Author Archives: David

A novel cannabidiol:tetramethylpyrazine cocrystal (CBD:TMP, ART12.11) improves the efficacy and bioavailability of cannabidiol in reducing stress-induced depressive and anxiety symptoms

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“Clinical and pre-clinical research has reported promising outcomes for cannabidiol (CBD) in treating mood and anxiety disorder symptoms. However, the pharmacokinetic properties of CBD, such as low and variable bioavailability and low aqueous solubility, limit its therapeutic applications.

This study investigated the effects of ART12.11, a novel cannabidiol:tetramethylpyrazine (CBD:TMP) cocrystal, that aims to improve the pharmacotherapeutic potential of CBD by combining it with the co-former tetramethylpyrazine (TMP) to improve CBD’s pharmaceutical properties.

We used an integrative combination of translational behavioural pharmacology alongside targeted gene and protein expression analyses to characterize the potential anti-depressant and anxiolytic-like effects of ART12.11 in male Sprague Dawley rats, following exposure to chronic stress. In addition, we investigated blood plasma concentrations of CBD and TMP following oral administration of ART12.11 to examine bioavailability.

We report that oral administration of ART12.11 reversed stress-induced behavioural deficits and produced significant anti-depressant and anxiolytic-like behavioural effects, which were superior to oral administration of CBD alone, TMP alone, or the co-administration of a non-crystalline mixture of CBD and TMP. Further, we report that ART12.11 resulted in higher blood plasma levels of CBD and its major metabolite, indicating superior bioavailability. Finally, we demonstrate that ART12.11 increased activation of the endocannabinoid and serotonergic systems directly in the prefrontal cortex, ventral hippocampus, and nucleus accumbens.

Collectively, our findings indicate that ART12.11 may offer significant advantages over delivering CBD by more traditional approaches in the treatment of mood and anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/40854502/

https://www.sciencedirect.com/science/article/abs/pii/S0278584625002325?via%3Dihub

Cannabinoid Receptors CB1 and CB2 Activation Restores Hippocampal Lipid Profiles and Alleviates Autism-Like Behaviors in Valproic Acid-Induced ASD Rats

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“Objective: Emerging evidence suggests lipid metabolism dysregulation contributes to autism spectrum disorders (ASD), with the endocannabinoid system (cannabinoid receptors CB1R/CB2R) implicated in lipid homeostasis. This study investigated whether CB1R/CB2R activation improves hippocampal lipid metabolism and ASD-like behaviors in a valproic acid (VPA)-induced ASD rat model.

Methods: Male offspring from dams exposed to VPA (600 mg/kg, i.p.) received the CB1R agonist ACPA (0.1 mg/kg) or the CB2R agonist AM1241 (3 mg/kg) from postnatal days 21-27. ASD-like behaviors (marble burying, self-grooming, social interaction, open-field tests) and hippocampal lipid profiles (UPLC-MS/MS) were analyzed.

Results: VPA-exposed rats displayed heightened repetitive behaviors, social deficits, and hyperactivity, all significantly alleviated by ACPA and AM1241. Lipidomics revealed marked reductions in hippocampal phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, and phosphatidylethanolamines in VPA rats. Both agonists restored lipid levels to near normal, comparable to controls.

Conclusions: CB1R/CB2R activation ameliorates behavioral abnormalities and rectifies hippocampal lipid dysregulation in VPA-induced ASD models, highlighting cannabinoid receptors as potential therapeutic targets for ASD-associated metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/40852923/

“This study provides new evidence linking ASD-like behaviors, lipid metabolism abnormalities, and endocannabinoid system regulation. Our results demonstrated that CB1R and CB2R activation alleviated VPA-induced ASD-like behaviors and restored disrupted lipid profiles in the hippocampus, suggesting a potential therapeutic approach for ASD. Further research should explore the molecular mechanisms underlying CB1R- and CB2R-mediated lipid regulation and their implications for ASD treatment strategies.”

https://onlinelibrary.wiley.com/doi/10.1111/cns.70591

Biotechnological potential of Cannabis sativa adventitious roots for producing immunomodulatory and anti-inflammatory bioactive compounds

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“Cannabis sativa L. (C. sativa), commonly known as hemp, is widely recognized for its diverse range of bioactive compounds with therapeutic potential in medicinal, industrial, and nutritional applications.

This study investigates the use of adventitious roots (ARs) derived from C. sativa as a scalable platform for producing bioactive metabolites with immunomodulatory and anti-inflammatory properties.

We first isolated extracts from C. sativa ARs (CS-AR) using various solvents: methanol (MeOH-E), chloroform (CHCl3-E), and hexane (Hexane-E), and explored their effects on dendritic cell (DC) maturation, a key process involved in immune responses.

Notably, MeOH-E demonstrated strong anti-inflammatory effects without inducing cytotoxicity in DCs, distinguishing it from the other extracts. Metabolomic analysis of these extracts annotated the presence of cannabinoid derivatives and metabolites, including cannabinoid glycoside derivatives, cannabigerolic acid-O-acetate (CBGA-O-acetate), cannabidiol diacetate derivatives, and cannabidiol mono-acetate mono-benzoate. Among these, cannabinoid glycoside derivatives and CBGA-O-acetate were found to be present at higher levels in MeOH-E.

Further investigation into the functional properties of MeOH-E revealed that it could suppress the expression of key surface molecules and antigen-presenting ability in mature DCs, alongside attenuating mitogen-activated protein kinase (MAPK) signaling pathways as well as nuclear factor kappa-B (NF-κB) signaling. Additionally, MeOH-E inhibited T cell proliferation and activation.

These findings underscore the CS-AR system as a promising, reproducible biotechnological platform for producing therapeutic bioactive compounds for inflammatory diseases, with significant potential for application in the pharmaceutical and nutraceutical industries.”

https://pubmed.ncbi.nlm.nih.gov/40847038/

“Cannabis sativa L. (C. sativa), commonly referred to as hemp, has been utilized for centuries in the medicinal, industrial, and nutritional domains, primarily owing to its broad spectrum of bioactive compounds1,2. Its various plant parts including roots, stems, leaves, and flowers possess distinct biological properties, such as anti-inflammatory, antioxidant, and antimicrobial activities, thus, positioning C. sativa as a versatile resource in diverse applications.”

https://www.nature.com/articles/s41598-025-16130-1

The anti-biofilm activity of cannabinoids against methicillin-resistant Staphylococcus aureus

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“Aims: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired pneumonia with resistance against beta-lactam antibiotics. New, potent antibiotics against MRSA with other mechanisms of action are thus urgently needed. Recently, cannabinoids have been evaluated for antimicrobial activity in the ongoing search for new anti-infective agents, but their anti-biofilm effect has not been extensively studied. In this study, five main phytocannabinoids – canndibidiol (CBD), delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC) were examined for their activity against a MRSA biofilm.

Methods and results: The anti-biofilm activity was assessed by crystal violet staining, resazurin metabolic assay, reactive oxygen species (ROS) assay, and propidium iodide membrane integrity test. The minimum inhibitory concentrations of all tested cannabinoids were between 1-2 µg/mL. CBN showed the most potent anti-MRSA biofilm activity, significantly reducing biofilm biomass and bacterial viability. It also induced the highest intracellular ROS levels. In contrast, CBD was the least effective among the tested cannabinoids in most of the anti-biofilm assays, yet it caused the greatest membrane damage to bacteria within the biofilm.

Conclusions: This study showed that despite being chemically similar, the cannabinoids demonstrated different potency and potentially different mechanisms of action against MRSA. More research is needed to investigate how they act on this pathogen and its biofilm.”

https://pubmed.ncbi.nlm.nih.gov/40844832/

https://academic.oup.com/jambio/advance-article/doi/10.1093/jambio/lxaf214/8239790?login=false

The Endocannabinoid System: Role in Ocular Physiology and Therapeutic Potential in Eye Diseases: A Narrative Review

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“The endocannabinoid system (ECS) is a multicomponent signaling network that controls several physiological processes, including neurological, immune, cardiovascular, digestive, and ocular functions. The components of ECS (i.e., receptors, ligands, metabolizing enzymes, and carriers) are expressed in eye structures and neurological areas involved in the visual process. Experimental evidence supports ECS involvement in ocular pathophysiology.

Preclinical and clinical studies indicate that cannabinoids (CBs) lower intraocular pressure and exert vasoactive, anti-inflammatory, and protective effects in the retina and ocular surface. However, CBs elicit modest and transient effects while inducing tolerance, dependence, and adverse effects, which prevent their use in ophthalmic clinics.

This review summarizes experimental and clinical data on the role of ECS in ocular pathophysiology. It also reports research on the therapeutic potential of CBs in common eye disorders. Lastly, it highlights promising alternative strategies for modulating ECS and improving ocular drug delivery to improve therapeutic efficiency in ophthalmic clinics.”

https://pubmed.ncbi.nlm.nih.gov/40838892/

Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study

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“Background: Cannabis constituents, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), show distinct pharmacological profiles with therapeutic relevance for neurological and psychiatric conditions. THC exerts euphoric effects primarily via CB1 receptor activation, while CBD displays non-euphoric properties affecting various pathways.

Aims: This study evaluated the effects of THC, CBD, and their combination on brain functional connectivity (FC) and cerebral blood flow (CBF) using multimodal neuroimaging.

Methods: Adult male Sprague Dawley rats received intraperitoneal doses of 10 mg/kg THC, 150 mg/kg CBD, 10.8:10 mg/kg THC:CBD, or vehicle. Resting-state blood oxygenation level dependent magnetic resonance imaging and arterial spin labelling assessed FC and CBF, approximately 2 h after drug administration. Graph-theory metrics and seed-based analyses identified connectivity and perfusion alterations, while plasma analyses determined cannabinoid concentrations.

Results: THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug.

Conclusions: In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development.”

https://pubmed.ncbi.nlm.nih.gov/40838351/

“Growing evidence supports the therapeutic potential of cannabis and its constituent phytocannabinoids in treating a range of neurological and psychiatric conditions.”

“In summary, we have demonstrated that acute THC administration resulted in increases in FC and regional CBF, acute CBD administration resulted in an overall reduction in FC with negligible effect on CBF, and the combination drug THC:CBD resulted in effects similar to, but lower than THC alone. Our application of functional neuroimaging has thus identified differential pharmacodynamic signatures for THC and CBD in anaesthetised adult male rats. Further work should encompass an investigation of the effects of sub-chronic administration of phytocannabinoids on brain activity in animal models with relevance to selected disease indications to investigate changes on FC in a perturbed system, more applicable to the disease state. “

https://journals.sagepub.com/doi/10.1177/02698811251360745

Release of delta-9-tetrahydrocannabinol from polyvinyl alcohol hydrogels and its safe interaction with human skin fibroblasts

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“This study aimed to design a THC-rich hydrogel to deliver cannabis derivatives topically. We developed hydrogels using polyvinyl alcohol (PVA) mixed with propylene glycol (PG), vegetable glycerin (VG), or both to facilitate the dissolution of delta-9-tetrahydrocannabinol (THC).

The hydrogels showed a brown color, confirming the presence of the cannabinoid. They exhibit a porous structure and better mechanical properties than PVA alone. Indeed, the hydrogel containing PG, VG, or both showed elastic deformation behaviors with lower water content. FTIR analysis demonstrated the presence of THC with two specific peaks at 1,575 and 1,619 cm-1, confirming the presence of THC in the hydrogels.

Human dermal fibroblast cultures onto the surface of all hydrogels confirmed the safety of the THC-rich hydrogel as the cell adhesion was comparable to the control (no THC). Furthermore, cells adhering to the hydrogels could proliferate, showing increased cell viability at 48 and 72 h, with a higher proliferation obtained with the THC-rich PVA-PG-VG hydrogels.

Such cell behavior could be due to the release of the THC in the culture medium, as demonstrated by ultra-high performance liquid chromatography (UPLC), showing the presence of THC in the culture medium, ranging from 203 to 290 μg after 24 h of incubation of the hydrogels containing PG and VG or both. In comparison, the released THC from the PVA hydrogel was higher, reaching 852 μg. It is interesting to note that the THC release at 24, 48, and 72 h was slower with the hydrogels containing PG, VG, and both, compared to PVA alone.

Overall, the present study has designed safe THC-rich PVA-PG-VG hydrogels as a functional delivery system for the topical use of cannabinoids to control tissue diseases, such as inflammation.”

https://pubmed.ncbi.nlm.nih.gov/40836986/

“Cannabis has long been used to relieve symptoms such as pain, fever, anxiety, and diarrhea in the context of numerous diseases. Furthermore, cannabis products were reported to reduce inflammatory diseases. Over the past decades, it has been demonstrated that cannabinoids have anti-inflammatory effects, as ascertained by the decrease in the secretion of inflammatory mediators. The human body is subjected to various conditions (stress, autocrine/endocrine changes, exposure to exogenous stimuli, etc.) leading to organ and tissue inflammatory disorders, such as those in the skin and the oral cavity. Such tissue inflammation could be controlled using cannabis products.”

“Altogether, our results demonstrated the possible combination of PVA with PG and VG to generate useful THC-rich hydrogels for cannabinoid delivery. Because THC is lipophilic, our study suggests the possible delivery of THC when in topical contact with the tissues, including skin and oral mucosa, as the cells have lipid-rich membranes. Our THC-rich PVA-PG-VG hydrogels, therefore, may have the potential as a drug carrier for topical use to treat tissue inflammation.”

https://www.frontiersin.org/journals/drug-delivery/articles/10.3389/fddev.2024.1303812/full

Folate-chitosan nanoparticle delivery of cannabidiol for targeted triple-negative breast cancer therapy

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“Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options. Cannabidiol (CBD) has demonstrated anticancer potential, but its clinical application is hindered by poor solubility and nonspecific distribution. This study aimed to develop a folic acid-modified chitosan (FA-CS) nanoparticle system to enhance the targeted delivery and therapeutic efficacy of CBD against TNBC.

Methods: FA-CS@CBD nanoparticles were synthesized and characterized for morphology, size distribution, zeta potential, and stability. Their in vitro anticancer effects were evaluated through cytotoxicity, cellular uptake, apoptosis, and reactive oxygen species (ROS) assays in 4T1 breast cancer cells. The in vivo antitumour efficacy and systemic toxicity were assessed using a TNBC mouse model.

Key findings: FA-CS@CBD nanoparticles exhibited uniform morphology, stable physicochemical properties, and efficient cellular uptake. Compared to free CBD, the nanoparticles significantly enhanced ROS production, induced apoptosis, and inhibited migration in 4T1 cells. In vivo studies demonstrated strong tumour-targeting capability and a tumour inhibition rate of 68.07%, with minimal systemic toxicity.

Conclusions: The FA-CS@CBD nanoparticle system improved the targeted delivery and therapeutic effects of CBD against TNBC while maintaining favorable biocompatibility. These findings highlight the potential of FA-CS-based nanocarriers for enhancing CBD clinical application in breast cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/40838692/

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgaf072/8239116?redirectedFrom=fulltext&login=false

Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice

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“Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain.

Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer’s disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer’s disease.

SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed.

High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety.

These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.”

https://pubmed.ncbi.nlm.nih.gov/40811673/

“Cannabidiol (CBD) is an abundant phytocannabinoid found in the Cannabis sativa plant.”

“CBD is thought by many to have medicinal properties. Except for a few conditions including two rare forms of epilepsy and multiple-sclerosis-associate spasticity, CBD has not been approved by the FDA”

“Here, we examine the potential use of CBD in treating age- related memory loss, anxiety, strength and dexterity impairment in the Senescence-accelerated mouse -prone 8(SAMP8) mice, a polygenic model of spontaneous onset AD.”

“Our results indicate that CBD can reverse age-related changes in the SAMP8 mice. CBD reversed memory impairment in both the T-maze and NOR with a 24-hour retention interval. These results indicate that CBD is able to reverse memory impairment in both spatial and recognition tasks. Taken together therefore, there appears to be an antioxidant effect of CBD contributing to the improvement in memory in the aged mice. These results show that CBD is an attractive therapeutic warranting further investigation in AD, and other neurodegenerative diseases.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296586

Neolignans isolated from industrial hemp (Cannabis sativa L.) roots have cytotoxic effects on cancer cells

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“Background: The 2018 Farm Bill states that cultivars of Cannabis sativa L. (industrial hemp) are legal for industrial use if total tetrahydrocannabinol (THC) concentrations are less than 0.30%. Due to this legislation, hemp cultivars with low total THC have found a wide range of uses, from animal feed to paper production. Although cannabinoids are the most widely studied compounds in hemp, hemp produces numerous other compound classes as well, and these phytochemicals may have uses in the functional food and pharmaceutical industry.

Methods: Initial liquid chromatography profiling of hemp root samples revealed a group of uncharacterized peaks, and these peaks were tentatively identified as neolignans by Oribitrap ID-X high resolution mass spectrometer. To further elucidate the structure of these neolignans, we used techniques in liquid-liquid extraction, as well as flash chromatography to isolate them in preparation for NMR analysis. We then tested their inhibitory concentration 50 (IC50) in a variety of cancer cell lines.

Results and discussion: Four neolignans were isolated from hemp roots and each differed in their molecular weight by 30 daltons. Two of the compounds were identified as dadahols A and B. We tested fractions of various purities containing neolignans against neuroblastoma cell lines CHLA15 and LAN5, hepatoblastoma cell line Hep3B, and Hodgkin’s lymphoma cell line L428. We found that semi-pure fractions containing dadahol A and/or dadahol B had the highest cytotoxic activity. We then tested pure dadahol A and dadahol B, and this revealed dadahol A exhibited the lowest IC50 values in all the cell lines.”

https://pubmed.ncbi.nlm.nih.gov/40818965/

“We report, for the first time, that dadahols, using the methodologies described herein, have antiproliferative effects. While our findings demonstrate the cytotoxic effects of hemp-derived compounds on multiple pediatric cancer cell lines, the underlying mechanisms driving these effects remain to be elucidated.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00316-5