Author Archives: David Worrell

Recent development of plant-derived and synthetic cannabinoids as novel antimicrobial agents

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“Antimicrobial resistance remains a critical global health threat, driving the urgent need for novel therapeutic agents. Cannabinoids, bioactive secondary metabolites derived from Cannabis sativa, have gained attention for their promising antimicrobial properties.

This review presents the latest advances in the antimicrobial properties of cannabinoids, emphasizing their activity against multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and selected Gram-negative bacteria.

We summarize their antibacterial and antifungal effects, along with insights into structure-activity relationships that reveal the critical roles of functional groups such as the resorcinol moiety and alkyl side chain.

Mechanistic studies suggest that membrane disruption, metabolic interference, and reactive oxygen species generation contribute to their antimicrobial action. Moreover, we summarize the synergistic potential of cannabinoids when used in combination with conventional antibiotics, highlighting both promising outcomes and notable limitations.

Despite these advances, challenges such as poor solubility, limited in vivo data, and regulatory barriers persist. Addressing these gaps through focused medicinal chemistry and translational research will be essential to harness the full potential of cannabinoids as next-generation antimicrobial agents.”

https://pubmed.ncbi.nlm.nih.gov/41200875/

“Natural and synthetic cannabinoids show activity mainly against Gram-positive bacteria and selected fungi.

Synthetic cannabinoid analogues can enhance potency, selectivity, and pharmacokinetic properties while minimizing psychoactive effects.

Rational modifications to cannabinoid scaffolds, such as the resorcinol ring and alkyl side chain, influence antimicrobial efficacy.

Cannabinoids disrupt microbial membranes, increasing permeability, altering membrane potential, and inducing apoptosis.

Cannabinoids interfere with intracellular metabolic and biosynthetic pathways, impairing energy production and cell wall synthesis.”

https://www.tandfonline.com/doi/full/10.1080/17568919.2025.2580915


Synthetic cannabinoid WIN 55,212-2 reduces CHIKV replication, modulates cytokine and chemokine production, and induces ER stress-related transcriptional responses in human monocyte-derived macrophages

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“Chikungunya virus (CHIKV), an emerging arbovirus of the family Togaviridae, causes Chikungunya fever (CHIKF), characterized by excessive inflammation and chronic arthralgia. Macrophages act as viral targets and amplifiers of inflammation, underscoring their crucial role in the pathogenesis of viral infections. Currently, no effective treatment exists for CHIKF, highlighting the need for novel therapeutic approaches.

Cannabinoids, known for their immunomodulatory and antiviral properties, have emerged as potential candidates. Here, we investigated the effects of cannabidiol (CBD) and WIN 55,212-2 (WIN) in CHIKV-infected human monocyte-derived macrophages (MDMs). Pre- and post-treatment efficacy were assessed at 6- and 24-h post-infection (h.p.i).

WIN, but not CBD, significantly reduced CHIKV replication in post-treatment assays, with effects most evident at 24 h.p.i. This antiviral activity occurred without significant changes in mRNA levels of IFNβ1, IFNλ1, and IL27p28, indicating that it did not alter the expression of type I/III interferons. Furthermore, WIN treatment reduced APOBEC3A mRNA levels. Additionally, WIN significantly reduced the production of CCL-2, as well as pro- (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines, while upregulating IRE1α and sXBP1 transcripts, suggesting modulation of ER stress pathways.

Overall, these findings identify WIN as a potential modulator of CHIKV replication and macrophage inflammatory response, acting through host-direct mechanisms that warrant further investigation.”

https://pubmed.ncbi.nlm.nih.gov/41197267/

“WIN 55,212-2 post-treatment reduced CHIKV replication and inflammation in MDMs by downregulating proinflammatory cytokines and chemokines and inducing ER stress via the PERK–IRE1α/sXBP1 pathway (Fig. 7B). Inhibiting these pathways partially restored viral load, suggesting their involvement in the antiviral effect. WIN 55,212-2 also decreased CHIKV nsP2 mRNA levels, without direct virucidal activity. These findings indicate that WIN functions as a dual-agent, both antiviral and immunomodulatory,”

https://www.sciencedirect.com/science/article/abs/pii/S1567576925017825?via%3Dihub

“WIN 55,212-2 is a synthetic cannabinoid and a potent full agonist of the cannabinoid receptors CB1 and CB2. Though it mimics the effects of tetrahydrocannabinol (THC), the compound has a distinctly different chemical structure. It has been extensively studied for its potential therapeutic effects due to its anti-inflammatory, analgesic, and neuroprotective properties. The compound is illegal in some countries, including the United States, where it is classified as a Schedule I controlled substance.”


Virucidal activity of Cannabis sativa L. (hemp) root and stem extracts against Japanese encephalitis virus: role of stigmasterol

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“Japanese encephalitis virus (JEV) poses a significant public health risk due to the lack of effective antiviral therapies.

To identify novel antiviral agents, we evaluated the antiviral activity of ethanol extracts and organic solvent fractions derived from the roots and stems of hemp (Cannabis sativa L.).

Noncytotoxic concentrations of the extracts and fractions were determined using in vitro cytotoxicity assays. At these concentrations, several fractions demonstrated potent virucidal activity, with the hexane and chloroform fractions showing the strongest effects.

Post-treatment of virus-infected cells with these fractions significantly suppressed viral replication, as evidenced by reduced JEV mRNA and E protein expression. In contrast, pre-treatment or co-treatment did not yield notable antiviral effects. GC-MS analysis revealed the presence of multiple known hemp-derived compounds in the active fractions.

Among them, stigmasterol exhibited strong virucidal and antiviral activity. It inhibited viral entry and growth when applied during or after infection and significantly decreased viral mRNA and E protein levels in infected cells.

These findings suggest that stigmasterol contributes to the antiviral effects of hemp extracts and may be one of the active compounds responsible for inhibiting JEV replication.

This study highlights the potential of hemp-derived natural products, particularly stigmasterol, as promising candidates for the development of antiviral agents against JEV infection.”

https://pubmed.ncbi.nlm.nih.gov/41196377/

https://link.springer.com/article/10.1007/s00705-025-06433-z

The Development and Therapeutic Potential of Classical and Next-Generation Cannabinoid Ligands

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“The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research.

Cannabinoid receptors, primarily CB1 and CB2, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators.

This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids.

Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function.

Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development.

This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.”

https://pubmed.ncbi.nlm.nih.gov/41192631/

“The endogenous cannabinoid system has broad therapeutic relevance. “

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475?via%3Dihub

Therapeutic Potential of Cannabidiol in Dentistry: A Systematic Review From Cellular Mechanisms to Clinical Trials

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“Background: CBD holds substantial promise in medical applications. This review aims to comprehensively analyse the current status of cannabidiol (CBD) in dentistry.

Methods: A systematic search of databases including PubMed-MEDLINE, Scopus, Embase, Cochrane Library, World Intellectual Property Organization (WIPO), European Patent Office (EPO), and the United States Patent and Trademark Office (USPTO) was conducted. Peer-reviewed journal manuscripts focusing on cell studies, clinical trials, and registered patents related to CBD and its derivatives in dentistry were summarised. Inclusion criteria were studies on CBD in dentistry, including original research and patents, published in English between 2013 and mid-2023 (articles) or early 2024 (patents), with full-text availability. Excluded were non-dentistry studies, unpublished or non-peer-reviewed reports, and duplicates using Microsoft Excel. The risk of bias was evaluated using the Cochrane RoB 2 tool. Two observers independently screened the articles for inclusion in the present study to mitigate bias. Cohen’s kappa was used to measure inter-rater agreement.

Results: The total number of included studies was 57. Cell-based studies demonstrated CBD’s effectiveness in modulating cellular responses and anti-inflammatory properties, especially in oral-origin cells, and its impact on osteogenic differentiation. Research, including clinical trials and patents, has shown CBD’s benefits in treating pain and inflammation in the maxillofacial area, notably in conditions such as radiation-induced mucositis. CBD research in dental pain and inflammation is advanced, but studies on CBD’s role in regenerative dentistry remain limited.

Conclusion: More studies on the mineralisation of oro-facial structures are necessary to fully understand CBD’s role in regenerative dentistry. This study was supported by the Faculty of Dentistry, Chulalongkorn University. This study was registered in the PROSPERO (ID: CRD4201055832) and Open Science Framework (OSF) database (osf.io/z3bd8). The PRISMA guideline was followed to include the relevant full-text papers.”

https://pubmed.ncbi.nlm.nih.gov/41194764/

https://onlinelibrary.wiley.com/doi/10.1111/jop.70081

History of cannabis use and cognitive function in older adults: findings from the UK biobank

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“Background: Cannabis is a commonly used psychoactive drug, but its cognitive effects remain unclear, particularly in older adults. This study examined associations between past and present cannabis use and cognitive function among dementia-free older adults.

Methods: Cross-sectional and longitudinal data were drawn from the UK Biobank, including adults aged ≥60 years. Cannabis use patterns were self-reported, and cognitive function was assessed via computerized tests of attention, executive function, processing speed, visual memory and working memory. Multivariable linear regression models adjusted for demographic, health and lifestyle-related covariates.

Results: Cross-sectional analyses included 67 713 participants; longitudinal analyses included 52 002 participants with two cognitive assessments (mean age 67.2 ± 4.4 years; 46.1% male). Lifetime cannabis users (17%) performed better across all cognitive domains: attention (B = 0.071), executive function (B = 0.047), processing speed (B = 0.363), visual (B = 0.062) and working memory (B = 0.181). Current use was associated with better working memory (B = 0.169). Mixed and contradictory results were found for early onset, duration and frequency of use with cognitive outcomes. Longitudinally, past use was associated with less decline in executive function, while longer duration of use predicted steeper decline in processing speed.

Conclusions: Cannabis use is not uniformly harmful to cognition in older adults. Past use was linked to better performance and slower decline in some cognitive domains. However, specific usage patterns, such as longer duration, were associated with poorer outcomes in other domains. These findings highlight the need for further research to clarify underlying mechanisms and guide evidence-based recommendations regarding cannabis use in aging populations.”

https://pubmed.ncbi.nlm.nih.gov/41189327/

“Cannabis use in older adults is not uniformly associated with cognitive decline; former users showed better cognitive perform.”

“These results offer preliminary evidence that cannabis use may not be uniformly detrimental to cognitive health in aging.”

https://academic.oup.com/ageing/article/54/11/afaf319/8313927?login=false

Cannabis sativa extracts reduce inclusion formation in a cell model of alpha-synuclein aggregation

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“Parkinson’s disease (PD) is classified as a synucleinopathy due to the accumulation of protein inclusions rich in the alpha-synuclein (aSyn) protein. Identifying effective pharmacological therapies is important to slow the progression and minimize the symptoms of these diseases.

Cannabis sativa has a diverse chemical profile depending on its genotype, including several classes of substances, such as cannabinoids, flavonoids, terpenes, and alkaloids.

In this study, we evaluated the effects of four C. sativa extracts with different phytocannabinoid chemical profiles in two cellular models that reproduce alterations in cellular homeostasis common during the cellular phase of PD and other synucleinopathies. We used Saccharomyces cerevisiae strains transformed with plasmid DNA and genetically modified human cells (H4), both expressing aSyn.

The results showed that all the extracts were antioxidants, decreasing intracellular oxidation levels and increasing the number of daughter cells in yeast cells, but did not prevent mitochondrial damage. Besides, the extracts reduced the number of intracellular inclusions in H4 cells and increased the number of cells without inclusions.

Phytochemical characterization revealed extracts rich in Tetrahydrocannabinol – THC (69.88 %), Cannabidiol – CBD (52.64 %), and Cannabinol – CBN (47.38 % and 58.64 %), and we concluded that, regardless of these percentages, all C. sativa extracts showed protective biological activity against toxicity caused by alpha-synuclein production, both in yeast cells and H4 cells.”

https://pubmed.ncbi.nlm.nih.gov/41187864/

“Four Cannabis sativa extracts rich in different phytocannabinoids (THC, CBD, and CBN) demonstrated antioxidant potential independent of their chemical profiles. A decrease in the intracellular oxidative environment in the Saccharomyces cerevisiae model with aSyn indicates that the extracts (E-THC, E-CBD, E-CBN and E-CBN+) may contribute to maintaining cellular redox homeostasis, minimizing potential effects related to the development of Parkinsonism.”

https://www.sciencedirect.com/science/article/abs/pii/S0367326X25005945?via%3Dihub

Cannabidiol sensitizes triple-negative breast cancer cells to NK cell-mediated killing via EGFR inhibition and FAS upregulation

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“Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype lacking targeted therapies, presenting a significant clinical challenge. The epidermal growth factor receptor (EGFR) plays a crucial role in TNBC progression, making it a promising target for therapeutic intervention. This study investigated the potential of cannabidiol (CBD) as a therapeutic agent that targets EGFR and associated signaling pathways in TNBC.

Methods: The TNBC cell lines MDA-MB-468 and MDA-MB-231 were treated with CBD in the presence or absence of epidermal growth factor (EGF). Cell proliferation, FAS protein expression, and activation of the EGFR signaling pathway were assessed. The cytotoxic effects of CBD on TNBC cells and natural killer (NK) cells were also evaluated.

Results: CBD significantly elevated FAS protein expression in MDA-MB-468 cells compared to EGF treatment alone (125.29 ± 5.87% vs. 83.07 ± 1.30%, p < 0.0001). Further molecular analysis revealed that CBD inhibited EGFR signaling by downregulating key oncogenic proteins, including KRAS, PI3K, and AKT. Moreover, CBD enhanced the cytotoxic effects of NK-92 cells, reducing the viability of MDA-MB-468 cells more effectively than EGF alone did (52.12 ± 1.28% vs. 113.69 ± 1.68%, p < 0.0001).

Conclusions: These findings suggest that CBD holds promise as a potential anticancer agent in TNBC by disrupting EGFR signaling and promoting apoptosis. However, further studies are necessary to optimize its therapeutic window and minimize adverse effects, particularly regarding its potential cytotoxicity to immune cells.”

https://pubmed.ncbi.nlm.nih.gov/41188939/

“Our findings underscore the therapeutic potential of CBD in TNBC by targeting EGFR-driven pathways, modulating FAS expression, and enhancing immune-mediated killing. This study offers renewed hope for patients facing this challenging disease, positioning CBD as a potentially potent and multifaceted therapeutic agent.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00340-5

The Endocannabinoid System: Pharmacological Targets and Therapeutic Potential in CNS Disorders

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“The endocannabinoid system (ECS) influences a wide range of brain functions, including synaptic transmission, neuroplasticity, emotion, and immune regulation within the central nervous system, with CB1 and CB2 receptors mediating various neurophysiological and pathophysiological outcomes. Thus, growing interest in its therapeutic potential has prompted extensive research into how cannabinoid receptors contribute to the pathophysiology of neurological and psychiatric disorders, particularly CB1 and CB2.

This review has integrated findings from studies published between 2015 and 2025, covering conditions, like depression, anxiety, pain, multiple sclerosis, and Parkinson’s disease. We have also examined recent advances in receptor pharmacology and experimental technologies, including cryo-EM, optogenetics, and chemogenetics.

Although ECS-targeted therapeutics hold considerable promise, some key challenges remain in establishing safe and effective dosing protocols and integrating these approaches into clinical frameworks.

This review has provided an updated perspective on the system’s role in brain health and its potential to inform future therapeutic directions. Thus, ECS-targeted strategies may become increasingly important in managing and treating central nervous system disorders.”

https://pubmed.ncbi.nlm.nih.gov/41178765/

https://www.eurekaselect.com/article/151549

Dysregulation of the endocannabinoid system – a key factor in the progression of multiple sclerosis?

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“The endocannabinoid system has been implicated in the pathophysiology of multiple sclerosis (MS), yet its role across different disease stages and under disease-modifying treatment remains incompletely understood.

This study aimed to evaluate plasma levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in patients with MS at different clinical stages, and to explore their associations with disability, cognition, and quality of life, as well as the potential influence of teriflunomide therapy.

Thirty participants were enrolled: ten healthy controls, ten newly diagnosed relapsing-remitting MS (RRMS) patients in acute relapse, and ten teriflunomide-treated RRMS patients in remission. Plasma AEA and 2-AG were measured by ELISA; clinical assessments included the Mini-Mental State Examination (MMSE) and the SF-36 quality-of-life questionnaire.

No significant group differences were observed overall in 2-AG (P > 0.05). AEA showed a non-significant overall group effect (ANOVA, P = 0.0919) with a trend toward lower AEA in newly diagnosed patients compared to healthy controls (mean difference = -5.95 ng/ml, SE = 2.66; P = 0.098). In the teriflunomide group, AEA and 2-AG were strongly positively correlated (r = 0.882, P < 0.001). Additionally, SF-36 scores were positively associated with MMSE (r = 0.706, P = 0.023). Furthermore, SF-36 total scores were significantly lower in newly diagnosed patients compared to controls (post-hoc P = 0.044).

These findings suggest possible early dysregulation of the endocannabinoid system in MS and indicate that teriflunomide treatment is associated with a strengthened AEA-2-AG relationship. Larger, longitudinal studies are warranted to confirm these observations and to assess clinical implications for disease progression and patient quality of life.”

https://pubmed.ncbi.nlm.nih.gov/41178906/