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Cannabidiol Enhances SIRT1 and Autophagy for the Maintenance of Human Mesenchymal Stem Cells

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“Background/aim: Mesenchymal stem cells (MSCs) are used to treat various degenerative diseases. However, their therapeutic potential is limited by cellular aging during in vitro cultivation. This study aimed to explore whether cannabidiol (CBD) can delay MSC aging by enhancing the expression of Sirtuin 1 (SIRT1) and autophagy, two key anti-aging regulators.

Materials and methods: CBD, the most important non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant, was used to up-regulate SIRT1 and autophagy in order to maintain MSC stemness. MSCs were treated with CBD and assessed for cell viability, doubling time, key gene/protein expression, relative senescence-associated β-galactosidase (SA-β-gal) assay, relative telomere length, and telomerase expression.

Results: CBD significantly increased the expression of SIRT1 and autophagy-related markers in MSCs. Furthermore, CBD preserved MSC stemness by promoting the deacetylation of SRY-box transcription factor 2 (SOX2) through SIRT1, and delayed cellular senescence by enhancing autophagy, reducing SA-β-gal activity, maintaining proliferation capacity, and supporting telomere function.

Conclusion: CBD promotes MSC stemness and delays cellular senescence, potentially through the activation of SIRT1 and autophagy. These findings suggest that CBD may serve as a promising agent for preserving MSC function in regenerative medicine.”

https://pubmed.ncbi.nlm.nih.gov/41482390

“Cannabidiol (CBD) is the major non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant. Numerous studies have demonstrated its broad pharmacological effects, including antidepressant, anti-inflammatory, antiemetic, neuroprotective, analgesic, antibacterial, anticonvulsant, anxiolytic, antipsychotic, antitumor, and immunomodulatory activities. Recently, CBD has been shown to extend lifespan and improve health span in various models”

“This study demonstrates that an optimal concentration of CBD enhances MSC proliferation and promotes SIRT1 activation, thereby inducing autophagy and maintaining stemness through the regulation of SOX2. Moreover, CBD was found to delay cellular senescence and preserve replicative potential in MSCs. Collectively, these findings highlight CBD as a promising modulatory agent for improving MSC longevity and therapeutic quality, with potential implications for regenerative and anti-aging applications.”

https://iv.iiarjournals.org/content/40/1/222

Phytocannabinoids as anti-inflammatory agents: Synergistic effects when combined with Cannabis sativa matrices

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“Ethnopharmacological relevance: Cannabis sativa L. has a long history of traditional use for the treatment of pain and inflammatory disorders in both Asian and European medical systems, which supports its investigation as a source of bioactive compounds with potential relevance for chronic immune-mediated diseases.

Aim of the study: This study evaluated the ten major non-psychotropic phytocannabinoids for their anti-inflammatory and antioxidant activities, and for synergistic interactions with non-cannabinoid matrices derived from the same plant (polar, non-polar and terpenoid).

Material and methods: Anti-inflammatory effects were assessed in macrophage-differentiated THP-1 cells by measuring pro-inflammatory cytokine production (ELISA) and nuclear factor kappa B (NF-κB) pathway activation (luciferase reporter assay).

Results: All tested phytocannabinoids demonstrated anti-inflammatory effects, in particular, cannabidivarin (CBDV) reduced IL-6, TNF-α production and also inhibited NF-κB activation. Several phytocannabinoids, especially their acidic forms, exhibited high oxygen radical absorption capacity (ORAC), but none showed significant cellular antioxidant activity (CAA), possibly due to limited bioavailability. Importantly, several phytocannabinoid-matrix mixtures displayed synergistic anti-inflammatory effects, with combinations containing cannabigerol (CBG) or cannabinol (CBN) being particularly potent.

Conclusion: These findings highlight the potential of lesser-known phytocannabinoids, especially in combination with specific C. sativa L. matrix components, to modulate inflammatory pathway supporting their development as functional ingredients for managing chronic gut-associated inflammation.”

https://pubmed.ncbi.nlm.nih.gov/41478536

“Full plant chemical complexity outperforms single phytocannabinoid alone.”

“Non-psychotropic phytocannabinoids present promising functional food ingredients.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874125018276?via%3Dihub

Extract engineering of Cannabis sativa yields novel antibacterial cannabinoids targeting Staphylococcus aureus and methicillin-resistant Staphylococcus aureus

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“Cannabis sativa is a phytochemically rich plant producing over 500 compounds, with cannabinoids recognized as its most bioactive constituents.

However, the natural exploration and exploitation of novel, pharmacologically active cannabinoids remain limited due to their trace abundance in the plant. To address this challenge, we employed an extract engineering strategy in which enriched fractions of major cannabinoids were chemically transformed through oxone/acetone oxidation under mild conditions.

This approach enabled the purification of seven cannabinoid analogs, including rare and previously undescribed compounds, in appreciable quantities. The structures of these analogs were elucidated using high-resolution mass spectrometry combined with comprehensive 1D and 2D NMR spectroscopy.

Antibacterial susceptibility assay revealed that out of seven compounds, Compound 1, 5, and 7 exerted significant inhibitory activity against both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) pathogens.

A Checkerboard study revealed the synergistic interaction between active hits and Rifampin in both S. aureus and MRSA. The biofilm-based assay demonstrated the antibiofilm potential of the identified hits. The mechanistic exploration elucidated the cell membrane-based targeting of the potent hits, validated through scanning electron microscopy. Moreover, the Propidium iodide assay performed using flow cytometry and fluorescence microscopy revealed the membrane disruption effect of the identified hits. In addition, the ATP quantification study demonstrated a major decline in ATP levels along with an augmentation in ROS production in the MRSA pathogen.

Thus, this work establishes extract engineering as a powerful strategy to unlock rare cannabinoid scaffolds and highlights their potential as leads for combating multidrug-resistant Staphylococcus infections.”

https://pubmed.ncbi.nlm.nih.gov/41478197


“Cannabis sativa has diverse phytochemical composition and therapeutic potential.”

“In summary, comprehensive antistaphylococcal evaluation of the cannabinoid-based molecules demonstrated strong antibacterial activity against both S. aureus and MRSA pathogens, along with synergistic interaction when combined with standard drugs. Notably, the potent molecules expressed low propensity for the development of resistance in the MRSA strain. Moreover, the antibiofilm action of the potent hits highlighted their curative role…”

https://www.sciencedirect.com/science/article/abs/pii/S0045206825013288?via%3Dihub

Clinical Endocannabinoid Deficiency and Cognitive Continuity: A Longitudinal Case Study Challenging the Neurodegeneration Paradigm

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“Despite expanding acceptance of cannabis for medicinal use, empirical literature remains sparse regarding the long-term mental and neurobiological outcomes of continuous cannabis exposure over several decades. This self-case study examines the psychobiological trajectory of a biomolecular psychologist who has used cannabis intermittently since the 1970s and therapeutically since 2010 to manage polypharmacy withdrawal, opioid dependence, and psychiatric symptoms. The analysis integrates self-observational data, neurocognitive assessments, pharmacological history, and psychosocial context to evaluate outcomes on affect regulation, cognitive performance, neuroplasticity, and motivation. The case challenges persistent assumptions of irreversible cannabis-induced cognitive decline and supports the hypothesis that sustained cannabinoid modulation may promote neural resilience when employed within a biomolecularly informed framework. Findings are illustrative and intended to generate testable hypotheses rather than establish causality.”

“For more than half a century, the United States has maintained one of the most comprehensive prohibitions on biological cannabinoid research in modern science. The enactment of the Controlled Substances Act in 1970 effectively silenced
the empirical study of the plant Cannabis sativa and its naturally occurring cannabinoids, leaving a void in scientific understanding that has persisted for decades. The policy was founded less on biomedical evidence than on sociopolitical ideology—a moral model of addiction that conflated psychoactivity with deviance. By classifying naturally occurring
cannabinoids as Schedule I substances, federal policy positioned them alongside heroin and LSD, asserting “no accepted medical use and a high potential for abuse”. Consequently, generations of scientists were restricted from exploring naturally occurring cannabinoids’ molecular, neurobiological, and psychopharmacological functions.”

“While modern prohibition sought to erase the plant’s legitimacy, cannabis itself represents a biological constant—molecules with 12,500 years of medicinal use, abruptly vilified in the modern era. Archaeological and historical records confirm its continuous application in treating pain, inflammation, convulsions, and psychological distress throughout diverse civilizations. Across that immense timeline, humans relied on the plant’s phytochemical complexity—its cannabinoids, terpenes, and flavonoids—to modulate physiological systems long before those systems were scientifically named.”

“The endocannabinoid system (ECS), now recognized as one of the body’s principal homeostatic regulators, mediates neural, immune, and endocrine balance. Yet its formal discovery in the 1990s came paradoxically after half a century of federally enforced ignorance.”


“From a biomolecular perspective, cannabinoids act not as foreign intruders but as complementary ligands within a preexisting molecular conversation between the human body and its endogenous signaling systems. Their therapeutic potential lies not in chemical novelty but in biological familiarity—a fact consistently reaffirmed by modern neurobiological research despite legal obstruction.”

“This five-decade longitudinal case study provides a rare and informative window into the long-term psychobiological effects of sustained botanic cannabinoid use within a cognitively demanding professional context. Contrary to prohibition-era narratives that associate chronic cannabis exposure with cognitive decline, emotional dysregulation and motivational impairment, the findings of this investigation demonstrate a trajectory of preserved neurocognitive integrity, stabilized affective functioning, and enhanced adaptive resilience. These outcomes are consistent with contemporary psychoneuroimmunological models in which the endocannabinoid system operates as a central regulator of homeostatic equilibrium across neural, immune, and endocrine domains.”

https://zealjournals.com/wjbpr/content/clinical-endocannabinoid-deficiency-and-cognitive-continuity-longitudinal-case-study

Antibacterial Effect of Cannabinoids on Bacteria Associated with Persistent Endodontic Infections

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“Cannabinoids have been shown to have effective antibacterial applications.

With the limitations of current intracanal endodontic medicaments and the rise of bacterial resistance, it is important to investigate novel treatment strategies for endodontic infections. The aim of this study was to test the antibacterial efficacy of cannabinoids on bacteria in persistent endodontic infections: Enterococcus faecalis, Streptococcus mutans, and Fusobacterium nucleatum.

Planktonic bacteria were exposed to a negative control (no exposure), a positive control (3% NaOCl), and the experimental groups Cannabidiol (CBD), Cannabinol (CBN), and Tetrahydrocannabinol (THC). The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were also investigated. Biofilms were cultured and treated with cannabinoids. A crystal violet assay (CVA) and live/dead analysis assessed the biofilm degradation and inhibition, respectively. A statistical analysis was performed using an ANOVA.

CBD, CBN, and THC reached a MIC for both E. faecalis and S. mutans in planktonic forms. The MBC was found for the tested cannabinoids on planktonic E. faecalis. No MBC was found for S. mutans. The live/dead analysis of E. faecalis and S. mutans biofilms showed a decrease in the viability of the biofilm with an increased cannabinoid concentration. The CVA revealed that cannabinoids only degrade the E. faecalis biofilm. Planktonic F. nucleatum had no MIC for tested cannabinoids.

Cannabinoids have inhibitory effects on E. faecalis and S. mutans in the planktonic and biofilm states. No inhibitory effects of F. nucleatum were found at tested concentrations of all three cannabinoids.

The findings suggest that cannabinoids have distinct antibacterial effects on certain pathogens associated with persistent endodontic infections.”

https://pubmed.ncbi.nlm.nih.gov/41465362

https://www.mdpi.com/1422-0067/26/24/11936

Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases

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“Cannabinoids, such as tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA), are bioactive and medicinally relevant compounds found in the cannabis plant (Cannabis sativa L.). These three compounds are synthesised from a single precursor, cannabigerolic acid (CBGA), through regioselective reactions catalysed by different cannabinoid oxidocyclase enzymes.

Despite the importance of cannabinoid oxidocyclases for determining cannabis chemotype and properties, the functional evolution and molecular mechanism of this enzyme family remain poorly understood. To address this gap, we combined ancestral sequence reconstruction and heterologous expression to resurrect and functionally characterise three ancestral cannabinoid oxidocyclases.

Results showed that the ability to metabolise CBGA originated in a recent ancestor of cannabis and that early cannabinoid oxidocyclases were promiscuous enzymes producing all three THCA, CBDA and CBCA. Gene duplication and diversification later facilitated enzyme subfunctionalisation, leading to extant, highly-specialised THCA and CBDA synthases. Through rational engineering of these ancestors, we designed hybrid enzymes which allowed identifying key amino acid mutations underlying the functional evolution of cannabinoid oxidocyclases. Ancestral and hybrid enzymes also displayed unique activities and proved to be easier to produce heterologously than their extant counterparts.

Overall, this study contributes to understanding the origin, evolution and molecular mechanism of cannabinoid oxidocyclases, which opens new perspectives for breeding, biotechnological and medicinal applications.”

https://pubmed.ncbi.nlm.nih.gov/41454532

“Cannabinoids are specialised metabolites produced by the plant Cannabis sativa L. (cannabis).”

https://onlinelibrary.wiley.com/doi/10.1111/pbi.70475

Cannabigerol Exerts In Vivo and In Vitro Anti-Inflammatory Effects via Inhibition of the MAPK and NF-κB Pathways

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“Cannabis sativa L. has a long history of use and contains more than 80 cannabinoids. However, although cannabigerol (CBG), which acts as a biosynthetic precursor of its most abundant phytocannabinoids, has anti-inflammatory effects, the exact mechanism of action remains underexplored.

In this study, we explored the anti-inflammatory potential of CBG to assess its potential for therapeutic and industrial applications.

CBG was extracted from the cannabis cultivar ‘Pink Pepper’ In vitro assays were performed via RAW 264.7 mouse macrophages stimulated with lipopolysaccharide, and in vivo efficacy was evaluated through a carrageenan-induced paw edema mouse model to confirm the activity of CBG in acute inflammation.

Nitric oxide production, mRNA, and protein expression of inflammatory mediators were suppressed by CBG treatment in a process downregulated through the MAPK and NF-κB pathways. Although paw edema was not statistically significantly reduced, oral administration of CBG suppressed the expression of COX-2, iNOS, TNF-α, IL-1β, and IL-6 in the carrageenan-induced mouse model.

CBG has been demonstrated to exert significant anti-inflammatory effects via modulation of key inflammatory mediators and signaling pathways in both in vivo and in vitro models.

Our findings further support the potential of CBG as a bioactive compound for further anti-inflammatory research.”

https://pubmed.ncbi.nlm.nih.gov/41423277

https://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.2509.09034

Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

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“Ethnopharmacological relevance: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.

Objective: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.

Methods: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD’s protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.”

https://pubmed.ncbi.nlm.nih.gov/41419044

“The natural plant extract cannabidiol (CBD) attenuates acute liver injury.”

“Cannabis sativa L. (family Cannabaceae) is a valuable natural plant resource that has been used as a folk medicine since ancient times.”

https://www.sciencedirect.com/science/article/abs/pii/S037887412501760X?via%3Dihub

Changes in sleep quality during the 12 months following medical cannabis initiation

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“Background: Poor sleep quality is a commonly reported reason for medical cannabis (MC) use, yet evidence regarding its long-term impact on sleep remains limited. This study evaluated changes in subjective sleep quality over a 12-month period among adults initiating MC treatment in Pennsylvania and explored whether preferred route of administration and referring condition were associated with observed changes.

Methods: A total of 137 adults newly referred for MC in PA completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and at 3, 6, 9, and 12 months. Linear mixed effects models assessed changes in PSQI global and subscale scores over time. Additional models evaluated whether preferred administration route (oral vs. other) and referring condition (chronic pain, anxiety, PTSD) were associated with differences in observed outcomes.

Results: Global sleep quality scores, where higher values indicate poorer sleep quality, were significantly higher at baseline than at each follow-up point (p < .0001), with no significant differences among follow-up assessments, suggesting early and sustained improvements in self-reported sleep quality. Improvements were observed across all PSQI subscales. No significant relationships were found between sleep quality scores and either administration route or referring condition.

Conclusions: These findings suggest that MC may be associated with improvements in subjective sleep quality, though its impact did not vary as a function of administration route or primary referring condition. Additional research using objective sleep measures and controlled designs is needed to clarify MC’s role in sleep quality.”

https://pubmed.ncbi.nlm.nih.gov/41422305

https://link.springer.com/article/10.1186/s42238-025-00376-7

Letters From the Field: Challenges and Opportunities in the Development of Botanical Drugs From Cannabis

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“Cannabis and cannabis-derived products (CCDPs) have gained recognition for their therapeutic potential, driving legal and social shifts worldwide. In the United States, state-level medical cannabis programs exist alongside the federal drug development framework, which remains the gold standard for ensuring safety and efficacy.

The Food and Drug Administration (FDA) botanical drug development guidance provides a structured approval pathway for plant-derived products, including CCDPs, accounting for their unique chemical complexity. Despite this guidance, significant gaps persist in preclinical and clinical data, particularly for minor cannabinoids.

Development of botanical drugs from cannabis is further complicated by regulatory oversight from the Drug Enforcement Administration, which constrains the cultivation, handling, and distribution of cannabis and imposes logistical and security requirements during drug development.

This article discusses the unique experience of drug developers navigating the scientific and regulatory challenges inherent in advancing CCDPs toward FDA drug approval. Collaborative efforts among federally compliant drug developers, regulatory bodies, healthcare providers, academic institutions, investors, and patients/patient advocacy groups are critical to generate rigorous, reproducible evidence to support the safe and effective use of CCDPs in medical conditions where they hold the greatest therapeutic potential. Such partnerships can advance studies that elucidate cannabinoid pharmacology, optimize dosing with rigorously characterized materials via clinically relevant routes, and identify clinical outcomes that are meaningful to patients.

Advancing CCDPs through federally compliant drug development pathways will enable the translation of promising botanical therapies into safe, effective, and evidence-based treatments, ultimately informing clinical practice and benefiting patients.”

https://pubmed.ncbi.nlm.nih.gov/41421888

https://www.clinicaltherapeutics.com/article/S0149-2918(25)00407-2/abstract