Comparative Analysis of Polyphenolic Profile and Chemopreventive Potential of Hemp Sprouts, Leaves, and Flowers of the Sofia Variety

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“This study investigates the phytochemical composition and biological activities of hemp (Cannabis sativa L.) leaves, flowers’ methanolic extracts from the Sofia variety, and its sprouts cultivated under different light conditions (natural light, darkness, blue, and white LED light for 5, 7, and 9 days).

Phytochemical analysis using HPLC identified four key polyphenolic compounds in sprouts’ extracts: chlorogenic, caffeic, and gallic acids, and myricetin, with a predomination of the chlorogenic acid. In contrast, leaves and flowers’ extracts contained cannflavins A and B and chlorogenic, p-coumaric, and ferulic acids, with a significant presence of isochlorogenic acid. Antioxidant capacity, assessed by FRAP method, revealed higher antioxidant potential in leaves compared to flowers and sprouts, with sprouts grown under blue and white LED lights exhibiting the highest activity.

Cytotoxic activity was evaluated on human colon cancer cell lines (HT29, HCT116, DLD-1) and normal colon epithelial cells (CCD 841 CoN).

Results demonstrated significant and selective cytotoxicity against cancer cell lines, with leaves showing more pronounced effects than flowers, and sprouts only moderate activity. All samples revealed an anti-inflammatory effect in vitro.

To conclude, sprouts, leaves, and flowers of the Sofia hemp may be considered promising products for chemoprevention in the future.”

https://pubmed.ncbi.nlm.nih.gov/39124141/

“Cannabis sativa L. is a species of Asian origin that has been cultivated since ancient times for commercial, nutritional, and medicinal purposes.

The results indicate the interesting chemopreventive potential of sprouts, leaves, and flowers from Sofia hemp variety, manifested as cytotoxic, antioxidant, and anti-inflammatory activity.”

https://www.mdpi.com/2223-7747/13/15/2023

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson’s Disease

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“The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson’s disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.”

https://pubmed.ncbi.nlm.nih.gov/39126088/

“The above indicates the undoubted therapeutic potential of the modulation of the ECS in PD . In recent decades, the ECS has attracted considerable interest as a potential therapeutic target for numerous disorders of the nervous system. Since PD is, clinically, a very polymorphic condition with a variety of motor and non-motor manifestations, it is a useful kind of “model” for assessing the multidimensional action of ECS modulators and is an adequate object for studying the cellular and molecular mechanisms of their action.

Cannabinoids and endocannabinoids hold promise as disease modifiers for the prevention or treatment of neurodegenerative diseases. Experimental and clinical experiences of using ECS modulators in PD and other neurodegenerative diseases create a basis for further intensive therapeutic studies of cannabis and its derivatives in chronic neurodegeneration.”

https://www.mdpi.com/1422-0067/25/15/8520

Development of Delivery Systems with Prebiotic and Neuroprotective Potential of Industrial-Grade Cannabis sativa L

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“This study delves into the transformative effects of supercritical carbon dioxide (scCO2) cannabis extracts and prebiotic substances (dextran, inulin, trehalose) on gut bacteria, coupled with a focus on neuroprotection.

Extracts derived from the Białobrzeska variety of Cannabis sativa, utilising supercritical fluid extraction (SFE), resulted in notable cannabinoid concentrations (cannabidiol (CBD): 6.675 ± 0.166; tetrahydrocannabinol (THC): 0.180 ± 0.006; cannabigerol (CBG): 0.434 ± 0.014; cannabichromene (CBC): 0.490 ± 0.017; cannabinol (CBN): 1.696 ± 0.047 mg/gD). The assessment encompassed antioxidant activity via four in vitro assays and neuroprotective effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract boasting the highest cannabinoid content exhibited remarkable antioxidant potential and significant inhibitory activity against both enzymes. Further investigation into prebiotic deliveries revealed their proficiency in fostering the growth of beneficial gut bacteria while maintaining antioxidant and neuroprotective functionalities.

This study sheds light on the active compounds present in the Białobrzeska variety, showcasing their therapeutic potential within prebiotic systems. Notably, the antioxidant, neuroprotective, and prebiotic properties observed underscore the promising therapeutic applications of these extracts.

The results offer valuable insights for potential interventions in antioxidant, neuroprotective, and prebiotic domains. In addition, subsequent analyses of cannabinoid concentrations post-cultivation revealed nuanced changes, emphasising the need for further exploration into the dynamic interactions between cannabinoids and the gut microbiota.”

https://pubmed.ncbi.nlm.nih.gov/39124978/

https://www.mdpi.com/1420-3049/29/15/3574

THC vapor inhalation attenuates hyperalgesia in rats using a chronic inflammatory pain model

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“Humans use cannabinoid drugs to alleviate pain.

As cannabis and cannabinoids are legalized in the U.S. for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain.

Here, we tested the effects of repeated THC vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (i.e., treated with Complete Freund’s Adjuvant [CFA]).

We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA, and also reduces mechanical hypersensitivity in CFA males but not females. Many of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure.

We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor (CB1) agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the CB1 inverse agonist AM251 (1mg/kg; i.p.) blocks the anti-hyperalgesic effects of THC vapor in males and females.

These data provide a foundation for future work that will explore the cells and circuits underlying the anti-hyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain.

PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.”

https://pubmed.ncbi.nlm.nih.gov/39121915/

https://www.jpain.org/article/S1526-5900(24)00599-6/abstract

Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response

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“Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood.

The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization.

This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.”

https://pubmed.ncbi.nlm.nih.gov/39120997/

“In conclusion, our study offers evidence for the involvement of CNR1 and CNR2 dysregulation in EM pathogenesis. Through an integrative analysis of transcriptomic profiles, immune cell dynamics, and spatial relationships within EM lesions from mice, we unveil the intricate interactions between ECS, immune responses, and cellular changes in EM. By identifying potential mechanisms through which ECS disruption could impact EM, our research provides a foundation for the development of targeted therapies addressing the ECS’s influence on EM. These findings will advance our understanding of EM and lead to innovative therapeutic strategies to manage this complex disorder.”

https://elifesciences.org/articles/96523

Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis

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“Background: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it.

Objective: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways.

Findings: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases.

Conclusion: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.”

https://pubmed.ncbi.nlm.nih.gov/39110084/

“So far, the exact mechanism of endometriosis is not fully understood. However, this phenomenon is known as a chronic inflammatory condition accompanied with angiogenesis. Herein, we reviewed the inflammatory aspects of this disease with an eye on angiogenesis. As we showed, the molecular pathways of angiogenesis and inflammation have a lot in common. Thus, it seems that targeting inflammation could be considered hitting two birds with one stone. Considering the potent anti-inflammatory and antiangiogenic effects of CBD under various other conditions, authors suggest in vitro and in vivo studies on CBD and endometriosis.”

https://onlinelibrary.wiley.com/doi/10.1002/iid3.1370

In Silico Approach for Assessment of the Anti-tumor Potential of Cannabinoid Compounds by Targeting Glucose-6-phosphate Dehydrogenase Enzyme

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“Glucose-6-phosphate dehydrogenase (G6PD) is a pentose phosphate pathway (PPP) enzyme that generates NADPH, which is required for cellular redox equilibrium and reductive biosynthesis.

It has been demonstrated that abnormal G6PD activation promotes cancer cell proliferation and metastasis. To date, no G6PD inhibitor has passed clinical testing successfully enough to be launched as a medicine. As a result, in this investigation, cannabinoids were chosen to evaluate their anticancer potential by targeting G6PD.

Molecular docking indicated that three molecules, Tetrahydrocannabinolic acid (THCA), Cannabichromenic acid (CBCA), and tetrahydrocannabivarin (THCV), have the highest binding affinities for G6PD of -8.61, – 8.39, and 8.01 Kcal/mol. ADMET analysis found that all of them were safe prospective drug candidates. Molecular dynamics (MD) simulation and MM-PBSA analysis confirm the structural compactness and lower conformational variation of protein-ligand complexes, thereby maintaining structural stability and rigidity.

Thus, our in silico investigation exhibited all three cannabinoids as potential competitive inhibitors of G6PD.”

https://pubmed.ncbi.nlm.nih.gov/39109709/

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202401338

Effects of ∆-9 tetrahydrocannabinol on the small intestine altered by high fructose diet: A Histopathological study

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“The consumption of fructose is increasing day by day. Understanding the impact of increasing fructose consumption on the small intestine is crucial since the small intestine processes fructose into glucose.

∆9-Tetrahydrocannabinol (THC), a key cannabinoid, interacts with CB1 and CB2 receptors in the gastrointestinal tract, potentially mitigating inflammation. Therefore, this study aimed to investigate the effects of the high-fructose diet (HFD) on the jejunum of rats and the role of THC consumption in reversing these effects.

Experiments were conducted on Sprague-Dawley rats, with the experimental groups as follows: control (C), HFD, THC, and HFD + THC. The HFD group received a 10% fructose solution in drinking water for 12 weeks. THC groups were administered 1.5 mg/kg/day of THC intraperitoneally for the last four weeks. Following sacrification, the jejunum was evaluated for mucus secretion capacity. IL-6, JNK, CB2 and PCNA expressions were assessed through immunohistochemical analysis and the ultrastructural alterations via transmission electron microscopy.

The results showed that fructose consumption did not cause weight gain but triggered inflammation in the jejunum, disrupted the cell proliferation balance, and increased mucus secretion in rats. Conversely, THC treatment displayed suppressed inflammation and improved cell proliferation balance caused by HFD. Ultrastructural examinations showed that the zonula occludens structures deteriorated in the HFD group, along with desmosome shrinkage. Mitochondria were found to be increased due to THC application following HFD.

In conclusion, the findings of this research reveal the therapeutic potential of THC in reversing HFD-related alterations and provide valuable insights for clinical application.”

https://pubmed.ncbi.nlm.nih.gov/39110194/

“Plant-derived cannabinoids and their synthetic analogs could be used medically. It is thought that THC could be used to prevent or reverse the effects of possible ultrastructural epithelial barrier damage caused by an HFD. In conclusion, our results show that high fructose consumption causes inflammation in the jejunum, increases mucus production, and disrupts the balance of cell proliferation. It has been determined that THC application is efficient in reversing these effects. In this context, new findings have been presented that THC can be a candidate as a therapeutic agent.”

https://link.springer.com/article/10.1007/s00418-024-02311-y

Regulation of cannabinoid and opioid receptor levels by endogenous and pharmacological chaperones

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“Cannabinoid and opioid receptor activities can be modulated by a variety of posttranslational mechanisms including the formation of interacting complexes.

This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB1 receptor (CB1R), delta opioid receptor (DOR), and CB1R-DOR interacting complexes.

Focussing on endogenous protein chaperones namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared to other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB1R, DOR, and CB1R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones.

Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of Cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord.

Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB1R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking. 

Significance Statement This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of CB1R, DOR, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.”

https://pubmed.ncbi.nlm.nih.gov/39103231/

https://jpet.aspetjournals.org/content/early/2024/08/05/jpet.124.002187

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

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“Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products.

In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies.

Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.”

https://pubmed.ncbi.nlm.nih.gov/39096481/

https://link.springer.com/article/10.1007/s40122-024-00643-0