Author Archives: David Worrell

Cannabidiol in pancreatic ductal adenocarcinoma: preclinical evidence, molecular mechanisms, and translational challenges

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“Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest and most treatment-resistant cancers, with limited progress in improving patient survival. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential anticancer agent due to its diverse molecular effects in preclinical cancer models.

Objective

This systematic review aims to evaluate the preclinical and early clinical evidence regarding CBD’s anticancer effects in PDAC, with emphasis on its molecular mechanisms, therapeutic synergies, and translational feasibility.

Methods

We systematically searched PubMed, Scopus, Web of Science, EMBASE, and Google Scholar (2006–2025) for studies examining the effects of CBD on PDAC in vitro, in vivo, and in clinical contexts. Studies were assessed for methodological quality and relevance to CBD-related antitumor activity.

Results

Fifteen studies met the inclusion criteria, including in vitro, animal, and limited clinical investigations. CBD exhibited antitumor properties via multiple pathways, such as CerS1-mediated ER stress and apoptosis, GPR55/MAPK inhibition, immune modulation, and chemosensitization to gemcitabine. Combination therapies (CBD with cannabinoids or chemotherapeutics) enhanced therapeutic outcomes in preclinical models. However, clinical evidence remains preliminary and insufficient to establish efficacy.

Conclusion

CBD demonstrates promising anticancer potential in PDAC through diverse molecular mechanisms and synergistic effects with chemotherapy. Nonetheless, significant translational barriers—including formulation variability, pharmacokinetics, and a lack of clinical trials—must be addressed. Further studies are warranted to validate these findings in human settings.”

https://pubmed.ncbi.nlm.nih.gov/41257868

“This systematic review provides a comprehensive synthesis of current evidence supporting cannabidiol (CBD) as a multifactorial anticancer agent in pancreatic ductal adenocarcinoma (PDAC).”

https://cancerci.biomedcentral.com/articles/10.1186/s12935-025-04062-9

Minor Cannabinoids CBD, CBG, CBN and CBC differentially modulate sensory neuron activation

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“The use of minor cannabinoids has been advanced, in part, by the idea of providing relief from pain and inflammation without the burden of unwanted psychogenic effects associated with Δ 9 THC. In this regard, investigators have focused on the effects of minor cannabinoid activation / desensitization of peripheral sensory neurons on nociceptive signaling and/or peripheral inflammation.

With a focus on peripheral nociception, four common minor cannabinoids: cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN) and cannabichromene (CBC) were studied in primary cultures of mouse Dorsal Root Ganglion (DRG) neurons.

We queried if calcium responses induced by the four cannabinoids differed in potency of activation, neuronal size preference, and dose-response relationships. Additionally, we determined the dependence of CBD and CBN on key channel-receptors that are known to mediate pain and/or antinociception.

Individually, CBD, CBG and CBC directed greater response magnitudes when compared to CBN. All four minor cannabinoids activated overlapping but distinct size populations of sensory neurons. CBD and CBG activated the widest range of DRG neuron sizes (smaller-larger) overlapping with smaller capsaicin-sensitive neurons. In contrast, CBN and CBC activated predominantly larger sensory neurons. CBD diverged from other minor cannabinoids in directing a linear dose-response profile whereas CBG and CBC directed sigmoidal dose-response profiles and CBN activated DRG neurons with an inverted U-shaped dose-response relationship. CBD-induced activation of DRG neurons was dependent on co-expression of the nociceptive channel TRPV1 plus cannabinoid receptor 1 (CB 1 R), whereas CBN-induced activation was independent of TRPV1.

Overall, we observed that minor cannabinoids CBD, CBG, CBN and CBC differed in their activation of DRG neurons and directed unique activation properties across a diverse population of sensory neurons. Such differences underly the hypothesis that a combination (entourage) of complimentary minor cannabinoids can direct synergistic antinociceptive activity.”

https://pubmed.ncbi.nlm.nih.gov/41256665

https://www.biorxiv.org/content/10.1101/2025.10.02.680148v1

Acute Effects of Cannabis on Alcohol Craving and Consumption: A Randomized Controlled Crossover Trial

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“Objective: Cannabis use is strongly linked with heavy drinking and worse alcohol treatment outcomes; however, it may also contribute to decreased alcohol consumption. To date, no human studies have established a causal effect of cannabis on alcohol motivation. The aim of this double-blind crossover randomized clinical trial was to examine dose-dependent acute effects of delta-9-tetrahydrocannabinol (THC) on alcohol craving and consumption.

Methods: Across three experimental days, 157 participants reporting heavy alcohol use and cannabis use two or more times weekly were randomized to smoke cannabis cigarettes containing 7.2% THC, 3.1% THC, or 0.03% THC (placebo), followed by exposures to neutral and personalized alcohol cues and an alcohol choice task for alcohol self-administration. A total of 138 participants completed two or more experimental sessions (mean age, 25.6 years [SD=5.1]; 35% women; 45% racial/ethnic minorities). Primary outcomes included craving, Alcohol Craving Questionnaire-Short Form, Revised (ACQ-SF-R), and an alcohol urge question; the secondary outcome was percent of total available milliliters of alcohol consumed.

Results: There were no significant effects of cannabis on ACQ-SF-R ratings after smoking and during alcohol cue exposure, but 7.2% THC reduced alcohol urge immediately after smoking. Participants consumed significantly less alcohol after smoking cannabis with 3.1% THC and 7.2% THC, reducing consumption by 19% and 27%, respectively.

Conclusions: Following overnight cannabis abstinence, smoking cannabis acutely decreased alcohol consumption compared to placebo. Further controlled research on a variety of cannabinoids is needed to inform clinical alcohol treatment guidelines.”

https://pubmed.ncbi.nlm.nih.gov/41254853

“These data provide preliminary evidence that cannabis may reduce alcohol consumption under some conditions”

https://psychiatryonline.org/doi/10.1176/appi.ajp.20250115

Bioactive metabolites and antidiabetic activity of Cannabis sativa-derived endophytic fungi

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“Cannabis sativa L. (Cannabaceae) has long been valued in traditional medicine, including Ayurveda, for managing disorders such as diabetes, cancer, and kidney diseases.

Although the plant itself is known to influence glucose metabolism, the therapeutic potential of its associated endophytic fungi remains underexplored. In this study, 56 fungal isolates were obtained from different tissues of C. sativa and evaluated for antidiabetic activity.

Two isolates, identified by ITS1/4 rDNA sequencing as Aspergillus micronesiensis and Nodulisporium verrucosum, exhibited strong inhibitory effects on α-amylase, α-glucosidase, DPP-IV, and lipase (IC₅₀ < 100 µg/mL). Their ethyl acetate extracts demonstrated low cytotoxicity, enhanced cell viability, and significantly promoted insulin secretion in MIN6 pancreatic β-cells. GC-MS analysis revealed bioactive metabolites, including 1-butyl-4-tert-butylbenzene, 7,9-di-tert-butyl-1-oxaspiro (4,5) deca-6,9-diene-2,8-dione, 2-methylcinnamic acid, and tetraneurin-A, which are reported to possess antidiabetic potential. FTIR further confirmed the presence of functional groups corresponding to these compounds.

Together, these findings highlight C. sativa-derived endophytic fungi as promising sources of novel antidiabetic agents, bridging traditional knowledge with modern drug discovery.”

https://pubmed.ncbi.nlm.nih.gov/41249583

https://link.springer.com/article/10.1007/s00203-025-04539-1

“The term “endophytic fungi” refers to fungi that live in plant tissues throughout the entire or partial life cycle by establishing a mutually beneficial symbiotic relationship with its host plant without causing any adverse effect or disease.” https://pmc.ncbi.nlm.nih.gov/articles/PMC8877053/


Cannabidiol and ∆9-Tetrahydrocannabinol in Endometriosis: A Literature Review on Therapeutic Applications and Mechanisms

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“Endometriosis is a chronic, inflammatory, and multifactorial disease characterized by the presence of endometrial tissue outside the uterine cavity, often associated with debilitating symptoms. It affects approximately 10% of women of reproductive age and is also related to infertility. Endometriosis can be classified as peritoneal, ovarian, or deep endometriosis, with primary symptoms including chronic pelvic pain, dysmenorrhea, and dyspareunia. Diagnosis and treatment are challenging, with laparoscopy and biopsy of ectopic tissue being the gold standard.

Cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) are two major cannabinoids found in the Cannabis sativa plant, widely known for their medicinal properties.

An experimental study conducted in rats demonstrated the anti-inflammatory, antioxidant, and antiangiogenic effects of intraperitoneal CBD use in the treatment of endometriosis. The objective of the present study was to conduct a literature review on the therapeutic potential of Cannabidiol (CBD) and ∆9-Tetrahydrocannabinol (THC) in the signs and symptoms of endometriosis. Research on PubMed, Embase, and Scopus platforms was conducted to determine the reproducibility and safety of treatment in humans, including dosage and administration route, as the current use is off-label.”

https://pubmed.ncbi.nlm.nih.gov/41248202


Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system

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“Although obesogenic high-fat/high-sugar diets impair memory function in humans and rodents, the underlying mechanisms remain elusive. Given that the brain endocannabinoid system and type-1 cannabinoid receptors (CB1Rs) control memory processes and are overactive under obesogenic conditions, we studied whether the effects of obesogenic diet consumption on memory function are dependent on this system.

Using an object recognition memory (ORM) task in male mice, we showed that CB1R activity is required for obesogenic-diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB1R, which also normalized training-induced hippocampal cellular and synaptic overactivation.

Consistently, the obesogenic diet potentiated the increase in hippocampal endocannabinoid levels and enhanced CB1R expression induced by ORM, and genetic CB1R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, the obesogenic diet enhanced the hippocampal mechanistic target of rapamycin (mTOR) pathway in a CB1R-dependent manner, and pharmacological mTOR inhibition after training rescued diet-induced ORM consolidation deficits.

Together, these results establish how an obesogenic environment can lead to hippocampal overactivation of the endocannabinoid system and the mTOR pathway to eventually impair memory consolidation. Thus, these results shed light on the mechanisms of diet-induced cognitive alterations and may pave the way for novel therapeutic strategies.”

https://pubmed.ncbi.nlm.nih.gov/41237773

“Foodomics Reveals Anti-Obesity Properties of Cannabinoids from Hemp Oil”

https://pubmed.ncbi.nlm.nih.gov/36382382

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

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

“Anti-Obesity diet drug from cannabis works!“

https://www.news-medical.net/news/2006/01/17/15421.aspx

A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study

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“Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored.

Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia.

ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment.

Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner.

This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.”

https://pubmed.ncbi.nlm.nih.gov/41240218

https://link.springer.com/article/10.1007/s12640-025-00770-2

Combination of CBD with minor cannabinoid CBDV suppresses CXCR4 via CB2 receptor and alleviates colitis in mice

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“Cannabis extracts, particularly those rich in cannabinoids like cannabidiol (CBD), have shown potential anti-inflammatory properties and are being examined in managing conditions involving inflammation.

One proposed mechanism is their modulation of chemokine expression and function in immune cells. C-X-C chemokine receptor type 4 (CXCR4) plays a pivotal role in immune cell trafficking and is implicated in the pathogenesis of inflammatory bowel disease (IBD).

Given emerging evidence that cannabinoids can influence chemokine signaling, we explored whether they could downregulate CXCR4 in immune cells.

In this study, we show that the combination of CBD and cannabidivarin (CBDV) at a 20:1 ratio significantly reduces CXCR4 expression in MOLT-4 cells, murine splenocytes and human peripheral blood mononuclear cells. This reduction in CXCR4 expression correlated with impaired chemotactic responses and suppressed actin polymerization, effects that were abrogated by CB2 receptor inhibition. In vivo, the CBD:CBDV combination ameliorated disease severity in a murine model of DSS-induced colitis, improving disease activity index, colon length, and histological outcomes. These therapeutic benefits were absent in CB2 knockout mice, confirming CB2 dependence.

Our findings support a CB2-mediated mechanism by which the CBD:CBDV combination downregulates CXCR4, providing a mechanistic basis for the entourage effect and highlighting the significance of CBDV as a modulator of the CBD effect.

Overall, this study implicates cannabinoid combinations as a promising therapeutic strategy for treating IBD.”

https://pubmed.ncbi.nlm.nih.gov/41237459

Insights into Thai and Foreign Hemp Seed Oil and Extracts’ GC/MS Data Re-Analysis Through Learning Algorithms and Anti-Aging Properties

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“This study successfully established a novel discriminative model that distinguishes between Thai and foreign hemp seed extracts based on gas chromatography/mass spectrometry (GC/MS) metabolic profiling combined with machine learning algorithms such as hierarchy clustering analysis (HCA), principal component analysis (PCA), and partial least square-discriminant analysis (PLS-DA).

The findings highlighted significant metabolic features, such as vitamin E, clionasterol, and linoleic acid, related with anti-aging properties via elastase inhibition.

Our biological validation experiment revealed that the individual compound at 2 mg/mL exhibited a moderate elastase inhibitory activity, 40.97 ± 1.80% inhibition (n = 3). However, a binary combination among these metabolites at 1 mg/mL of each compound demonstrated a synergistic effect against elastase activities up to 89.76 ± 1.20% inhibition (n = 3), showing 119% improvement. Molecular docking experiments aligned with biological results, showing strong binding affinities and enhanced inhibitory effects in all combinations.

This integrated approach provided insights into the bioactive compounds responsible for anti-aging effects and established a dependable framework for quality control and standardization of hemp seed-based skincare products. Additionally, the developed models enable effective discrimination between Thai and foreign strains, which is valuable for sourcing and product consistency.

Overall, this research advances our understanding of hemp seed phytochemicals and their functional potential, paving the way for optimized natural anti-aging formulations and targeted functional foods.”

https://pubmed.ncbi.nlm.nih.gov/41227709/

“Integrating hemp actives into cosmeceuticals offers sustainable and natural substitutes for conventional skincare products with a variety of advantages, such as moisturizing and anti-aging effects.”

https://www.mdpi.com/2304-8158/14/21/3739

Acute effects of cannabis on core and co-occurring features associated with autism spectrum disorder in adults

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“Pharmacological interventions that treat core and co-occurring features of autism spectrum disorder (ASD) are a persistent unmet need.

As such, use of cannabis to manage ASD features is common in the autistic community. Yet, few studies have examined the acute effects of cannabis on symptoms associated with ASD. Therefore, we measured changes in symptom ratings from before to after cannabis use in a sample of 111 self-identified autistic adults.

Anonymized archival data sourced from the Strainprint® app were analyzed. A subset of tracked information that reflected changes in core and co-occurring symptoms associated with ASD (i.e., Sensory Sensitivity, Repetitive Behaviors, Mental Control, and Negative Affect) were used to assess the impacts of cannabis on symptom severity.

Overall, symptom severity ratings were reduced by 73.09% from before to after cannabis use. More severe symptoms were associated with greater reductions in severity ratings after use.

Higher doses predicted greater reductions in severity of Repetitive Behaviors, Mental Control, and Negative Affect but dose of cannabis used to manage all symptoms remained static across time.

Results from this first empirical examination of the perceived acute effects of cannabis in autistic adults suggest that cannabis provides temporary relief from symptoms associated with ASD.”

https://pubmed.ncbi.nlm.nih.gov/41233406/

“The present study represents the first to demonstrate acute perceived beneficial effects of inhaled cannabis on core and co-occurring symptoms associated with ASD in a large adult sample.”

“These findings indicate that well-powered placebo-controlled trials are warranted to examine the acute effects of various cannabinoids and manipulations of the endocannabinoid system on ASD symptoms.”

“In sum, data from clinical trials of children and adolescents presents an evidence base that supports a continued focus on the impact of CBD on ASD features, while the present data from cannabis-using autistic adults indicates that a sole focus on CBD may not fully capture the potential impact of cannabinoids as a pharmacological intervention for adults with ASD. Thus, additional placebo-controlled clinical trials are needed where THC, CBD, and other non-intoxicating cannabinoids (e.g., cannabigerol), terpenes, and/or medications that modulate the functioning of the endocannabinoid system are administered to autistic adults to determine their relative effects on symptoms associated with ASD.”

https://www.nature.com/articles/s41598-025-23472-3