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Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery

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“G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects.

Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases.

This review examines the structural conformations of CB1 coupling to different signaling pathways and explores the mechanisms underlying biased signaling, which are critical for the design of functionally selective ligands. We discuss the structure-function relationships of endogenous cannabinoids (eCBs), phytocannabinoids, and synthetic cannabinoid ligands with biased properties. Challenges such as the complexity of ligand bias screening, the limited availability of distinctly biased ligands, and the variability in receptor signaling profiles in vivo have hindered clinical progress.

Although the therapeutic potential of biased ligands in various clinical conditions remains in its infancy, retrospective identification of such molecules provides a strong foundation for further development. Recent advances in CB1 crystallography, particularly insights into its conformations with G proteins and β-arrestins, now offer a framework for structure-based drug design. While there is still a long way to go before biased CB1 ligands can be widely used in clinical practice, ongoing multidisciplinary research shows promise for achieving functional selectivity in targeting specific pathways.

These progresses could lead to the development of safer and more effective cannabinoid-based therapies in the future.”

https://pubmed.ncbi.nlm.nih.gov/39828030/

https://www.sciencedirect.com/science/article/abs/pii/S0163725825000075?via%3Dihub

∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo

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“Background: Because of its biocompatibility and its soft and dynamic nature, the grafting of adipose tissue is regarded an ideal technique for soft-tissue repair. The adipose stem cells (ASCs) contribute significantly to the regenerative potential of adipose tissue, because they can differentiate into adipocytes and release growth factors for tissue repair and neovascularization to facilitate tissue survival. The present study tested the effect of administering a chronic low dose of ∆9-tetrahydrocannabinol (THC) on these regenerative properties, in vitro and in vivo.

Methods: Human ASCs were exposed to increasing concentrations of THC. Resazurin conversion was applied to investigate the effect on metabolic activity, cell number was assessed by crystal violet staining, tri-linear differentiation was evaluated by specific colorimetric approaches, and the release of growth factors was analyzed by ELISA. Two groups of mice were treated daily either with a low dose of THC (3 mg/kg) or a vehicle solution. After 3 weeks, adipose tissue was obtained from excised fat deposits, homogenized and tested for growth factor contents.

Results: THC decreased ASC proliferation but increased metabolic activity as well as adipogenic and chondrogenic differentiation. A low concentration of THC (1 µM) enhanced the growth factor release by ASCs. The concentration of these cytokines was also increased in adipose tissue of mice treated with THC.

Conlusion: Our results indicate that chronic activation of the endocannabinoid system promoted differentiation and growth factor release of ASCs, which could be of specific value for enhancing the regenerative potential of adipose tissue.”

https://pubmed.ncbi.nlm.nih.gov/39825991/

“Our findings may offer a new approach for improved application of adipose tissue in regenerative medicine.”

https://link.springer.com/article/10.1007/s13770-024-00692-8

[Impact of dronabinol shortage on a population of chronic pain patients: A retrospective observational study]

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“Objective: A supply shortage of dronabinol occurred between December 2023 and February 2024, forcing chronic pain patients to discontinue this treatment. We assessed the impact of this shortage on patients in our hospital.

Method: A retrospective observational study of patients treated with dronabinol was conducted. Collected data included socio-demographic, pharmacological and clinical data. Pain intensity and its interference, the intensity of other pain dimensions (mood, relationship with others, etc.) and quality of sleep were collected before discontinuation (dronabinol dosage balanced, M0) and at the end of discontinuation (dronabinol stopped for several weeks, M3). The patient’s perception of his state of health evolution was collected at the end of the shortage.

Results: Health deterioration was reported by 86% of patients after 3 months of rupture. Pain intensity and its interference with patients’ daily lives increased significantly. Patients’ sleep deteriorated significantly. The number of patients with permanent pain increased 5-fold (n=2 at M0 and n=10 at M3). The number of patients with more than 20 painful attacks per 24hours increased 2-fold (n=2 at M0 and n=4 at M3).

Conclusion: Although data on the efficiency of dronabinol are currently limited, this supply disruption has had negative clinical consequences for our patients. With drug shortages multiplying in recent years, the marketing of new specialties and therefore the availability of therapeutic alternatives could help reduce the clinical impact of a possible new dronabinol shortage in these refractory chronic pain patients.”

https://pubmed.ncbi.nlm.nih.gov/39824703/

https://www.sciencedirect.com/science/article/abs/pii/S0040595724002191?via%3Dihub

“Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns”

https://pubmed.ncbi.nlm.nih.gov/26775260/

Evaluation of the Antibacterial Potential of Ethanolic Cannabis sativa L. (Hang Kra Rog Phu Phan ST1) Extracts Against Human Pathogenic Bacteria

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“Background and Objective: Amid the escalating challenge of antibiotic resistance, the exploration of new sources has become essential, with plants serving as a promising reservoir of bioactive compounds.

Cannabis sativa has attracted significant research interest for its antimicrobial properties and broad applications in medicine, industry and nutrition.

This study aimed to investigate the antibacterial activity of ethanolic extracts from the stems and leaves of the Hang Kra Rog Phu Phan ST1 strain against twelve human pathogenic bacteria.

Materials and Methods: Stems and leaves from the Hang Kra Rog Phu Phan ST1 strain were subjected to ethanol extraction. The primary antibacterial activity of ethanolic extracts from Tanao Si Kan Dang RD1 was assessed using the disc diffusion method, while the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined via the broth microdilution method. The inhibition zone diameter (mm) was analyzed using Duncan’s Multiple Range Test (DMRT) with the SAS software.

Results: The findings revealed that the ethanolic extract from the leaves of Hang Kra Rog Phu Phan ST1 produced the largest inhibition zone diameter of 10.00 mm against <i>Bacillus subtilis</i> TISTR 008. The MIC and MBC of the leaf extract showed the lowest values of 0.09 and 0.19 mg/mL, respectively, recorded against <i>Staphylococcus aureus</i> TISTR 1466.

Conclusion: This is the first report on the antibacterial activity of the ethanolic extracts from the leaves and stems of Hang Kra Rog Phu Phan ST1, which offers potential benefits for developing natural antibiotic drugs to combat infections caused by the tested pathogenic bacteria.”

https://pubmed.ncbi.nlm.nih.gov/39820562/

https://scialert.net/abstract/?doi=pjbs.2025.1.7

Cannabidiol abrogates cue-induced anxiety associated with normalization of mitochondria-specific transcripts and linoleic acid in the nucleus accumbens shell

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“Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant.

This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior.

Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1 h prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion.

Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms.

These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/39815058/

https://www.nature.com/articles/s41380-024-02881-2

Cannabinoid-based Pharmacology for the Management of Substance Use Disorders

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“In the last two decades, the endocannabinoid system has emerged as a crucial modulator of motivation and emotional processing. Due to its widespread neuroanatomical distribution and characteristic retrograde signaling nature, cannabinoid type I receptors and their endogenous ligands finely orchestrate somatic and axon terminal activity of dopamine neurons.

Owing to these unique features, this signaling system is a promising pharmacological target to ameliorate dopamine-mediated drug-seeking behaviors while circumventing the adverse side effects of, for instance, dopaminergic antagonists.

Despite considerable preclinical efforts, an agreement on the efficacy of endocannabinoid-targeting compounds for treating drug substance use disorders in humans has not been reached. In the following chapter, we will summarize preclinical and clinical evidence addressing the therapeutic potential of cannabinoids and endocannabinoid-targeting compounds in substance use disorders.

To bridge the gap between animal and clinical research, we capitalize on studies evaluating the impact of endocannabinoid-targeting compounds in relevant settings, such as the management of drug relapse.

Finally, we discuss the therapeutic potential of novel cannabinoid compounds that hold promise for treating substance use disorders.”

https://pubmed.ncbi.nlm.nih.gov/39813001/

https://link.springer.com/chapter/10.1007/7854_2024_551

Determination of the Negative Allosteric Binding Site of Cannabidiol at the CB1 Receptor: A Combined Computational and Site-Directed Mutagenesis Study

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“Cannabinoid receptor 1 (CB1R) has been extensively studied as a potential therapeutic target for various conditions, including pain management, obesity, emesis, and metabolic syndrome. Unlike orthosteric agonists such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) has been identified as a negative allosteric modulator (NAM) of CB1R, among its other pharmacological targets. Previous computational and structural studies have proposed various binding sites for CB1R NAMs. An X-ray crystal structure revealed a binding site for the NAM, ORG27569, at an extrahelical location within the inner leaflet of the membrane. In contrast, multiple computational studies have previously proposed several potential allosteric binding sites for CBD within the CB1R structure. Given that a prior structural study suggested CBD might occupy the same site as ORG27569, we conducted a comprehensive investigation of potential CBD binding sites using molecular docking, molecular dynamics (MD) simulations, metadynamics (MTD) simulations, binding free-energy calculations, and in vitro mutagenesis experiments. Molecular docking, MD, and MTD simulations results, along with binding free-energy calculations, suggest that CBD may potentially bind to either the same extrahelical site as ORG27569 or a previously unidentified intracellular site located near TMHs 2, 6, and 7 and helix 8. This intracellular site is consistent with allosteric binding sites observed in other G protein-coupled receptors (GPCRs). To establish the most favorable allosteric site for CBD, we conducted site-directed mutagenesis of key residues at each site. Mutations at S4018.47ΔA and D4038.49ΔA augmented the binding of [3H]-SR141716A, suggesting these residues play critical roles in CBD binding. As a result, the combined computational and mutagenesis results identified a binding site for CBD between TMHs 2, 6, and 7 and helix 8, involving residues Y1532.40, I1562.43, M3376.29, L3416.33, S4018.47, and D4038.49. These findings provide valuable insights into how CBD binds to CB1R, thereby informing the rational design of new, selective, and potent NAMs. Moreover, the elucidation of this previously unexplored allosteric site might explain the polypharmacology of CBD due to structural conservation among Class A GPCRs.”

https://pubmed.ncbi.nlm.nih.gov/39812521/

https://pubs.acs.org/doi/10.1021/acschemneuro.4c00343

An Unexpected Activity of a Minor Cannabinoid: Cannabicyclol (CBL) Is a Potent Positive Allosteric Modulator of Serotonin 5-HT1A Receptor

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“Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT1A receptor but weak interaction with CB1 and CB2 receptors. At 10 μM and 1 μM, (±)-CBL inhibited [3H]-8-hydroxy-DPAT binding to 5-HT1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.”

https://pubmed.ncbi.nlm.nih.gov/39811943/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00977

“Positive allosteric modulators of the 5-HT1A receptor can help relieve anxiety and depression.”

Plant-Derived Compounds in Hemp Seeds (Cannabis sativa L.): Extraction, Identification and Bioactivity-A Review

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“The growing demand for plant-based protein and natural food ingredients has further fueled interest in exploring hemp seeds (Cannabis sativa L.) as a sustainable source of and nutrition.

In addition to the content of proteins and healthy fats (linoleic acid and alpha-linolenic acid), hemp seeds are rich in phytochemical compounds, especially terpenoids, polyphenols, and phytosterols, which contribute to their bioactive properties.

Scientific studies have shown that these compounds possess significant antioxidant, antimicrobial, and anti-inflammatory effects, making hemp seeds a promising ingredient for promoting health. Since THC (tetrahydrocannabinol) and CBD (cannabidiol) are found only in traces, hemp seeds can be used in food applications because the psychoactive effects associated with cannabis are avoided.

Therefore, the present article reviews the scientific literature on traditional and modern extraction methods for obtaining active substances that meet food safety standards, enabling the transformation of conventional foods into functional foods that provide additional health benefits and promote a balanced and sustainable diet.

Also, the identification methods of biologically active compounds extracted from hemp seeds and their bioactivity were evaluated. Mechanical pressing extraction, steam distillation, solvent-based methods (Soxhlet, maceration), and advanced techniques such as microwave-assisted and supercritical fluid extraction were evaluated. Identification methods such as high-performance liquid chromatography (HPLC) and mass spectrometry (MS) allowed for detailed chemical profiling of cannabinoids, terpenes, and phenolic substances.

Optimizing extraction parameters, including solvent type, temperature, and time, is crucial for maximizing yield and purity, offering the potential for developing value-added foods with health benefits.”

https://pubmed.ncbi.nlm.nih.gov/39795183/

https://www.mdpi.com/1420-3049/30/1/124

Effects of a Cannabinoid-Based Phytocomplex (Pain ReliefTM) on Chronic Pain in Osteoarthritic Dogs

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“Twenty-one adult crossbreed dogs with chronic pain due to severe osteoarthrosis were enrolled in the study (placebo vs. treatment groups). The dogs in the experimental group received the dietary supplement (Pain ReliefTM, Giantec, Isernia, Italy) for 30 days to evaluate its effects on metabolism and pain relief. During the trial, the Helsinki Chronic Pain Index significantly decreased (p < 0.01) in the experimental group, indicating reduced pain and improved quality of life. Additionally, the treated group showed improvements in oxidative stress, demonstrated by a reduction in reactive oxygen metabolites, and an increase in biological antioxidant potential. Interleukins 6 levels decreased in the treated group, while interleukins 10 levels increased, thus suggesting an anti-inflammatory effect of the supplement. Importantly, no adverse effects were observed. Results suggest that Pain ReliefTM is effective in ameliorating osteoarthritis in dogs, improving their quality of life.”

https://pubmed.ncbi.nlm.nih.gov/39795044/

“Chronic pain is one of the most disabling conditions in dogs, as it affects various aspects of a dog’s life and should be managed regardless of the severity of symptoms. This research investigates the effects of a cannabidiol-based nutritional supplement in dogs affected by severe osteoarthritis. The treated group showed a reduction in pain due to an improvement of some cytokines expression and oxidative status. This suggests that Pain ReliefTM possesses an anti-inflammatory effect and reduces pain perception in dogs, thereby enhancing their quality of life.”

https://www.mdpi.com/2076-2615/15/1/101