Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids

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“Pain impacts billions of people worldwide, but treatment options are limited and have a spectrum of adverse effects. The search for safe and nonaddictive pain treatments has led to a focus on key mediators of nociceptor excitability.

Voltage-gated sodium (Nav) channels in the peripheral nervous system-Nav1.7, Nav1.8, and Nav1.9-play crucial roles in pain signaling. Among these, Nav1.8 has shown promise due to its rapid recovery from inactivation and role in repetitive firing, with recent clinical studies providing proof-of-principal that block of Nav1.8 can reduce pain in humans.

We report here that three nonpsychotomimetic cannabinoids-cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN)-effectively inhibit Nav1.8, suggesting their potential as analgesic compounds.

In particular, CBG shows significant promise due to its ability to effectively inhibit excitability of peripheral sensory neurons. These findings highlight the therapeutic potential of cannabinoids, particularly CBG, as agents that may attenuate pain via block of Nav1.8, warranting further in vivo studies.”

https://pubmed.ncbi.nlm.nih.gov/39835903/

“Chronic pain is a major health problem worldwide; however, treatment options remain limited and often involve adverse side-effects or addiction risk. Targeting voltage-gated sodium (Nav) channels in sensory neurons, particularly Nav1.8, represents a promising therapeutic approach. Our work demonstrates that nonpsychotomimetic cannabinoids, including cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN), effectively inhibit Nav1.8. CBG, in particular, exhibits a potent inhibition of dorsal root ganglion neuron excitability, suggesting its potential as a nonaddictive analgesic. Our findings open different avenues for the development of cannabinoid-based treatments for pain therapy, with a focus on Nav1.8 inhibition as a therapeutic target.”

https://www.pnas.org/doi/10.1073/pnas.2416886122

Investigation of Cannabidiol’s Protective Effects on Cadmium-Induced Toxicity in Mice

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“Current chelation treatments used for cadmium poisoning may cause some serious side effects. Thus, safer novel treatments could be promising for clinical use.

This study evaluated the effects of cannabidiol on Cd toxicity.

Four groups of 10 mice were formed: Groups I and III were cadmium-free, while groups II and IV received 50 mg/L cadmium in drinking water. Groups III and IV received daily cannabidiol (25 mg/kg) via intragastric gavage. After 30 days, the animals were killed, and blood and tissue samples were collected. Oxidative stress and inflammation markers, including glutathione, catalase, myeloperoxidase, TNF-α, IL-1β and IL-6, were analysed using ELISA. Additionally, histological evaluations of the liver, kidney and testis were performed. Cadmium exposure reduced glutathione and catalase levels in the blood, liver, kidney and testis, while increasing myeloperoxidase.

Cannabidiol mitigated these effects on oxidative stress markers. Cannabidiol also reduced the increase in proinflammatory cytokines. Histopathological analysis revealed reduced liver and kidney damage in cannabidiol-treated groups compared to cadmium-only groups. In addition, histopathological evaluation showed CBD had no protective effect on the testicular tissue against Cd toxicity.

Our results indicate that cannabidiol protects against some toxic effects of cadmium. If confirmed by future studies, cannabidiol may be proposed as a novel treatment for cadmium toxicity.”

https://pubmed.ncbi.nlm.nih.gov/39832793/

“Cadmium (Cd) is a heavy metal that can have toxic effects on multiple organs. Chelation treatments that are used for treating Cd toxicity can have serious side effects, which limit their use. This study aimed to investigate cannabidiol (CBD), a non-psychoactive compound derived from hemp, for its potential to reduce Cd toxicity.

Our experiments on mice showed CBD had significant protective effects against Cd-induced tissue damage in the liver and the kidneys by reducing oxidative stress and inflammation. These findings suggest that CBD can be explored as a safer treatment option for Cd toxicity in a clinical setting.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14131

Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery

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“G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects.

Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases.

This review examines the structural conformations of CB1 coupling to different signaling pathways and explores the mechanisms underlying biased signaling, which are critical for the design of functionally selective ligands. We discuss the structure-function relationships of endogenous cannabinoids (eCBs), phytocannabinoids, and synthetic cannabinoid ligands with biased properties. Challenges such as the complexity of ligand bias screening, the limited availability of distinctly biased ligands, and the variability in receptor signaling profiles in vivo have hindered clinical progress.

Although the therapeutic potential of biased ligands in various clinical conditions remains in its infancy, retrospective identification of such molecules provides a strong foundation for further development. Recent advances in CB1 crystallography, particularly insights into its conformations with G proteins and β-arrestins, now offer a framework for structure-based drug design. While there is still a long way to go before biased CB1 ligands can be widely used in clinical practice, ongoing multidisciplinary research shows promise for achieving functional selectivity in targeting specific pathways.

These progresses could lead to the development of safer and more effective cannabinoid-based therapies in the future.”

https://pubmed.ncbi.nlm.nih.gov/39828030/

https://www.sciencedirect.com/science/article/abs/pii/S0163725825000075?via%3Dihub

∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo

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“Background: Because of its biocompatibility and its soft and dynamic nature, the grafting of adipose tissue is regarded an ideal technique for soft-tissue repair. The adipose stem cells (ASCs) contribute significantly to the regenerative potential of adipose tissue, because they can differentiate into adipocytes and release growth factors for tissue repair and neovascularization to facilitate tissue survival. The present study tested the effect of administering a chronic low dose of ∆9-tetrahydrocannabinol (THC) on these regenerative properties, in vitro and in vivo.

Methods: Human ASCs were exposed to increasing concentrations of THC. Resazurin conversion was applied to investigate the effect on metabolic activity, cell number was assessed by crystal violet staining, tri-linear differentiation was evaluated by specific colorimetric approaches, and the release of growth factors was analyzed by ELISA. Two groups of mice were treated daily either with a low dose of THC (3 mg/kg) or a vehicle solution. After 3 weeks, adipose tissue was obtained from excised fat deposits, homogenized and tested for growth factor contents.

Results: THC decreased ASC proliferation but increased metabolic activity as well as adipogenic and chondrogenic differentiation. A low concentration of THC (1 µM) enhanced the growth factor release by ASCs. The concentration of these cytokines was also increased in adipose tissue of mice treated with THC.

Conlusion: Our results indicate that chronic activation of the endocannabinoid system promoted differentiation and growth factor release of ASCs, which could be of specific value for enhancing the regenerative potential of adipose tissue.”

https://pubmed.ncbi.nlm.nih.gov/39825991/

“Our findings may offer a new approach for improved application of adipose tissue in regenerative medicine.”

https://link.springer.com/article/10.1007/s13770-024-00692-8

Unveiling cellular changes in leukaemia cell lines after cannabidiol treatment through lipidomics

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“The present study was aimed at revealing the metabolic changes that occurred in the cellular lipid pattern of acute and chronic myeloid leukaemia cells following treatment with cannabidiol (CBD).

CBD is a non-psychoactive compound present in Cannabis sativa L., which has shown an antiproliferative action in these type of cancer cells.

CBD treatment reduced cell viability and initiated apoptotic and necrotic processes in both cancer cell lines in a time and dose-dependent manner, showing acute myeloid leukaemia (HL-60) cells greater sensitivity than chronic myeloid leukaemia ones (K-562), without differences in the activation of caspases 3/7. Then, control and treated cells of HL-60 and K-562 cell lines were studied through an untargeted lipidomic approach.

The treatment was carried out with CBD at a concentration of 10 μM for HL-60 cells and 23 µM CBD for K-562 cells for 48 h. After the extraction of the lipid content from cell lysates, the samples were analysed by UHPLC-QTOF-MS/MS both in the positive and the negative ionization modes. The comprehensive characterization of cellular lipids unveiled several classes significantly affected by CBD treatment. Most of the differences correspond to phospholipids, including cardiolipins (CL), phosphatidylcholines (PC) and phosphosphingolipids (SM), and also triacylglycerols (TG), being many TG species increased after CBD treatment in the acute and chronic models, whereas phospholipids were found to be decreased.

The results highlight some important lipid alterations related to CBD treatment, plausibly connected with different metabolic mechanisms involved in the process of cell death by apoptosis in cancer cell lines.”

https://pubmed.ncbi.nlm.nih.gov/39824876/

“Cannabinoids have shown to be effective both as a single agent and in combination with antineoplastic drugs.”

https://www.nature.com/articles/s41598-025-86044-5

[Impact of dronabinol shortage on a population of chronic pain patients: A retrospective observational study]

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“Objective: A supply shortage of dronabinol occurred between December 2023 and February 2024, forcing chronic pain patients to discontinue this treatment. We assessed the impact of this shortage on patients in our hospital.

Method: A retrospective observational study of patients treated with dronabinol was conducted. Collected data included socio-demographic, pharmacological and clinical data. Pain intensity and its interference, the intensity of other pain dimensions (mood, relationship with others, etc.) and quality of sleep were collected before discontinuation (dronabinol dosage balanced, M0) and at the end of discontinuation (dronabinol stopped for several weeks, M3). The patient’s perception of his state of health evolution was collected at the end of the shortage.

Results: Health deterioration was reported by 86% of patients after 3 months of rupture. Pain intensity and its interference with patients’ daily lives increased significantly. Patients’ sleep deteriorated significantly. The number of patients with permanent pain increased 5-fold (n=2 at M0 and n=10 at M3). The number of patients with more than 20 painful attacks per 24hours increased 2-fold (n=2 at M0 and n=4 at M3).

Conclusion: Although data on the efficiency of dronabinol are currently limited, this supply disruption has had negative clinical consequences for our patients. With drug shortages multiplying in recent years, the marketing of new specialties and therefore the availability of therapeutic alternatives could help reduce the clinical impact of a possible new dronabinol shortage in these refractory chronic pain patients.”

https://pubmed.ncbi.nlm.nih.gov/39824703/

https://www.sciencedirect.com/science/article/abs/pii/S0040595724002191?via%3Dihub

“Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns”

https://pubmed.ncbi.nlm.nih.gov/26775260/

Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies

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“Moroccan Cannabis sativa L. seeds were investigated for their phenolic profile and antidiabetic potential.

Ultra-high-performance liquid chromatography with diode array detection and electrospray ionization mass spectrometry analysis revealed a rich phenolic composition, including benzoic acid, cannabisin B, genistein, and epicatechin. 

In vitro, the seed extract exhibited potent α-amylase inhibitory activity (half-maximal inhibitory concentration = 25.02 ± 4.03 μg/mL). In vivo studies in diabetic rats demonstrated significant hypoglycemic, hypolipidemic, hepatoprotective, and nephroprotective effects. Molecular docking studies further supported these findings, revealing strong interactions between identified phenolic and the α-amylase enzyme.

These results highlight the potential of C. sativa seeds as a natural source of bioactive compounds for diabetes management.”

https://pubmed.ncbi.nlm.nih.gov/39822379/

“Our findings demonstrate that C. sativa L. seed extract (CSSE) holds significant promise as a novel therapeutic approach for managing diabetes and its associated complications.”

https://www.degruyter.com/document/doi/10.1515/biol-2022-1024/html

Cannabis use in Crohn’s disease: a systematic review and meta-analysis of randomized controlled trials (RCTs)

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“Objective: This meta-analysis aims to systematically evaluate the efficacy and safety of cannabis in the management of Crohn’s disease (CD) by synthesizing evidence from randomized controlled trials (RCTs). By adhering to the 2020 PRISMA guidelines and registering the study protocol with PROSPERO, this research intends to offer robust, evidence-based recommendations for healthcare practitioners on the therapeutic potential and clinical implications of cannabis use in CD management.

Methods: A literature search encompassing PubMed, Google Scholar, and the Cochrane Library was conducted to identify relevant RCTs comparing cannabis to placebo or standard therapy in CD patients. Inclusion criteria focused on outcomes such as remission rates, C-reactive protein (CRP) levels, quality of life (QoL), and adverse events (AEs). Statistical analysis using RevMan 5.3 involved weighted mean differences (MD) and 95% confidence intervals to compare outcomes between the cannabis and control groups.

Results: The meta-analysis revealed significant findings regarding the impact of cannabis on CD management. The cannabis group exhibited significantly higher clinical remission rates at 8 weeks compared to the control group, with low heterogeneity [MD = – 67.98; 95% CI: (- 100.68, – 35.29)]. However, a statistically significant improvement in QoL was observed in the placebo group compared to the cannabis-treated group [MD = 19.62; 95% CI (14.24 to 25.00)]. There was a non-significant lowering in serum CRP levels compared to the placebo group [MD: – 0.51; 95% CI: (- 1.05, 0.02)].

Conclusion: The study concludes that cannabis shows promise as a therapeutic option for CD, demonstrating higher remission rates and potential benefits for disease management. However, it also highlights the need for larger, standardized research studies to solidify conclusions regarding efficacy, safety, and biomarker responses in CD patients.”

https://pubmed.ncbi.nlm.nih.gov/39821383/

https://link.springer.com/article/10.1007/s11845-024-03844-w

Evaluation of the Antibacterial Potential of Ethanolic Cannabis sativa L. (Hang Kra Rog Phu Phan ST1) Extracts Against Human Pathogenic Bacteria

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“Background and Objective: Amid the escalating challenge of antibiotic resistance, the exploration of new sources has become essential, with plants serving as a promising reservoir of bioactive compounds.

Cannabis sativa has attracted significant research interest for its antimicrobial properties and broad applications in medicine, industry and nutrition.

This study aimed to investigate the antibacterial activity of ethanolic extracts from the stems and leaves of the Hang Kra Rog Phu Phan ST1 strain against twelve human pathogenic bacteria.

Materials and Methods: Stems and leaves from the Hang Kra Rog Phu Phan ST1 strain were subjected to ethanol extraction. The primary antibacterial activity of ethanolic extracts from Tanao Si Kan Dang RD1 was assessed using the disc diffusion method, while the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined via the broth microdilution method. The inhibition zone diameter (mm) was analyzed using Duncan’s Multiple Range Test (DMRT) with the SAS software.

Results: The findings revealed that the ethanolic extract from the leaves of Hang Kra Rog Phu Phan ST1 produced the largest inhibition zone diameter of 10.00 mm against <i>Bacillus subtilis</i> TISTR 008. The MIC and MBC of the leaf extract showed the lowest values of 0.09 and 0.19 mg/mL, respectively, recorded against <i>Staphylococcus aureus</i> TISTR 1466.

Conclusion: This is the first report on the antibacterial activity of the ethanolic extracts from the leaves and stems of Hang Kra Rog Phu Phan ST1, which offers potential benefits for developing natural antibiotic drugs to combat infections caused by the tested pathogenic bacteria.”

https://pubmed.ncbi.nlm.nih.gov/39820562/

https://scialert.net/abstract/?doi=pjbs.2025.1.7

Lebanese Cannabis sativa L. extract protects from cisplatin-induced nephrotoxicity in mice by inhibiting podocytes apoptosis

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“Background: Cisplatin is an anti-cancer drug used to treat a plethora of solid tumors. However, it is associated with dose dependent nephrotoxicity limiting its use as anticancer agent.

Objective: The current study aimed to investigate the nephroprotective effect of native Lebanese Cannabis sativa in both in vitro and in vivo mice model of cisplatin-induced nephrotoxicity.

Methods: Podocytes cell viability was assessed using MTS assay with cisplatin (30µM) in presence or absence of Cannabis oil extract (COE) at 0.5, 1 and 2µg/ml for 24h. Acute renal injury was established in adult female C57BL/6 mice with 20mg/kg, i.p. single dose cisplatin. Mice were divided into control group (vehicle), COE group, cisplatin group and cisplatin plus COE (2.5, 5 and 20mg/kg, i.p.). Animal body weight, serum creatinine, blood urea nitrogen (BUN), and proteinuria were measured.

Results: Cell viability assay and western blot analysis revealed that COE prevented apoptosis induced by cisplatin in cultured immortalized rat podocytes. In addition, in vitro scratch assay demonstrated the ability of COE to promote and restore the migratory capacity of podocytes in cisplatin-treated cells. Interestingly, COE treatment improved urinary and serum parameters characterized by a significant decrease in serum creatinine, urea, and proteinuria at various COE doses. Western blot analysis showed that COE inhibited COX-2 protein induction as well as apoptosis marker production (Bax/Bcl2 ratio) in cisplatin-treated mice when compared to mice treated with cisplatin alone.

Conclusion: Collectively, the aforementioned findings indicate that COE could be a promising approach to protect against cisplatin-induced nephrotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/39819647/

“In conclusion, our results corroborated previous findings but on kidney podocytes. We strongly suggest that the Lebanese Cannabis oil extract may be of significant therapeutic benefits against the renal complications of cisplatin. Thus, Lebanese COE produces its renoprotective effects partly through activating antiinflammatory and antiapoptoric mechanisms in podocytes.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00260-4