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

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“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

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“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

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

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“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/

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

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“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

Cannabidiol exerts anti-inflammatory effects but maintains T effector memory cell differentiation: A Single-Cell Study in Humans

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“Cannabidiol is widely available and often used for pain management.

Individuals with kidney disease or renal allografts have limited analgesia options. We conducted a Phase 1 human study to compare the peripheral immune cell distribution before (pre-cannabidiol) and after exposure to cannabidiol at steady state (post-cannabidiol).

This ex vivo study included specimens from 23 participants who received oral cannabidiol (up to 5 mg/kg twice daily) for 11 days. Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus. Pharmacodynamic responses were assessed via CellTiter-Glo® proliferation, scRNA-seq, cytokine assays, and flow cytometry. Steady-state plasma concentrations of CBD were quantified via tandem mass spectrometry.

We identified an increased proportion of T effector memory (TEM) cells post-cannabidiol (22% increase, P-value of 3.2 x 10 -32 ), which correlated with CBD plasma concentrations ( Pearson Corr= 0.77, P-value < 0.01 ). Post-cannabidiol cytokine assays revealed elevated proinflammatory IL-6 protein levels and anti-inflammatory IL-10 levels ( adjusted P-values < 0.0001 ). Cannabidiol reduced overall T and B lymphocyte proliferation with additive immunosuppressive effects to tacrolimus. In flow cytometry, the proportion of TEM and TEMRA increased post-cannabidiol with tacrolimus ( P-values < 0.05 ).

Cannabidiol exhibits mixed immunomodulatory effects with pro- and anti-inflammatory signals. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations.”

https://pubmed.ncbi.nlm.nih.gov/40766582/

https://www.biorxiv.org/content/10.1101/2025.07.30.667742v1

Cannabidiol as a therapeutic agent for rosacea through simultaneous inhibition of multiple inflammatory pathways

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“Rosacea is a chronic inflammatory skin disorder characterized by facial erythema, papules, pustules, and telangiectasia, affecting approximately 5.5% of the global population. Current treatments, primarily topical and oral antibiotics and anti-inflammatories, often show limited efficacy and may cause undesirable side effects, prompting the need for alternative therapies.

Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has shown promise as a therapeutic agent for rosacea due to its anti-inflammatory, antioxidant, and anti-apoptotic properties. CBD interacts with the endocannabinoid system, which plays a crucial role in cutaneous homeostasis.

This study evaluated the efficacy of CBD, both alone and in combination with metronidazole (MET), in reducing inflammation and modulating immune responses in a rosacea-like mouse model.

Our results demonstrated that both CBD and MET significantly inhibited redness, epidermal thickness, and mast cell infiltration, with their combination being more effective. Mechanistic analyses revealed that the therapeutic effect of CBD is associated with the suppression of key inflammatory regulators in the MAPK signaling pathway, particularly the ERK, JNK, and p38 pathways. CBD treatment also led to a significant reduction in proinflammatory cytokines and chemokines, indicating immune modulation.

These findings suggest that CBD, especially in combination with MET, may represent a novel therapeutic option for rosacea and offer a scientific basis for its clinical application in managing inflammatory skin conditions.”

https://pubmed.ncbi.nlm.nih.gov/40754776/

Is hemp (Cannabis sativa) safe to feed pregnant sheep?

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“Cannabis sativa (varieties for industrial use or animal feed are termed hemp), and its extracted byproducts are being considered for animal feed due to their high protein content. However, if hemp disrupts fertility and reproduction in livestock, it should not be used as a feed source.

We hypothesized that the phytocannabinoids in hemp would disrupt fertility and reproduction, cause craniofacial defects (cyclops, cleft palate, misshapen head), and low birth weight in lambs. To test this hypothesis, 22 timed pregnant ewes were dosed with hemp in the form of dried ground hemp plant material at 150 mg/kg body weight per day total cannabinoids, and from gestational days 10 to 20 and a separate 22 timed pregnant ewes were dosed similarly with dried ground grass hay as a control.

The most prevalent cannabinoids in the plant material were cannabidiolic acid (CBDA) at a concentration of 23.2 mg/g, and cannabidiol (CBD) at a concentration of 5.8 mg/g. Delta 9-tetrahydrocannabidiol was present in the plant material at a concentration of 0.3 mg/g. The hemp used in this study had crude protein concentrations of 15.6%, neutral detergent fiber concentrations of 42.2%, and in vitro true digestibility concentrations of 83.6%.

After 10 d of dosing with hemp, a serum sample was obtained from each of the ewes, CBDA was measured at a concentration of 652 ± 38 ng/mL and CBD was measured at 16 ± 0.9 ng/mL. THC was not detected in the serum. The average gestation length for lambs from the hemp treated ewes was 148 ± 0.38 d, and the average gestation length for lambs from the grass hay treated ewes was 149 ± 0.38 d (P = 0.23). The numbers of male and female lambs did not significantly vary from expected (50:50) (P = 0.32). There were no significant fetal deformities (P > 0.05) or weight differences between the treatment groups (P > 0.05), and as expected, the lamb weights significantly increased over time (P < 0.05).

These results suggest that Cannabis sativa may have the potential with further research to be a suitable protein source for gestating sheep.”

https://pubmed.ncbi.nlm.nih.gov/40756673/

“Cannabis sativa L. is a plant of many uses.”

“The study data suggests that hemp, or its byproducts, may be a suitable feed source for sheep, including pregnant ewes.”

https://academic.oup.com/tas/article/doi/10.1093/tas/txaf093/8211445?login=false

Will you precrastinate? Sensitivity to potential performance costs and effort in chronic cannabis users and non-users

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“We examined whether those who chronically use cannabis (chronic users), compared to those who do not use cannabis (non-users), tend to precrastinate (start or complete a subgoal as soon as possible) and engage in reactive (vs. proactive) decision-making incurring greater potential costs in task performance and perhaps costs in cognitive and physical effort. Participants walked down a hallway and retrieved two full cups of water (one near and one far from their starting position) in the order of their choice and carried both back to their start location with the goal of not spilling. First-cup choice (near or far) and attributions of first-cup choice were recorded.

Counter to expectations, chronic users tended to choose the far cup first (i.e., avoided precrastination), the more efficient choice, and this tendency was not different from non-users. Participants’ attributions confirmed that those who chose the far cup first likely engaged in proactive decision-making while those who chose the near cup first likely engaged in reactive decision-making. Additionally, chronic users and non-users utilized proactive control in the AX-Continuous Performance Task even though chronic users had lower short-term and working memory span scores.

These results contradict research suggesting chronic users (vs. non-users) are more impulsive, lack inhibitory control, tend to invest physical effort regardless of reward, and tend not to invest cognitive effort for reward. We suggest that chronic cannabis use may not impair decision making as profoundly as previously thought if individuals are motivated by potential consequences of their decisions in tasks with low memory demand.”

https://pubmed.ncbi.nlm.nih.gov/40760056/

https://link.springer.com/article/10.1007/s00426-025-02139-8

Expanding the Therapeutic Profile of Topical Cannabidiol in Temporomandibular Disorders: Effects on Sleep Quality and Migraine Disability in Patients with Bruxism-Associated Muscle Pain

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“Background: Cannabidiol (CBD) has demonstrated potential as a therapeutic agent for muscle tension, pain, and sleep bruxism, yet its broader impact on comorbid conditions such as sleep disturbance and migraine disability remains underexplored. This study aimed to assess the effects of topical CBD on sleep quality and migraine-related disability in patients with bruxism-associated muscular pain. 

Methods: In a randomized, double-blind clinical trial, 60 participants with bruxism were allocated equally into three groups: control (placebo gel), 5% CBD gel, and 10% CBD gel. Participants applied the gel intraorally to the masseter muscles nightly for 30 days. Sleep quality and migraine-related disability were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Migraine Disability Assessment Scale (MIDAS), respectively. Surface electromyography (sEMG) and the Bruxoff® device were used for objective evaluation of muscle tension and bruxism intensity. 

Results: Both CBD treatment groups demonstrated statistically significant improvements in PSQI and MIDAS scores compared to the control group (p < 0.001). No significant differences were observed between the 5% and 10% CBD groups, suggesting comparable efficacy. The sEMG findings corroborated a reduction in muscle tension. Improvements in sleep and migraine outcomes were positively correlated with reductions in muscle activity and pain. 

Conclusions: Topical CBD gel significantly improved sleep quality and reduced migraine-related disability in patients with bruxism-associated muscular pain, supporting its role as a multifaceted therapeutic option in the management of TMD and related comorbidities. Further research is needed to confirm long-term benefits and determine optimal dosing strategies.”

https://pubmed.ncbi.nlm.nih.gov/40732351/

“This study demonstrates that topical application of cannabidiol (CBD) gel, at both 5% and 10% concentrations, significantly improves sleep quality and reduces migraine-related disability in patients with bruxism-associated muscular pain. These effects were observed alongside reductions in muscle tension and pain, suggesting a broader therapeutic impact of CBD beyond localized symptom relief. Notably, no substantial differences were found between the two concentrations, indicating that lower doses may achieve comparable clinical outcomes.

The findings support the use of topical CBD as a well-tolerated, non-invasive adjunct in the multimodal management of temporomandibular disorders (TMD), especially in patients experiencing comorbid sleep and headache disturbances. Future research should explore long-term efficacy, optimal dosing, and underlying mechanisms through objective neurophysiological and sleep assessments”

https://www.mdpi.com/1424-8247/18/7/1064

The impact of cannabis use on ageing and longevity: a systematic review of research insights

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“With aging emerging as a global challenge linked to chronic diseases, identifying interventions that support a healthy lifespan and health span has become imperative. Cannabinoids derived from cannabis, particularly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), have gained attention for their potential to promote healthy aging through interactions with the endocannabinoid system. While CBD has often been highlighted for its benefits, emerging evidence indicates that THC, under certain conditions and doses, may also play a therapeutic role in aging. Despite this interest, significant knowledge gaps persist in understanding cannabis’s role in promoting healthy aging and longevity.Aim

We reviewed recent literature to investigate the effect of cannabinoid use, particularly CBD and THC on aging and longevity. By synthesizing findings from preclinical models, clinical studies, and real-world evidence, we aimed to elucidate the potential of cannabinoids, in fostering healthy aging, mitigate age-related decline, and promote well-being in older populations.Method

We conducted a systematic review guided by PRISMA to investigate the impact of cannabinoids on aging and longevity. Studies involving preclinical models (e.g., Caenorhabditis elegans, rodents, zebrafish, and mice) and clinical populations aged 50 years and older were included. Exclusion criteria targeted acute effects and mechanisms of action in different medical conditions. Aging was explicitly defined as biological and psychological changes associated with advancing age, and longevity was defined as the extension of lifespan and factors influencing healthy aging.Findings

Eighteen studies investigating the direct impact of cannabinoids on aging and longevity were identified in preclinical models (11) and human studies (7). Preclinical studies have shown promising results regarding the potential benefits of cannabinoids including improved lifespan, cognitive function, inflammation, memory, sleep quality, and social interaction. The effects of THC appear more complex, with potential benefits at low doses and drawbacks at higher doses, highlighting their complex role in aging. However, the limited number of human studies hinders a comprehensive understanding. Clinical studies also suggest potential therapeutic applications for cannabinoids in aging populations, although further research is needed to understand their mechanisms of action and long-term effects fully.”

Conclusion

“Cannabinoids hold promise for supporting healthy aging and enhancing the quality of life in older populations. While preliminary research suggests intriguing possibilities, more studies are needed to solidify the link between cannabis use, the ECS, and healthy aging in humans. Rigorous clinical trials are crucial to evaluate their safety and efficacy. Longitudinal studies and well-designed clinical trials are critical to understanding the safety, efficacy, and long-term effects of cannabis use in aging populations. Future research should optimize dosages, investigate mechanisms of action, and explore the influence of cannabis use initiated in aging as opposed to lifetime exposure. Clarifying these aspects is vital for informing public health strategies and developing targeted therapeutic interventions for age-related conditions.”

“These findings open exciting avenues for exploring novel therapeutic interventions for age-related cognitive decline and neurological disorders.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00267-x

https://pubmed.ncbi.nlm.nih.gov/40731362/