Author Archives: David Worrell

The Associative Impact of Recreational Cannabis Use on Sinonasal Diseases

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“Objectives: With growing cannabis use in the US, it is crucial to understand the impact of recreational use on sinonasal diseases like chronic rhinosinusitis (CRS), allergic rhinitis (AR), and chronic rhinitis (CR).

Methods: This cross-sectional study leveraged the NIH AllOfUs database to query patient surveys assessing cannabis usage frequency (lifetime never, monthly, weekly, or daily within the past 3 months) and consumption route (smoking or non-smoking). Cannabis users were matched to never users for demographics, healthcare visit frequency, and insurance. A stringent logistic regression model calculated odds ratios (OR) of developing AR, CRS, or CR after survey completion. Cox regression hazard ratios (HR) compared consumption routes.

Results: Twenty-five thousand one hundred sixty-four cannabis users were matched with 113,418 never users. Users demonstrated significantly lower odds of AR, CRS, and CR than never users. For CRS, the ORs compared to never users are as follows: daily users 0.64 (95% CI 0.53-0.78), weekly users 0.61 (95% CI 0.48-0.77), and monthly users 0.80. For AR, the ORs were 0.64 (95% CI 0.58-0.71) for daily users, 0.62 (95% CI 0.54-0.71) for weekly users, and 0.69 (95% CI 0.58-0.80) for monthly users. For CR, the ORs were 0.61 (95% CI 0.47-0.79) for daily users, 0.64 (95% CI 0.47-0.87) for weekly users, and 0.41 (95% CI 0.26-0.65) for monthly users. There was no significant difference between smokers and non-smokers (HR 0.64, 95% CI 0.27-1.5).

Conclusion: There is an inverse, associative relationship between cannabis use and sinonasal disease. This relationship is insufficiently understood, and there remain significant concerns about the impact of cannabis use, especially smoking, on airway pathologies.”

https://pubmed.ncbi.nlm.nih.gov/41064579/

“This is the largest study to specifically comment on the association between cannabis use and three of the most common sinonasal diseases—AR, CRS, and CR. We found lower odds of AR, CRS, and CR in patients who use cannabis compared to those who do not, which is strengthened by the size of our cohorts and by incorporating demographic and comorbidity information in our analysis. Route of consumption did not change CRS incidence. “

https://onlinelibrary.wiley.com/doi/10.1002/lio2.70261

Efficacy of non-psychotropic Cannabis sativa L. standardized extracts in a model of intestinal inflammation

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“Background: The use of Cannabis sativa L. (Cannabis) was reported by observational studies on inflammatory bowel diseases (IBD) patients. However, this indication is poorly supported by clinical trials. Several pre-clinical studies demonstrated the anti-inflammatory activity of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) at intestinal level. On the contrary, minor cannabinoids, such as cannabigerol (CBG), were less investigated. Moreover, several authors suggested that complex Cannabis extracts might display a higher efficacy in respect to pure cannabinoids against inflammatory disorders.

Methods: This study was aimed at investigating the role of Cannabis extracts, standardized in CBD and CBG content, in a model of in vitro-induced intestinal inflammation using CaCo-2 cells. Inflammatory mediators at transcriptional (PCR arrays) and protein level (ELISA assays) were investigated and correlated with enterocyte layer permeability. The two evaluated extracts, A and B, come from the mix of the same Cannabis varieties (Cannabis sativa L. Chemotype III and Chemotype IV), and are standardized in CBD and CBG at the same level, by changing the polarity of the primary extraction solvents.

Results: Pro-inflammatory cytokines involved in IBD, such as IL-1β and IFN-γ, induced the expression and the release of chemokines for lymphocytes (CXCL-9, CXCL-10, CCL20) in CaCo-2, while Cannabis extracts (100 µg/mL) or individual compounds (8 µM) showed inhibitory activity. After simulated digestion, extract A abrogated the release of CCL-20, while extract B abrogated the release of CXCL-9 and CXCL-10. The inhibition of CXCL-9 was demonstrated at transcriptional level also. The inhibitory activity paralleled with the content of CBD or CBG, acting at least in part through NF-κB impairment (-42% and – 66%, respectively). However, Cannabis extracts showed greater effect in the CaCo-2-THP-1 co-culture inflammation model compared to individual cannabinoids, thus partially recovering the epithelial barrier measured by transepithelial electrical resistance (TEER), and zonula occludens (ZO-1) expression.

Conclusions: Data collected within this study showed the importance of standardization and extraction method reproducibility through manufacturing and process control, besides demanding future investigations focusing on the effect of Cannabis extracts against intestinal inflammation, which show in this context effects higher than individual cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/41053843/

“At the best of our knowledge, this is one of the few works in which the biological properties of standardized Cannabis extracts were compared with their major cannabinoids. More generally, the role of CBG in intestinal inflammation is matter of interest for its non-psychotropics nature, but it was investigated by few articles before. However, our data suggest that the use of Cannabis extracts against intestinal inflammation might be preferred in respect to single cannabinoids. Nevertheless, specific studies should be conducted with the aim to translate the evidence to in vivo models.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00335-2

Rethinking Alzheimer’s: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control

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“Alzheimer’s disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential.

This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway.

Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions.

CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation.

These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.

Significance statement This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer’s disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/41052930/

https://www.eneuro.org/content/early/2025/09/26/ENEURO.0114-25.2025

Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model

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“Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD) decreases the expression of drug-resistant seizures in specific syndromes. However, it is unknown if CBD prevents the development of drug-resistant condition in epilepsy.

This research was conducted to investigate if subchronic administration of CBD with sodium channel blockers modifies the mortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared with those elicited by antiseizure medications acting on the GABAA receptors.

Male Wistar rats were used to evaluate CBD combined with different antiseizure medications (phenobarbital, diazepam, valproic acid, lamotrigine and oxcarbazepine) during the repetitive administration of 3-MP. The mortality rate and development of drug-resistant seizures were estimated. Computational experiments explored interactions between CBD and sodium channel blockers in the NaV1.7 receptor.

Subchronic administration of CBD alone did not modify neither the mortality rate nor the development of drug-resistant seizures. CBD combined with phenobarbital or diazepam reduced the mortality rate and prevalence of drug-resistant seizures. In contrast, coadministration of CBD with valproic acid or lamotrigine did not modify neither the mortality rate nor the expression of drug-resistant seizures. Contrariwise, combining CBD with oxcarbazepine at ED50 increases the incidence of drug-resistant seizures. Computational experiments suggested that CBD acting on NaV1.7 interferes with the action of sodium channel blockers and precludes their inhibitory effects.

Our results indicate that repeated administration of CBD with GABAergic antiseizure medications, but not sodium channel blockers, decreases the mortality and prevents the development of the drug-resistant phenotype induced by repeatedly provoked severe seizures.”

https://pubmed.ncbi.nlm.nih.gov/41050418/

“The present study confirms that CBD alone does not modify the mortality rate induced by severe seizures. Our results also support that CBD combined with GABAergic drugs but not with sodium channel blockers reduces the mortality rate during the repetitive induction of clonic-tonic seizures and prevents the development of drug-resistance seizures in a preclinical model.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1644018/full

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

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“The favorable lipid profile of hemp seed could be a potential source of unsaponifiable matter rich in fat-soluble phytochemicals such as phytosterols, vitamin E, and cannabidiol (CBD). Despite its nutritional value, studies investigating the functional properties of hemp seed, particularly its anti-obesity potential, remain limited.

The aim of this study was to obtain unsaponifiable matter from hemp seed (HUSM), analyze its fat-soluble phytochemicals and evaluate its anti-obesity activity using both in vitro and in vivo experimental models.

The results showed that HUSM contained abundant carotenoids, vitamin E, phytosterols, policosanols, and CBD, with trace amounts of THC (0.06%), Furthermore, HUSM inhibited adipocyte differentiation and lipid accumulation in a dose-dependent manner, significantly reducing lipid accumulation by up to 79% without cytotoxicity in 3T3-L1 adipocytes.

HUSM treatment led to reduced abdominal size and body weight gain, decreased adipose tissue and liver size, and lower plasma triglycerides, total cholesterol, and LDL cholesterol levels. These effects were mediated through the AMPK signalling pathway, which plays a pivotal role in regulating adipogenesis and lipogenesis. Additionally, HUSM improved adipokine balance, reducing leptin and increasing adiponectin levels, indicating recovery of dysfunctional adipose tissues.

These findings highlight the potential of HUSM as a natural anti-obesity therapeutic, offering new avenues for the treatment and prevention of obesity and related metabolic disorders through the AMPK signalling pathway.”

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

https://pubs.rsc.org/en/content/articlelanding/2025/fo/d5fo02231b

Ex vivo study of the vasorelaxant activity induced by cannabigerol in human pulmonary artery- the role of endothelium, sex and selected clinical factors

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“Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with an antioxidant and anti-inflammatory properties.

Because CBG has a promising pharmacological profile involving activation of α2adrenergic and peroxisome proliferator-activated γ (PPARγ) receptors it may have relevance in the pharmacotherapy of cardiovascular diseases.

Cannabigerol was also effective in lowering blood pressure in normotensive mice. In addition, it has been shown that cannabinoids can exhibit vasorelaxant effects in various vascular beds, and another plant cannabinoid-cannabidiol-has been shown to be effective in attenuating the development of pulmonary arterial hypertension.

In view of these reports, the aims of our study were to investigate whether CBG, exhibits a vasorelaxant effect on human pulmonary arteries (hPAs), to determine the mechanisms of CBG’s potentiating effects and to assess the influence the selected clinical factors and patients’ comorbidities on the vascular response induced by CBG.

Our study reports that CBG relaxes hPAs, and post-hoc analysis has shown that this response can be modified by hypertension and hypercholesterolaemia. We showed that the vasorelaxant effect of CBG depends on the vascular endothelium and the following mechanisms are involved: 1) cyclooxygenase-dependent pathway, 2) nitric oxide-dependent pathway, 3) voltage- and calcium-dependent K+ channels and 4) probably cannabinoid type 1 and 2, PPARγ, G-protein-coupled 55 and transient receptor potential vanilloid 1 receptors.

At all, CBG appears to be a possible vasorelaxant agent, but its therapeutic efficacy may vary based on the patient’s condition and comorbidities. CBG’s mild vasorelaxant property may provide an added benefit in addition to its anti-inflammatory and antioxidant properties in hemp preparations.”

https://pubmed.ncbi.nlm.nih.gov/41046075/

“In conclusion, this study reports for the first time that CBG causes a vasorelaxant effect in hPAs. This effect is primarily mediated by vascular endothelium-dependent mechanisms. CBG-induced vasorelaxation was mediated by the 1) COX-1/COX-2-dependent pathway, 2) NO-dependent pathway, 3) voltage- and calcium-dependent K+ channels and 4) probably by the CB1, CB2, PPARγ, GPR55 and TRPV1 receptors.

This study provides evidence that CBG may be a potentially important agent with vasorelaxant effect, but its therapeutic efficacy may be modified by the patient’s condition and comorbidities. In addition to the well-documented anti-inflammatory and antioxidant properties, the mild vasorelaxant effect of CBG may be an additional advantage in the context of the use of hemp preparations.”

https://www.sciencedirect.com/science/article/pii/S0006295225006483?via%3Dihub

Cannabidiol releases CB1R from A2AR repression in ischemic stroke

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“Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate.

CBD targets a variety of proteins, adenosine A2AR and cannabinoid CB1R receptors included. These two receptors may interact to form heteromers (A2AR-CB1R Hets) that are also a target of CBD. Thus, we aimed to assess whether the expression and function of A2AR-CB1R-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen deprived (GOD) neurons and microglial cells.

Results indicated that the formation of A2AR-CB1R heteromers increased A2AR affinity for its selective agonist CGS21680. Moreover, resonance energy transfer assays showed that CBD and cannabigerol (CBG) affected the structure of the heteromer. Regarding functionallity, CBD partially bloked A2AR induced signalling in transfected HEK-293 T cells, while it recovered CB1R signalling in glucose/oxygen-deprived neurons and microglial cells. The expression of A2AR-CB1R Hets increased in GOD neurons and microglial cells.

This increase was counteracted with a pre-treatment with CBD and CBG. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of A2AR-CB1R Hets.

In conclusion, CBD effects in the hypoxia of the neonate can be mediated by A2AR-CB1R complex. CBD partially blocks A2AR signalling while potentiates the neuroprotective effect of CB1R in hypoxic-ischemic conditions.”

https://pubmed.ncbi.nlm.nih.gov/41046105/

“In conclusion, the relevance of A2A-CB1 heteromers formations lies in the fact that these receptors can regulate each other. At the first stages after the injury A2A acquires a more important role, while days after CB1R signalling would provide an improvement.

Interestingly, CBD treatment plays an important effect by controlling A2AR and CB1R competition. This compound could be really beneficial to fight ischemic stroke by regulating A1R-CB1R complex function in the different stages of the disease.”

https://www.sciencedirect.com/science/article/pii/S0969996125003481?via%3Dihub

Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection

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“Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection.

We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques.

This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia.

Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-κb and STAT1 activation when mediating its antiviral and anti-inflammatory effects.

These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.”

https://pubmed.ncbi.nlm.nih.gov/41040324/

https://www.biorxiv.org/content/10.1101/2025.09.25.678534v1

Optimal Cannabinoid-Terpene Combination Ratios Suppress Mutagenicity of Gastric Reflux in Normal and Metaplastic Esophageal Cells

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“Background: Esophageal adenocarcinoma (EAC) frequently arises from chronic exposure to acid and bile reflux, with secondary bile acids, such as deoxycholic acid (DCA), contributing to its pathogenesis through mechanisms involving reactive oxygen species (ROS), oxidative DNA damage, and resistance to apoptosis. The human endocannabinoid system (ECS) regulates diverse anti-inflammatory, antioxidant, and analgesic pathways implicated in disease modulation. Despite its therapeutic promise, effective pharmacological activation of the ECS remains challenging.

Objectives: This study aimed to evaluate whether specific cannabinoid-terpene combinations targeting the ECS could attenuate the mutagenic and cytotoxic effects of bile acid-induced stress in esophageal cell models. Additionally, we assessed the clinical significance of ECS-related protein receptors in the progression of EAC.

Design: In vitro experimental models combined with clinical samples analyses.

Methods: We utilized in vitro models, including human esophageal epithelial cell lines exposed to DCA and a Barrett’s esophagus gastroesophageal reflux (GER) model subjected to low pH and a bile acid cocktail. Patient-derived samples were analyzed to investigate the clinical association of ECS pathway markers with EAC progression. Experimental models were treated with varying ratios of phyto-cannabinoids and terpenes. Endpoints included assessment of DNA damage, mitochondrial membrane potential, and ROS production to identify optimal compound combinations. Expression of ECS-related protein receptors was evaluated in clinical samples to elucidate their role in EAC development.

Results: A 1:5 ratio of cannabigerol (CBG) to Phytol (Phy) was found to significantly reduce DCA-induced DNA damage, preserve mitochondrial membrane potential, and decrease ROS levels. This combination also enhanced apoptosis in damaged cells and diminished mutagenicity. Analysis of patient samples revealed that the expression of the ECS-associated receptor protein CB1 correlated with EAC progression, suggesting a broader clinical role for ECS modulation in cancer prevention.

Conclusion: Modulation of the ECS through carefully selected cannabinoid-terpene ratios can mitigate bile acid-induced esophageal damage and may reduce carcinogenic progression. These findings support further in vivo investigations and raise the possibility of expanding cannabinoid-terpene therapeutics to other conditions involving similar pathogenic processes.”

https://pubmed.ncbi.nlm.nih.gov/41040236/

https://www.biorxiv.org/content/10.1101/2025.09.23.678062v1

No differences in neural responses or performance during cannabis cue-specific inhibitory control tasks between recreational cannabis users and non-users: Insights from fNIRS

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“Background: Impaired inhibitory control has been observed in regular cannabis users. Theories suggest that regular cannabis use is maintained by reward-driven behaviour, which may be underpinned by adaptations in neural reward and inhibitory control systems, thus increasing vulnerability to dependency.

Aims: This study investigated neural correlates of cannabis cue-specific inhibitory control in regular cannabis users and non-users using functional near-infrared spectroscopy (fNIRS).

Methods: Thirty regular cannabis users and thirty non-user controls completed two inhibitory control tasks (Go/No/Go and Stop-Signal Task), and a measure of attentional bias (Cannabis Stroop task). fNIRS recorded prefrontal and orbitofrontal haemodynamic responses (oxygenated haemoglobin and deoxygenated haemoglobin). Group comparisons and exploratory regressions examined cannabis use characteristics as predictors of behavioural and neural outcomes.

Results: No significant group differences were found in behavioural performance or haemodynamic activity across tasks. Exploratory regressions showed no significant associations between cannabis use characteristics and behavioural or neural outcomes after adjusting for covariates.

Conclusions: No evidence of impaired inhibitory control, attentional bias, or differences in prefrontal function were found in non-dependent cannabis users. Future studies should investigate whether such deficits emerge with heavier or dependent use.”

https://pubmed.ncbi.nlm.nih.gov/41037310/

“In summary, this study found no significant differences in behavioural performance or neural activation between regular cannabis users and non-user controls during cue-specific inhibitory control tasks.”

https://journals.sagepub.com/doi/10.1177/02698811251358814