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Structural and dynamic mechanisms of cannabinoid receptors

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“Cannabinoids and their G protein-coupled receptors (GPCRs) within the endocannabinoidome are pivotal regulators of neuromodulation, inflammation, and metabolic homeostasis.

Dysregulation of this system has been associated with a wide spectrum of pathological conditions, including neuropsychiatric disorders, chronic pain, and immune dysfunction.

In this review, we summarize recent structural advances in cannabinoid receptors that have deepened our understanding of receptor activation, allosteric modulation, transducer coupling selectivity, and dynamic conformational mechanisms.

These structural insights will facilitate cannabinoid receptor-targeted drug discovery, enabling the development of therapeutics with improved subtype selectivity, enhanced signaling precision, and reduced off-target effects.”

https://pubmed.ncbi.nlm.nih.gov/41319927

“The medicinal use of phytocannabinoids has been documented for millennia, with applications across diverse cultures in the treatment of insomnia, pain, epilepsy, headaches, and inflammation. Modern scientific investigation into cannabis began in the 1930 s, culminating in the isolation and structural characterization of its major constituents.”

“Taken together, these findings highlight cannabinoid receptors as multifaceted and dynamic therapeutic targets positioned at the intersection of neurology, immunology, and metabolism. A deeper understanding of its structural and signaling mechanisms will be critical for the rational design of next-generation cannabinoid-based therapies that harness its extensive regulatory potential with precision.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225008330?via%3Dihub


Dual-Function Plant-Derived Nanovesicles From Regenerated Cannabis sativa Roots for Immunotherapy and Vaccine Delivery

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“Cannabis sativa is a medicinal plant that produces a diverse array of pharmacologically active metabolites, making it a valuable resource for pharmaceutical applications.

In this study, an adventitious root (AR) culture system was established from C. sativa using two representative plant growth regulators-naphthaleneacetic acid (NAA; hereafter referred to as N-ARs) and indole-3-butyric acid (IBA; hereafter referred to as I-ARs) -from which plant-derived nanovesicles (PDNVs) were subsequently isolated (hereafter N-PDNVs and I-PDNVs, respectively).

The resulting N-PDNVs and I-PDNVs exhibited average diameters of 128 ± 2 and 124 ± 4 nm, respectively, with zeta potentials of -12.9 and -15.7 mV. Both PDNV types maintained structural integrity and colloidal stability under diverse external stress conditions, underscoring their physicochemical robustness. Metabolite profiling of PDNVs revealed 25 distinct metabolites. Functionally, I-PDNVs markedly enhanced dendritic cell maturation through Toll-like receptor 2 (TLR2)- and TLR4-dependent pathways, promoted T cell proliferation and activation (notably IFN-γ- and IL-17A-producing subsets), and increased natural killer (NK) cell activity compared with N-PDNVs.

In immunosuppressed and tumour-bearing mouse models, I-PDNVs further augmented NK cell, Th1 and cytotoxic T lymphocyte (CTL) responses, thereby confirming their superior potential as immunotherapeutic agents. Moreover, in immunized mouse models, OVA257-264-encapsulated I-PDNVs demonstrated a clear advantage as a vaccine delivery platform by eliciting a potent OVA257-264-specific CTL response.

When applied as a prophylactic cancer vaccine, they not only delayed tumour growth but also reshaped the antitumour immune landscape, characterized by enhanced CTL responses, reduced regulatory T cell frequencies and diminished exhausted CD8⁺ T cell populations.

Collectively, these findings highlight the potential of I-PDNVs as dual-function PDNVs, serving both as immunotherapeutic agents and as vaccine delivery platforms for applications requiring reinforced Th1, CTL and NK cell responses.”

https://pubmed.ncbi.nlm.nih.gov/41316982

“Nanovesicles, commonly referred to as extracellular vesicles (EVs) are secreted by various organisms or are artificially isolated under various conditions, with their sizes ranging from 30 nm to 10 µm. Owing to their functional properties, such as immunity promotion, inflammation control and antioxidant activities, nanovesicles have attracted attention as promising candidates for drug delivery systems (DDS) and for treating various immune-related diseases, including cancers, infectious diseases and autoimmune disorders.”

“Our study is the first to report the differences in the metabolic properties and immunoenhancing efficacy between I-PDNVs and N-PDNVs isolated from C. sativa AR induced by two distinct plant hormones, IBA and NAA. I-PDNVs strongly promoted a Th1-biased immune response by inducing both innate and adaptive immune activation, demonstrating their superior potential as an immunotherapeutic agent for immunosuppression and cancer treatment. Furthermore, the multifunctionality of I-PDNVs is highlighted by validating their potential as an integrated adjuvant and DDS in a cancer vaccine model.

Our findings suggest that I-PDNVs are promising immunotherapeutic candidates not only for cancer treatment, but also for intracellular infectious diseases and chronic viral infections, emphasizing their role as a multifunctional nanomaterial capable of integrating adjuvant and vaccine delivery functions for next-generation vaccine development.”

https://isevjournals.onlinelibrary.wiley.com/doi/10.1002/jev2.70206

Cannabinomics in the flower of Cannabis sativa: a systematic review of extraction, analytical identification, and micro/nanoencapsulation methods for bioactive metabolites

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“Introduction: The use of Cannabis sativa has evolved from textile applications in ancient times to a growing interest in its therapeutic and nutraceutical properties. Its regulation varies worldwide, with restrictions on ∆9-THC concentrations depending on the country. Cultivation factors, such as temperature, humidity and photoperiod, affect the concentration of their bioactive metabolites, among which phytocannabinoids have demonstrated impact on the biological regulation of the human organism. Their application in the pharmaceutical, cosmetic and food industries has prompted research into the optimization of their production and extraction.

Objective: The purpose of this systematic review is to identify methodologies for the extraction, analysis and application of cannabinoids in various industries, focusing on agro-industrial transformation to increase their added value and optimize their therapeutic use.

Methodology: A systematic search was performed in the Scopus database on November 14, 2024, identifying keywords and their synonyms for each research question, using Boolean operators. Studies published between 2015 and 2025 related to cannabinoid extraction, identification and application methodologies were included, excluding non-scientific papers. The PRISMA methodology was applied to filter and select articles.

Results: The studies analyzed show that extraction and metabolomic analysis methodologies have gained relevance in recent years, especially for obtaining bioproducts for therapeutic purposes. It was identified that cannabinoids, mainly THC and CBD, have potential in the treatment of inflammatory, neurological and chronic pain diseases. In addition, the application of emerging technologies for the micro and nanoencapsulation of cannabinoids, optimizing their bioavailability, was evidenced. However, there are still gaps in the literature on the correlation between extraction operating conditions and the efficiency of the final product, which hinders its industrial scalability.

Conclusions: The growing interest in Cannabis sativa research has led to the exploration of various techniques for the extraction and analysis of its metabolites. However, despite advances in laboratory methodologies, the industrial application of these processes remains a challenge. The lack of studies correlating operational variables with extraction efficiency limits the standardization of bioproducts. Future research should focus on articulating technology and applied science to establish production models to improve the traceability and safety of Cannabis sativa extracts, favoring their integration into the pharmaceutical and agro-industrial industry.”

https://pubmed.ncbi.nlm.nih.gov/41291955

https://link.springer.com/article/10.1186/s42238-025-00350-3

Chemical Profile, Bioactive Constituents and In Vitro Growth Stimulation Properties of Cold-Pressed Hemp Seed Oils from Romanian Varieties: In Vitro and In Silico Evaluation

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“Industrial hemp (Cannabis sativa L.; Cannabaceae), traditionally cultivated for fiber, also represents a valuable source of nutrient-rich seed oil.

In this study, cold-pressed hemp seed oils from three Romanian varieties (Teodora, Silvana, and Armanca) were evaluated for their fatty acid composition, minor bioactive constituents, antioxidant activity, growth-promoting property toward probiotic strains in vitro, and molecular docking interactions with probiotic targets.

Gas chromatography revealed a fatty acid profile dominated by linoleic (49.4-51.9%), oleic (16.3-22.8%), and α-linolenic acids (9.8-14.4%), resulting in favorable PUFA/SFA ratios (5.17-6.39) and ω-6/ω-3 ratios (3.93-5.53).

The oils also contained phenolics (118-160 mg GAE/kg), chlorophylls (6.18-8.31 mg/kg), and carotenoids (2.58-3.37 mg/kg), which contributed to their antioxidant activity (DPPH inhibition 35.92 µM TE/100 g-43.37 µM TE/100 g).

Broth microdilution assays against Lacticaseibacillus rhamnosus GG, L. paracasei ATCC BAA-52, and L. acidophilus ATCC 4356 demonstrated strain- and dose-dependent potential to promote probiotic growth under in vitro conditions. While L. rhamnosus and L. paracasei were inhibited at low concentrations and only mildly stimulated at higher levels, L. acidophilus showed robust growth promotion, reaching +54.7% effect and CP = 1.55 with Teodora oil at 16 mg/mL.

Molecular docking highlighted strong binding affinities of γ-linolenic and linoleic acids with key metabolic enzymes involved in probiotic metabolism (hydratase, enolase, glyceraldehyde-3-phosphate dehydrogenase, ribonucleoside hydrolase), forming stable hydrophilic and hydrophobic interactions which are explored in defining the stability of the ligand-protein complexes.

These results indicate that both major fatty acids and minor bioactive constituents contribute to the nutritional and antioxidant value of Romanian hemp seed oils and reveal a potential to promote probiotic growth under in vitro conditions, as supported by complementary in silico evidence.”

https://pubmed.ncbi.nlm.nih.gov/41304617

“This study demonstrated that cold-pressed hemp seed oils from Romanian varieties are rich in polyunsaturated fatty acids, with favorable PUFA/SFA and ω-6/ω-3 ratios that support their role as health-promoting dietary fats. Alongside their fatty acid profile, the oils contain phenolic compounds, chlorophylls, and carotenoids, which contribute to antioxidant stability and may synergize with PUFAs to enhance biological effects.”

https://www.mdpi.com/2223-7747/14/22/3465


Characterization of cell-type specific knockout of different elements of the endocannabinoid system in cortical glutamatergic neurons in the context of stress-induced behavioral phenotype

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“Background: Chronic stress is an important factor for the development of mental health impairments, such as depression and generalized anxiety disorder. Chronic social defeat (CSD) stress is an ethologically valid model of chronic stress in rodents, combining elements of psychological and physical stress. The endocannabinoid (eCB) system plays important roles in maintaining the homeostasis of biological systems through the tuning of neuronal excitability, thereby mediating a protective role after prolonged stress exposure.

Methods: In the present study, we investigated genetically modified adult male mice where the eCB signal via anandamide (AEA) was reduced (by deletion of the AEA synthesizing enzyme NAPE-PLD) or enhanced (by deletion of the AEA degradation enzyme FAAH), as well as mice lacking the cannabinoid CB1 receptor. These genetic manipulations were induced in glutamatergic neurons of the dorsal telencephalon. After the application of CSD stress, the phenotypes of these mutant mice were investigated in a battery of behavioral tests assessing sociability, anxiety, memory, shelter-seeking behavior, and despair.

Results: We could confirm a robust anxiogenic effect of CSD in the EPM test. Interestingly, we have not observed a stress effect on the sociability of any of the mouse lines as identified in the SI test. Under non-stress conditions, we observed an anxiogenic phenotype in Glu-CB1-KO and Nex-NAPE-PLD KO, and hyperlocomotion in Nex-FAAH KO mice. Additionally, we could confirm a drastic reduction of FAAH protein levels in cortical and subcortical regions of Nex-FAAH line, and a moderate reduction of NAPE-PLD protein in cortical regions of Nex-NAPE-PLD KO mice.

Conclusions: In conclusion, genetic manipulation of the endocannabinoid system in cortical glutamatergic neurons did not result in persistent effects of prolonged stress exposure. Detected differences between the genotypes in the non-stressed groups points toward baseline differences that could mask or over-power the effect of stress.”

https://pubmed.ncbi.nlm.nih.gov/41310892

https://link.springer.com/article/10.1186/s42238-025-00368-7

The Endocannabinoid System in Human Disease: Molecular Signaling, Receptor Pharmacology, and Therapeutic Innovation

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“The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system.

This review has the goal of evaluating the unique opportunity for the ECS to provide a regulatory axis within the microbiota-gut-brain axis, particularly with regard to neurodevelopment, immune tolerance, and gut health.

Cannabinoid receptors CB1 and CB2 and endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG have the ability to provide a variety of signaling pathways that can regulate cognitive resilience, emotional tuning, and immune regulation. Because the ECS has the ability to regulate multiple neurochemicals, alter immune cell functions, and maintain gut barriers, the ECS exists at the crossroads of many physiological systems, which also have a predictive role in neurodegenerative disease, chronic inflammation, and mental illness.

Our goal is to present the latest and best recent advances in the ECS literature and establish evidence that there exists some modest potential for the therapeutic modulation of the ECS to improve pathological manifestations of cross-system dysregulation. In addition to cellular signaling pathways, the ECS affects other homeostatic processes, such as synaptic plasticity and the level of neuroprotection in the CNS, immune-related homeostasis, and coordinating the composition of gut microbiota.

We argue that the ECS represents a suitable new therapeutic target that could modulate dysregulation across these systems more inclusively. This paper aims to emphasize the proposed potential of the ECS’s position in this axis and propose advanced cannabinoid-based interventions as a novel mechanism for developing personalized medicine and health systems through multi-system integration.”


https://pubmed.ncbi.nlm.nih.gov/41303613/

“In summary, the ECS presents the opportunity to appreciate how modern biology is reconstituting the definition of health—not as an absence of disease but in promoting maintenance of the homeostatic ability of the organism to interact with heterogeneous systems.”

“Collectively, the convergence of biotechnology, engineering, AI, and multi-omics is transforming ECS research and its translational potential. This convergence provides a platform for developing personalized ECS interventions that consider the interplay among the neural, immune, and microbiota systems in a unified therapeutic approach.”

https://www.mdpi.com/1422-0067/26/22/11132

Enhanced Antibacterial and Anti-Inflammatory Activities of the Combination of Cannabis sativa and Propolis Extracts: An In Vitro Study

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“Sore throat, commonly associated with pharyngitis and tonsillitis, is primarily caused by bacterial pathogens. Conventional therapies rely on antibiotics and anti-inflammatory drugs; however, concerns about adverse effects, antibiotic resistance, and drug interactions have encouraged the search for alternative remedies. 

Cannabis sativa L. (CS) has demonstrated potential in relieving sore throat and inflammation, while propolis, a bee-derived natural product, exhibits notable antibacterial and anti-inflammatory activities.

This study aimed to investigate the enhanced antibacterial and anti-inflammatory effects of combining CS and propolis extracts (PE).

Results found that CS and PE exhibited antibacterial effects against Streptococcus pyogenes DMST 4369, Staphylococcus aureus ATCC 25923, and Pseudomonas aeruginosa ATCC 9027. Their combination produced additive antibacterial effects against S. pyogenes and S. aureus.

Cannabidiol (CBD) was identified as an active antibacterial constituent against S. pyogenes. Additionally, the PE-CBD in CS solution combination at concentration 625:0.125 µg/mL significantly reduced NO production and suppressed proinflammatory cytokines in LPS-stimulated macrophages.

This study highlights the enhanced antibacterial and anti-inflammatory potential of the C. sativa and propolis combination, emphasizing the need to verify synergistic effects and determine the appropriate ratio for rational product development. Further research is needed to investigate the underlying mechanisms of action, particularly the anti-inflammatory pathways, in animal models. In addition, studies on hepatotoxicity should be conducted to ensure safety.”

https://pubmed.ncbi.nlm.nih.gov/41303662

“PE is commonly used for sore throat relief and is recommended for bacterial infections, and CBD derived from C. sativa is known for its analgesic and anti-inflammatory properties. This study explores the combination of propolis and C. sativa extract, hypothesizing that an optimized combination may work additively to enhance the antibacterial and anti-inflammatory effects.

The findings demonstrate that propolis and C. sativa extract exhibit antibacterial activity against pathogens such as S. pyogenes and S. aureus. Moreover, a combination of C. sativa solution and propolis solution at a ratio of 1:0.5 and 1:1 indicated that they exerted additive antibacterial effects.

Notably, CBD and Δ9-THC were identified as active compounds against S. pyogenes, an important respiratory tract pathogen.

In addition, the combination of C. sativa solution and propolis at a ratio of 1:0.5 at concentrations of 0.125 µg/mL and 625 µg/mL, respectively, significantly reduced NO generation and suppressed the release of proinflammatory cytokines (TNF-α, IL-6, and IL-8), thereby providing enhanced anti-inflammatory effects compared to the individual extracts.

Overall, this novel combination shows significant advantages over existing treatments by enhancing both antibacterial and anti-inflammatory effects, suggesting its potential for further development in herbal pharmaceutical formulations. Given its local action and ease of administration, this combination may be considered promising for future formulation as an oral spray.”

https://www.mdpi.com/1422-0067/26/22/11181

The Effect of Growth and Nutrition in Black Soldier Fly Larvae Fed by Hemp Seed Oil Mixed Diets

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“The black soldier fly (BSF), Hermetia illucens, has gained increasing attention as a sustainable protein source for animal feed. This study investigated the effects of dietary supplementation with hemp seed oil (HSO) at 0.5-6% concentrations on the growth performance and nutritional composition of black soldier fly larvae (BSFL).

Larval development, survival rate, body weight, and adult longevity were evaluated under controlled conditions. In addition, chemical characterization of HSO was performed, and the proximate composition, mineral content, and amino acid profile of dried larvae were analyzed.

The results indicated that HSO supplementation had no statistically significant effect on developmental time, survival rate, biomass accumulation, or adult lifespan compared to the control. Gas Chromatography-Mass Spectrometry (GC-MS) profiling of HSO revealed a wide range of bioactive compounds, including unsaturated fatty acids (UFAs), phytosterols, cannabinoids, and tocopherols. The BSFL showed high levels of fat and energy, with essential amino acids and minerals present in favorable concentrations for feed applications. The HSO improves the protein levels at the 0.5-1.0% concentration, with negative correlations at higher concentrations.

The findings suggest that HSO can be integrated into BSFL diets without adverse effects on growth performance, while potentially enhancing the functional value of the larvae. This supports the feasibility of incorporating hemp by-products into insect-rearing systems to promote circular and value-added feed production.”

https://pubmed.ncbi.nlm.nih.gov/41302827

“Black soldier fly larvae (BSFL) are being studied as a new source of protein for animals, as they can turn food waste into valuable nutrients. This study explores whether adding hemp seed oil (HSO) to the BSFL diet causes no harm to the larvae and no negative impact on their growth or survival. Results of this study suggest that dietary enrichment with HSO increases the valuable nutrient content of the BSFL diet due to high levels of essential nutrients in both of them. This approach benefits both the environment and animal farming by reducing waste and producing high-quality insect-based animal feed.”

https://www.mdpi.com/2075-4450/16/11/1081

Potential Antimicrobial Use of Cannabidiol in Dentistry: A Scoping Review

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“Background/Objectives: The use of cannabidiol (CBD) as an antimicrobial and antifungal agent has gained interest in medicine, with studies suggesting potential against various microorganisms. However, its effectiveness against oral pathogens remains underexplored in dental research, highlighting the need for further studies. This scoping review summarizes current evidence on the antimicrobial properties of CBD in dental and oral health. 

Methods: A systematic search was conducted across seven databases (PubMed, the Cochrane Library, Scopus, Embase, Web of Science, SciELO, and LILACS) up to January 2025. The inclusion criteria encompassed studies that explored the effects of CBD on oral microbiology (in vitro and in vivo in animal models), regardless of language or year of publication. The gray literature was evaluated in the Google Scholar database. 

Results: A total of 1284 articles were identified, of which 10 met the inclusion criteria for this scoping review. These studies, published between 2019 and 2025, primarily focused on bacterial and fungal cultures. The most commonly used methods were the minimum inhibitory concentration test and counting colony-forming units. The contact methods between CBD and bacterial/fungal cell cultures were either dilution or direct contact. 

Conclusions: CBD shows promising antimicrobial properties against a range of oral bacteria and fungi, suggesting its potential application in managing oral health conditions.”

https://pubmed.ncbi.nlm.nih.gov/41294500

“The current knowledge regarding the microbiological properties of CBD indicates its antimicrobial potential against oral microorganisms such as P. gingivalis, S. mutans, and C. albicans. Several studies have evaluated CBD antimicrobial effects through assays such as the MIC test and bacterial growth assays, with varying concentrations and formulations. These studies suggest that CBD can inhibit microbial growth, though its effectiveness varies according to CBD concentration, microbial strain, and the delivery system.”

https://www.mdpi.com/2304-6767/13/11/519

Impact of Hemp Flour on the Nutritional, Sensory and Functional Characteristics of Wheat and Whole Wheat Muffins

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“The growing consumer demand for plant-based, protein- and fiber-enriched foods has encouraged the incorporation of novel functional ingredients into bakery products.

Hemp flour (HF), obtained from cold-pressed hemp seeds, represents a sustainable ingredient rich in proteins, dietary fibers, lipids, and bioactive compounds, making it suitable for nutritional fortification.

This study investigated the impact of HF addition (5-40%) on the quality of muffins prepared with wheat flour (WF) and whole wheat flour (WWF).

An initial hedonic sensory evaluation identified 5-20% HF as the most acceptable substitution range, which was then subjected to detailed physicochemical, sensory, textural, colorimetric, and microbiological analyses.

Incorporation of HF significantly increased protein (up to +44%), fiber (up to +172%), and ash (up to +76%) contents, while decreasing moisture (-39%). Both WF and WWF muffins darkened with HF incorporation, with a greater lightness reduction in WF. Texture changes (increased firmness and gumminess) were more pronounced in WF muffins. Sensory analysis revealed that WF muffins were best accepted at 10-15% HF, whereas WWF muffins maintained good acceptability up to 20% HF, indicating better integration of HF in the whole grain matrix. All samples complied with microbiological safety requirements.

Overall, the optimal substitution level was 10-15% HF in WF muffins and 20% HF in WWF muffins, demonstrating that HF can enhance the nutritional profile of muffins while maintaining acceptable technological and sensory properties in a matrix-dependent manner.”

https://pubmed.ncbi.nlm.nih.gov/41154114

“In conclusion, HF offers clear advantages as a sustainable, plant-based ingredient for functional food development. It improves the protein, fiber, and mineral content of muffins, while the type of base flour plays a decisive role in determining texture, sensory quality, and overall acceptability. Future research should focus on optimizing formulations to achieve a balance between nutritional enhancement and sensory appeal, with particular attention paid to moisture retention and improving the palatability of higher HF levels in WF-based products.”

https://www.mdpi.com/2304-8158/14/20/3578