A pharmacological roadmap for the Cannabaceae family: Prioritizing the therapeutic potential of neglected genera beyond Cannabis and Humulus

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“The Cannabaceae family presents a significant paradox in modern pharmacology; it is simultaneously one of the most intensely researched and most profoundly neglected plant families. The immense scientific, cultural, and economic significance of Cannabis and Humulus has cast a long shadow, obscuring the potential of the family’s other nine genera.

This paper provides the first comprehensive synthesis of the available ethnobotanical, phytochemical, and pharmacological data across all 11 genera to systematically expose this research disparity. It argues that genera such as Trema, Celtis, and Aphananthe, which possess a rich history of use in traditional medicine, represent an underexplored frontier for discovering novel, safer, and non-psychoactive therapeutics.

These genera are rich in flavonoids, polyphenols, triterpenoids, and alkaloids, offering alternatives to THC-based medicines and their associated adverse effects. By juxtaposing the well-characterized pharmacology of Cannabis and Humulus with the nascent data and vast potential of their relatives, this analysis reveals critical knowledge gaps and opportunity costs.

Ultimately, this report presents a strategic roadmap for future research, outlining a multidisciplinary approach and a prioritization model to guide the scientific community.

The aim is to rebalance research priorities and unlock the full medicinal promise of the entire Cannabaceae family, bridging the gap between traditional wisdom and modern drug discovery.”

https://pubmed.ncbi.nlm.nih.gov/41946416

https://www.sciencedirect.com/science/article/abs/pii/S0367326X26001486?via%3Dihub

Dynamic Mechanism for Subtype Selectivity of Endocannabinoids

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“Endocannabinoids are naturally occurring lipid-like molecules that bind to cannabinoid receptors (CB1 and CB2) and regulate many of human bodily functions via the endocannabinoid system.

There is a tremendous interest in developing selective drugs that target the CB receptors.

However, the biophysical mechanisms responsible for the subtype selectivity for endocannabinoids have not been established. Recent experimental structures of CB receptors show that endocannabinoids potentially bind via membrane using the lipid access channel in the transmembrane region of the receptors. Furthermore, the N-terminus of the receptor could move in and out of the binding pocket thereby modulating both the pocket volume and its residue composition.

On the basis of these observations, we propose two hypotheses to explain the selectivity of the endocannabinoid, anandamide for CB1 receptor. First, the selectivity arises from distinct enthalpic ligand-protein interactions along the ligand binding pathway formed due to the movement of N-terminus and subsequent shifts in the binding pocket composition. Second, selectivity arises from the volumetric differences in the binding pocket allowing for differences in ligand conformational entropy.

To quantitatively test these hypotheses, we perform extensive molecular dynamics simulations (∼0.9 milliseconds) along with Markov state modeling and deep learning-based VAMPnets to provide an interpretable characterization of the anandamide binding process to cannabinoid receptors and explain its selectivity for CB1.

Our findings reveal that the distinct N-terminus positions along lipid access channels between TM1 and TM7 lead to different binding mechanisms and interactions between anandamide and the binding pocket residues. To validate the critical stabilizing interactions along the binding pathway, relative free energy calculations of anandamide analogs are used. Moreover, the larger CB2 pocket volume increases the entropic effects of ligand binding by allowing higher ligand fluctuations but reduced stable interactions. Therefore, the opposing enthalpy and entropy effects between the receptors shape the endocannabinoid selectivity.

Overall, the CB1 selectivity of anandamide is explained by the dominant enthalpy contributions due to ligand-protein interactions in stable binding poses. This study shed lights on potential selectivity mechanisms for endocannabinoids that would aid in the discovery of CB selective drugs.”

https://pubmed.ncbi.nlm.nih.gov/41962866

“By situating these results within the broader landscape of pharmacological and structural evidence, we provide a cohesive mechanistic framework for endocannabinoid selectivity that can inform the rational design of CB1-selective therapeutics.”

https://www.jbc.org/article/S0021-9258(26)00304-2/fulltext

Inhibition of extracellular vesicle secretion by cannabidiol: A promising approach for oral squamous cell carcinoma therapy

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“Cannabidiol (CBD), a bioactive phytochemical derived from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and emerging antitumor properties.

Oral squamous cell carcinoma (OSCC), the most common oral cancer, remains challenging to treat due to its aggressive nature and limited therapeutic options. Extracellular vesicles (EVs) have been increasingly recognized as key mediators of tumor progression, facilitating intercellular communication, remodeling the tumor microenvironment (TME), and promoting metastasis, angiogenesis, and chemoresistance in OSCC.

This review discusses the pharmacological properties of CBD, including its bioavailability limitations, multi-target mechanisms, and potential for combination therapy. Notably, we explore the hypothesis that CBD may exert antitumor effects through modulation of EV secretion-a novel and underexplored mechanism in OSCC. Although direct evidence in OSCC models remains limited, studies in non-OSCC systems suggest that CBD influences EV biogenesis and release via pathways involving Wnt/β-catenin, STAT3 signaling, and mitochondrial calcium homeostasis.

Based on these findings, we propose a hypothetical framework linking CBD-mediated EV modulation to OSCC therapy. Despite its therapeutic promise, the clinical translation of CBD faces key hurdles, including poorly characterized mechanisms of EV regulation in OSCC, a lack of targeted delivery systems that compromises specificity and bioavailability, and a general scarcity of OSCC-specific evidence.

This review underscores the urgent need for future research to prioritize long-term evaluations, explore synergistic CBD-drug combinations, develop advanced CBD delivery systems, and assess its dual role in tumor suppression and pain management to enable clinical use.”

https://pubmed.ncbi.nlm.nih.gov/41966486

“Cannabidiol (CBD) is a non-psychoactive phytocannabinoid derived from Cannabis sativa L., characterized by low toxicity and a broad spectrum of pharmacological activities.These include antiepileptic, anti-inflammatory, neuroprotective, antiemetic, anticonvulsant, anxiolytic, antispasmodic, and anticancer effects.”

https://www.sciencedirect.com/science/article/pii/S0006295226002819?via%3Dihub

Cannabidiol and diabetic heart disease: Mechanistic evidence and translational challenges

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“Diabetic heart disease (DHD) is a major contributor to global cardiovascular morbidity, driven by a complex interplay of metabolic, inflammatory, oxidative, and fibrotic mechanisms. These interconnected pathways are not fully addressed by current cardiometabolic therapies, highlighting the need for novel multi-target interventions.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential modulator of several key processes implicated in DHD pathogenesis.

Preclinical evidence demonstrates that CBD attenuates oxidative stress by reducing reactive oxygen species (ROS) production, suppresses nuclear factor-κB (NF-κB)-mediated inflammatory signaling, preserves endothelial function by improving nitric oxide (NO) bioavailability, and inhibits transforming growth factor-β (TGF-β)-driven fibrotic remodeling.

These effects have been observed across in vitro and in vivo models of diabetic cardiomyopathy, where CBD improves both myocardial and vascular function. Mechanistically, CBD exerts its actions through negative allosteric modulation of CB₁ receptors and interaction with non-cannabinoid targets, including transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled receptor 55 (GPR55).

Despite this robust preclinical foundation, clinical evidence supporting the efficacy of CBD in DHD remains limited. Existing human studies are largely restricted to non-diabetic populations or short-term metabolic and hemodynamic outcomes, and do not address disease-specific cardiac endpoints. Furthermore, translational challenges, including variability in dosing, product standardization, and potential drug-drug interactions, remain significant barriers to clinical implementation.

Collectively, CBD represents a promising investigational candidate with multi-target potential to modulate the core pathophysiology of DHD. However, well-designed, disease-specific clinical trials are required to establish its therapeutic relevance and safety in diabetic populations.”

https://pubmed.ncbi.nlm.nih.gov/41966803

“Diabetic heart disease involves oxidative, inflammatory, and fibrotic pathways.”

“Cannabidiol (CBD) targets multiple pathological processes implicated in diabetic heart disease, including oxidative stress, inflammation, endothelial dysfunction, and fibrotic remodeling.”

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing interest due to its pleiotropic pharmacological actions across multiple molecular targets.”

https://www.sciencedirect.com/science/article/pii/S0753332226003872?via%3Dihub

Cannabidiol synergizes with methotrexate to attenuate rheumatoid arthritis via STAT3/NF-κB signalling-mediated M1 macrophage polarization

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“Background: Methotrexate (MTX) is the anchor drug for rheumatoid arthritis (RA) treatment, but its clinical application is limited by dose-dependent adverse events, such as hepatotoxicity and gastrointestinal intolerance, and incomplete efficacy in some patients. Cannabidiol (CBD) is a nonpsychotropic cannabinoid that has powerful therapeutic efficacy in alleviating pain and inflammation, as well as favourable safety and tolerability profiles. However, whether CBD can synergize with MTX to enhance therapeutic outcomes and mitigate toxicity remains unclear. This study aimed to investigate the synergistic efficacy, safety profile, and underlying molecular mechanism of the CBD-MTX combination in the treatment of RA.

Methods: Mice were randomly divided into 8 groups (n = 5 per group): a normal control group (NC), a model control group (MC), 3 MTX monotherapy groups (low/medium/high dose), and 3 CBD + MTX combination groups (low/medium/high dose). Arthritis severity was assessed by clinical scoring and micro-CT. Systemic safety was evaluated via histopathological examination of the liver, kidney, and testis. Flow cytometry, ELISA and Western blotting were used to validate the mechanisms involved. Network pharmacology and molecular docking were used to predict potential targets.

Results: Compared with MTX monotherapy, the CBD-MTX combination had dose-dependent synergistic effects, significantly attenuating joint swelling, inflammation, and bone erosion. The medium-dose combination approached the efficacy of high-dose MTX (dose-sparing effect). CBD mitigated MTX-induced testicular toxicity and spermatogenic failure. Mechanistically, the combination suppressed M1 macrophage polarization and proinflammatory cytokine (TNF-α, IL-6, and IL-1β) secretion by inhibiting STAT3 and NF-κB signalling (downregulation of p-STAT3 and p-NF-κB p65).

Conclusion: The CBD-MTX combination exerts superior antiarthritic effects by inhibiting STAT3/NF-κB-mediated M1 macrophage polarization and protecting against MTX-induced reproductive toxicity. This study provides a preclinical rationale for this novel combination strategy in RA management.”

https://pubmed.ncbi.nlm.nih.gov/41955700

“In summary, our findings identify the combination of CBD and MTX as a robust therapeutic strategy for RA management. We demonstrate that this regimen exerts synergistic antiarthritic effects by inhibiting the STAT3/NF-κB axis and suppressing M1 macrophage polarization. Importantly, CBD not only enhances MTX efficacy but also mitigates MTX-induced reproductive toxicity.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576926004728?via%3Dihub

Effect of cannabinol, tetrahydrocannabivarin and cannabidiol on voluntary alcohol consumption

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“Aims: Previous studies have demonstrated that the endocannabinoid system plays a significant role in the development of alcohol use disorder (AUD), and CB1 receptor antagonists/inverse agonists show promise as a novel AUD pharmacotherapy. However, these compounds failed in clinical trials due to the severe psychiatric side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat AUD. The aim of this study was to test the potential of three phytocannabinoids in reducing alcohol consumption: CB1 receptor partial agonist cannabinol (CBN), neutral antagonist tetrahydrocannabivarin (THCV) and negative allosteric modulator cannabidiol (CBD).

Methods: Male Wistar rats were subjected to a long-term voluntary alcohol drinking procedure that lasted for several months. Thereafter, rats were given three once daily administrations of CBN, THCV, or CBD. Their side-effect profile was examined by recording changes in water consumption, body weight and locomotor activity. Ultrasonic vocalisations were recorded in alcohol-naïve group-housed rats to monitor if treatment induced discomfort, distress, or other changes in emotional states.

Results: Our data demonstrated that all phytocannabinoids reduced voluntary alcohol consumption; however, the compounds differed in their effectiveness and side-effect profile. Treatment with CBN and THCV reduced alcohol intake and alcohol preference and had a mild sedative effect. CBD had a minor effect on alcohol consumption, did not affect alcohol preference, reduced the locomotor activity and lowered the positive emotional states of rats. None of the compounds caused discomfort or distress.

Conclusions: We conclude that CBN and THCV may have potential in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/41947574

“Cannabis plants have long been used both medicinally and recreationally, mainly due to the psychoactive compound delta9-tetrahydrocannabinol (THC, a partial agonist of the CB1 receptor). However, the health benefits of these plants may be attributable to over a hundred of other, non-psychoactive compounds or their metabolites, collectively termed phytocannabinoids.”

“In summary, the present study demonstrated that CBN and THCV were more effective in reducing the maintenance of voluntary alcohol consumption and had a better safety profile compared to CBD. The effect of all three phytocannabinoids on alcohol consumption may be related to their action on the CB1 receptor.”

https://academic.oup.com/alcalc/article/61/3/agag019/8607733

A multifunctional conductive physiomimetic scaffold: synergy of rGO coating and cannabis-derived nanotopography for infection-resistant bone repair

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“Conventional bone grafts cannot reliably fulfill the dual requirements of rapid osseoinduction and intrinsic infection-resistance to meet clinical needs. We therefore aimed to overcome this dual challenge by fabricating a novel physiomimetic three-dimensional scaffold.

This was achieved by coating the unique nano-grooved cellulosic matrix derived from Cannabis sativa leaf trichomes with reduced graphene oxide (rGO) to mimic the native osteogenic niche.

The plant-derived skeleton serves as a ready-made, topographically complex framework, while the rGO coating provides a microenvironment well suited for bone repair. Comprehensive characterization verified a measurable surface energy, hydrophilicity, roughness, and proper conductivity due to rGO coating. Moreover, in vitro examination confirmed that rGO biofunctionalization synergized with the innate nano-topography, dynamically accelerated the osteogenic differentiation of human adipose-derived stem cells. An upregulated expression of key bone markers, COL1A1, RUNX2, and OPN, sustained alkaline phosphatase activity, and augmented deposition of collagen and mineralized matrix exhibited the potential of the proposed approach for efficient osteal regeneration. An equally important finding was the scaffold’s inherent antibacterial property against Gram-positive and Gram-negative pathogens.

We demonstrated that augmenting a natural cannabis-derived nanostructure with a conductive nanomaterial coating creates a multifaceted therapeutic strategy capable of promoting bone formation and potentially antibacterial effects, addressing two critical obstacles in regenerative orthopedics.”

https://pubmed.ncbi.nlm.nih.gov/41958836

“In conclusion, the rGO-functionalized cannabis-derived scaffold offers a multifaceted therapeutic route toward bone repair, while bioinspired microenvironment is not only structurally supportive but also biologically instructive and inherently protective against microbial threats.”

https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2026.1766388/full


The iron fist of nature: Cannabinoid derivatives alter iron homeostasis and activate ferroptotic pathways in glioblastoma cells

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“Glioblastoma multiforme is the most commonly diagnosed type of brain tumor, with a poor prognosis and a high rate of recurrence. Because of its highly aggressive nature and the lack of efficient treatment options, novel therapeutic strategies are needed.

Ferroptosis is an iron-dependent, unique type of cell death, which provides an alternative way to eradicate cancer cells that are resistant to apoptosis and other cell death mechanisms.

CP55-940 (CP) and WIN 55212-2 (WIN) are synthetic cannabinoid receptor agonists with various biological activities, including neuroprotective and anticancer effects; however, their mechanism of action has not been fully uncovered.

In the present study, the potential of CP and WIN in glioblastoma cells was investigated.

Cell viability was determined with the MTT assay. Labile iron pool and reactive oxygen species generation were visualized with confocal microscopy. Malondialdehyde assay was performed to detect lipid peroxidation. Gene expressions of ferroptotic hallmarks, glutathione peroxidase-4, and transferrin receptor 1 were determined by RT-qPCR. Protein expression levels of iron-responsive element-binding protein 2, solute carrier family 7 member 11, and glutathione peroxidase-4 were analyzed by western blotting.

Results demonstrated that CP and WIN significantly induce ferroptotic pathways in glioblastoma cells via increased oxidative stress, labile iron pool, and lipid peroxidation. Furthermore, it was determined for the first time that both compounds significantly upregulate the transferrin receptor 1 gene expression.

In conclusion, the present study demonstrated for the first time that cannabinoid derivatives CP and WIN alter iron regulation and initiate ferroptosis in glioblastoma cells, rendering them potential candidates in therapy.

SIGNIFICANCE STATEMENT: We explored the ferroptotic activity of cannabinoid derivatives (CP and WIN) in glioblastoma cells for the first time. Additionally, we report for the first time that cannabinoid derivatives alter cellular iron levels, causing increased labile iron pool via upregulating the transferrin gene significantly.”

https://pubmed.ncbi.nlm.nih.gov/41962357

https://jpet.aspetjournals.org/article/S0022-3565(26)00518-5/abstract

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used as a research tool to study the endocannabinoid system.”

“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.”

Therapeutic potential of phytocannabinoids in depression and cognitive dysfunction: Evidence from preclinical models

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“Depression is a highly prevalent and incident mental illness. Current pharmacological therapies fail in approximately 30-40% of patients, highlighting the urgent need for novel agents with pleiotropic effects.

This preclinical study aimed to identify new antidepressants and cognitive modulators among five phytocannabinoids: cannabichromene, cannabidiol, cannabidivarin, cannabigerol and cannabinol.

Phytocannabinoids were first evaluated in BV-2 microglial cells for cell viability and then, for anti-inflammatory activity, where BV-2 cells were previously stimulated with lipopolysaccharide (50 ng/mL). Based on these profiles, and comparing with ketamine, cannabidiol, cannabidivarin and cannabigerol were selected to be administered (55 µmol/kg, i.p.) once to healthy CD-1 male mice, and subsequently, administered six times to mice submitted to the unpredictable chronic mild stress (UCMS) protocol, which is a validated model of depression.

Among the phytocannabinoids under investigation, cannabigerol exhibited the lowest cytotoxicity, whereas cannabidiol and cannabidivarin demonstrated the strongest anti-inflammatory effects, significantly reducing nitrite, iNOS and pro-IL1β levels. In healthy mice, only cannabigerol produced consistent antidepressant-like effects in the forced swimming test compared to ketamine. Under UCMS protocol, cannabidivarin was anxiogenic and impaired cognitive and hepatic functions. Cannabidiol, despite its favorable safety profile, failed to ameliorate depressive phenotype or cognitive deficits. Notably, cannabigerol significantly improved cognitive performance, associated with increased dendritic spine density in the hippocampus.

Overall, our unprecedented findings demonstrated that a single administration of cannabigerol ameliorates depressive-like behavior in healthy animals, while multiple administrations improved cognitive function in mice exhibiting depressive-like phenotypes.

Together, these results highlight the therapeutic potential of cannabigerol in mood and cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/41934896

“CBG has anxiolytic and antidepressant effects in healthy male CD-1 mice.”

https://www.sciencedirect.com/science/article/pii/S0753332226003318?via%3Dihub


The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives

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“Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs – including Alzheimer’s, Parkinson’s, Huntington’s diseases and multiple sclerosis – the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions.

The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes.

Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation.

In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision.

By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41937092

“These findings are particularly relevant for the development of next-generation cannabinoid therapeutics designed to selectively engage beneficial signaling pathways while minimizing adverse effects.”

https://www.sciencedirect.com/science/article/pii/S1043661826001003?via%3Dihub