Cannabidiol impairs tumor-associated behaviors and modulates apoptosis- and autophagy-related pathways in cisplatin-resistant head and neck squamous cell carcinoma

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Cannabidiol (CBD), a naturally occurring cannabinoid found in the Cannabis plant, reduced the survival, movement, and invasion of cisplatin-resistant head and neck cancer cells. In the HPV-negative HN13 cell model, CBD reduced colony formation by 98% and suppressed the growth of three-dimensional tumor spheroids.

CBD preferentially affected cancer cells compared with the non-tumor cells tested and reduced MMP-2 and MMP-9 activity—enzymes that help cancer cells invade surrounding tissue. It also altered pathways involved in programmed cell death, cellular recycling, and cell-cycle regulation.

CBD reduced tumor growth and blood-vessel area in a chick embryo membrane model without causing vascular irritation. Selected combinations of CBD and cisplatin produced synergistic cancer-cell killing, supporting further investigation of CBD as a potential addition to treatment for chemotherapy-resistant head and neck cancer.

“Head and neck squamous cell carcinoma (HNSCC) remains a challenge due to recurrence, metastasis, and resistance to conventional therapies, particularly in human papillomavirus (HPV)-negative tumors.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has demonstrated antitumor activity in several cancer models; however, its effects in chemoresistant HNSCC are not well established.

This study evaluates the antitumor effects of CBD and cellular mechanisms in a cisplatin -resistant, HPV-negative HNSCC model.

Cytotoxic effects of CBD were assessed in HN13 cells and compared with fibroblasts and keratinocytes using MTT and selectivity index analysis. Migration, invasion, metalloproteinase activity, clonogenic survival, and cytotoxicity on 3D spheroids were evaluated. Cell death-related mechanisms were investigated using acridine orange/propidium iodide staining and Western blot analysis of apoptosis, autophagy, and cell-cycle regulation. Antitumor activity and vascular safety were further assessed using the chorioallantoic membrane model and HET-CAM assay. The combined effect of CBD and CIS was evaluated using the combination index analysis.

CBD exhibited selective cytotoxicity toward HN13 cells and reduced migration, invasion, matrix metalloproteinase-2/9 activity, clonogenic survival, and 3D spheroid growth. CBD altered proteins associated with apoptosis, autophagy, and cell-cycle regulation. Pharmacological inhibition with 3-MA enhanced CBD-associated apoptotic signaling, increasing PARP and caspase-3 cleavage. In the CAM, CBD reduced tumor growth and vascular area without inducing vascular irritation. Furthermore, CBD and CIS demonstrated synergistic cytotoxic effects in HN13 cells. CBD exerted selective antitumor effects on CIS-resistant HN13 HNSCC cells, affecting tumor-associated behaviors and modulating apoptosis and autophagy-related signaling, while acting synergistically with cisplatin.

These findings support further preclinical investigation of CBD as a potential adjunct approach in HNSCC, particularly in chemoresistant settings.”

https://pubmed.ncbi.nlm.nih.gov/42932045

“This study provides preclinical evidence that cannabidiol (CBD) exerts selective antitumor effects in HPV-negative HNSCC models evaluated in this study.

CBD reduced tumor cell viability, impaired migration, invasion and clonogenic capacity, modulated matrix metalloproteinase activity, reduced the area of 3D spheroids and was associated with modulation of apoptosis- and autophagy-related signaling pathways in vitro. Furthermore, it acted synergistically with the chemotherapeutic agent CIS. In vivo, CBD reduced tumor growth and vascular area in the chorioallantoic membrane model without inducing vascular irritation.

Collectively, these findings support CBD as a potential candidate for further investigation in HNSCC, particularly in chemoresistant settings.”

https://link.springer.com/article/10.1007/s12032-026-03480-7

Cannabidiol-loaded hydrogel contact lenses for on-demand pH regulation and enhanced corneal alkali burn repair

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Cannabidiol-loaded hydrogel contact lenses improved repair of corneal alkali burns in preclinical experiments. Researchers developed a lens that releases CBD and citric acid in response to alkaline conditions, helping neutralize residual chemicals while delivering treatment directly to the injured eye.

The combined lens system reduced inflammatory signals, removed damaging hydroxyl radicals, and inhibited the growth of E. coli and Staphylococcus aureus by more than 90% in laboratory testing. Under alkaline conditions, approximately 59% of its CBD and 52% of its citric acid were released within 24 hours.

In animal experiments, the lenses promoted corneal repair by reducing inflammation and inhibiting unwanted blood-vessel growth. Published in the Journal of Controlled Release, these findings support further development of CBD-containing contact lenses as a targeted treatment approach for chemical injuries to the cornea—the clear front surface of the eye.

“Corneal alkali burn (CAB) poses a significant therapeutic challenge due to alkali infiltration, bacterial infection, inflammation, and angiogenesis, which collectively hinder recovery. The pH microenvironment after CAB is critical for the healing process, but there are few functional biomaterials for this purpose at present.

Herein, we develop a multifunctional hydrogel contact lens (CL) with on-demand release of citric acid (CA) and cannabinoid (CBD), triggered by alkaline conditions, to regulate the microenvironment pH and enhance CAB repair. The CA-functionalized polyvinyl alcohol (PC) and quaternary ammonium chitosan (QCS) are used as hydrogel frameworks, with CBD incorporated as a functional component. The (CBD/QCS/PC, CBD/QPC) hydrogel CL is fabricated using a repeated freeze-thaw process to achieve an interpenetrating network structure.

The findings suggest that the 1CBD/QPC hydrogel CL exhibit superior mechanical properties and biocompatibility (hemolysis rate < 0.6 %, cell viability>90 %). These properties enhance wearing comfort and reducing secondary inflammation. Notably, this hydrogel can release CA (52.23 ± 2.78 %) and CBD (59.24 ± 5.15 %) within 24 h under alkaline conditions to neutralize pH, significantly down-regulate the expression level of inflammatory factors and remove hydroxyl radicals. This mechanism fundamentally addressing the secondary damage of residual lye following CAB. Moreover, the hydrogel CL exhibit potent inhibitory effects on the colonization and growth of both E. coli and S. aureus by destroying bacterial membranes, with an inhibition rate > 90 %.

In vivo results show that hydrogel CL promote the repair of CAB through anti-inflammatory effects and angiogenesis inhibition.

In conclusion, these results demonstrate the potential of this hydrogel CL for treating corneal alkaline burns, providing new insights into treatment of CAB.”

https://pubmed.ncbi.nlm.nih.gov/40383160

“After CAB, the persistent alkaline residue remains a major obstacle to corneal repair. In this study, a novel CBD/QPC hydrogel CL with IPN structure was prepared by blending QCS, PC polymers, and CBD using a repeated freeze-thaw strategy. The findings suggested that the physicochemical properties of the hydrogel CL can be customized by adjusting the concentrations of QCS and CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0168365925004791?via%3Dihub

Estrogen receptor modulation by a newly-identified cannabinoid in a preclinical model of breast cancer

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A newly identified cannabis-derived cannabinoid, 373.15b, reduced breast tumor volume and weight in mice, with stronger effects when combined with tamoxifen. Researchers isolated the compound from a cannabis extract called CANN14, which increased the sensitivity of estrogen receptor-positive breast cancer cells to tamoxifen.

The cannabinoid reduced the production and activity of estrogen receptor alpha (ERα), a protein that helps estrogen drive cancer growth. Its effects may involve RASSF1A and the Hippo signaling pathway, which help regulate cell growth.

These findings identify a potential way to strengthen hormone therapy for estrogen-dependent breast cancer. The researchers suggest that combining 373.15b with drugs such as tamoxifen could eventually permit lower treatment doses and fewer adverse effects—a possibility requiring clinical testing.

“Background: Breast cancer is a diverse group of diseases comprising subtypes with distinct behavior and response to therapy. Tumors that express estrogen receptor alpha (ERα) and depend on estrogen constitute ∼65% of all breast cancer cases. Common endocrine therapy for this kind of breast cancer includes Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen. However, despite the clear benefits, many patients do not complete the recommended 5 and sometimes 10 years of treatment because of adverse effects. Medical cannabis is increasingly used by cancer patients, primarily for palliative care, yet its direct antitumor potential in breast cancer remains poorly understood.

Purpose: Examine whether cannabis-derived compounds exert selective antitumor effects in breast cancer and elucidate the underlying molecular mechanisms.

Study design: A combination of in vitro experiments in multiple ER-positive breast cancer cell lines with in vivo validation in an estrogen-dependent xenograft mouse model.

Methods: Breast cancer cell lines representing different molecular subtypes were evaluated. A panel of chemically distinct cannabis extracts was initially screened for cytotoxic activity and subsequently tested in combination with SERMs. Extracts were chemically profiled using ESI-LC/MS. Phytocannabinoid fractionation, chemical analyses, and structural elucidation were performed to isolate and characterize the bioactive phytocannabinoid in the only cannabis extract identified in the initial screen as effective in combination with tamoxifen. The mechanism of action of this phytocannabinoid was investigated in vitro using molecular and biochemical assays. Finally, antitumor efficacy was assessed in vivo using an estrogen-dependent ER-positive breast cancer xenograft mouse model.

Results: We found a unique cannabis extract, CANN14, capable of sensitizing ER-positive breast cancer cells to the cytotoxic effect of tamoxifen. We identified a novel phytocannabinoid 373.15b that mimicked the effect of the whole extract without any toxicity by itself. It has a unique structure of a dihydroxyphenol with an acetate group attached to the aromatic ring, distinguishing it from known cannabinoid scaffolds. Cannabinoid 373.15b modulated estrogen signaling by decreasing the mRNA and protein expression levels of ERα, as well as its transcriptional activity, possibly through a signaling pathway involving RASSF1A and Hippo signaling components. In an in vivo mouse model, treatment with 373.15b reduced tumor volume and weight, with a more profound effect when combined with tamoxifen.

Conclusion: The work presented here identifies a novel cannabinoid that modulates ERα signaling and enhances the antitumor efficacy of SERMs. The findings suggests that co-therapy of 373.15b with SERMs may allow dose reduction of conventional therapy, and by that, diminish the associated adverse effects and improve patient quality of life.

One-sentence summary: The newly identified cannabinoid 373.15b reduces ERα expression and activity through RASSF1A and Hippo signaling pathway thus exerting antitumor effects.”

https://pubmed.ncbi.nlm.nih.gov/42927724

“Overall, our findings demonstrate that a specific cannabis-derived compound can decrease ER signaling and inhibit ER-positive breast cancer, particularly in combination with tamoxifen. Our initial screen further highlights the substantial variability between cannabis cultivars, showing that even extracts with similar major cannabinoid compositions can produce different biological outcomes.

Through fractionation and chemical characterization, we identified a previously uncharacterized phytocannabinoid, 373.15b, which modulates ERα expression and activity. Based on our preliminary results, we hypothesize that the reduction in ERα expression occurs through a mechanism involving RASSF1A and the Hippo signaling pathway.

Both the CANN14 extract and purified 373.15b significantly inhibited tumor progression in vivo, with a more pronounced effect when combined with tamoxifen.

These findings support the use of experimentally selected cannabis-derived components in combination with endocrine therapy. In ER-positive breast cancer, enhancing therapeutic efficacy may allow dose reduction of SERMs, potentially mitigating adverse effects and improving patient adherence and quality of life.”

https://www.sciencedirect.com/science/article/pii/S0753332226009789?via%3Dihub

Cannabis sativa L. stem ethanol extract suppresses ERα-mediated endocrine disrupting effects induced by bisphenol A in a breast cancer cell line

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Researchers found that an ethanol extract made from Cannabis sativa stems suppressed the endocrine-disrupting effects of bisphenol A (BPA) in an estrogen-sensitive breast cancer cell line. BPA can mimic estrogen and activate estrogen receptor alpha (ERα), a signaling pathway involved in the growth and proliferation of many hormone-sensitive breast cancers.

The cannabis stem extract interfered with this BPA-driven ERα activity, reducing the estrogen-like effects produced by BPA in the breast cancer cells. Rather than simply testing cannabis for direct cancer-cell toxicity, the researchers examined whether compounds in the plant could counteract a specific molecular pathway activated by an environmental endocrine disruptor.

These findings suggest that Cannabis sativa stems—often treated as agricultural waste—may contain bioactive compounds capable of modifying BPA-induced estrogen signaling. The study adds a new dimension to cannabis and breast cancer research by identifying a potential interaction between cannabis-derived compounds, environmental contaminants, and hormone-responsive cancer pathways.

“Cannabis sativa L. (hemp), a Cannabaceae family member, has been extensively studied for its diverse secondary metabolites with physiological activities. However, stems that lack detectable levels of the delta-9-tetrahydrocannabinol have been understudied.

Herein, we aimed to investigate the antagonistic effects using C. sativa L. stem ethanol extract (CSE) and its bioactive compounds on human ERα activity induced by exogenous estrogen, bisphenol A (BPA), through genomic and non-genomic pathways.

CSE inhibited BPA-induced ERα transcriptional activation in VM7Luc4E2 cells and suppressed cell proliferation. Among the secondary metabolites in CSE, cyclopentane-1,2-dione (CPD), 4-vinylguaiacol (4-VG), and 4-([1E]-hydroxy-1-propenyl)-2-methoxyphenol (4-HMP) exhibited antagonistic effects on ERα transcriptional activation and inhibited cell proliferation. Cell proliferation suppression was mediated by downregulation of p38 phosphorylation in the MAPK signaling pathway.

CPD inhibited exogenous estrogen-induced activation of ERα without significant affecting the translocation of cytosolic ERα to the nucleus. In contrast, 4-VG and 4-HMP exerted antagonistic effect based on suppressing the nuclear translocation of cytosolic ERα.

Collectively, the results showed that CSE suppressed ERα-mediated endocrine disruption induced by exogenous estrogen, suggesting its potential as a natural ingredient to reduce endocrine disruption from dietary sources.”

https://pubmed.ncbi.nlm.nih.gov/42777654

“This study demonstrated that CSE exerted antagonistic effects on activation of ERα induced by BPA, a representative exogenous estrogen, and that these effects were mediated through the regulation of ERα signaling and nuclear translocation. Furthermore, inactivation of ERα caused BPA-induced cell proliferation of human breast cancer cells by modulating the MAPK/p38 pathway. The active compounds in CSE that suppressed BPA-induced endocrine disrupting were CPD, 4-VG, and 4-HMP. Three secondary metabolites had inhibitory effects on BPA-induced cell proliferation of human breast cancer cells based on their ERα antagonistic effects.

Accordingly, these findings suggest the potential of CSE as a natural product to alleviate endocrine disruption associated with exogenous estrogen exposure from environmental or dietary sources.”

https://www.sciencedirect.com/science/article/pii/S0147651326011620?via%3Dihub

Terpenes from Cannabis sativa Induce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A 2A Receptors

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Cannabis terpenes produced strong pain-relieving effects in mice with chemotherapy-induced peripheral neuropathy and inflammatory pain. Researchers tested geraniol, linalool, β-pinene, α-humulene and β-caryophyllene and found that, at the tested dose, their antinociceptive effects were roughly comparable to 10 mg/kg morphine or 3.2 mg/kg of the synthetic cannabinoid WIN55,212.

The terpenes also enhanced morphine’s pain-relieving effect when the two were given together at lower doses, while none of the terpenes produced reward in the conditioned-place-preference test. In the neuropathic pain model, blocking the adenosine A2A receptor significantly reduced the pain-relieving effect of every terpene tested.

Spinal-cord-specific A2A receptor knockdown further supported that mechanism, while laboratory and computer modeling suggested the terpenes can act as A2A receptor agonists. The authors concluded that Cannabis terpenes may represent potential therapeutics for chronic neuropathic pain and identified a specific receptor pathway through which that activity occurs.

“Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa .

A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action.

In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain.

We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212.

We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists.

Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.”

https://pubmed.ncbi.nlm.nih.gov/38709489/

https://journals.lww.com/pain/abstract/10.1097/j.pain.0000000000003265~terpenes-from-cannabis-sativa-induce-antinociception-in-a?redirectionsource=fulltextview

Enhancing Anti-Cancer Efficacy in Colorectal Cancer Through Cannabinoid and Sodium Pentaborate Co-Therapy

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Cannabidiol (CBD) and cannabigerol (CBG), naturally occurring cannabinoids found in the Cannabis sativa plant, enhanced growth-suppressing effects at selected doses when combined with sodium pentaborate, a boron-based compound, in laboratory-grown human colorectal cancer cells. Researchers tested two cell lines, HT-29 and HCT-116, and found that responses depended strongly on the cancer cells’ characteristics and the combination used.

In HT-29 cells, the combinations reduced cell proliferation and increased early apoptosis—programmed cell death—with synergistic effects occurring only at certain dose combinations. HCT-116 cells responded mainly by arresting the cell cycle and activating stress-response pathways, rather than showing consistently enhanced cell killing.

The treatments also altered genes involved in oxidative balance and iron metabolism, processes associated with ferroptosis, an iron-dependent form of cell death. These findings support further investigation of boron–cannabinoid combinations tailored to tumor biology, with validation in three-dimensional tumor models and animal studies identified as the next steps.

“Background: Colorectal cancer (CRC) is characterized by pronounced genetic and phenotypic heterogeneity, which substantially influences therapeutic response and limits the efficacy of uniform treatment strategies. Cannabinoid-derived phytochemicals and boron-based compounds have independently been reported to modulate cancer cell proliferation, survival, and redox balance. However, the extent to which these agents interact at the cellular level and whether such interactions are dependent on tumor-specific molecular contexts remains poorly defined.

Methods: Sodium pentaborate (NaB) was combined with non-cytotoxic concentrations of cannabidiol (CBD) or cannabigerol (CBG) and evaluated in HCT-116 and HT-29 colorectal cancer cell lines. Cell viability and drug interactions were assessed by MTS and combination index analyses. Apoptotic responses were examined by Annexin V/PI staining, caspase-3/7 activity assays, and transcriptional profiling of apoptosis-related genes. Cell cycle dynamics and proliferation-associated markers were analyzed by flow cytometry and quantitative PCR. In parallel, ferroptosis-associated gene expression patterns were investigated to evaluate alterations in redox and iron metabolism pathways.

Results: NaB-cannabinoid combinations produced divergent biological outcomes depending on cellular background. HT-29 cells exhibited dose-dependent antiproliferative responses to NaB + CBD and NaB + CBG, with synergistic interactions observed only at selected dose combinations accompanied by increased early apoptosis. In contrast, HCT-116 cells primarily responded with cell cycle arrest and transcriptional stress signaling rather than enhanced cytotoxicity. Modulation of ferroptosis-related gene expression further indicated differential redox adaptation between the two cell models.

Conclusions: NaB-cannabinoid combinations elicit distinct biological outcomes in colorectal cancer cells that are strongly determined by cellular context. While HT-29 cells are selectively sensitized to combination dose level, HCT-116 cells predominantly respond through cell cycle arrest and adaptive stress-response pathway activation. These findings emphasize the necessity of context-aware combination strategies and provide a mechanistic framework for the further development of boron-cannabinoid-based therapeutic approaches in colorectal cancer.”

https://pubmed.ncbi.nlm.nih.gov/42796493

“In conclusion, our findings indicate that co-treatment with NaB and phytocannabinoids provides a cell line-specific therapeutic strategy in colorectal cancer.”

https://www.mdpi.com/1420-3049/31/18/3206

Use of Purified Cannabidiol in Treatment-Resistant Pediatric Epilepsy: Beyond Lennox-Gastaut Syndrome, Dravet Syndrome, and Tuberous Sclerosis Complex

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Purified cannabidiol may help a much broader range of children with treatment-resistant epilepsy than the three syndromes for which it is currently FDA-approved. In this real-world study of 144 pediatric patients, 63 had epilepsy diagnoses outside Lennox–Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex.

The response rate was nearly identical between the groups. At least a 50% reduction in seizure frequency was documented in 65% of children with an FDA-labeled diagnosis and 63% of those with other forms of epilepsy. The median age when CBD was started was 10 years, and patients were already taking a median of three other antiseizure medications.

The authors concluded that purified CBD was effective across a broad range of treatment-resistant pediatric epilepsies and was generally well tolerated as an add-on antiseizure medication. They specifically state that CBD may be considered in pharmacoresistant pediatric epilepsy beyond its currently labeled indications.

“Background: The pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex) is approved by the the US Food and Drug Administration for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis in patients one year of age and older. Among the large volume of drug-resistant cases treated at pediatric Level 4 Epilepsy Centers, many patients fall outside of these categories but are still prescribed CBD for off label use. This study sought to characterize the real-world experience with CBD of a large single pediatric comprehensive epilepsy center and to compare response to CBD within and outside of its FDA-approved indications.

Methods: A retrospective chart review was performed of patients with a prescription for CBD at our institution between January 2020 and January 2022, excluding patients who were previously included in our center’s 2019 analysis. Patients were not included in the analysis if initially prescribed CBD elsewhere, follow-up was outside our institution, medication was not started, patient expired during the study period, or diagnostic data was not available. Between-group differences were assessed via Wilcoxon rank-sum and Fisher exact tests, as appropriate.

Results: Of 223 patients with a CBD prescription during the study period, 144 patients had sufficient data available for review. Of these patients, 81 (56%) carried diagnoses of Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis, and 63 (44%) carried other diagnoses outside of FDA-labeled indications. Median (interquartile range) age at initiation was 10.0 years (5.0, 13.0), and median (interquartile range) number of concurrent anti-seizure medications was 3.0 (2.0, 3.0). There was no significant difference in the proportion of patients treated concurrently with vagus nerve stimulation or ketogenic diet between the two groups. The FDA-labeled (63%) group had a significantly higher proportion of patients with tonic seizures compared to the non-FDA labeled (29%) group (P < 0.001), otherwise there were no significant differences in baseline seizure types. Overall, 53 patients (65%) in the FDA-labeled group and 40 (63%) of the non-FDA labeled group had a documented responder rate at least 50% on CBD (P = 0.9). The most common side effects reported were nausea/diarrhea/gastrointestinal upset (19%), agitation (7.6%), insomnia (4.9%), weight loss (6.3%), and secretions/drooling (2.8%, seen only in patients on concurrent clobazam).

Conclusions: Among our cohort of treatment-resistant pediatric epilepsy, purified CBD was efficacious in a broad range of pediatric epilepsies and was well tolerated as an adjunctive anti-seizure medication. This medication may be considered in pharmacoresistant pediatric epilepsies in conditions beyond its FDA-labeled indications.”

https://pubmed.ncbi.nlm.nih.gov/42753320

https://www.pedneur.com/article/S0887-8994(26)00274-2/abstract

Exploring the potential benefits of combining cannabidiol and beta-caryophyllene for neuropathic and inflammatory pain: A systematic review

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A new systematic review found that combining cannabidiol (CBD) with beta-caryophyllene (BCP) consistently reduced neuropathic and inflammatory pain in preclinical studies. The review searched research published from 2009 through 2026 and identified five studies that met its inclusion criteria, all using rodent pain models.

Across those studies, the CBD–BCP combination reduced both neuropathic and inflammatory pain, with the authors describing evidence of a possible synergistic analgesic effect. Importantly, the reported pain relief was not accompanied by the central adverse effects associated with cannabinoid receptor 1 (CB1) activation.

The authors concluded that CBD and beta-caryophyllene may work together synergistically in chronic pain and said the findings provide a rationale for future preclinical and clinical studies. Because the evidence so far is entirely preclinical, the next step is determining whether the same combination can produce meaningful pain relief in people.

“Purpose: In this review, we examined the analgesic effect of the combination of cannabidiol (CBD) and beta-caryophyllene (BCP) in different pain conditions.

Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Literature searches were performed across major academic databases (Google Scholar, Web of Science, and PubMed) from 2009 to 2026 to identify studies investigating the analgesic effect of the combination of CBD and BCP.

Results: The search identified 31 records. Ten reports were screened and assessed for eligibility, and five studies met the inclusion and exclusion criteria. Findings consistently demonstrate that the combination of CBD and BCP reduces neuropathic and inflammatory pain in rodent models. This effect does not result in adverse outcomes associated with cannabinoid receptor 1 (CB1). This review discusses potential mechanisms by which this combination produces synergistic analgesic effects.

Conclusion: The literature discussed in this review suggests that the combination of CBD and BCP can work in synergy in chronic pain without cannabinoid receptor 1 central side effects. These preclinical findings provide the rationale for future preclinical and clinical studies.”

https://pubmed.ncbi.nlm.nih.gov/42753475

“In summary, these data suggest that combining CBD and BCP may be especially effective in reducing neuropathic pain caused by spinal cord injury. Additionally, this combination resulted in minimal cannabinoid-like side effects.”

https://www.sciencedirect.com/science/article/pii/S0944711326010287?via%3Dihub

Effect of solvent polarity on phenolic antioxidant extraction from Cannabis sativa L. leaves and inflorescences: mixture design optimization and HPLC-DAD/ESI-MS2 profiling

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A new 2026 study shows that how cannabis is extracted can dramatically change which beneficial compounds are recovered. Researchers tested water, ethanol and acetone mixtures on Cannabis sativa leaves and inflorescences and found that solvent composition significantly affected total phenolics, cannabinoids and antioxidant activity.

Inflorescences produced their highest total phenolic content — 16.05 mg GAE/g dry weight — with an acetone-rich mixture, while leaves reached 13.65 mg GAE/g with one-third ethanol and two-thirds acetone. Chemical profiling identified 32 compounds, including phenolic acids, flavonoids, hydroxycinnamic acid amides, lignanamides and cannabinoid derivatives.

The extracts also showed notable antioxidant activity across DPPH, ABTS, FRAP, CUPRAC and TAC assays. The authors concluded that cannabis leaves and flowers may be valuable targeted sources of antioxidant phytochemicals for pharmaceutical, nutraceutical and cosmetic applications.

“Cannabis (Cannabis sativa L.) is a source of bioactive compounds with promising applications in the nutraceutical, pharmaceutical, and cosmetic fields.

Applying a mixture design approach with three solvents (water, acetone and ethanol), this study investigated how solvent composition modulates the recovery of phenolic compounds from cannabis inflorescences and leaves. Extracts were assessed for total phenolic content (TPC) and antioxidant activities using DPPH, ABTS, FRAP, CUPRAC, and TAC assays, and their chemical profiles were characterized by HPLC-DAD/ESI-MS2.

Solvent composition significantly affected extraction efficiency across plant organs. For inflorescences, the highest TPC value (16.05 mg GAE per g dry weight) was obtained with an acetone-enriched mixture (1/6 water-1/6 ethanol-2/3 acetone), whereas leaves reached their maximum (13.65 mg GAE per g DW) with 1/3 ethanol-2/3 acetone.

Multi-response optimization identified 1/3 water-1/3 ethanol-1/3 acetone for inflorescences and 50% water-30% ethanol-20% acetone for leaves as the optimal solvent mixtures.

HPLC-DAD/ESI-MS2 analysis identified 32 compounds belonging to several classes, including phenolic acids, flavonoids, hydroxycinnamic acid amides, lignanamides, and cannabinoid derivatives. These classes showed diverse content depending on the solvent and plant matrix. The acetone rich mixture produced the highest total cannabinoids (10.56 and 8.45 mg CBN equivalents per g dry weight) for inflorescences and leaves, respectively.

These results reveal clear organ and solvent-dependent selectivity in Moroccan Cannabis. These differences were reflected in the antioxidant activities, with extracts showing notable reducing and radical-scavenging capacities across DPPH, ABTS, FRAP, CUPRAC, and TAC assays.

These findings support the targeted valorization of cannabis leaves and inflorescences as sources of antioxidant phytochemicals for pharmaceutical and cosmetic applications.”

https://pubmed.ncbi.nlm.nih.gov/42751042

“The chemical diversity of Cannabis sativa metabolites has stimulated extensive research into their extraction and characterization. In this study, water, ethanol, and acetone were combined to enhance the extraction of phenolic compounds and antioxidants from Cannabis sativa L. leaves and inflorescences.

Multi-response optimization showed that each plant matrix required a specific optimal solvent mixture, confirming matrix-dependent extraction behavior: 1/3 water–1/3 acetone–1/3 ethanol for inflorescences and 50% water–30% ethanol–20% acetone for leaves. HPLC-DAD/ESI-MS2 enabled the tentative identification of several compound classes, including cannabinoids, hydroxycinnamic acid amides, flavonoids, and lignanamides. Inflorescences were characterized by higher total cannabinoid contents, whereas leaves contained higher levels of hydroxycinnamic acid amides. These differences highlight both the importance of solvent selection and the distinct chemical composition of Cannabis sativa L. organs.

Overall, these results support the potential valorization of the optimized Cannabis sativa leaf and inflorescence extracts as sources of antioxidant and bioactive compounds for prospective applications in natural cosmetic formulations, such as antioxidant creams, serums or other topical skincare products, as well as in nutraceutical formulations, including functional supplements enriched with plant-derived antioxidants. However, additional studies on formulation stability, bioavailability, efficacy, and safety are required before practical application.”

https://pubs.rsc.org/ra/article/doi/10.1039/d6ra05874d/1356587/Effect-of-solvent-polarity-on-phenolic-antioxidant

Standardized Curcuma longa-Cannabis sativa extract derived from a traditional Thai formulation for psoriasis: anti-inflammatory activity, keratinocyte modulation, and skin-targeted delivery

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A new study tested a standardized combination of Curcuma longa (turmeric) and Cannabis sativa derived from a traditional Thai topical formulation for psoriasis. The combined extract contained curcuminoids, ar-turmerone and cannabidiol, including 35.47 mg/g CBD, and was evaluated for anti-inflammatory activity, effects on psoriasis-related keratinocytes and its ability to remain concentrated in the skin.

At 12.5 µg/mL, the combined extract reduced nitric oxide production by 48.97% and PGE₂ production by 91.15%. It also altered psoriasis-associated gene expression in TNF-α/IL-17A-stimulated keratinocytes, showing activity against several biological processes involved in psoriasis.

The skin-delivery experiments found strong deposition of the extract’s markers in the skin, with none detected in the receptor compartment during the 24-hour test. The authors concluded that the standardized turmeric–cannabis combination showed anti-inflammatory, psoriasis-relevant and skin-targeted activity supporting further development as a localized phytotherapeutic approach for psoriasis.

“Ethnopharmacological relevance: Curcuma longa rhizomes and Cannabis sativa leaves are traditionally combined in Thai topical remedies using cottonseed oil. However, the pharmacological basis and dermal delivery of this combination remain unclear.

Aim of the study: This study evaluated a standardized Thai CL-CS combined extract (CLCS) by integrating phytochemical characterization, psoriasis-relevant biological activities, and ex vivo skin deposition and permeation, with comparison to the single extracts.

Materials and methods: CLCS was standardized by validated HPLC using curcuminoids, ar-turmerone, and cannabidiol as markers. Anti-inflammatory activity was evaluated in RAW264.7 macrophages, while psoriasis-relevant activity was assessed in TNF-α/IL-17A-stimulated HaCaT keratinocytes. Skin deposition and permeation were evaluated using porcine ear skin and Franz diffusion cells.

Results: CLCS contained bisdemethoxycurcumin (18.79 ± 1.54 mg/g), demethoxycurcumin (12.89 ± 1.02 mg/g), curcumin (22.12 ± 1.62 mg/g), ar-turmerone (75.35 ± 3.94 mg/g), and cannabidiol (35.47 ± 2.39 mg/g). IC50 values were 41.22 ± 1.70 and 22.91 ± 0.51 μg/mL in HaCaT and RAW264.7 cells, respectively. At 12.5 μg/mL, CLCS inhibited NO and PGE2 production by 48.97 ± 0.88% and 91.15 ± 3.66%, respectively, and modulated psoriasis-associated genes. Cottonseed oil containing 20% DG achieved the highest skin deposition of BCM, DCM, and CM, with no detectable markers in the receptor compartment over 24 h.

Conclusions: Standardized CLCS exhibited anti-inflammatory and psoriasis-relevant activities and preferential skin deposition, supporting its potential as a localized phytotherapeutic approach for psoriasis.”

https://pubmed.ncbi.nlm.nih.gov/42772617

“The present study provides an integrated chemical, biological, and skin-targeted delivery evaluation of a standardized CLCS co-extract derived from a traditional Thai topical formulation. The extract was successfully standardized by its characteristic bioactive constituents derived from both botanical components. CLCS demonstrated anti-inflammatory and psoriasis-relevant biological activities”

https://www.sciencedirect.com/science/article/abs/pii/S0378874126012833?via%3Dihub