Author Archives: David Worrell

Cannabidiol Reprograms Glucose Metabolism in Colorectal Adenocarcinoma by Targeting HIF-1α/LDHA Pathway

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“Colon adenocarcinoma (COAD) is characterized by the metabolic reprogramming, such as the Warburg effect, which drives tumor progression and immunosuppression. Hypoxia-inducible factor 1 (HIF-1) and lactate dehydrogenase A (LDHA) are critical regulators of this metabolic shift, but existing therapies are insufficiently specific to it.

This study investigates the antitumor mechanisms of cannabidiol, a non-psychoactive phytocannabinoid, by using integrative multi-omics and functional validation.

Single-cell transcriptomics revealed that cannabidiol reduced tumor cell proportions and suppressed glycolytic activity in COAD.

Network pharmacology identified PTGS2 as a central target, with proteomic data confirming its overexpression in COAD tissues and association with poor prognosis. In vitro, cannabidiol inhibited COAD cell proliferation, migration, and colony formation while downregulating HIF-1[Formula: see text], LDHA, and GLUT1 expression.

Metabolic assays demonstrated associated dose-dependent reductions in ATP production, glucose uptake, and lactate levels. Rescue experiments using the HIF-1agonist DMOG partially reversed cannabidiol’s antiglycolytic and antitumor effects, and thus confirmed pathway dependency. Synergy with the glycolysis inhibitor 2-DG enhanced therapeutic efficacy, which highlighted cannabidiol’s potential to overcome metabolic resistance.

These findings establish cannabidiol as a novel inhibitor of HIF-1/LDHA-driven glycolysis, and thus provide a translational strategy for metabolic vulnerability in COAD.”

https://pubmed.ncbi.nlm.nih.gov/41219135/

https://www.worldscientific.com/doi/10.1142/S0192415X25500958

“The phrase “Cannabidiol Reprograms Glucose Metabolism in Colorectal Adenocarcinoma by Targeting HIF-1α/LDHA Pathway” means that cannabidiol (CBD) helps fight colon cancer cells by altering how they use glucose (sugar) for energy, specifically by interfering with a key biological pathway involving the proteins HIF-1α and LDHA.”

“In summary, the study found that CBD acts as a novel inhibitor of the HIF-1α/LDHA pathway, suppressing the abnormal glucose metabolism essential for colorectal cancer growth and providing a potential therapeutic strategy for treatment.”

Enhancing wheat-bread with hemp flour: Impact on chemical, volatile, and sensory properties

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“Consumer interest in nutrient-rich and sustainable bakery products is stimulating the use of novel flours. Hemp (Cannabis sativa L.) flour represents a promising ingredient, even though its application in breadmaking remains limited.

This study explored the partial substitution of wheat flour with a mixture of two hemp cultivars, Felina 32 and Futura 75, at 10 %, 15 %, and 25 % inclusion levels. Comprehensive characterization addressed chemical composition, antioxidant properties, volatile profile, and sensory quality.

Hemp fortification increased the nutritional value of bread, particularly enhancing polyunsaturated fatty acids (notably linoleic acid), essential amino acids (lysine, leucine, phenylalanine), and total polyphenols, leading to enhance the antioxidant capacity. Volatile compound analysis showed an enrichment in compounds such as hexanoic acid, humulene, and citral. Sensory evaluation confirmed consumer acceptance, despite minor bitterness note.

These results demonstrate hemp flour’s potential as a functional and sustainable ingredient.”

https://pubmed.ncbi.nlm.nih.gov/41214949/

“Hemp (Cannabis sativa L.) is an herbaceous and multipurpose plant that can be used in different fields such as agriculture, food and feed, cosmetics, pharmaceuticals, and building.”

“Hemp flour (HF), naturally gluten-free, has been used to enrich various types of bread to increase the protein content, essential fatty acids, phenolic and antioxidant compounds.”

“Based on these data, HF can be consider an excellent ingredient to improve the nutritional profile of bread.”

“We can conclude that HF is a valuable ingredient, to improve the nutritional properties of bread.”

https://www.sciencedirect.com/science/article/pii/S0963996925017776?via%3Dihub

Therapeutic Potential of Cannabidiol-Rich Cannabis sativa to Mitigate the Severity of Inflammation and Pain: A Pre-Clinical Study

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“Ethnopharmacological relevance: Pain and inflammation are among the many conditions for which Cannabis sativa L. has historically been used. However, little research has been done on the potential therapeutic benefits of employing green extraction techniques to generate an extract from C. sativa that is high in cannabidiol for the treatment of severe pain and inflammation.

Aim of the study: This study investigates the potential chemico-pharmacological profile of a supercritical CO2 extract of Cannabis sativa genotype CIM-CS-64 (CSFE) for managing inflammation and pain responses using an experimental pharmacology approach.

Materials and methods: A combination of complementary analytical techniques (GC-FID, GC-MS, HPLC, HRMS, NMR) was used to examine the chemical composition of the CSFE to ensure comprehensive chemical coverage. The experiments were conducted on small laboratory animals to investigate the therapeutic efficacy of CSFE in mitigating inflammation and pain responses.

Results: Altogether, sixty-two compounds with cannabidiol, β-caryophyllene, cannabidivarin, cannabichromene, (E)-phytol, and α-bisabolol as major constituents were annotated in CSFE by GC-FID and GC-MS techniques. The HPLC analysis revealed the presence of CBD (9.75 ± 0.85%), CBDA (2.76 ± 0.69%) and Δ9-THC (4.40±0.16%) as major cannabinoids in the CSFE. In LPS-stimulated macrophages, the CSFE markedly reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) at concentrations of 3, 10, and 30 μg/ml without causing any cytotoxicity. The results demonstrated a significant decrease in inflammation and considerable improvement in pain-relieving potential in a dose-dependent manner.

Conclusions: The present research revealed that CSFE possesses promising analgesic and anti-inflammatory properties in small laboratory animals.”

https://pubmed.ncbi.nlm.nih.gov/41213439/

“Altogether, sixty-two compounds with cannabidiol, β-caryophyllene, cannabidivarin, cannabichromene, (E)-phytol, and α-bisabolol as major constituents were annotated in CSFE by GC-FID and GC-MS techniques.

The HPLC analysis revealed the presence of CBD (9.75 ± 0.85 %), CBDA (2.76 ± 0.69 %) and Δ9-THC (4.40 ± 0.16 %) as major cannabinoids in the CSFE. In LPS-stimulated macrophages, the CSFE markedly reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) at concentrations of 3, 10, and 30 μg/ml without causing any cytotoxicity.

The results demonstrated a significant decrease in inflammation and considerable improvement in pain-relieving potential in a dose-dependent manner.”

“The present research revealed that CSFE possesses promising analgesic and anti-inflammatory properties in small laboratory animals.”

“The findings validate the use of the plant for managing pain and inflammation in traditional medicine.”

https://www.sciencedirect.com/science/article/abs/pii/S037887412501548X?via%3Dihub

Combination CBD/THC in the management of chemotherapy-induced peripheral neuropathy: a randomized double blind controlled trial

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“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) can greatly impair function, leading to disability or truncated treatment in cancer patients. Previous animal studies show that cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC) can ameliorate CIPN. This study assessed the effect of combined CBD and THC on CIPN symptoms amongst cancer patients treated with taxane- or platinum-based agents.

Materials and methods: This 12-week randomized, double-blind, placebo-controlled trial included participants with nonmetastatic breast, colorectal, endometrial, or ovarian cancer experiencing grade 2-3 CIPN. The active group received CBD (125.3-135.9 mg) combined with THC (6.0-10.8 mg) in gelcaps. The Quality-of-Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20) sensory subscale was used as the primary outcome. Additional outcomes assessed pain, sleep, and function. Neurologic exams evaluated touch, pressure, and vibration sense. Following the randomized controlled trial, participants were invited to enroll in a 12-week open-label observational study.

Results: Of 230 participants identified, 124 met eligibility, 54 were enrolled, 46 were randomized, and 43 completed 12 weeks of treatment. This was lower than our goal of 100 randomized participants. The mean age was 60 +/- 9 years, 88% were female, 63% had breast cancer. All participants had completed chemotherapy. The primary analysis showed no differences in outcome measures between active and placebo groups, likely due to sample size. Although an increase in bilirubin (one participant in active group, and one in placebo) and alkaline phosphatase (one participant in active group) was seen, this did not exceed the exit criteria. A secondary analysis showed that the active group experienced greater improvement in the QLQ-CIPN20 measures of sensory impairment relative to placebo (-10.4 (95% -20.5, -0.3), p = 0.044). There was also improvement in light touch and vibration sensation of the feet on neurological exam that approached significance. There was no effect on other measures, including pain, and no between-group differences in side effects. The uncontrolled observational study showed similar results.

Discussion: The primary analysis showed no between-group difference in CIPN symptoms. The secondary analysis indicated that CBD with THC could improve sensory impairment and might increase touch and vibration sense, although these findings require confirmation in a future, more fully powered study. Nonetheless, our results show that combination CBD/THC can be safely delivered to participants with CIPN and suggest that these cannabinoids should be further investigated for this indication.”

https://pubmed.ncbi.nlm.nih.gov/41211445/

“Overall, this study suggests that combination CBD/THC could help with the sensory impairment seen in CIPN. Since the disorder is prevalent and incurs significant hardship, even a modest sensory improvement could enhance patients’ quality of life, given the lack of alternatives.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1590168/full

The impact of tetrahydrocannabinol on central pain modulation in chronic pain: a randomized clinical comparative study of offset analgesia and conditioned pain modulation in fibromyalgia

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“Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation.

This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization.

Methods

In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo.

Results

THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo (P = 0.01 and P = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo (P = 0.04 and P = 0.008), while no effect was observed on CPM (P = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P = 0.003), whereas CPM did not show a significant association (P = 0.121).

Conclusions

This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders.”

https://pubmed.ncbi.nlm.nih.gov/41199355/

“Cannabis, particularly its psychoactive component delta-9-tetrahydrocannabinol (THC), has attracted increasing attention as a therapeutic option for chronic pain management. Clinically, THC has been shown to reduce pain intensity, improve quality of life and attenuate hyperalgesia in various chronic pain conditions, including neuropathic pain and fibromyalgia “

“THC is thought to exert its analgesic effects in part by modulating disrupted pain networks. Specifically, THC interacts with the endocannabinoid system.”

“To conclude, this study corroborates the possible effectiveness of THC in alleviating experimental and spontaneous pain in FMS, a study case of central sensitization, and shows an enhancement of OA responses after THC treatment in FMS patients compared to baseline and placebo.”

“This, in turn, reinforces the potential of OA as a reliable marker of pain modulation in FMS and may pave the way for personalized cannabinoid-based therapies for chronic pain in the future.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00348-x

Cannabidiol as Adjunctive Treatment in Drug-Resistant Epilepsy With Epileptic Spasms Beyond Two Years of Age

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“Background: To assess the efficacy and safety of adjunctive cannabidiol (CBD) in children with drug-resistant epileptic spasms (ES) beyond age 2 years.

Methods: We conducted a retrospective longitudinal study of patients with childhood epileptic spasms (CESs) treated with purified CBD (Epidyolex) at Niño Jesus Hospital in Madrid, Spain, from 2020 to 2024. All patients were older than 2 years and had drug-resistant epilepsy and ES as the primary seizure type. Efficacy was assessed by comparing ES frequency before and after CBD treatment, with a good response defined as a ≥50% reduction in ES. Adverse effects (AEs) were recorded to assess safety and tolerability.

Results: Of the 53 patients included, 58.5% achieved a ≥50% reduction in ES frequency, 15% of whom attained complete freedom from ES. Patients with malformations of cortical development and Down syndrome showed the highest response rates. Clobazam was the most frequently associated medication (77.3%), indicating a potential synergistic effect. AEs were reported in 62.2% of patients, with drowsiness, hyperammonemia, and behavioral disturbances being the most common. CBD was discontinued in 17% due to lack of efficacy and in 11.3% due to AEs.

Conclusions: CBD appears to be an effective and well-tolerated adjunctive treatment for drug-resistant ES in children older than 2 years. Significant response rates were found, particularly in patients with Down syndrome and malformations of cortical development. Future studies with larger cohorts and longer follow-up are needed to validate these findings and explore the potential for earlier use of CBD in treatment-resistant epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/41197417/

https://www.pedneur.com/article/S0887-8994(25)00314-5/abstract

Cannabinoids Shape Synaptic Activity and Adult Neurogenesis in the Zebrafish Pallium

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“The endocannabinoid system regulates neuronal activity and plasticity, but its role in non-mammalian vertebrates remains poorly understood.

In zebrafish (Danio rerio), the pallium processes cognitive functions such as memory, learning, and emotional behavior. This region expresses cannabinoid receptors and undergoes continuous neuronal remodeling through adult neurogenesis.

Here, we investigate whether cannabinoid receptor type 1 (CB1R) modulates synaptic activity and adult neurogenesis in zebrafish pallial circuits.

Using immunofluorescence and single-cell mRNA analysis, we mapped CB1R expression in the pallium and found it to be distributed in a scattered pattern within the dorsomedial (Dm) and dorsolateral (Dl) regions, predominantly in glutamatergic neurons.

Electrophysiological recordings showed that acute application of rimonabant, a CB1R antagonist, reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without altering intrinsic or other synaptic properties, suggesting a tonic role for CB1R in modulating synaptic transmission. Additionally, prolonged rimonabant treatment (13 days) significantly reduced ERK phosphorylation, a marker of neuronal activity, further supporting the involvement of CB1R in maintaining basal synaptic activity in the pallium.

To assess whether cannabinoid signaling shapes adult neurogenesis, we analyzed the proliferation of neural stem cells (NSCs) and maturation of adult-born neurons.

Acute phytocannabinoid exposure resulted in a reduction in NSC proliferation, specifically in the anterior Dm. To assess the neurogenic outcome, the cannabinoid treatment was administered during neuronal maturation (12-24 days after BrdU labeling).

We observed an increase in the number of 25-day-old neurons (BrdU+, HuC/D+) in both Dm and Dl regions. This effect was reverted by the CB1R antagonist rimonabant.

These results indicate that cannabinoid signaling modulates synaptic activity and neuronal integration, highlighting a conserved control of neurogenesis by the endocannabinoid system across vertebrates.”

https://pubmed.ncbi.nlm.nih.gov/41200796/

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70289

“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats”

https://link.springer.com/article/10.1007/s12640-017-9806-x


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