Author Archives: David Worrell

The use of cannabis in supportive care and treatment of brain tumor

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“Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC.

Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive.

Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further.

Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.”

https://pubmed.ncbi.nlm.nih.gov/31385997

“For medicinal use, evidence goes back 5000 years to the Chinese emperor Chen Nung. Archeological findings suggest that palliative cancer treatment with cannabis was already in use 2500 years ago.”

“Cannabinoids Can be Used in Palliative Care for a Wide Range of Symptoms.”

“Cannabinoids Reduce Nausea and Vomiting.”

“Increase of Appetite and Weight is Only Seen with CB1 Agonists such as THC.”

“Cannabinoids Moderately but Consistently Improve Chronic Pain.”

“Cannabinoids Demonstrate Antitumor Effects on Glioma Cells.”

“Cannabinoids are Highly Effective in Animal Glioma Models.”

“Anticancer Effects of Cannabinoids may be able to Prolong Life.”

“Funded by the National Institutes of Health to find evidence that marijuana damages the immune system, the study found instead that THC slowed the growth of 3 kinds of cancer in mice—lung and breast cancer, and a virus-induced leukemia. The US Drug Enforcement Agency quickly shut down the Virginia study and all further cannabis/tumor research even though the researchers demonstrated remarkable antitumor effects.”

https://academic.oup.com/nop/article/4/3/151/2918616?login=false

RSM-Based Optimization of Dose Response and Antibacterial Potential of Cannabis sativa (L.) Leaves Using Computational Analysis

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“Background: In light of the growing problem of antibiotic resistance, it is imperative to investigate new sources, and plants offer a promising supply of bioactive chemicals. Because of its numerous uses in industry, health, and nutrition as well as its antibacterial qualities, Cannabis sativa (C.sativa) has garnered a lot of study interest. This study sought to determine whether ethanolic extracts from C.sativa leaves have antibacterial properties against six human pathogenic microorganisms.

Methodology: The antibacterial activity of C.sativa ethanolic extract was tested against six bacteria according to design of experiments made by Agar diffusion method accompanied by response surface method (RSM) of Minitab 17 software. The different combinations set were, concentration: 5.0, 7.5, and 10.0, pH: 5.0, 6.5, 8.0 and temperature: 35°C, 37.5°C, 40°C. By using RSM, maximum antibacterial activity has been checked for ethanolic extract of C.sativa against six bacteria by choosing three independent variables, temperature, pH, and concentration. In in-Silico studies, homology, threading approach, structure prediction, ligands designing and docking studies was performed against the antimicrobial target sequences for Beta-Lactamase, GABA Receptor, Lipoteichoic Acid, N-Acetylglucosamine (NAG), Peptidoglycan and Topoisomerase-IV through FASTA format from UniProt for structure prediction.

Results: The results indicated that the three concentrations were effective against tested bacteria. Moreover, effect of pH caused a significant variation in zone of inhibition. The graphs presented in this study indicate the highest zone of inhibition for plant extract; have been achieved at concentration of 10.0, pH 5.1 and temperature 37.5°C. It shows that by keeping the pH low, antibacterial activity will increase. Through the multiple regression analysis on the experimental data, the fitted regression model for the response variable and the test variable x1, x2, x3 are correlated by the second order polymeric equation.

Conclusion: It has been concluded that C.sativa can be considered as an effective drug in curing diseases caused by bacteria. Using the optimized values of temperature and pH analyzed in this experiment.”

https://pubmed.ncbi.nlm.nih.gov/41324030

“Humans have been employing C.sativa since ancient times, and numerous historians have recorded multiple uses of this plant abroad. This plant has been cultivated for religious and recreational purposes, as well as for food, fiber, and oil, according to recorded history. C.sativa is also used therapeutically to treat depression, inflammation, and chronic pain, according to numerous ethnobotanical surveys.”

“This study is the continuation of the research to examine the effectiveness of ethanolic extracts made from C. sativa leaves against harmful microorganisms in humans. The results show that this extract has strong antibacterial activity against a variety of pathogens, such as Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Bacillus subtilis, Staphylococcus typhi, and Staphylococcus aureus which is affected more strongly by the pH and temperature variations rather than the concentrations of the extract. Moreover, it is confirmed by the application of the RSM model which indicates its activity. The zones of inhibition produced in the repetitive study has been concluded that C. sativa may be qualified as the drug of the future that can be efficacious for combating bacterial infections. The said plant is of high importance to synthesize a very high potency antibacterial drug by using the optimized ranges of temperature and pH.”

https://journals.sagepub.com/doi/10.1177/15593258251404067

Cannabis Use in Central Disorders of Hypersomnolence in the Netherlands

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“Introduction: The endocannabinoid system plays a role in sleep-wake regulation. In clinical practice, people with central disorders of hypersomnolence (CDH) frequently report use of cannabis.

Methods: We compared lifetime and current use of cannabis of people with CDH to the Dutch general population. Additionally, we assessed cannabis use in relation to hypersomnolence symptoms.

Results: In total, 76 (out of 88) patients completed the online questionnaire. Lifetime cannabis use (42% vs. 23%, p < 0.001) and current use (18% vs. 4%, p < 0.001) were higher in people with CDH compared to the Dutch general population. For 57% of patients currently using cannabis, improvements of at least one CDH symptom were the motivation for use. Additionally, 79% of current cannabis users reported cannabis-related effects on a symptom, which were mostly positive (43%), some negative (7%), or mixed effects (29%). Patients that stopped using mostly started using cannabis before symptom onset and for recreational purposes. The most reported reasons to stop using were disadvantages of using or changes in the social environment.

Conclusion: This study provides a rationale for future research on the potential benefits of cannabis in CDH.”

https://pubmed.ncbi.nlm.nih.gov/41321442

https://karger.com/mca/article/8/1/181/935204/Cannabis-Use-in-Central-Disorders-of

Cannabis Use and Risk of Chronic Rhinosinusitis and Sinus Surgery

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“Objective: While cannabis’ link to asthma is well-studied, its impact on CRS is less clear. This study explores the association between cannabis use and rates of new-onset chronic rhinosinusitis (CRS), chronic rhinosinusitis with nasal polyps (CRSwNP), and functional endoscopic sinus surgery (FESS) rates.

Methods: The TriNetX Analytics Research Network was queried for adults ≥ 18 years old, stratified into cannabis user and non-user cohorts based on electronic health record data from January 2012 to December 2019. Separate cohorts of patients with pre-existing CRS-with and without cannabis use-were analyzed to evaluate associations with FESS. Primary outcomes were relative risks of new-onset CRS and CRSwNP encounter diagnosis and FESS 1, 2, and 5 years after initial cannabis use diagnosis.

Results: After 1:1 propensity score matching, cohorts analyzing CRS and CRSwNP included 73,091 patients each. Cannabis use was associated with reduced risk of unspecified CRS at 1 year (aRR = 0.87, 95% CI 0.80-0.95), 2 years (aRR = 0.84, 95% CI 0.78-0.90), and 5 years (aRR = 0.83, 95% CI 0.78-0.87). There was no difference in risk of CRSwNP at any timepoints. For FESS outcomes, matched cohorts included 5591 patients with pre-existing CRS; cannabis users had lower risk at 1 year (aRR = 0.67, 95% CI 0.47-0.96), 2 years (aRR = 0.64, 95% CI 0.46-0.88), and 5 years (aRR = 0.69, 95% CI 0.52-0.91).

Conclusions: Patients with cannabis use demonstrated significantly reduced risks in new-onset diagnoses of CRS and FESS compared to non-users. Further studies are warranted to examine the cause of this relationship.”

https://pubmed.ncbi.nlm.nih.gov/41323660

“Our findings suggest that cannabis use is associated with a reduced incidence of new-onset CRS and a lower need for FESS in patients already diagnosed with CRS.”

https://onlinelibrary.wiley.com/doi/10.1002/lio2.70320

“The Associative Impact of Recreational Cannabis Use on Sinonasal Diseases. Users demonstrated significantly lower odds of AR, CRS, and CR than never users. There is an inverse, associative relationship between cannabis use and sinonasal disease.”

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

Modulatory Effects of “Minor” Cannabinoids in an in vitro Model of Neuronal Hypersensitivity

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“Aim: Effective treatment for neuropathic pain remains an unmet clinical need. The therapeutic benefits of the Cannabis plant are well known, especially for pain relief. Here, we have assessed ten “minor” cannabinoids for their analgesic effects in an established model of neuronal hypersensitivity, a key mechanism which underlies neuropathic pain.

Methods: Adult rat DRG neurons were cultured in medium containing 100 ng/mL nerve growth factor (NGF) and 50 ng/mL glial cell-line derived neurotrophic factor (GDNF) for 48 hours to sensitize the neurons. Ca2+ imaging was used to measure the responses to pain stimulation using capsaicin, and to determine the modulatory effects of the cannabinoids, in individual neurons.

Results: Control neurons (nociceptors) showed robust responses of Ca2+ influx to capsaicin application, while neurons treated with ten minor cannabinoids tetrahydrocannabiorcol (THCC), cannabitriol (CBT), cannabidivarin (CBDV), cannabinol (CBN), cannabichromene (CBC), cannabichromevarin (CBCV), cannabicitran (CBCT), cannabigerol monomethyl ether (CBGM), tetrahydrocannabutol (THCB) or tetrahydrocannabiphorol (THCP), at concentrations of 0.001-100 μM, showed differential dose-related effects on the responses to capsaicin. Ca2+ influx in response to capsaicin application was completely inhibited for each compound in 35-78% capsaicin-sensitive neurons, while other neurons showed reduced responses. The opioid receptor agonist morphine and α2δ1- Ca2+ channel inhibitor gabapentin were also tested for comparison and showed similar results. All the cannabinoids tested here inhibited calcium influx in response to capsaicin, and two, namely, CBN and THCC elicited calcium influx at higher doses. Inhibition of Ca2+ influx due to cannabichromene (CBC) was reversed by the potassium channel inhibitor Tertiapin Q.

Conclusion: All the cannabinoids tested here inhibited TRPV1 signalling. CBC targeted K+ channels to block TRPV1 mediated Ca2+ influx, demonstrating potential analgesic effects in vitro.”

https://pubmed.ncbi.nlm.nih.gov/41322279

“The therapeutic benefits of the Cannabis plant are well known, especially for pain relief.”

“In conclusion, our results show that the minor cannabinoids potently inhibit TRPV1 signaling in sensitized DRG neurons, and for CBC by blocking Ca2+ influx via K+ channel activation. This conclusion is based on the reversal of CBC-mediated inhibition in the presence of the K+ channel inhibitor Tertiapin Q. Further studies are necessary to confirm the mechanism, pathways and targets involved in the observed inhibitory effects of the other minor cannabinoids. This will facilitate the identification of cannabinoid combinations likely to have the maximum effect in providing analgesia for inhibiting neuronal sensitization that underlies chronic pain.”

https://www.dovepress.com/modulatory-effects-of-minor-cannabinoids-in-an-in-vitro-model-of-neuro-peer-reviewed-fulltext-article-JPR

Advances in Extraction and Quantification of Minor Phytocannabinoids

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“Ever since the chemical structures of major phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), were elucidated, the majority of research has focused primarily on these compounds, often overlooking the other ~160 minor cannabinoids identified in Cannabis sativa to date. However, in recent years, these previously understudied cannabinoids have garnered increasing scientific attention due to advancements in highly sensitive analytical techniques that enable their detection in plant matrices.

Moreover, early-stage clinical trials have demonstrated that several minor cannabinoids exhibit promising therapeutic potential.

This review aims to provide a comprehensive summary of recent developments in the extraction, analysis, and potential applications of selected minor phytocannabinoids, with the goal of facilitating future research in this field. A thorough analysis of the latest data has been conducted to offer a detailed overview of current extraction and quantification methodologies for minor cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/41321142

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pca.70040

Structural and dynamic mechanisms of cannabinoid receptors

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“Cannabinoids and their G protein-coupled receptors (GPCRs) within the endocannabinoidome are pivotal regulators of neuromodulation, inflammation, and metabolic homeostasis.

Dysregulation of this system has been associated with a wide spectrum of pathological conditions, including neuropsychiatric disorders, chronic pain, and immune dysfunction.

In this review, we summarize recent structural advances in cannabinoid receptors that have deepened our understanding of receptor activation, allosteric modulation, transducer coupling selectivity, and dynamic conformational mechanisms.

These structural insights will facilitate cannabinoid receptor-targeted drug discovery, enabling the development of therapeutics with improved subtype selectivity, enhanced signaling precision, and reduced off-target effects.”

https://pubmed.ncbi.nlm.nih.gov/41319927

“The medicinal use of phytocannabinoids has been documented for millennia, with applications across diverse cultures in the treatment of insomnia, pain, epilepsy, headaches, and inflammation. Modern scientific investigation into cannabis began in the 1930 s, culminating in the isolation and structural characterization of its major constituents.”

“Taken together, these findings highlight cannabinoid receptors as multifaceted and dynamic therapeutic targets positioned at the intersection of neurology, immunology, and metabolism. A deeper understanding of its structural and signaling mechanisms will be critical for the rational design of next-generation cannabinoid-based therapies that harness its extensive regulatory potential with precision.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225008330?via%3Dihub


Dual-Function Plant-Derived Nanovesicles From Regenerated Cannabis sativa Roots for Immunotherapy and Vaccine Delivery

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“Cannabis sativa is a medicinal plant that produces a diverse array of pharmacologically active metabolites, making it a valuable resource for pharmaceutical applications.

In this study, an adventitious root (AR) culture system was established from C. sativa using two representative plant growth regulators-naphthaleneacetic acid (NAA; hereafter referred to as N-ARs) and indole-3-butyric acid (IBA; hereafter referred to as I-ARs) -from which plant-derived nanovesicles (PDNVs) were subsequently isolated (hereafter N-PDNVs and I-PDNVs, respectively).

The resulting N-PDNVs and I-PDNVs exhibited average diameters of 128 ± 2 and 124 ± 4 nm, respectively, with zeta potentials of -12.9 and -15.7 mV. Both PDNV types maintained structural integrity and colloidal stability under diverse external stress conditions, underscoring their physicochemical robustness. Metabolite profiling of PDNVs revealed 25 distinct metabolites. Functionally, I-PDNVs markedly enhanced dendritic cell maturation through Toll-like receptor 2 (TLR2)- and TLR4-dependent pathways, promoted T cell proliferation and activation (notably IFN-γ- and IL-17A-producing subsets), and increased natural killer (NK) cell activity compared with N-PDNVs.

In immunosuppressed and tumour-bearing mouse models, I-PDNVs further augmented NK cell, Th1 and cytotoxic T lymphocyte (CTL) responses, thereby confirming their superior potential as immunotherapeutic agents. Moreover, in immunized mouse models, OVA257-264-encapsulated I-PDNVs demonstrated a clear advantage as a vaccine delivery platform by eliciting a potent OVA257-264-specific CTL response.

When applied as a prophylactic cancer vaccine, they not only delayed tumour growth but also reshaped the antitumour immune landscape, characterized by enhanced CTL responses, reduced regulatory T cell frequencies and diminished exhausted CD8⁺ T cell populations.

Collectively, these findings highlight the potential of I-PDNVs as dual-function PDNVs, serving both as immunotherapeutic agents and as vaccine delivery platforms for applications requiring reinforced Th1, CTL and NK cell responses.”

https://pubmed.ncbi.nlm.nih.gov/41316982

“Nanovesicles, commonly referred to as extracellular vesicles (EVs) are secreted by various organisms or are artificially isolated under various conditions, with their sizes ranging from 30 nm to 10 µm. Owing to their functional properties, such as immunity promotion, inflammation control and antioxidant activities, nanovesicles have attracted attention as promising candidates for drug delivery systems (DDS) and for treating various immune-related diseases, including cancers, infectious diseases and autoimmune disorders.”

“Our study is the first to report the differences in the metabolic properties and immunoenhancing efficacy between I-PDNVs and N-PDNVs isolated from C. sativa AR induced by two distinct plant hormones, IBA and NAA. I-PDNVs strongly promoted a Th1-biased immune response by inducing both innate and adaptive immune activation, demonstrating their superior potential as an immunotherapeutic agent for immunosuppression and cancer treatment. Furthermore, the multifunctionality of I-PDNVs is highlighted by validating their potential as an integrated adjuvant and DDS in a cancer vaccine model.

Our findings suggest that I-PDNVs are promising immunotherapeutic candidates not only for cancer treatment, but also for intracellular infectious diseases and chronic viral infections, emphasizing their role as a multifunctional nanomaterial capable of integrating adjuvant and vaccine delivery functions for next-generation vaccine development.”

https://isevjournals.onlinelibrary.wiley.com/doi/10.1002/jev2.70206

Evaluating cannabis substitution for alcohol within the context of a canadian managed alcohol program

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“Introduction: Managed Alcohol Programs (MAPs) provide beverage alcohol alongside housing and social supports to mitigate alcohol-related harms among individuals experiencing severe alcohol use disorder (AUD) and unstable housing. MAPs have been shown to stabilize alcohol use, reduce alcohol-related harms, improve quality of life, and decrease emergency service utilization. However, concerns about the long-term health risks associated with high levels of alcohol use have driven interest in cannabis substitution as an additional harm reduction strategy. Given the lower harm profile of cannabis, its integration into MAPs offers a promising avenue for further reducing alcohol-related harms. This study evaluates a novel cannabis substitution program within a Canadian MAP, leveraging the unique context of cannabis legalization and harm reduction programming.

Methods: Beginning in January 2023, participants (N = 35) were offered the choice of a pre-rolled cannabis joint or their prescribed alcohol dose multiple times per day. Data were drawn from five waves of quantitative surveys (January 2023 to February 2024; n = 20), two years of program records (January 2022 to February 2024; N = 35), and qualitative interviews (n = 14). Hierarchical mixed-effects models were used to predict alcohol use by cannabis use and time. Qualitative data were analyzed using interpretive description methodology.

Results: The final model found evidence of a substitution effect: participants who used more cannabis on average also consumed less alcohol overall. Specifically, each additional 0.4-gram joint consumed (approximately 15.2 standard THC units or 76 mg THC) was associated with an estimated 2.43 fewer mean daily standard drinks. Within-person cannabis use was not a significant predictor, indicating that short-term fluctuations in cannabis use were not associated with concurrent changes in alcohol consumption. Alcohol use also declined over time. Qualitative findings provide insights into the dynamic factors shaping drinking and cannabis use patterns.

Conclusion: This study highlights the potential for cannabis substitution to meaningfully reduce alcohol-related harms. Implications for program development and future research evaluating changes in health, wellbeing, and harm outcomes are discussed.”

https://pubmed.ncbi.nlm.nih.gov/41313909

“Emerging evidence suggests that cannabis substitution for alcohol may offer a promising approach to mitigating alcohol-related harms. Cannabis is associated with lower toxicity, fewer long-term health risks, and a lower likelihood of overdose compared to alcohol.”

https://www.sciencedirect.com/science/article/pii/S0955395925003792?via%3Dihub

Cannabidiol alleviates methamphetamine-induced autophagy and oxidative stress by suppressing sigma 1 receptor expression

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“Methamphetamine (METH) is currently considered one of the most notorious drugs globally. Chronic long-term METH abuse results in severe neurotoxicity, wherein oxidative stress and autophagy are key pathological phenomena and toxic phenotypes. However, the molecular mechanism by which METH induces oxidative stress and autophagy remains elusive.

In this study, METH-induced autophagy and oxidative stress were replicated in both HT22 cells and C57BL/6 J mice. Notably, METH up-regulated the expression of chaperon protein sigma 1 receptor (S1R). However, METH-induced autophagy and oxidative stress were alleviated after targeted intervention with S1R using the chemical inhibitor, gene knockdown, or knockout techniques.

More importantly, cannabidiol (CBD), a non-psychoactive natural cannabinoid derived from cannabis, exhibited therapeutic efficacy by down-regulating the high expression of S1R, autophagy, and oxidative stress following METH exposure both in vivo and in vitro.

Overall, these results suggest that METH mediates autophagy and oxidative stress by up-regulating S1R expression, whereas CBD alleviates METH-induced autophagy and oxidative stress by suppressing S1R expression.

This study expands our understanding of METH-induced neurotoxicity, identifying S1R as a potential therapeutic target against aberrant autophagy and oxidative stress, and further validates the medical value of CBD for the treatment of METH use disorder.”

https://pubmed.ncbi.nlm.nih.gov/41314517

“Cannabidiol (CBD), a non-psychoactive natural cannabinoid derived from cannabis, exerts distinct pharmacological effects, such as antioxidant, anti-inflammatory, and neuroprotective effects, demonstrating therapeutic potential in several neurological diseases.”

“CBD alleviated METH-induced autophagy and oxidative stress by suppressing S1R expression.”

https://www.sciencedirect.com/science/article/abs/pii/S0898656825006953?via%3Dihub