Author Archives: David Worrell

Durable complete response of advanced hepatocellular carcinoma using cannabis oil: a report of two cases

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“Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a grim prognosis. Current treatment options for advanced HCC are limited, and a large proportion of patients is not amenable to any form of treatment, with best supportive care as the only remaining option.

Meanwhile, the use of cannabis-derived products is rising in oncological patients who are seeking symptom relief. Cannabinoids, similar to endogenous endocannabinoids, have shown promise in recent preclinical cancer research due to their ability to interact with various signaling pathways and molecular mechanisms of interest.

Case presentation

In this report, we present two patients (A aged 82 and B 77, respectively) with advanced HCC with a high tumor burden who demonstrated durable and complete regression after use of cannabis oil (A 10% delta-9-tetrahydrocannabinol (THC) and 5% cannabidiol (CBD), two droplets sublingually three times daily and B 15% THC and 2% CBD, 5 droplets sublingually two times daily) for symptom relief. The observations in this report build on previous (pre)clinical research highlighting the potential anti-tumor qualities of cannabinoids and stress the need for clinical trials investigating the anti-tumor effects of cannabinoids in cancer patients.

Conclusion

Based on the two cases presented here, we call for further research into the potential beneficial effect of cannabinoids in patients with advanced HCC.”

“The authors present two cases of durable and complete remission in two patients with advanced hepatocellular carcinoma using cannabinoids, thus stressing the call for further research into the anti-tumor effects of cannabinoids in this patient population with limited therapeutic options. These findings are hypothesis-generating and underscore the urgent need for controlled clinical trials.”

https://link.springer.com/article/10.1186/s42238-025-00353-0

https://pubmed.ncbi.nlm.nih.gov/41287047

A Preliminary Investigation of Brain Cannabinoid Receptor Type 1 (CB1R) Availability in Men with Opioid Use Disorder

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“The endocannabinoid (eCB) system has been proposed as a potential target for developing new medications for opioid use disorder (OUD). However, the status of the eCB system, specifically brain cannabinoid receptor type 1 (CB1R) in OUD, is unknown.

In this study, CB1R availability was measured in males with OUD on stable opioid agonist treatment (OAT) (n = 10) versus healthy controls (HC) (n = 18), using High-Resolution Research Tomography (HRRT) and the CB1R-specific radiotracer, [ 11 C]OMAR. The average volume of distribution ( V T ) across 13 regions was compared between the OUD and HC groups. Average V T was 15% lower in OUD vs. HC subjects (p = 0.04). Lower V T in OUD compared to HC was also observed in several corticolimbic areas.

Within OUD no effects on CB1R availability were observed for treatment medication (methadone vs. buprenorphine), current stress levels, or antidepressant medication. No associations between the average V T and duration of OAT treatment or time since the last illicit opioid use were observed.

This preliminary study suggests lower CB1R availability in men with OUD. Larger studies are necessary to replicate these findings. Future research should also draw from a more heterogeneous population, particularly by incorporating females, to better assess the potential confounding and moderating clinical factors. If confirmed, the observed alterations in CB1R availability in OUD may provide a rationale for targeting the eCB system in the treatment of OUD.”

https://pubmed.ncbi.nlm.nih.gov/41282260

https://www.researchsquare.com/article/rs-7715611/v1

Repolarization of inflammatory macrophages into reparative stage targeting cannabinoid receptor2: a potential perspective to dampen lung injury/ARDS

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“The inflammatory response during acute lung injury and ARDS leads to an overactive immune response, causing further damage and irreparable recovery. While there are drugs to target various pathogens that cause acute lung diseases, still, the consequences of infection-induced inflammatory signaling and damage prevention are limited with available drugs.

With the rise of cannabinoids as a potential therapeutic agent in several inflammatory disease states, many studies have specifically evaluated their anti-inflammatory effects via CB2 receptors and non-cannabinoid receptors, such as GPR18, in infectious lung injury. However, the exact mechanisms behind CB2 receptor agonism in the application of acute lung injury are still not clear.

Lung macrophages are major immune cells that play a major role in checking and defending the primary and secondary consequences of lung infectious injury. The exact mechanism by which macrophages differentiate to produce anti-inflammatory effects over inflammation is still widely debated during episodes of acute lung injury or respiratory distress.

Using systematic literature evaluation and analysis of current trends and gaps in the literature, we have analyzed the mechanisms that CB2 agonists involve in dampening inflammatory signaling and redirecting the response in acute lung injuries/ARDS by modifying the nature of inflammatory macrophages to anti-inflammatory.

Our systematic review indicated that within the inflammatory macrophage response, CB2 agonists impact several signaling pathways involved in the excessive immune response, reducing the expression of inflammatory transcription factors and inflammatory cytokine storm, and redirecting the macrophages to resolve the lung injury/ARDS.”

https://pubmed.ncbi.nlm.nih.gov/41282589

“Various studies suggest that monocyte/macrophage adoptive transplantation reverses inflammatory injury. However, these studies showed various signaling pathways, but the question is which signaling pathway is important among those to resolve the ALI/ARDS inflammation? Thus, the full therapeutic implications of CB2 agonists are still unknown. Determining the CB2 receptor agonist signaling pathway for reducing cytokine storm and inflammation by repolarizing inflammatory macrophages into reparative macrophages will have the greatest impact in a clinical context. Studies suggested that CB2 receptor agonists, lacking central unwanted side effects, may be promising therapeutic targets in lung inflammatory diseases by modulating the pulmonary immune system and converting inflammatory macrophages to the reparative stage.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1623857/full

Cannabinoids shift the basal ganglia microRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

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“Epitranscriptomic modifications [N6-methyladenosine (m6A)] regulate various diseases, including cancer and inflammation. Despite their functional relevance in neural development and differentiation, the role of m6A modifications in HIV neuropathogenesis is unknown. Using anti-N6-methyladenosine (m6A) antibody-immunoprecipitation and microarray profiling, we identified m6A modifications in miRNAs in basal ganglia (BG) of uninfected (VEH) and SIV-infected Rhesus macaques (RMs) on combination anti-retroviral therapy (ART) and either VEH-treated (VEH/SIV/ART) or THC:CBD-treated (THC:CBD/SIV/ART).

HIV/SIV infection promoted an overall hypomethylated miRNA m6A profile. While THC:CBD did not significantly impact the overall hypomethylated m6A profile, specific miRNAs predicted to target proinflammatory genes showed marked m6A hypomethylation compared to VEH-treated RMs. Additionally, specific BG m6A-modified miRNAs were detected in BG-derived extracellular vesicles. Mechanistically, the DRACH motif in the miR-194-5p seed region was significantly m6A hypomethylated in THC:CBD/SIV/ART RMs. Unlike wild-type, in-vitro transfected m6A-modified miR-194-5p mimics failed to downregulate STAT1 protein expression. Further, compared to VEH/SIV/ART RMs, THC:CBD significantly reduced m6A methylation of 44 miRNAs directly involved in regulating CNS network genes.

Our findings indicate that m6A epi-transcriptomic marks in the seed nucleotides can impair miRNA function and that cannabinoids may preserve it by reducing m6A methylation levels, thus providing a mechanistic explanation underlying their anti-neuroinflammatory effects in HIV/SIV infection.”

https://pubmed.ncbi.nlm.nih.gov/41286161

https://www.nature.com/articles/s42003-025-09049-w

Medical Cannabis and Epilepsy: The Evidence

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“Epilepsy is a serious neurological condition that can affect individuals of all ages. Treatment is far from perfect, and roughly 30% of patients can experience seizures that are resistant to antiseizure medications.

Interestingly, the cannabis plant, specifically the phytocannabinoids, cannabidiol and delta-9-tetrahydrocannabinol, has been shown to possess anticonvulsant properties and are effective in the treatment of seizures.

The clinical evidence base for cannabis for epileptic conditions has been growing in the last few decades with studies aiming to establish the clinical efficacy and safety profile of the plant. Despite the advancements that are being made, clinicians and medical regulatory bodies are still reluctant for epilepsy patients to use cannabis. Thus, it is essential that individuals are educated about the therapeutic properties of cannabis and the clinical evidence base to help patients gain access to cannabis medicines.”

https://pubmed.ncbi.nlm.nih.gov/41284246

“Evidence has shown that the plant possesses a range of therapeutic properties and has suggested its use as a potentially effective treatment for a variety of medical conditions. Consequently, the evidence base for the medicinal use of cannabis has been significantly growing over the years.”

https://www.magonlinelibrary.com/doi/full/10.12968/hmed.2024.0903

Cannabis use is associated with alterations in NLRP3 inflammasome related gene expression in monocyte-derived macrophages from people living with HIV

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“Introduction: Human immunodeficiency virus (HIV) infection is often associated with chronic inflammation and cognitive dysfunction in people living with HIV (PWH). The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role in the secretion of pro-inflammatory cytokines, specifically interleukin (IL)-18 and IL-1β.

Cannabis use and certain phytocannabinoids, such as cannabidiol (CBD), may provide therapeutic benefits in conditions associated with chronic inflammation.

Methods: In this cross-sectional study, we investigated the relationship between cannabis use and NLRP3-related gene expression in monocyte-derived macrophages (MDMs) from PWH (n = 43) and people without HIV (PWoH; n = 22). Participants were categorized as naïve, moderate, or daily cannabis users. Donor-derived MDMs were treated with CBD (30 μM), IL-1β (20 ng/mL), or CBD + IL-1β for 24 hours to examine effects on NLRP3-related gene expression. Gene expression data were analyzed using one-way and two-way ANOVA with Holm-Sidak’s multiple comparisons tests. Correlations between gene expression and clinical parameters were assessed using Pearson’s correlation coefficient. Statistical significance was determined at p < 0.05.

Results: MDMs without treatment from PWH exhibited 83% higher NLRP3 mRNA expression compared to MDMs from PWoH. Furthermore, MDMs without treatment from moderate cannabis users expressed 61% less IL1β mRNA compared to naïve users, and MDMs from daily users expressed a 64% increase in IL18 expression compared to moderate users. Additionally, MDMs treated with CBD and IL-1β showed a 22% decrease in NLRP3 mRNA expression compared to IL-1β treated MDMs. When treated with CBD and IL-1β, we observed a significant increase in both IL1β (3-fold, p < 0.01) and IL18 (2-fold, p < 0.01) expression compared to vehicle. The relationship between NLRP3 mRNA expression in MDMs and global deficit scores in PWH not using cannabis was inverse to that relationship in PWH using cannabis.

Discussion: Overall, these findings suggest that CBD, as consumed through cannabis use, may mitigate NLRP3 activation in PWH, potentially offering therapeutic benefits for chronic inflammation. However, the unexpected effects on downstream cytokine mRNA expression, combined with product heterogeneity, underscore the need for future mechanistic studies to fully delineate cannabinoid-inflammasome interactions in the context of HIV.”

https://pubmed.ncbi.nlm.nih.gov/41280902

“Given the need for effective strategies to address neuroinflammation in PWH, these findings support further exploration of NLRP3 inhibitors, including cannabinoids like CBD, to mitigate chronic inflammation and improve cognitive outcomes.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1634203/full

Cannabidiol modulates brain molecular alterations, gut microbiota dysbiosis and alcohol self-administration in a mouse model of fetal alcohol spectrum disorder

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“Fetal Alcohol Spectrum Disorder (FASD) is a range of neurodevelopmental abnormalities caused by Perinatal Alcohol Exposure (PAE), leading to profound behavioral and molecular disturbances in the offspring. Unraveling the central and peripheral mechanisms involved, including the microbiota-gut-brain axis, is crucial to improving our understanding of the disease and developing new treatment strategies from a sex perspective.

In this study, we investigated the impact of PAE on emotional behavior, brain biomarkers, and gut microbiota composition and diversity in a preclinical C57BL/6 J mouse model, as well as the extent of their vulnerability to alcohol consumption. Furthermore, we have also explored the potential modulatory effects of cannabidiol (CBD) administered chronically (30 mg/kg/day, i.p.) from weaning on PAE-induced sex-dependent emotional and brain molecular impairments, gut microbiota dysbiosis, and increased alcohol reinforcing and motivational actions.

FASD model mice showed increased anxiety- and depressive-like behavior accompanied by sex-dependent changes in synaptic density, dopamine D2/D3 receptors availability, cannabinoid receptors 1 and 2 (Cnr1/Cnr2), tyrosine hydroxylase (Th), and serotonin transporter (Slc6a4) gene expression, and gut microbiota dysbiosis.

Interestingly, CBD sex-dependently improved and/or normalized PAE-induced behavioral and molecular disturbances. In addition, females but not males exposed to the animal model of FASD showed a higher motivation to drink alcohol, which CBD abolished.

Our findings provide new insights into the brain and gut microbiota sex-dependent mechanisms involved in FASD pathophysiology and further highlight the therapeutic potential of CBD to improve the management of FASD-induced emotional disturbances and alcohol addiction from a sex-oriented approach.”

https://pubmed.ncbi.nlm.nih.gov/41273930

“FASD model mice displayed emotional disturbances (anxiety- and depressive-like behaviors), which CBD alleviated.”

“Together, our findings reveal that PAE profoundly alters gut microbiota and that CBD can modulate this dysbiosis, promoting beneficial taxa and modifying community structure in a sex-dependent manner.

CBD administration also mitigated anxiety- and depression-like behaviors and modulated gene expression of endocannabinoid and monoaminergic markers.

This study opens the door to the development of personalized interventions aimed at restoring the microbiota and modulating the gut-brain axis to mitigate the cognitive and behavioral deficits characteristic of this disorder.”

https://www.sciencedirect.com/science/article/pii/S0753332225009850?via%3Dihub

Cannabidiol inhibits TGF-β1-induced epithelial-mesenchymal transition in human conjunctival epithelial cells by interrupting TGF-β/Smad signaling

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“Epithelial-mesenchymal transition (EMT) plays a significant role in conjunctival fibrosis-related pathologies and has emerged as a promising therapeutic target for managing conjunctival fibrosis.

Cannabidiol (CBD), a predominant non-psychoactive cannabinoid derived from the cannabis plant, has demonstrated antifibrotic effects in various extraorbital tissues. However, its influence on fibrosis-associated EMT in conjunctiva remains unexplored.

Given the ubiquitous expression of cannabinoid targets in ocular tissues, including the conjunctiva, and evidence suggesting that modulation of the endocannabinoid system ameliorates ocular pathologies, this study aimed to evaluate the effects of CBD on conjunctival EMT.

Cultured human conjunctival epithelial cells were stimulated with transforming growth factor-beta 1 (TGF-β1) to induce EMT.

CBD treatment effectively mitigated EMT-related changes induced by TGF-β1, including increased cell elongation and migration, reduced epithelial markers (E-cadherin and zonula occludens-1, and elevated mesenchymal markers (alpha-smooth muscle actin and fibronectin) and EMT-associated transcription factor Snail.

Furthermore, CBD suppressed TGF-β1-mediated Smad-2/3 phosphorylation and nuclear translocation. Treatment with a specific TGF-β/Smad pathway inhibitor (SB431542) yielded comparable results, suggesting that the inhibitory effects of CBD on EMT involve disruption of TGF-β/Smad signaling. Additionally, the EMT phenotype was associated with increased interleukin-6 (IL-6) secretion, which was also attenuated by CBD treatment.

This study confirms that CBD effectively prevents EMT and EMT-associated IL-6 secretion by targeting TGF-β/Smad signaling, highlighting its therapeutic potential in mitigating conjunctival fibrosis.”

https://pubmed.ncbi.nlm.nih.gov/41272047

“Our study revealed the anti-EMT effects of CBD in conjunctival epithelial cells, mediated through inhibition of the TGF-β-Smad-Snail axis. “

“Overall, as a compound with diverse properties, CBD may improve ocular surface pathologies resulting from inflammation and fibrosis through regulation of EMT and the associated inflammatory secretome, while also exerting neuroprotective and antinociceptive effects.”

https://www.nature.com/articles/s41598-025-25216-9

Effects of Cannabis sativa L. Leaves on Opisthorchis viverrini Metacercariae in Infected Barbonymus gonionotus

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“This study is aimed at evaluating the effects of dietary Cannabis sativa L. leaf supplementation on superoxide dismutase (SOD) levels and the prevention of liver fluke (Opisthorchis viverrini) metacercaria infection in Barbonymus gonionotus.

The experiment included five treatment groups, with varying concentrations of C. sativa leaves (0.0%, 0.5%, 1.0%, 1.5%, and 2.0%) in the experimental feed. Six hundred parasite-free B. gonionotus (50 days old) were infected with 50 cercariae each. After 24 h, they were fed the experimental feed for 0 (control group), 7, 14, or 21 days. The infection rate, intensity of O. viverrini metacercaria, survival rates, immunoglobulin M (IgM) levels, lysozyme activity, and SOD levels in B. gonionotus were investigated.

The results showed that cannabis leaves effectively prevented O. viverrini infection.

Fish fed with higher doses of cannabis leaf diets had a decreased infection rate and intensity of O. viverrini metacercariae and higher survival rates. Conversely, there was an increase in SOD, lysozyme activity, and IgM levels. Moreover, after the fish were fed 2.0% cannabis leaves for 14 and 21 days, no O. viverrini metacercariae were degenerated. The highest SOD levels were exhibited by fish fed 2.0% cannabis leaves for 14 days (1497.96 U/g FW), and the metacercariae were inactive and degenerated.

In summary, dietary supplementation of cannabis leaves can be used as a preventive measure against liver fluke infection in B. gonionotus.”

https://pubmed.ncbi.nlm.nih.gov/41262377

“Opisthorchiasis is a disease caused by trematode infection in fish, specifically members of the Opisthorchiidae family, including Opisthorchis viverrini, Opisthorchis felineus, and Clonorchis sinensis.”

“Cannabis, Cannabis sativa L., possesses a rich historical background of human utilization, with indications of its use dating back thousands of years. “

“The aim of the study was to investigate the effects of cannabis leaves on liver fluke infection and the immune response in fish.”

“This study concludes that supplementation of cannabis leaves at 2.0% in the feed can prevent infection by metacercariae of the liver fluke in silver barb fish on Days 14 and 21. The supplementation of cannabis leaves was effective in preventing infection, reducing infection intensity, decreasing the survival rate of metacercariae, and enhancing the immune response in fish. The metacercaria encysted within fibrous tissue was densely surrounded by white blood cells, leading to their destruction and inhibiting the growth of the liver fluke parasite. Consequently, consumers can safely consume fish devoid of liver fluke parasites and fish meat free from any residual contaminants.”

https://onlinelibrary.wiley.com/doi/10.1155/japr/6233585

Advances in the Quest for Safe and Effective Drugs That Target the Cannabinoid Receptor Type 1 (CB1)

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“Pain management costs the world billions of dollars each year, and there are limited nonopioid options to treat people suffering from chronic pain. Opioids are excellent analgesics but are liable to abuse and fatal overdoses. This Microperspective summarizes challenges and opportunities pertaining to creating nonopioid drugs that could be used to treat chronic pain, substance abuse, fatty liver, or obesity by targeting the cannabinoid receptor type 1 (CB1).”

https://pubmed.ncbi.nlm.nih.gov/41257001

https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00402