Author Archives: David

Cannabivarin and Tetrahydrocannabivarin Modulate Nociception via Vanilloid Channels and Cannabinoid-Like Receptors in Caenorhabditis elegans

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“Cannabis has attracted growing interest for its therapeutic potential, especially in pain management.

This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using Caenorhabditis elegans (C. elegans), a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors.

Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in C. elegans. Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response.

Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses.

These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.”

https://pubmed.ncbi.nlm.nih.gov/41135090/

https://cdnsciencepub.com/doi/10.1139/cjpp-2025-0243

Efficacy and safety of cannabidiol in children with developmental and epileptic encephalopathies: A systematic review

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“Background: Developmental and epileptic encephalopathies (DEEs) constitute rare epileptic conditions characterized by treatment-resistant seizures, neurodevelopmental delay, and various comorbidities. None of the currently available drugs have proven effective in suppressing epileptiform activity in those conditions.

Objectives: We aimed to assess the efficacy and safety of cannabidiol in children with DEEs through a systematic review.

Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, trial registries, and reference lists of included studies. We conducted the last search on March 9, 2024. All study types investigating pharmaceutical cannabidiol in children with DEEs were considered eligible, with no language or date restrictions. Risk of bias was assessed using RoB2 and ROBINS-I V2.

Results: Of the 722 records identified, 14 met the inclusion criteria. The included studies varied in design and involved a total of 682 children. Cannabidiol was administered to a maximum dose of 50mg/kg/day. Almost all studies reported positive outcomes with cannabidiol, leading to a reduction of a 50% or above in seizure frequency in at least 20% of patients included in 11 studies. Adverse events were relatively common across studies and included somnolence, loss of appetite, diarrhea, fatigue, and increased serum aminotransferases. Most of them were mild to moderate and reversible.

Conclusions: Cannabidiol is generally well tolerated and has been shown to effectively reduce seizure frequency in children with DEEs whose seizures are refractory to concomitant antiepileptic medications. Future research should explore the long-term effects of cannabidiol on seizure control, developmental outcomes, and quality of life in this population.”

https://pubmed.ncbi.nlm.nih.gov/41135306/

https://www.seizure-journal.com/article/S1059-1311(25)00269-9/abstract

Dietary hempseed and cardiovascular health: nutritional composition, mechanisms and comparison with other seeds

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“Cardiovascular disease (CVD) remains the leading cause of global mortality, with dietary habits playing a significant role in its prevention and management.

Hempseed (Cannabis sativa L.) has gained recognition as a functional food due to its rich nutritional profile, including high-quality plant proteins, optimal omega-6 to omega-3 fatty acid ratios, and a variety of bioactive compounds such as tocopherols, phytosterols, and polyphenols.

This review critically evaluates the potential cardioprotective effects of hempseed, focusing on its impact on lipid metabolism, inflammation, oxidative stress, and other cardiometabolic markers.

Preclinical studies suggest that hempseed can improve lipid profiles, reduce blood pressure, and reduce oxidative stress and inflammation, though clinical evidence remains limited and findings from animal models may not directly translate to human cardiovascular benefits due to physiological differences between species.

This review further evaluates hempseed’s potential in cardiovascular disease prevention and highlights its potential advantages when compared with other widely consumed seeds (flaxseed and chia seeds), emphasizing its unique fatty acid composition, optimal omega-6 to omega-3 ratio, and diverse bioactive compounds. Despite the promising findings, there is a need for long-term randomized controlled trials to establish the efficacy and safety of hempseed in diverse populations.

This review emphasizes the potential of hempseed as a dietary intervention for CVD prevention and calls for further research to optimize its use in clinical and public health settings.”

https://pubmed.ncbi.nlm.nih.gov/41132555/

“The integration of hempseed into various dietary patterns worldwide offers a versatile and sustainable approach to enhance dietary quality and promote cardiovascular health.”

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2025.1669375/full

The association between cannabis use and electrocardiographic abnormalities in people living with HIV

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“Cardiovascular disease is a leading cause of morbidity and mortality among people with and without HIV. Among PWoH, cannabis has been associated with cardiovascular outcomes, including coronary artery disease, myocardial infarction (MI), and stroke. However, data on subclinical changes and other cardiovascular outcomes are limited among PWH.

In this study, we examined the association of cannabis use and HIV with electrocardiogram (ECG) findings -evidence of MI, other abnormalities, and normal findings. Data from study visits between 2007 and 2017 from the MACS/WIHS Combined Cohort Study (N=3,610) were used. Descriptive statistics were derived, and unadjusted and adjusted odds ratios were estimated via baseline logistic regression.

Most participants were PWH (n = 2272, 63%), and 28% reported cannabis use, with no significant difference in prevalence between PWH (27%) and PWoH (28%). Overall, 59% of participants had normal ECG findings.

Cannabis use was not significantly associated with evidence of ECG abnormalities in unadjusted or adjusted analyses (aOR for MI: 1.02, 95% CI: 0.82-1.26, p = 0.85; aOR for other abnormalities: 1.02, 95% CI: 0.80-1.32, p = 0.86). Abnormal findings were more common in females than males (41% vs. 35%, p = 0.0002). Among males, PWH had higher odds of evidence of non-MI abnormalities compared to PWoH (aOR = 1.35, 95% CI: 1.01 – 1.81, p = 0.0464).

While cannabis use was not independently associated with evidence of ECG abnormalities, sex and HIV status are important determinants. Future studies should explore the role of cannabis metabolites and usage patterns in cardiovascular outcomes among PWH.”

https://pubmed.ncbi.nlm.nih.gov/41129190/

https://journals.lww.com/jaids/abstract/9900/the_association_between_cannabis_use_and.735.aspx

Proof of concept for high-dose Cannabidiol pretreatment to antagonize opioid induced persistent apnea in mice

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“Background: Opioid related fatalities remain a public health crisis in the US. Currently, the only way to restore breathing following an opioid induced persistent apnea is with the administration of the opioid antagonist naloxone, but it also reverses analgesia, euphoria, and induces precipitated withdrawal in opioid dependent individuals.

Methods: Using whole-body plethysmography, we assessed changes in breathing frequency in awake behaving mice resulting from a single fentanyl dose (50 mg/kg i.p.) that followed i.p. pretreatment with saline, vehicle, naloxone (100 mg/kg), cannabidiol (CBD) (250 mg/kg), or CBD + naloxone. Then we assessed the delay to opioid-induced persistent apnea (OIPA) and the median lethal dose (LD50) of fentanyl during a continuous i.c.v. infusion of fentanyl (100 ng/min), in urethane anesthetized mice, following pretreatment with saline, vehicle, naloxone (100 mg/kg), CBD (250 mg/kg), or CBD + naloxone i.p.

Results: Here we show acute pretreatment with CBD is as effective as naloxone at preventing opioid-induced respiratory depression from fentanyl in awake mice, and increasing LD50 of fentanyl in urethane anesthetized mice. When pre-administered together, CBD + naloxone, increased LD50 of fentanyl even more than CBD or naloxone alone in urethane anesthetized mice.

Conclusion: CBD may be an effective preventative therapy for OIPA by increasing the time before apnea onset and potentially enhancing the efficacy of naloxone as an additional strategy to save lives.”

https://pubmed.ncbi.nlm.nih.gov/41132595/

“This proof of concept using CBD as a prophylactic therapeutic for prevention of fatal OIPA in mice has considerable potential for public health benefit.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1654787/full

Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP-ADO-A1R signaling pathway

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“Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating methamphetamine (METH) addiction. Nonetheless, the molecular target and the mechanism through which CBD treats METH addiction remain unexplored.

Herein, CBD was shown to counteract METH-induced locomotor sensitization and conditioned place preference. Additionally, CBD mitigated the adverse effects of METH, such as cristae loss, a decline in ATP content, and a reduction in membrane potential. Employing an activity-based protein profiling approach, a target fishing strategy was used to uncover CBD’s direct target.

ATP5A1, a subunit of ATP synthase, was identified and validated as a CBD target. Moreover, CBD demonstrated the ability to ameliorate METH-induced ubiquitination of ATP5A1 via the D376 residue, thereby reversing the METH-induced reduction of ATP5A1 and promoting the assembly of ATP synthase. Pharmacological inhibition of the ATP efflux channel pannexin 1, blockade of ATP hydrolysis by a CD39 inhibitor, and blocking the adenosine A1 receptor (A1R) all attenuated the therapeutic benefits of CBD in mitigating METH-induced behavioral sensitization and CPP. Moreover, the RNA interference of ATP5A1 in the ventral tegmental area resulted in the reversal of CBD’s therapeutic efficacy against METH addiction.

Collectively, these data show that ATP5A1 is a target for CBD to inhibit METH-induced addiction behaviors through the ADO-A1R signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/41132843/

“This study verifies that ATP5A1 directly binds with CBD both in vitro and in vivo, counteracting METH-triggered ATP5A1 ubiquitination and enhancing the assembly of ATP synthase, thereby preventing METH-induced mitochondrial damage. Additionally, CBD inhibits METH-induced addictive behaviors through the ADO–A1R signaling pathway. The results indicate that CBD alleviates methamphetamine addiction by targeting ATP5A1. Besides METH, CBD has shown potential therapeutic effects on addiction to opioids18 and THC66. This implies that CBD has therapeutic potential for various forms of substance abuse. Consequently, ATP5A1 may serve as a target in the treatment of polysubstance use disorders, which warrants further exploration.”

https://www.sciencedirect.com/science/article/pii/S221138352500560X?via%3Dihub

Efficacy of different cannabinoid compounds on migraine-like responses in female rats

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“Aim: To investigate the effect of different cannabinoid compounds on the periorbital mechanical allodynia and photosensitivity in acute and chronic migraine models.

Methods: Female Wistar rats were treated systemically with different cannabinoid compounds (cannabidiol, CBD, 30 mg/kg; CBD and cannabigerol, CBD/CBG – 2:1; CBD and 0.3% tetrahydrocannabinol (CBD/THC); or CBD/CBG/THC) followed by injection of calcitonin-gene-related peptide (CGRP) or pituitary adenylate cyclase-activating polypeptide (PACAP) into the trigeminal ganglion to induced immediate periorbital mechanical allodynia and late photosensitivity. The effect of CBD and CBD/THC was also assessed on periorbital mechanical allodynia and photosensitivity in the chronic migraine model induced by repeated nitroglycerin (NTG) injections.

Results: Periorbital mechanical allodynia induced by CGRP was significantly reduced by CBD alone and combined with THC or CBG. CBD/THC was the most effective treatment in this condition since it presented the longer effect (up to three hours) and was the only treatment capable of reducing late photosensitivity associated with CGRP. All four compounds presented antinociceptive effect on acute migraine-like responses induced by PACAP, with CBD alone presenting the longer effect (from 30 minutes up to two hours). Except for CBD/CBG, all compounds also reduced (up to two hours) late photosensitivity associated with PACAP. In the chronic migraine model induced by NTG, CBD reduced periorbital mechanical allodynia on days 5, 7 and 11, while CBD/THC suppressed the development of periorbital allodynia up to day 13 and significantly reduced photosensitivity up to three hours.

Conclusion: Altogether, these results suggest that cannabinoid compounds may represent effective alternatives for the treatment of episodic and chronic migraine.”

https://pubmed.ncbi.nlm.nih.gov/41129688/

“The present findings highlight the potential of specific cannabinoid formulations, particularly the low-THC and CBD/THC combination, as candidates for migraine management.

This compound consistently attenuated periorbital allodynia and photosensitivity across acute (CGRP- and PACAP-induced) and chronic (nitroglycerin-induced) migraine models, without producing locomotor or anxiety-like effects. CBD alone demonstrated moderate efficacy, with shorter duration of action and limited effects on light-induced sensitization, while CBG-containing combinations showed variable results depending on the trigger, suggesting distinct interactions with CGRP- and PACAP-mediated pathways.

These data support further controlled clinical studies to evaluate CBD- and CBD/THC-based therapies as potential preventive or adjunctive options for patients with episodic or chronic migraine, particularly those with suboptimal responses to current targeted treatments.”

https://journals.sagepub.com/doi/10.1177/03331024251386794

Isoorientin Modulates Gut Microbes and Their Metabolites to Alleviate Caco-2 Cell Monolayer Inflammation by Reducing Intestinal Permeability via P-Gp/eCBs

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“Introduction: Isoorientin (ISO) is a naturally occurring flavonoid that studies have shown to have strong experimental antioxidant, anti-inflammatory, anti-diabetic and anti-obesity properties. It has been shown that ISO alleviates Dextran sodium sulfate (DSS) induced colitis in mice by modulating gut microbes and their metabolites. The aim of this study was to modulate gut microbes and their metabolism by ISO to investigate its anti-inflammatory effects and its specific molecular mechanisms in a lipopolysaccharide (LPS)-induced monolayer inflammation model in Caco-2 cells.

Methods: Feces from ISO-treated DSS colitis mice were collected and gut flora culture supernatants were prepared. Detection of the effect of intestinal flora supernatants on the monolayer barrier of Caco-2 cells by inoculation of Caco-2 cells into the Transwell transmembrane culture system to simulate the intestinal mucosal barrier.

Results: The results revealed that ISO-conditioned intestinal flora supernatant significantly increased TEER values, decreased intestinal epithelial FITC-dextran flux permeability, and restored LPS-induced occludin, ZO-1 protein expression in Caco-2 cells. Meanwhile, intestinal flora supernatant significantly ameliorated the LPS-induced inflammatory response. In addition, ISO further enhanced its protective effect on intestinal permeability by regulating the expression of P-glycoprotein (P-gp) and endogenous cannabinoid system (eCB)-related proteins, which may attenuate the inflammatory response by activating the P-gp/eCB signaling pathway.

Conclusion: The present study offers fresh perspectives into the application of ISO-conditioned intestinal flora supernatant as a potential anti-inflammatory agent and intestinal barrier protector in vitro. The unique regulation of the P-gp/eCBs pathway by ISO-conditioned intestinal flora supernatant was the novel mechanistic insights provided in this study.”

https://pubmed.ncbi.nlm.nih.gov/41126978/

“Overall, these findings could be instrumental in formulating treatment approaches involving ISO for managing inflammation-associated conditions in patients with IBD.”

https://www.dovepress.com/isoorientin-modulates-gut-microbes-and-their-metabolites-to-alleviate–peer-reviewed-fulltext-article-JIR

“Isoorientin is a flavonoid found in cannabis and hemp plants.”

  • “Hemp seed: Isoorientin has been detected in the seeds of Cannabis sativa (hemp) and shown to possess bioactivity, including neuroprotective effects.
  • Cannabis plant: The overall flavonoid content, including isoorientin, can vary depending on environmental factors like growing conditions.”

Plant-Derived Compounds: A Potential Treasure for Development of Analgesic and Antinociceptive Therapeutics

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“Pain is one of the most pervasive health problems associated with a negative impact on thinking, mood, psychological, and social communication.

The medicinal plants and their derived compounds have recently attracted great interest as potential candidates for defeating pain because of their worldwide safety, availability, and affordability.

This review was constructed to summarize all in vitro and in vivo studies and clinical trials regarding plant-derived compounds’ analgesic and antinociceptive effects. Further, we focus on structural aspects, molecular mechanisms, and pharmacological effects. A literature survey was performed in “PubMed,” “Science Direct,” and “Google Scholar,” using the keywords “Pain, Analgesic activity, Flavonoids, Phenolics, Medicinal plants, Volatile oils, Tannins, Saponins, Alkaloids” to assess the activities of each compound.

The main natural compounds studied were flavonoids, alkaloids, phenolic acids, lignans, anthraquinones, and volatile oils. Different in vitro studies utilized nucleus pulposus cells, VK2/E6E7, End1/E6E7, and LPS-stimulated RAW264.7 cells to assess analgesic effects. The frequently defined animal models of analgesic activity included acetic acid-induced abdominal constrictions, hot-plate test, tail-flick test, formalin test, complete Freund’s adjuvant-induced pain, and hind paw incisional surgery.

For the natural compounds described, the opioids, serotonergic, and cannabinoid receptors appeared to be the most promising targets for pain management. This review suggested a wealthy resource of natural compounds as analgesic and antinociceptive candidates for pharmacists and drug researchers to launch a new drug with promising efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/41126401/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.70113

The potential role of cannabidiol (CBD) in lung cancer therapy: a systematic review of preclinical and clinical evidence

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“Background: Lung cancer is one of the most prevalent and lethal cancers worldwide, with limited therapeutic options in advanced stages. Cannabinoids have recently attracted attention as potential anticancer agents; however, cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has emerged as the most promising candidate. Unlike Δ9-tetrahydrocannabinol (THC), CBD lacks psychoactive properties, is generally well tolerated, and demonstrates a favorable safety profile. Moreover, CBD influences multiple cancer-relevant pathways-including apoptosis, epithelial-to-mesenchymal transition (EMT), and immune modulation-that are particularly relevant to non-small cell lung cancer (NSCLC). These features provide a strong rationale for focusing on CBD in lung cancer therapy.

Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, and Google Scholar, using defined keywords such as “CBD,” “lung cancer,” and “non-small cell lung cancer.” Studies from 2007 to 2025 were screened following PRISMA guidelines, and 19 studies met the inclusion criteria.

Results: Nineteen studies met the inclusion criteria, comprising 13 in vitro studies, 4 in vivo animal studies, and 2 clinical reports. Across these studies, CBD was administered at concentrations ranging from low micromolar levels (1-10 µM) in cell-based experiments to oral doses of 200-600 mg/day in human cases. Mechanistically, CBD induced apoptosis through pathways such as PPAR-γ activation, mitochondrial dysfunction, and oxidative stress. It inhibited epithelial-to-mesenchymal transition (EMT), downregulated invasive markers, and modulated the tumor microenvironment by enhancing CD8 + T cell and NK cell activity. Furthermore, CBD showed synergistic effects with conventional therapies (e.g., cisplatin, radiotherapy) by increasing drug uptake and overcoming resistance.

Conclusions: CBD holds promise as an adjunct in lung cancer therapy, addressing key cancer hallmarks such as tumor growth, metastasis, and treatment resistance. While preclinical evidence is robust, clinical trials remain limited. Future research should focus on optimizing dosing regimens, evaluating long-term safety, and validating these findings in large-scale human studies.”

https://pubmed.ncbi.nlm.nih.gov/41126219/

“Cannabidiol (CBD) demonstrates strong preclinical activity against lung cancer, targeting multiple hallmarks of cancer including apoptosis induction, suppression of EMT and metastasis, modulation of immune responses, and sensitization to chemotherapy and radiotherapy.”

https://cancerci.biomedcentral.com/articles/10.1186/s12935-025-04010-7