Author Archives: David Worrell

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

A Longitudinal Assessment of Endometriosis Patients Prescribed Cannabis-Based Medicinal Products: A Case Series From the UK Medical Cannabis Registry

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“Background: Although there is growing evidence supporting the use of cannabis-based medicinal products (CBMPs) for the management of chronic pain, there is a paucity of data on their effect on endometriosis-associated chronic pain.

Aims: This study aimed to perform an analysis of pain-specific and general health-related quality of life (HRQoL) outcomes for patients with endometriosis-associated chronic pain treated with CBMPs.

Materials and methods: Primary outcomes included changes in patient-reported outcome measures (PrOMs) from baseline to 1, 3, 6, 12 and 18 months. A repeated measures ANOVA was applied to assess changes in PrOMs at 1 to 18 months from baseline. Secondary outcomes included incidence and frequency of adverse events (AEs).

Results: Sixty-three patients met inclusion criteria. Initiation of CBMPs was associated with improvements in all pain-specific PrOMs from baseline to 18 months (p < 0.050). EQ-5D-5L index value showed improvements between baseline and all months (p < 0.050). Anxiety and sleep quality PrOMs showed improvements from baseline to 18 months (p < 0.050). Minimal clinically significant differences (11%-37%), moderately important improvements (5%-22%) and substantial improvements (0%-11%) were observed in the Brief Pain Inventory (BPI) and pain severity visual analogue scale. Sixty-two adverse events were reported by 16 (25.40%) participants.

Conclusions: This study observed an association between CBMP treatment and improvements in pain and HRQoL in patients with endometriosis. Causality cannot be inferred due to the nature of this observational study; however, these findings provide complementary evidence for the development of randomised controlled trials to assess the efficacy of CBMPs for endometriosis-associated chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41305963

“Cannabis-based medicinal products (CBMPs) that contain phytocannabinoids, such as (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), have been identified with potential to manage endometriosis-related pain.”

“Overall, these results provide a signal towards improvement in short-term pain severity and interference for endometriosis patients after the initiation of CMBP treatment, although there was diversity at different pain intervals.”

https://obgyn.onlinelibrary.wiley.com/doi/10.1111/ajo.70078

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

CBD Disrupts Malme-3M Cell Metabolism via Glycolytic Shift and Redox Imbalance

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“Background: Accumulating evidence suggests that cannabidiol (CBD) exerts variable effects on cancer cells that influence cellular activity, including growth. While anecdotal evidence abounds, mechanistic studies have lagged.

Methods: Malme-3M cells derived from melanoma and less-aggressive BJ fibroblast cells were incubated with CBD. CE-MS mass spectroscopy was used to measure metabolite changes resulting from CBD treatment.

Results: Data indicate a differential response between malignant Malme-3M cells and BJ fibroblasts with respect to metabolites critical for primary metabolic function. A significant reduction in TCA metabolites is seen with a corresponding increase in glycolytic output in the Malme-3M cell line. A similar reduction in TCA activity in BJ fibroblasts appears to differentially activate fatty acid oxidation. ATP is significantly reduced in the Malme-3M cells with a corresponding decrease in metabolites associated with redox maintenance.

Conclusions: This is the first metabolomics analyses of malignant Malme-3M cells and less-aggressive BJ fibroblasts after pre-treatment with CBD. The data suggest that the CBD-induced metabolic perturbation could reprogram cellular metabolism and affect ATP production and redox maintenance of the more-aggressive Malme-3M cells.”

https://pubmed.ncbi.nlm.nih.gov/41296432

“For the first time, an analysis of metabolomics of both less-aggressive BJ fibroblasts and malignant Malme-3M cells after pre-treatment with CBD has been made. As a result of CBD treatment, there is reprogramming of key metabolic processes including the TCA cycle, redox maintenance, and fatty acid oxidation. While more studies are needed to fully elucidate the mechanistic effects of CBD treatment, there is a clear and differential cellular metabolic consequence of CBD treatment between these cell types.”

https://www.mdpi.com/1467-3045/47/11/928

“This title means that the compound cannabidiol (CBD) disrupts the metabolism of Malme-3M cancer cells by forcing them to switch from their normal energy-producing processes to a more primitive, less efficient one called glycolysis, and by throwing off their cellular “redox” balance (a state of chemical reactions that are key to maintaining cell health). This metabolic disruption is a mechanism through which CBD may have anti-cancer effects.”

Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy

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“Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects.

Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality.

Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis. However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC.

This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime.”

https://pubmed.ncbi.nlm.nih.gov/36696005/

https://link.springer.com/article/10.1007/s10555-023-10078-2

Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts

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“Cannabis sativa is one of the oldest cultivated plants. Many of the medicinal properties of cannabis are known, although very few cannabis-based formulations became prescribed drugs. Previous research demonstrated that cannabis varieties are very different in their medicinal properties, likely due to the entourage effect-the synergistic or antagonistic effect of various cannabinoids and terpenes.

In this work, we analyzed 25 cannabis extracts containing high levels of delta-9-tetrahydrocannabinol (THC). We used HCC1806 squamous cell carcinoma and demonstrated various degrees of efficiency of the tested extracts, from 66% to 92% of growth inhibition of cancer cells.

Inflammation was tested by induction of inflammation with TNF-α/IFN-γ in WI38 human lung fibroblasts. The efficiency of the extracts was tested by analyzing the expression of COX2 and IL6; while some extracts aggravated inflammation by increasing the expression of COX2/IL6 by 2-fold, other extracts decreased inflammation, reducing expression of cytokines by over 5-fold.

We next analyzed the level of THC, CBD, CBG and CBN and twenty major terpenes and performed clustering and association analysis between the chemical composition of the extracts and their efficiency in inhibiting cancer growth and curbing inflammation.

A positive correlation was found between the presence of terpinene (pval = 0.002) and anti-cancer property; eucalyptol came second, with pval of 0.094. p-cymene and β-myrcene positively correlated with the inhibition of IL6 expression, while camphor correlated negatively. No significant correlation was found for COX2. We then performed a correlation analysis between cannabinoids and terpenes and found a positive correlation for the following pairs: α-pinene vs. CBD, p-cymene vs. CBGA, terpenolene vs. CBGA and isopulegol vs. CBGA.

Our work, thus, showed that most of high-THC extracts demonstrate anti-cancer activity, while only certain selected extracts showed anti-inflammatory activity. Presence of certain terpenes, such as terpinene, eucalyptol, cymene, myrcene and camphor, appear to have modulating effects on the activity of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/36144796

“Cannabis sativa is a plant with a long history of consumption as food and medicine. Delta-9-tetrahydrocannabinol (THC) is one of the main cannabinoids in cannabis; it has many properties, including anti-cancer, anti-inflammatory, analgetic and others.”

https://www.mdpi.com/1420-3049/27/18/6057/htm

Administration of Δ9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function

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“Hypothesis: Administration of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) will enhance brain repair and improve short-term spatial working memory in mice following controlled cortical impact (CCI) by upregulating granulocyte colony-stimulating factor (G-CSF) and other neurotrophic factors (brain-derived neurotrophic factor [BDNF], glial-derived neurotrophic factor [GDNF]) in hippocampus (HP), cerebral cortex, and striatum. 

Materials and Methods: C57BL/6J mice underwent CCI and were treated for 3 days with Δ9-THC 3 mg/kg intraperitoneally (i.p.). Short-term working memory was determined using the spontaneous alternations test during exploratory behavior in a Y-maze. Locomotor function was measured as latency to fall from a rotating drum (rotometry). These behaviors were recorded at baseline and 3, 7, and 14 days after CCI. Groups of mice were euthanized at 7 and 14 days. Extent of microgliosis, astrocytosis, and G-CSF, BDNF, and GDNF expression were measured at 7 and 14 days in cerebral cortex, striatum, and HP on the side of the trauma. Levels of the most abundant endocannabinoid (2-arachidonoyl-glycerol [2-AG]) was also measured at these times. 

Results: Δ9-THC-treated mice exhibited marked improvement in performance on the Y-maze indicating that treatment with the phytocannabinoid could reverse the deficit in working memory caused by the CCI. Δ9-THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. Δ9-THC-treated mice, compared with vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in the cerebral cortex, striatum, and HP. Levels of 2-AG were also increased in the Δ9-THC-treated mice. 

Conclusion: Administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke.”

https://pubmed.ncbi.nlm.nih.gov/34747647

https://www.liebertpub.com/doi/10.1089/can.2021.0053