Author Archives: David

α-Glucosidase Inhibitors from the Leaves of Cannabis sativa: Structure-Activity Relationship, Kinetic Investigation, and Molecular Docking

Posted on by
Reply
pubmed logo

“Cannabis sativa L. is a valuable agricultural crop, extensively utilized in various fields and comprising diverse chemical constituents. In preliminary experiments for rat intestinal α-glucosidase inhibition, the methanolic extract of Cannabis sativa demonstrated potential for inhibiting maltase and sucrase. Bioassay-guided isolation led to 30 metabolites, including five new cannabinoids (1, 2, 3, 4, 30) and four new spiroindans (5, 6, 10, 11). Their structures were elucidated using spectroscopic techniques such as NMR, and absolute configurations were determined by Mosher’s method. Cannabinoids were the main contributors to inhibitory potency (IC50: 0.09-0.8 mM), while spiroindans and simple phenolics showed lower activity (IC50: 1.0-2.2 mM). 8-Hydroxycannabinol (18) was the most potent inhibitor retarding the enzymes through a noncompetitive mechanism. Molecular dynamics simulations of compounds 15 and 18 showed that hydrogen bonding between phenolic hydroxyl groups and specific amino acid residues at the allosteric site was essential for strong α-glucosidase binding.”

https://pubmed.ncbi.nlm.nih.gov/40788893/

“Cannabis sativa L., a member of the Cannabaceae family derived from Western Asia, has been grown for centuries for food, fiber, and medicine.”

“This study reveals that the leaves of Cannabis sativa are a prolific source of α-glucosidase inhibitors with cannabinoids, particularly cannabinol derivatives exhibiting the most pronounced bioactivity.

Among 30 isolated compounds, 8-hydroxycannabinol demonstrated the strongest inhibitory effect, outperforming other cannabinoids through an uncompetitive inhibition mechanism. Structure–activity relationship analysis indicated that additional phenolic hydroxyl groups and extended aromatic rings substantially enhance inhibitory potency.

Molecular docking and molecular dynamics simulations confirmed that active cannabinol derivatives bind stably to an allosteric site on the α-glucosidase enzyme, supported by favorable binding energies and consistent hydrophobic interactions. However, the limited structural diversity of the isolated compounds restricts the full elucidation of SAR trends, underscoring the need for broader analog libraries.

These findings not only highlight the therapeutic potential of C. sativa leaf cannabinoids as natural antidiabetic agents but also lay a foundation for future research. In particular, the semisynthesis of novel cannabinol derivatives via rational modifications such as halogenation or esterification represents a promising strategy to enhance α-glucosidase inhibitory activity and to systematically probe the structure–activity relationship of this pharmacophore class.”

https://pubs.acs.org/doi/10.1021/acs.jafc.5c08443

“Alpha-glucosidase inhibitors are a class of medications used to treat type 2 diabetes by slowing down the digestion and absorption of carbohydrates from the small intestine.”

Lifetime Cannabis Use and Incident Hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Posted on by
Reply
pubmed logo

“Background: Observational evidence investigating associations between cannabis use and hypertension is inconsistent.

Methods: The association between cumulative lifetime cannabis use (cannabis-years) and incident hypertension was examined over 35 years in a sample of CARDIA study (Coronary Artery Risk Development in Young Adults) participants free of hypertension at baseline. Marginal structural models with inverse probability weighting were used to adjust for potential time-dependent confounding and censoring. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression. Sensitivity analyses included modeling cannabis-years using restricted cubic splines, stratifying the primary analyses by sex, race, alcohol and cigarette smoking, and evaluating an additional exposure measure (days of use in the past month).

Results: The analytic sample consisted of 4328 participants at baseline and 64.9% (n=2810) at year 35. Median cannabis-years increased minimally and remained low across visits: 0.0 (Q1-Q3, 0.0-0.3) at baseline and 0.2 (Q1-Q3, 0.0-0.7) by year 35. There were 2478 cases of incident hypertension over 88 292 person-years (28.1 cases per 1000 person-years). Cannabis-years were not significantly associated with incident hypertension (adjusted hazard ratio, 0.99 [95% CI, 0.97-1.00]; P=0.18). The association remained unchanged in sensitivity analyses.

Conclusions: In a cohort of Black and White young adults with 35 years of follow-up, no association was found between cumulative lifetime use of cannabis and risk of incident hypertension. This finding was robust to restricted cubic spline analyses, analyses stratified by sex, race, alcohol use and tobacco cigarette smoking, and an additional measure of exposure (days of use in the past month).”

https://pubmed.ncbi.nlm.nih.gov/40785536/

“No association was found between cumulative lifetime use of cannabis, measured as cannabis-years, and incident hypertension over 35 years of follow-up in a cohort of relatively young Black and White adults free of hypertension at baseline. This finding was consistent across sensitivity analyses, including post hoc RCS analyses, analyses stratified by sex, race, alcohol use, and tobacco cigarette smoking, and an alternative measure of cannabis exposure (days of use in the past month).”

“Our findings suggest that cannabis use, even when accumulated over decades, may not independently elevate hypertension risk.”

https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.125.25005

Opioid reduction in patients with chronic non-cancer pain undergoing treatment with medicinal cannabis

Posted on by
Reply
pubmed logo

“Introduction: Opioid sparing by co-prescription of cannabinoids may enable patients to reduce their opioid consumption prescribed for chronic benign pain.

Methods: One cohort attending a small private pain clinic (N = 102), already taking opioids, was co-prescribed cannabinoids and another cohort (N = 53) attending a separate pain clinic nearby received only opioids. The two groups were studied prospectively for a year before their drug consumption was assessed.

Results: At baseline, median opioid consumption was 40 mg/day in both cohorts. Medicinal cannabis was administered daily in an oil formulation usually starting at 2.5 mg/day and was titrated to maximize benefits. At 12 months, the median dose contained 15 mg delta-9-tetrahydrocannabinol and 15 mg cannabidiol. At one-year follow-up, 46 of 102 cases had dropped out compared with only one of 53 controls. Opioid consumption had decreased significantly at one-year follow-up, the final median dose being lower in cases (2.7 mg/day) than controls (42.3 mg/day) (p < 0.05 in an intention-to-treat analysis). Disability and insomnia had also decreased in cases.

Conclusion: The introduction of cannabinoids can produce useful reductions in opioid consumption in real-world settings, with additional benefits for disability and insomnia. However, this treatment is tolerated by only a subgroup of patients.”

https://pubmed.ncbi.nlm.nih.gov/40788193/

“Plain language summary

Morphine-like drugs (opioids) decrease pain but can cause severe breathing problems and death if these drugs are consumed in excessive amounts. Stopping these drugs suddenly (going “cold turkey”) can cause severe adverse effects and, as time goes on, increasing amounts may be required to reduce pain. It might be possible to reduce opioid consumption by also taking medicinal cannabis; otherwise, reduction can be difficult to achieve. Cannabis treatment is safe when the hallucinatory component of cannabis is kept to low levels, causing minimal euphoric effects (a “stoned” sensation).In this study, two groups of patients with chronic pain were studied. Both were taking opioid drugs, but one group also took medicinal cannabis. About half of the medicinal cannabis group were not able to keep taking it due to unpleasant side effects. In the remainder, opioid consumption decreased significantly after both 6 and 12 months. Physical activity and sleep also improved. These findings indicate that medicinal cannabis can help patients to reduce their opioid consumption and improve their physical activity and sleep.”

“These findings indicate that medicinal cannabis can help patients to reduce their opioid consumption and improve their physical activity and sleep.”

https://www.tandfonline.com/doi/full/10.1080/17581869.2025.2544511

Local release of fibroblast growth factor 21 and cannabidiol promoting spinal cord nerve injury repair through activation of cannabinoid receptor 2

Posted on by
Reply
pubmed logo

“Spinal cord injury (SCI) is a debilitating condition that leads to severe motor and sensory dysfunction, largely due to inflammation, neuronal damage, and disrupted neural circuits.

In this study, we developed an injectable hydrogel (C/F/Gel) co-loaded with fibroblast growth factor 21 (FGF21) and cannabidiol micelles (CBDm) to enhance SCI repair. The hydrogel, composed of PF127 and α-cyclodextrin (α-CD), provides sustained drug release and improves drug stability at the injury site.

Our findings demonstrate that C/F/Gel effectively modulates the inflammatory microenvironment by promoting microglial polarization toward the anti-inflammatory M2 phenotype via cannabinoid receptor 2 (CB2R) activation.

Additionally, it regulates the balance between excitatory and inhibitory neurons, and significantly improves motor function in SCI mice. Behavioral assessments, histological analysis, and molecular studies confirmed the superior therapeutic efficacy of C/F/Gel compared to single-agent treatments.

These results highlight C/F/Gel as a promising biomaterial-based strategy for SCI repair, offering a synergistic approach that integrates inflammation modulation, neuroprotection, and functional recovery.”

https://pubmed.ncbi.nlm.nih.gov/40782447/

“Our study shows that the developed C/F/Gel is a promising therapeutic strategy for SCI repair, offering a multi-faceted approach through controlled drug release, inflammation modulation, neural regeneration, and motor function recovery. The synergy between FGF21 and CBDm, particularly via CB2R activation, highlights a novel mechanistic pathway for SCI treatment.”

https://www.sciencedirect.com/science/article/abs/pii/S0142961225005289?via%3Dihub

Medical cannabis for the management of pain in chronic pancreatitis with recurrent exacerbations: a case report

Posted on by
Reply
pubmed logo

“Introduction: Control of pain in patients affected by chronic pancreatitis with recurrent exacerbations is a challenging condition, with conventional therapies often providing limited relief. This case report describes the use of medical cannabis as a novel approach in a patient with refractory chronic pancreatitis, contributing to the growing interest in alternative treatments for pain and inflammation in similar complex cases.

Case presentation: A 54-year-old woman with a 24-year history of chronic pancreatitis caused by recurrent acute pancreatitis presented with persistent, severe abdominal pain and recurrent exacerbations despite undergoing numerous conventional interventions, including cholecystectomy, enzyme supplementation, repeated endoscopic retrograde cholangiopancreatographies (ERCPs), and stent placements. Imaging and laboratory findings confirmed chronic pancreatitis, with evidence of Oddi sphincter stenosis and microlithiasis. The patient was initially managed with standard pain relief therapy, digestive enzymes, and endoscopic interventions, all of which failed to provide lasting relief. In February 2024, she began treatment with a medical cannabis formulation rich in Cannabidiol, under the supervision of her healthcare provider. This intervention led to substantial pain reduction, cessation of acute episodes, improved appetite, and enhanced quality of life.

Conclusion: This case illustrates that medical cannabis may offer a promising alternative for managing chronic pancreatitis, especially when conventional treatments prove ineffective. This outcome underscores the need for further research on cannabinoids as a therapeutic option in chronic pain and inflammation management for pancreatitis and other challenging conditions.”

https://pubmed.ncbi.nlm.nih.gov/40781340/

“This case illustrates the potential of medical cannabis as an effective treatment option for chronic, treatment-resistant pancreatitis, a condition notoriously difficult to manage with conventional therapies. The patient’s experience demonstrates how cannabinoids can provide substantial pain relief, reduce inflammation, and improve quality of life, even when standard interventions fail to yield lasting benefits. Her case underscores the importance of exploring alternative therapies for complex, chronic conditions like pancreatitis, suggesting that medical cannabis may offer a transformative option for patients with few viable treatment paths.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00303-w

Recent Advances in the Therapeutic Potential of Cannabinoids Against Gliomas: A Systematic Review (2022-2025)

Posted on by
Reply
pubmed logo

“Glioma is the most common and lethal primary brain tumor in adults, with glioblastoma (GBM) representing the most aggressive subtype, characterized by diffuse infiltration, resistance to therapy, and a poor prognosis. Despite standard treatments, survival remains only approximately 14 months.

Cannabinoids have been increasingly investigated for their therapeutic potential in gliomas, particularly GBM. Although multiple reviews on this field of research have been published, most are current only up to 2022. This systematic review aims to provide an updated summary of studies published between 2022 and 2025, capturing recent developments in anti-glioma mechanisms, combinational strategies, immune modulation, and novel therapeutic platforms.

Following PRISMA guidelines, PubMed, Scopus, ScienceDirect, and SpringerLink were searched for original English-language journal articles published between January 2022 and February 2025, using search terms related to cannabinoids and brain cancer. From 1031 records, 45 original research articles were included after removing duplicates, non-primary studies, and irrelevant topics. The studies were categorized into seven thematic domains based on content.

Recent studies have elaborated on the anti-cancer mechanisms of cannabinoids beyond endocannabinoid signaling via the CB1/CB2 receptor, including ferroptosis induction, mitochondrial dysfunction, integrated stress response activation, and epigenetic modulation. Synthetic cannabinoids and their analogs demonstrated enhanced blood-brain barrier penetration and cytotoxicity in glioma models.

Cannabinoids have been shown to modulate immune responses in glioma, influencing T cell infiltration, myeloid suppressor cell recruitment, and tumor-associated macrophage function. Novel formulation and delivery strategies have improved cannabinoid solubility, stability, and tumor targeting. Combination therapies, particularly cannabidiol with temozolomide or radiotherapy, exhibited additive or synergistic anti-tumor effects, although variability between glioma subtypes suggests the need for personalized approaches.

Although cannabinoid-based glioma research has expanded our understanding of the mechanisms, discrepancies between preclinical findings and clinical data highlight the need for rigorous clinical trials and mechanistic research before cannabinoid-based treatments can be reliably integrated into standard glioma care.”

https://pubmed.ncbi.nlm.nih.gov/40781861/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.70160

Changes in Local Community Spatial Trends of Motor Vehicle Accidents Near Cannabis Dispensaries after Recreational Cannabis Legalization

Posted on by
Reply
pubmed logo

“Introduction: In recent years, the impact of recreational cannabis legalization (RCL) on road safety and motor vehicle accidents (MVAs) has become a growing area of research, given increasing cannabis legalization and the impact of cannabis on motor control and attention. In 2023, Connecticut legalized recreational cannabis, and this study explored changes in MVAs both in a statewide analysis and in the local vicinity of recreational cannabis dispensaries. 

Materials and Methods: We conducted an ecological study to assess the impact of recreational cannabis dispensaries on MVAs in Connecticut after legalization on January 10, 2023. Using crash data from Connecticut and Maryland (as a control) for two 24-week periods before and after legalization, we performed a difference-in-differences analysis with negative binomial regression, controlling confounders. At the dispensary level, we compared MVAs within an 800-m radius 8 weeks before and after opening, employing interrupted time series analysis with negative binomial mixed-effects regression models. 

Results: In the statewide analysis comparing Connecticut with Maryland over two 24-week periods before and after RCL in Connecticut, no significant effect on MVAs was found after adjusting for autocorrelation and seasonal variations (interaction term coefficient = -0.0391, p = 0.0696). In the local analysis, examining accident rates within an 800-m radius of 13 dispensaries over 8 weeks before and after their openings, the negative binomial mixed-effects model showed no significant change (incidence rate ratio = 1.10, 95% confidence interval: 0.74-1.64, p = 0.63). 

Discussion: These findings suggest that cannabis legalization and dispensary openings did not significantly impact motor vehicle accident rates during the study period.”

https://pubmed.ncbi.nlm.nih.gov/40779507/

Clinically Meaningful Reduction in Drop Seizures in Patients with Lennox-Gastaut Syndrome Treated with Cannabidiol: Post Hoc Analysis of Phase 3 Clinical Trials

Posted on by
Reply
pubmed logo

“Background and objective: In clinical trials of patients with Lennox-Gastaut syndrome (LGS), a ≥ 50% reduction in drop seizure frequency is generally accepted as a key endpoint. However, smaller reductions (< 50%) may yet be impactful for patients in real-world settings. This exploratory analysis evaluated the threshold for a clinically important response in drop seizures that is associated with the Caregiver Global Impression of Change (CGIC) scale score in patients with LGS treated with cannabidiol (CBD) oral solution and assessed the suitability of CGIC as an anchor for meaningful change.

Methods: This exploratory post hoc analysis included patients with LGS (N = 215, age 2-55 years) receiving CBD (Epidiolex® [USA]/Epidyolex® [EU]; 100 mg/mL oral solution) in two phase 3 randomized placebo-controlled trials (NCT02224690, April-October 2015, and NCT02224560, June- December 2015). Reduction in drop seizures (involving sudden loss of muscle tone) was anchored to CGIC scores of “slightly improved” or better or “much improved” or better, to determine the threshold at which seizure reduction can be considered clinically meaningful to patients. Spearman’s correlation indicated suitability of anchors (absolute value ≥ 0.30 deemed appropriate).

Results: In the 215 patients receiving CBD with a CGIC score recorded, CGIC was “slightly improved” or better in 60% of patients, and “much improved” or better in 31% after 14 weeks of treatment. With a CGIC rating of “slightly improved” or better, the best threshold for a clinically important response in drop seizure reduction was – 30.6% (57.7% of patients). Mean and median percentage reductions in drop seizures were – 46.9% and – 58.6%, respectively. Using “much improved” or better, the best threshold was – 49.6% (40.5% of patients). Mean and median percentage reductions in drop seizures were – 57.6% and – 66.0%, respectively. Spearman’s correlation was 0.47.

Conclusion: Anchoring to CGIC of “slightly improved” or better, the threshold for a clinically meaningful reduction in drop seizure frequency was 31%, suggesting that a 50% cutoff may overlook patients with meaningful improvements in their overall condition, as perceived by their caregivers. CGIC scores, although potentially less nuanced than other standardized clinical assessments, were appropriate anchors to determine thresholds. This exploratory analysis may help contextualize clinical trial data to better understand potential patient benefit attained by reductions in drop seizure frequency observed in real-world settings that are < 50%.”

https://pubmed.ncbi.nlm.nih.gov/40775196/

https://link.springer.com/article/10.1007/s40263-025-01201-8

Hybrid Cannabis sativa L. inflorescences exert an anti-inflammatory effect through the modulation of MAPK/NF-κB/NLRP3 inflammasome and JAK1/STAT6 pathway in HaCaT cells

Posted on by
Reply
pubmed logo

“Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching. Reducing mediators of skin inflammation and itching is crucial for the treatment of AD. Cannabis sativa L. contains many types of cannabinoids and flavonoids, which exhibit antioxidant and anti-inflammatory effects. This study aims to demonstrate the anti-inflammatory and anti-atopic dermatitis effects of hybrid C. sativa L. inflorescence extracts (HCIE) in human keratinocytes.

Methods: Cannabis sativa extracts were analyzed using UPLC. Gene expression levels in HCIE-treated HaCaT cells were measured by RT-PCR, and intracellular ROS were evaluated using DCF-DA. Protein expression levels related to MAPK, NF-κB, NLRP3 inflammasome, and JAK1/STAT6 pathways were determined by immunoblotting.

Results: The UPLC analysis revealed that a total of 8 cannabinoids were detected in HCIE. Among the cannabinoids identified in HCIE, CBDA and CBD were the most abundant, collectively accounting for approximately 28% of the total extract. The gene expression of MDC, RANTES, and TARC exhibited dose-dependent suppression in the HCIE-treated group. MAPK phosphorylation was inhibited in the HCIE-treated group. Additionally, NF-kB, p-NF-kB, NLRP3, and caspase-1 were reduced in a dose-dependent manner by HCIE. The activation of JAK1 and STAT6 was diminished in HaCaT cells treated with HCIE. Conversely, the levels of filaggrin and involucrin were significantly elevated in the HCIE-treated group compared to the control group.

Conclusion: Taken together, HCIE suppresses inflammation mediators through the regulation of the MAPK/NF-κB/NLRP3 inflammasome and JAK1/STAT6 pathways, while up-regulating skin moisturizing factors in keratinocytes. These results suggest that HCIE may be utilized in the treatment of skin inflammatory diseases, such as AD.”

https://pubmed.ncbi.nlm.nih.gov/40777996/

“HCIE exerts anti-inflammatory and anti-atopic dermatitis effects in human keratinocytes by modulating the MAPK/NF-κB/NLRP3 inflammasome, JAK1/STAT6 pathway, and skin moisturizing factors. To further elucidate the effects of HCIE on AD, additional studies using in vivo models are required. Nevertheless, considering the effects of HCIE proven in this study, HCIE is a valuable substance for improving skin inflammation, potentially serving as an effective therapeutic agent or adjuvant for AD.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1617180/full

Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging

Posted on by
Reply
pubmed logo

“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.

Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.

Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.

Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.

While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40770774/

“Targeting the ECS could be a promising strategy for developing therapies aimed at promoting healthy aging and longevity.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00313-8