Neuroprotective Effects of Cannabispirenone A against NMDA-Induced Excitotoxicity in Differentiated N2a Cells

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“The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 is critical in preventing neurotoxicity caused by N-methyl-D-aspartate receptor activation (NMDARs). The activity of NMDARs places demands on endogenous cannabinoids to regulate their calcium currents.

Endocannabinoids keep NMDAR activity within safe limits, protecting neural cells from excitotoxicity. Cannabinoids are remembered to deliver this outcome by repressing presynaptic glutamate discharge or obstructing postsynaptic NMDAR-managed flagging pathways.

The endocannabinoid system must exert a negative influence proportional to the strength of NMDAR signaling for such control to be effective. The goal of this paper is to draw the attention towards the neuroprotective mechanism of constituents of Cannabis sativa against NMDA-induced excitotoxic result.

Phytochemical investigation of the cannabis flowers led to the isolation of nine secondary metabolites. A spiro-compound, Cannabispirenone A, which on treatment of the cells prior to NMDA exposure significantly increases cell survival while decreasing ROS production, lipid peroxidation, and intracellular calcium.

Our findings showed that this compound showed neuroprotection against NMDA-induced excitotoxic insult, has antioxidative properties, and increased cannabinoid receptor 1 expression, which may be involved in the signaling pathway for this neuroprotection.”

https://pubmed.ncbi.nlm.nih.gov/38855429/

“In the current study, we assessed the flowers of the cannabis plant that showed ability to protect cells from NMDA-induced insult and discovered that it could prevent cell death. To our knowledge, we here reporting the first-time neuroprotective properties of the molecule isolated from the flowers of the cannabis plant.”

https://onlinelibrary.wiley.com/doi/10.1155/2024/3530499

The development of cannabinoids as therapeutic agents in the United States

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“Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis’ effects through interactions with the body’s endogenous cannabinoid system.

This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use.

This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use.

In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers.

Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.”

https://pubmed.ncbi.nlm.nih.gov/38849155/

https://pharmrev.aspetjournals.org/content/early/2024/06/07/pharmrev.123.001121

Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients

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“Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability.

Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility. that is particularly well suited to infants and in low economy settings.

Therefore, this study has investigated the in vitro solubilization enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula.

The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilization of drug and their oral bioavailability.”

https://pubmed.ncbi.nlm.nih.gov/38782154/

https://www.sciencedirect.com/science/article/pii/S0378517324004915?via%3Dihub

Assessment of Moroccan Cannabis sativa Seed Oil: Chemical Analysis and Evaluation of Antioxidant, Toxicological, and Antinociceptive Effects

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“Cannabis sativa L. is a plant known locally as “El kif” of the Cannabaceae family. This study aimed to conduct a chemical analysis of Cannabis sativa seed oil (CSSO) and assess its acute toxicity, antioxidant properties, and analgesic effects.

The chemical analysis was performed using gas chromatography and mass spectrometry (GC/MS) to identify its fatty acids (FAs) content. Antioxidant activity was evaluated in vitro using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method and the FRAP (ferric reducing antioxidant power) method. Concurrently, acute toxicity, along with antinociceptive activity, was studied through three distinct animal models: writhing test, formalin test, and hot plate test.

The results revealed that linoleic acid, oleic acid, α-linolenic acid, and palmitic acid were the main components of CSSO. The LD50 of CSSO was greater than 5 g/kg, indicating low toxicity. Additionally, CSSO exhibited a significant content of flavonoids and total polyphenols, along with notable antioxidant activity with values. The results indicated a significant increase in thermal stimulus latency, a reduction in the number of writhes induced by acetic acid, and a decrease in licking time in both phases of the formalin test.

In conclusion, this study suggests promising results for CSSO emphasizing its potential as a therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/38795371/

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202400591

Cannabis Sativa Oil Promotes Social Interaction and Ultrasonic Communication by Acting on Oxytocin Pathway

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“Objective: Cannabis sativa is the most used recreational drug worldwide. In recent years, there has been a growing interest in the potential therapeutic benefits of medicinal cannabis to treat a variety of psychiatric and neurological conditions. In particular, cannabidiol (CBD), a nonpsychoactive cannabis constituent, has been investigated for its potential prosocial effects on behavior, although the molecular mechanisms underlying this effect are still largely unknown. The aim of this study was to investigate the effect of a C. sativa oil CBD rich (CS oil) on social interaction and ultrasonic communication in mice. 

Study Design: Twenty-seven adult male mice (B6; 129P F2) were treated daily with vehicle or CS oil for 2 weeks. At Day 14, mice were tested for behavior (social interaction test and ultrasonic communication). Forty minutes before the behavioral tests, mice were exposed to intranasal treatment with vehicle or the oxytocin receptor antagonist, L-371,257. After behavioral tests, VH- and CS oil-treated mice were sacrificed, RNA was extracted from the hypothalamus and used for quantitative Real Time-PCR experiments. 

Results: We found that a 2-week treatment with the CS oil on mice exerted a prosocial effect associated with an increase in ultrasonic vocalizations. These effects were inhibited by pretreating mice with an oxytocin receptor antagonist. In addition, at the molecular level, we found that CS oil treatment caused a significant increase in oxytocin and a decrease in oxytocin receptor expression levels in the brain hypothalamus. 

Conclusion: Our results suggest that CS oil promotes social behavior by acting on oxytocin pathway.”

https://pubmed.ncbi.nlm.nih.gov/38800950/

https://www.liebertpub.com/doi/10.1089/can.2024.0062

Cannabis sativa (Hemp) seed-derived peptides WVYY and PSLPA modulate the Nrf2 signaling pathway in human keratinocytes

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“Cannabis sativa (Hemp) seeds are used widely for cosmetic and therapeutic applications, and contain peptides with substantial therapeutic potential.

Two key peptides, WVYY and PSLPA, extracted from hemp seed proteins were the focal points of this study. These peptides have emerged as pivotal contributors to the various biological effects of hemp seed extracts. Consistently, in the present study, the biological effects of WVYY and PSLPA were explored.

We confirmed that both WVYY and PSLPA exert antioxidant and antibacterial effects and promote wound healing.

We hypothesized the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in these observed effects, given that Nrf2 is reported to be a central player in the regulation of these observed effects. Molecular-level investigations unequivocally confirmed the role of the Nrf2 signaling pathway in the observed effects of WVYY and PSLPA, specifically their antioxidant effects.

Our study highlights the therapeutic potential of hemp seed-derived peptides WVYY and PSLPA, particularly with respect to their antioxidant effects, and provides a nuanced understanding of their effects. Further, our findings can facilitate the investigation of targeted therapeutic applications and also underscore the broader significance of hemp extracts in biological contexts.”

https://pubmed.ncbi.nlm.nih.gov/38781174/

“Although a more in-depth investigation into the precise roles of each peptide is necessary, we believe that a thorough examination of the highly specific roles of various peptides could lead to a broad range of medical and biological applications. In conclusion, we confirmed that the peptides WVYY and PSLPA derived from hemp seed extracts exhibit multiple effects, including antioxidant mechanisms. We propose that the overall “effect” of hemp extract originates from these contributions.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298487

Evaluating the Metabolomic Profile and Anti-Pathogenic Properties of Cannabis Species

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“The Cannabis species is one of the potent ancient medicinal plants acclaimed for its medicinal properties and recreational purposes. The plant parts are used and exploited all over the world for several agricultural and industrial applications. For many years Cannabis spp. has proven to present a highly diverse metabolomic profile with a pool of bioactive metabolites used for numerous pharmacological purposes ranging from anti-inflammatory to antimicrobial. Cannabis sativa has since been an extensive subject of investigation, monopolizing the research. Hence, there are fewer studies with a comprehensive understanding of the composition of bioactive metabolites grown in different environmental conditions, especially C. indica and a few other Cannabis strains. These pharmacological properties are mostly attributed to a few phytocannabinoids and some phytochemicals such as terpenoids or essential oils which have been tested for antimicrobial properties. Many other discovered compounds are yet to be tested for antimicrobial properties. These phytochemicals have a series of useful properties including anti-insecticidal, anti-acaricidal, anti-nematicidal, anti-bacterial, anti-fungal, and anti-viral properties. Research studies have reported excellent antibacterial activity against Gram-positive and Gram-negative multidrug-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA). Although there has been an extensive investigation on the antimicrobial properties of Cannabis, the antimicrobial properties of Cannabis on phytopathogens and aquatic animal pathogens, mostly those affecting fish, remain under-researched. Therefore, the current review intends to investigate the existing body of research on metabolomic profile and anti-microbial properties whilst trying to expand the scope of the properties of the Cannabis plant to benefit the health of other animal species and plant crops, particularly in agriculture.”

https://pubmed.ncbi.nlm.nih.gov/38786730/

“Cannabis extracts and their phytochemicals have so far been demonstrated to be a solution.”

https://www.mdpi.com/2218-1989/14/5/253

Cannflavin A inhibits TLR4-induced chemokine and cytokine expression in human macrophages

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“Cannflavin A (CFL-A), a flavonoid present in the hemp plant Cannabis sativa L. (C. sativa), has anti-inflammatory and neuroprotective capacity.

Research continues to elucidate the anti-inflammatory effects of components of C. sativa, with evidence that plant-derived cannabinoids and terpenes can mediate anti-inflammatory activity by targeting toll-like receptor (TLR) signalling, the sensors of pathogen-associated molecules.

This study set out to determine if TLR-mediated inflammatory signalling is a CFL-A target using the endotoxin lipopolysaccharide (LPS) to induce TLR4 signalling in human THP-1-derived macrophages. TLR4 activation promoted the production of the chemokine CXCL10 and cytokines IL-1β and TNFα. Treatment with CFL-A dose-dependently attenuated TLR4-induced CXCL10 and IL-1β secretion, with our findings also indicating that the inhibitory effects of CFL-A on chemokine/cytokine secretion are in line with an NF-κB inhibitor.

This study highlights TLR4 signalling as a cannflavin target in macrophages.”

https://pubmed.ncbi.nlm.nih.gov/38780010/

“This study highlights TLR4-induced inflammatory signalling as a cannflavin target. TLR4 is a key player in controlling innate immune responses to infection, and targeted TLR4 immunotherapies are under investigation for chronic inflammatory disorders. This study indicates that CFL-A warrants further study to decipher its anti-inflammatory potential in terms of regulating innate immune inflammatory signalling. Our findings also suggest that the therapeutic value of components of the hemp plant C. sativa should be broadened to include cannflavins.”

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2358382

The Potential of Cannabichromene (CBC) as a Therapeutic Agent

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“There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa 

The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). While the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials.

In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. 

Significance Statement Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on THC and CBD. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.”

https://pubmed.ncbi.nlm.nih.gov/38777605/

https://jpet.aspetjournals.org/content/early/2024/05/22/jpet.124.002166

[Cannabinoid Drugs in the Treatment of Psychiatric Disorders – Data from the German Federal Institute for Drugs and Medical Devices]

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“Background: Since 2017 physicians in Germany can prescribe cannabis based medicines or medical cannabis with subsequent funding by the statutory health insurance system.

Methods: Physicians prescribing cannabinoid drugs were legally required to take part in a survey conducted by the Federal Institute for Drugs and Medical Devices. This study analyses data from 16.809 case reports that were collected from 30.3.2017 to 31.12.2021.

Results: There were 5582 cases documenting the use of cannabinoid drugs in psychiatric disorders. More than half of the prescriptions were Dronabinol. 80% of the treatments concerned somatoform disorders. Most of the treatments for other psychiatric disorders also targeted pain. Doctors reported a positive effect on symptoms in at least 75% of the cases.

Discussion: Most patients with psychiatric disorders received cannabinoid drugs for pain. The evidence from randomized controlled clinical trials for the use of cannabinoid drugs in psychiatric indications is weak.”

https://pubmed.ncbi.nlm.nih.gov/38749455/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2296-1358