ratings after use.

Higher doses predicted greater reductions in severity of Repetitive Behaviors, Mental Control, and Negative Affect but dose of cannabis used to manage all symptoms remained static across time.

Results from this first empirical examination of the perceived acute effects of cannabis in autistic adults suggest that cannabis provides temporary relief from symptoms associated with ASD.”

https://pubmed.ncbi.nlm.nih.gov/41233406/

“The present study represents the first to demonstrate acute perceived beneficial effects of inhaled cannabis on core and co-occurring symptoms associated with ASD in a large adult sample.”

“These findings indicate that well-powered placebo-controlled trials are warranted to examine the acute effects of various cannabinoids and manipulations of the endocannabinoid system on ASD symptoms.”

“In sum, data from clinical trials of children and adolescents presents an evidence base that supports a continued focus on the impact of CBD on ASD features, while the present data from cannabis-using autistic adults indicates that a sole focus on CBD may not fully capture the potential impact of cannabinoids as a pharmacological intervention for adults with ASD. Thus, additional placebo-controlled clinical trials are needed where THC, CBD, and other non-intoxicating cannabinoids (e.g., cannabigerol), terpenes, and/or medications that modulate the functioning of the endocannabinoid system are administered to autistic adults to determine their relative effects on symptoms associated with ASD.”

https://www.nature.com/articles/s41598-025-23472-3

Cannabidiol (CBD) as a novel inhibitor of HLA-G expression in human choriocarcinoma cell line (JEG-3)

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“Cannabinoids have emerged as promising agents in cancer research due to their antitumor properties. While their effects on tumor growth and survival are well documented, their influence on immune checkpoint regulation remains poorly understood.

Here, we investigated the effects of cannabidiol (CBD) and a high-CBD extract (CBD-HCE) on HLA-G expression in human choriocarcinoma JEG-3 cells, a non-classical HLA class I molecule linked to tumor immune escape.

Safe concentrations of CBD and CBD-HCE were determined by MTT assays. Apoptosis (Caspase-3), proliferation (Ki-67), and migration (wound healing and MMP-9 immunostaining) were assessed, and HLA-G expression was quantified by RT-qPCR and immunocytochemistry.

Both CBD and CBD-HCE reduced cell proliferation and migration, increased apoptosis, and significantly downregulated HLA-G expression at both the mRNA and protein levels. This inhibitory effect was dose- and time-dependent, and fully reversible after treatment withdrawal, indicating a dynamic and CBD-dependent modulation.

These results provide the first experimental evidence of HLA-G downregulation by CBD and CBD-HCE, highlighting a novel immunomodulatory mechanism with potential therapeutic implications.

By simultaneously impairing tumor viability and reversing immune evasion, CBD-based compounds may enhance antitumor immunity and potentiate immunotherapy efficacy. Further research involving additional tumor cell lines, in vivo models, and immune-relevant systems are necessary to validate and expand upon these findings.”

https://pubmed.ncbi.nlm.nih.gov/41233461/

“A great number of studies have shown that THC, CBD and other cannabinoids exhibit antitumor effects in a wide range of in vitro and in vivo cancer models.”

“Taken together, our study provides novel in vitro evidence that CBD and CBD-rich extracts inhibit tumor cell proliferation and migration while downregulating HLA-G, a critical IC molecule involved in tumor immune escape. “

https://www.nature.com/articles/s41598-025-23554-2

The Action of Cannabidiol on Doxycycline Cytotoxicity in Human Cells-In Vitro Study

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“Improper use of drugs in both animal and human therapy, such as doxycycline (DOX), lead to the accumulation of residues in edible animal tissues as well as in the environment.

Plant-derived compounds reduce the adverse effects of drugs.

This study aimed to evaluate the effect of cannabidiol (CBD) in two concentrations: lower (1.56 µg/mL) (DOX + C1) and higher (3.125 µg/mL) (DOX + C2) on the cytotoxicity of doxycycline in human cells.

The toxicity of DOX and its CBD-containing mixtures was assessed after 72 h of exposure in three human cell lines: neural (SH-SY5Y), hepatic (HepG2), and kidney (HEK-293). The exposure to DOX resulted in inhibition of mitochondrial activity (SH-SY5Y) and inhibition of DNA synthesis (HepG2 and HEK-293). IC50 values for DOX ranged from 9.8 to >200 µg/mL in SH-SY5Y cells, 13.4 to 200 µg/mL in HepG2 cells, and 8.9 to 30.4 µg/mL in HEK-293 cells. The nature of the interaction depended on both the cell lines and the concentration of CBD in the mixture.

Both CBD mixtures demonstrated a synergistic interaction in neuronal cells. In HepG2 cells, both mixtures showed additive and antagonistic interactions. In HEK-293 cells, the DOX + C1 mixture exhibited an antagonistic (protective) effect, while the DOX + C2 mixture showed an additive effect. There were no changes in oxidative stress levels; however, alterations in apoptosis levels and cell morphology were observed following exposure to the mixtures.

The presence of doxycycline in the diet and the environment poses a health risk to consumers. The increasing consumption of CBD-containing products may reduce the risk associated with the presence of this drug in food.

It is worth emphasizing the need for research aimed at minimizing the adverse effects of pharmaceuticals on the health of humans and animals.”

https://pubmed.ncbi.nlm.nih.gov/41226279/

“These results suggest that cannabidiol may be a promising candidate for preventing doxycycline-induced damage and dysfunction in healthy cells.”

https://www.mdpi.com/1420-3049/30/21/4319

“Doxycycline is a widely used, broad-spectrum tetracycline antibiotic that treats a variety of bacterial infections and certain parasitic conditions.”

Regulation of inflammatory pathways by cannabigerol in the collagen induced arthritis model in rats

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“Objectives: This study aims to assess the anti-inflammatory properties of cannabigerol (CBG) in collagen-induced arthritis (CIA) model in rats, and to determine which inflammatory signaling pathways it affects.

Study design: Rats were randomized into four groups: placebo (PCB)-p.o. Treated with 1 mL of 0.9% saline once daily, CBG-p.o. Treated with 30 mg of CBG/day, glucocorticoids (GC)-p.o. Treated with methylprednisolone 0.5 mg/kg/day, and negative control (CO)-p.o. Treated with 1 mL of 0.9% saline once daily. CIA was induced in the PCB, GC, and CBG groups. The effect of CBG was assessed by clinical scoring, paw width measurements, ELISA, and analysis of gene (qPCR) and protein (Western blot) expression of selected inflammatory markers in blood and synovial membrane.

Results: Clinical scores showed significant improvement in the CBG vs. PCB on day 29 and in the GC vs. PCB on days 24, 27, and 29. MMP-3 levels in serum were significantly reduced in the GC vs. PCB. CBG demonstrated a selective anti-inflammatory and immunomodulatory profile, notably through the downregulation of key signaling molecules such as TLRs, systemic NF-κB p65, STAT-3, and inflammasome-related components including NLRP1A, NLRP3, AIM2, gasdermin D, and caspase-1. It also reduced IL-1β and TNF expression during the early phase of disease and increased expression of the anti-apoptotic gene BCL-2.

Conclusion: Our findings indicate that CBG modulates distinct components of the inflammatory signaling pathways, and its effects translated into significant improvement in clinical scoring based on swelling, erythema, stiffness in rat CIA model.”

https://pubmed.ncbi.nlm.nih.gov/41230096/

“Taken together, our findings indicate that CBG modulates distinct components of the inflammatory signaling pathways, and its effects translated into significant improvement in clinical scoring based on swelling, erythema and stiffness in rat CIA model.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1705962/full

Skin-Whitening Effects of Cannabinol (CBN) Through Melanin Inhibition in B16F10 Melanoma Cells

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“Melanogenesis, the key biological process underlying skin hyperpigmentation, is tightly regulated by complex molecular signaling pathways. Consequently, targeting molecular regulators of this pathway is a crucial strategy for developing effective skin-whitening agents.

Cannabinol (CBN), a minor cannabinoid, has been largely unexplored owing to its role in modulating skin pigmentation. This study aimed to elucidate the molecular mechanisms of CBN’s depigmenting effects using an α-MSH-induced B16F10 melanoma cell model.

High-purity CBN was obtained via conversion of cannabidiol (CBD) and confirmed by HPLC. CBN significantly inhibited melanin synthesis and tyrosinase activity in a concentration-dependent manner, without any cytotoxicity. Furthermore, we investigated CBN’s impact on the melanogenesis signaling cascade.

Our analysis revealed that CBN significantly downregulated the mRNA and protein levels of key melanogenic master regulators, including MITF, TYR, TYRP1, and TYRP2.

Importantly, we also observed that CBN treatment selectively suppressed the protein phosphorylation of upstream signaling molecules such as p38 and JNK MAP kinases and NF-κB, while ERK phosphorylation remained unaffected. This finding indicates that its mechanism of action involves the selective modulation of pro-melanogenic signaling components.

Collectively, these findings demonstrate that CBN effectively modulates the melanogenesis signaling pathway by targeting both upstream kinases and downstream melanogenic genes.

These findings suggest that CBN holds great promise as a bioactive agent for skin-whitening applications and warrants further research to confirm its clinical efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/41226788/

“In conclusion, our study successfully demonstrated that cannabinol (CBN) possesses potent anti-melanogenic properties without inducing cytotoxicity. We found that CBN exerts its inhibitory effects by downregulating the expression of key melanogenic genes and proteins, including MITF, TYR, TYRP1, and TYRP2.

Our most significant finding was that this action was mediated through the selective suppression of crucial upstream signaling pathways: specifically, the p38 and JNK components of the MAPK cascade and the NF-κB pathway. This selective modulation targeting pro-melanogenic pathways, while preserving the ERK pathway, provides a comprehensive explanation for CBN’s powerful skin-brightening effects, positioning it as a promising new bioactive compound for cosmetic and therapeutic applications in hyperpigmentation.”

https://www.mdpi.com/1422-0067/26/21/10752

Liposomal-Cannabidiol Nanoformulation to Suppress HIV Replication and Reduce Oxidative Stress in Infected Microglia

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“The advent of antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. However, persistent HIV infection in the central nervous system continues to drive HIV-associated neurocognitive disorders (HAND).

Cannabidiol (CBD), a nonpsychoactive cannabinoid with antioxidant and anti-inflammatory properties, has shown promise in clinical trials as a candidate to address cognitive impairments.

Despite this potential, further research is required to elucidate CBD’s molecular mechanisms in HIV infection and to improve its brain bioavailability. To overcome these challenges, we investigated CBD’s effects on oxidative stress pathways and developed a liposomal nanoformulation (NF) to enhance its delivery and efficacy in brain cells.

CBD treatment significantly upregulated APOE3 gene and protein expression while reducing HIV long terminal repeat (LTR) gene expression in infected microglia. The NF was characterized by hydrodynamic size, polydispersity index, zeta potential, encapsulation efficiency, cellular uptake, HIV infection levels, and APOE3 secretion. Successful CBD encapsulation was confirmed by liquid chromatography-mass/mass spectrometry.

Importantly, the CBD-loaded NF reduced p24 antigen levels and LTR expression, increased APOE secretion, and attenuated mitochondrial reactive oxygen species production more rapidly than free CBD.

This liposomal CBD NF enhances the pharmacological profile of CBD, offering a promising nanotherapeutic strategy to suppress HIV replication, reduce oxidative stress, and mitigate neurocognitive dysfunction associated with HAND.”

https://pubmed.ncbi.nlm.nih.gov/41222925/

https://pubs.acs.org/doi/10.1021/acsbiomaterials.5c01218