Monthly Archives: June 2024

Effects of Cannabinoids on Intestinal Motility, Barrier Permeability, and Therapeutic Potential in Gastrointestinal Diseases

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“Cannabinoids and their receptors play a significant role in the regulation of gastrointestinal (GIT) peristalsis and intestinal barrier permeability. This review critically evaluates current knowledge about the mechanisms of action and biological effects of endocannabinoids and phytocannabinoids on GIT functions and the potential therapeutic applications of these compounds.

The results of ex vivo and in vivo preclinical data indicate that cannabinoids can both inhibit and stimulate gut peristalsis, depending on various factors. Endocannabinoids affect peristalsis in a cannabinoid (CB) receptor-specific manner; however, there is also an important interaction between them and the transient receptor potential cation channel subfamily V member 1 (TRPV1) system.

Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact gut motility mainly through the CB1 receptor. They were also found to improve intestinal barrier integrity, mainly through CB1 receptor stimulation but also via protein kinase A (PKA), mitogen-associated protein kinase (MAPK), and adenylyl cyclase signaling pathways, as well as by influencing the expression of tight junction (TJ) proteins.

The anti-inflammatory effects of cannabinoids in GIT disorders are postulated to occur by the lowering of inflammatory factors such as myeloperoxidase (MPO) activity and regulation of cytokine levels. In conclusion, there is a prospect of utilizing cannabinoids as components of therapy for GIT disorders.”

https://pubmed.ncbi.nlm.nih.gov/38928387/

“In summary, our narrative review highlights the complex interaction between cannabinoids and gastrointestinal physiology, shedding light on their potential therapeutic applications in the treatment of GIT diseases.

The findings highlight the diverse effects of cannabinoids on motility, intestinal permeability, and inflammation, which are mediated by interactions with endocannabinoids and cannabinoid receptors. It is noteworthy that cannabinoids such as THC and CBD exhibit receptor-specific effects on GIT motility via CB1 receptors, causing inhibition of muscle contractility, which may suggest targets for therapeutic interventions. Moreover, the involvement of CB1 and CB2 receptors in regulating intestinal permeability underscores the complexity of mechanisms mediated by cannabinoids in gastrointestinal health.

In addition, cannabinoids show promise as anti-inflammatory agents, offering potential benefits in the treatment of Crohn’s disease, ulcerative colitis, and IBD. Moreover, their role in modulating intestinal motility and relieving pain implicates cannabinoids as potential agents for improving quality of life in gastrointestinal disorders, especially chronic such as IBS. The results of clinical trials and data on the adverse effects of phytocannabinoids indicate that further research is needed to elucidate the exact mechanisms and optimize therapeutic strategies to realize the full potential of cannabinoids in clinical practice.”

https://www.mdpi.com/1422-0067/25/12/6682

Combinations of Cannabinoids with Silver Salts or Silver Nanoparticles for Synergistic Antibiotic Effects against Methicillin-Resistant Staphylococcus aureus

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“Silver has been shown to improve the antibiotic effects of other drugs against both Gram- positive and -negative bacteria. In this study, we investigated the antibiotic potential of cannabidiol (CBD), cannabichromene (CBC) and cannabigerol (CBG) and their acidic counterparts (CBDA, CBCA, CBGA) against Gram-positive bacteria and further explored the additive or synergistic effects of silver nitrate or silver nanoparticles using 96-well plate growth assays and viability (CFUs- colony-forming units).

All six cannabinoids had strong antibiotic effects against MRSA with minimal inhibitory concentrations (MICs) of 2 mg/L for CBG, CBD and CBCA; 4 mg/L for CBGA; and 8 mg/L for CBC and CBDA. Using 96-well checkerboard assays, CBC, CBG and CBGA showed full or partial synergy with silver nitrate; CBC, CBDA and CBGA were fully synergistic with silver nanoparticles against MRSA.

Using CFU assays, combinations of CBC, CBGA and CBG with either silver nitrate or silver nanoparticles, all at half or quarter MICs, demonstrated strong, time-dependent inhibition of bacterial growth (silver nitrate) and bactericidal effects (silver nanoparticles). These data will lead to further investigation into possible biomedical applications of specific cannabinoids in combination with silver salts or nanoparticles against drug-resistant Gram-positive bacteria.”

https://pubmed.ncbi.nlm.nih.gov/38927140/

“In conclusion, these studies confirm the antibiotic activity of CBG, CBC and CBD and the acidic forms of these agents against drug-resistant Gram-positive bacteria. The addition of silver, either as salts or nanoparticles, to select cannabinoids allows for much improved and, in some cases, synergistic antibiotic activity. Collectively, these findings strongly support further investigation of cannabinoid-enhanced silver preparations to assess their antimicrobial spectrum of activity and potential application in wound dressings or catheter coatings for an extended and more powerful antibiotic profile.”

https://www.mdpi.com/2079-6382/13/6/473

Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke

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“Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia.

Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential.

These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential.

On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, or stroke.

On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect.

Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.”

https://pubmed.ncbi.nlm.nih.gov/38928415/

“Phytocannabinoids not presenting psychoactive effects such as cannabidiol show an interesting potential to decrease neuroinflammation and neurodegeneration in animal models of hypoxia-ischemia, becoming a new promising therapy to improve stroke.”

https://www.mdpi.com/1422-0067/25/12/6708

Cannabidiol (CBD) Inhibits Foam Cell Formation via Regulating Cholesterol Homeostasis and Lipid Metabolism

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“Scope: The cannabidiol (CBD) in hemp oil has important pharmacological activities. Accumulating evidence suggests that CBD is beneficial in the cardiovascular system and has been applied as a health supplement for atherosclerosis. However, the mechanism remains unclear.

Methods and results: This study investigates the impact of CBD on foam cell formation, cholesterol homeostasis, and lipid metabolism in macrophages. CBD elevates the levels of peroxisome proliferator-activated receptor gamma (PPARγ) and its associated targets, such as ATP binding transporter A1/G1 (ABCA1/ABCG1), thus reducing foam cell formation, and increasing cholesterol efflux within macrophages. Notably, the upregulation of ABCA1 and ABCG1 expression induced by CBD is found to be attenuated by both a PPARγ inhibitor and PPARγ small interfering RNA (siRNA). Moreover, transfection of PPARγ siRNA results in a decrease in the inhibitory effect of CBD on foam cell formation and promotion of cholesterol efflux. Through lipidomics analysis, the study finds that CBD significantly reverses the enhancement of ceramide (Cer). Correlation analysis indicates a negative association between Cer level and the expression of ABCA1/ABCG1.

Conclusion: This study confirms that CBD can be an effective therapeutic candidate for atherosclerosis treatment by activating PPARγ, up-regulating ABCA1/ABCG1 expression, and down-regulating Cer level.”

https://pubmed.ncbi.nlm.nih.gov/38932553/

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202400154

Cannabidiol Protects against the Reinstatement of Oxycodone-Induced Conditioned Place Preference in Adolescent Male but Not Female Rats: The Role of MOR and CB1R

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“Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/kg, i.p.) induced conditioned place preference (CPP) could attenuate the reinstatement of CPP brought about by OXY (1.5 mg/kg, i.p.) priming in adolescent rats of both sexes, and whether this effect is sex dependent. Accordingly, a priming dose of OXY produced reinstatement of the previously extinguished CPP in males and females. In both sexes, this effect was linked to locomotor sensitization that was blunted by CBD pretreatments. However, CBD was able to prevent the reinstatement of OXY-induced CPP only in adolescent males and this outcome was associated with an increased cannabinoid 1 receptor (CB1R) and a decreased mu opioid receptor (MOR) expression in the prefrontal cortex (PFC). The reinstatement of CCP in females was associated with a decreased MOR expression, but no changes were detected in CB1R in the hippocampus (HIP). Moreover, CBD administration during extinction significantly potentialized the reduced MOR expression in the PFC of males and showed a tendency to potentiate the reduced MOR in the HIP of females. Additionally, CBD reversed OXY-induced deficits of recognition memory only in males. These results suggest that CBD could reduce reinstatement to OXY seeking after a period of abstinence in adolescent male but not female rats. However, more investigation is required.”

https://pubmed.ncbi.nlm.nih.gov/38928357/

“In conclusion, our findings indicate that CBD is effective in preventing OXY seeking behavior after a period of abstinence in adolescent male, but not in female rats. This effect in males appears to be due to the interaction between CB1R and MOR. Further research is needed to determine whether the lack of effect in female adolescent rats is related to gonadal hormone status, dose of CBD, or other mechanisms, such as that, for example, of CB2R. It is important to investigate the mechanisms behind these sex differences, especially since previous research has shown that CBD reduces cue-induced cravings in humans with heroin use disorder.”

https://www.mdpi.com/1422-0067/25/12/6651

Cannabinoids’ Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases

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“Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases.

The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases.

To our knowledge, few reviews are devoted to cannabinoids’ impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.”

https://pubmed.ncbi.nlm.nih.gov/38928109/

“The increasing acceptance of cannabinoids caused novel preclinical research of neurodegenerative diseases, which was collected and analyzed in this review. These studies demonstrated the neuroprotective properties of many cannabinoids through various cellular and molecular pathways in neurodegenerative diseases. The strengthening connection between the periphery and the CNS in the context of neurodegenerative diseases, together with the extensive immune activities of cannabinoids in both arenas, shows the complexity of immune modulation and the enormous therapeutic potential of cannabinoids in neurodegenerative diseases, which are very difficult to manage.”

https://www.mdpi.com/1422-0067/25/12/6402

Cannabinoids: Potential for Modulation and Enhancement When Combined with Vitamin B12 in Case of Neurodegenerative Disorders

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“The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis.

This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like Δ9-THC and CBD. Cannabinoids exert distinct regulatory effects on physiological processes, prompting their investigation in neurodegenerative diseases. Recent research highlights their potential in modulating protein aggregation and mitochondrial dysfunction, crucial factors in conditions such as Alzheimer’s Disease, multiple sclerosis, or Parkinson’s disease.

The discussion emphasizes the importance of maintaining homeodynamics in neurodegenerative disorders and explores innovative therapeutic approaches such as nanoparticles and RNA aptamers. Moreover, cannabinoids, particularly CBD, demonstrate anti-inflammatory effects through the modulation of microglial activity, offering multifaceted neuroprotection including mitigating aggregation. Additionally, the potential integration of cannabinoids with vitamin B12 presents a holistic framework for addressing neurodegeneration, considering their roles in homeodynamics and nervous system functioning including the hippocampal neurogenesis.

The potential synergistic therapeutic benefits of combining CBD with vitamin B12 underscore a promising avenue for advancing treatment strategies in neurodegenerative diseases. However, further research is imperative to fully elucidate their effects and potential applications, emphasizing the dynamic nature of this field and its potential to reshape neurodegenerative disease treatment paradigms.”

https://pubmed.ncbi.nlm.nih.gov/38931480/

“Since neurodegenerative diseases like Alzheimer’s, Parkinson’s, multiple sclerosis, Huntington’s, and amyotrophic lateral sclerosis present significant healthcare and therapeutic challenges due to not only their complex etiology or pathophysiology but symptoms severity as well, it is important to keep the attention on improving constantly effective therapeutic methods devoted to neurodegenerative diseases treatment.

Recent studies indicate cannabinoids, particularly from Cannabis sativa, to hold promise in addressing key pathological processes associated with these disorders.

Cannabinoids, especially THC and CBD, demonstrate anti-aggregative effects, modulating the endocannabinoid system and interacting with cannabinoid receptors 1 and 2, offering potential in mitigating protein aggregation seen in disorders like multiple sclerosis. They also activate CBR1, protecting against mitochondrial dysfunction, crucial in diseases disrupting energy distribution, such as demyelination.

Emerging evidence suggests that vitamin B12, essential for cellular processes, could complement therapeutic strategies, potentially enhancing the effects of CBD. Additionally, CBD shows promise in reversing locomotor changes in Parkinson’s disease independently of NPR-19 receptors, while also protecting dopaminergic neurons and reducing reactive oxygen species accumulation. Thus, the integration of nanoparticles of β-caryophyllene, a CB2R binder, as explored by Alberti et al. (2020) [4], represents potential advancement in developing therapies that improve drug BBB crossing and enhance overall treatment efficacy, moreover, accordingly, the process aimed at combining RNA aptamers with cannabinoids and vitamin B12 may offer precise targeted therapies, but rigorous testing is necessary before clinical use.

This combined approach represents a promising frontier in neurodegenerative disease treatment, highlighting ongoing research into cannabinoids’ effects and applications across various disease contexts. Understanding their interaction with mitochondrial function and cellular communication holds potential for novel therapeutic strategies. Further investigation is needed to fully grasp cannabinoids’ effects and applications in diverse disease contexts.”

https://www.mdpi.com/1424-8247/17/6/813

Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations

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“The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global COVID-19 pandemic, challenging healthcare systems worldwide. Effective therapeutic strategies against this novel coronavirus remain limited, underscoring the urgent need for innovative approaches.

The present research investigates the potential of cannabis compounds as therapeutic agents against SARS-CoV-2 through their interaction with the virus’s papain-like protease (PLpro) protein, a crucial element in viral replication and immune evasion. Computational methods, including molecular docking and molecular dynamics (MD) simulations, were employed to screen cannabis compounds against PLpro and analyze their binding mechanisms and interaction patterns.

The results showed cannabinoids with binding affinities ranging from -6.1 kcal/mol to -4.6 kcal/mol, forming interactions with PLpro. Notably, Cannabigerolic and Cannabidiolic acids exhibited strong binding contacts with critical residues in PLpro’s active region, indicating their potential as viral replication inhibitors. MD simulations revealed the dynamic behavior of cannabinoid-PLpro complexes, highlighting stable binding conformations and conformational changes over time.

These findings shed light on the mechanisms underlying cannabis interaction with SARS-CoV-2 PLpro, aiding in the rational design of antiviral therapies. Future research will focus on experimental validation, optimizing binding affinity and selectivity, and preclinical assessments to develop effective treatments against COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/38932170/

“In summary, targeting PLpro with cannabinoids offers a promising approach for inhibiting viral replication, attenuating pathogenicity, and enhancing therapeutic outcomes in the fight against COVID-19 and other viral infections.”

https://www.mdpi.com/1999-4915/16/6/878

The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth

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“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia. 

Methods: We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture. 

Results: Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir® Medium dried flowers (NC1) and Cannabixir® THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48 h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24 h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values. 

Discussion and Conclusion: Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/38933665/

“Our study paves the way for the benefits of either synthetic cannabinoids or phytocannabinoids for the palliation of chemotherapy-induced peripheral neuropathy.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1395951/full

Cheungsam Seed Husk Extract Reduces Skin Inflammation through Regulation of Inflammatory Mediator in TNF-α/IFN-γ-Induced HaCaT Cells

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“Cannabis contains numerous natural components and has several effects such as anticancer, anti-inflammatory and antioxidant.

Cheungsam is a variety of non-drug-type hemp, developed in Korea and is used for fiber (stem) and oil (seed). The efficacy of Cheungsam on skin is not yet known, and although there are previous studies on Cheungsam seed oil, there are no studies on Cheungsam seed husk.

In this study, we investigated the potential of Cheungsam seed husk ethanol extract (CSSH) to alleviate skin inflammation through evaluating the gene and protein expression levels of inflammatory mediators.

The results showed that CSSH reduced pro-inflammatory cytokines (IL-1β, IL-6, IL-8, MCP-1 and CXCL10) and atopic dermatitis-related cytokines (IL-4, CCL17, MDC and RANTES) in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, ERK, JNK and p38 phosphorylation were decreased and p-p65, p-IκBα, NLRP3, caspase-1, p-JAK1 and p-STAT6 were suppressed after CSSH treatment. CSSH significantly increased the level of the skin barrier factors filaggrin and involucrin.

These results suggest that Cheungsam seed husk ethanol extract regulates the mechanism of skin inflammation and can be used as a new treatment for skin inflammatory diseases.”

https://pubmed.ncbi.nlm.nih.gov/38931136/

“The extract exerted anti-inflammatory and anti-atopic effects through mechanism regulation and skin barrier recovery. Therefore, Cheungsam seed husk extract may be useful for treating atopic dermatitis as well as other skin inflammatory diseases.”

https://www.mdpi.com/2223-7747/13/12/1704