Category Archives: Endocannabinoid System

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

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

Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders

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“An impact of legalization and decriminalization of marijuana is the gradual increase in the use of cannabis for recreational purposes, which poses a potential threat to society and healthcare systems worldwide. However, the discovery of receptor subtypes, endogenous endocannabinoids, and enzymes involved in synthesis and degradation, as well as pharmacological characterization of receptors, has led to exploration of the use of cannabis in multiple peripheral and central pathological conditions.

The role of cannabis in the modulation of crucial events involving perturbed physiological functions and disease progression, including apoptosis, inflammation, oxidative stress, perturbed mitochondrial function, and the impaired immune system, indicates medicinal values.

These events are involved in most neurological diseases and prompt the gradual progression of the disease. At present, several synthetic agonists and antagonists, in addition to more than 70 phytocannabinoids, are available with distinct efficacy as a therapeutic alternative in different pathological conditions. The present review aims to describe the use of cannabis in neurological diseases and psychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/39796008/

“Cannabis sativa L. (marijuana), an ancient plant with medicinal values, has been used for medicinal, recreational, and spiritual purposes for a long time worldwide.”

“The discovery of the ECS has sparked the interest of many researchers worldwide due to its potential therapeutic contribution to some of the incurable neurodegenerative diseases such as AD, PD, HD, and psychological abnormalities. To date, studies have uncovered the expression, location, structures, and mechanism of cannabinoid receptors.

When the endocannabinoid system’s associations with other biochemical pathways are fully elucidated, many medical and political changes will be seen, such as the legalization of marijuana and new therapeutic approaches to neurodegenerative diseases.

Recent developments regarding crystal structure and cryoEM open the door to understanding the structural complexity and future therapeutic implication of cannabinoids in neurological and psychiatric disorders. Most genes associated with neurological diseases have been defined; however, the molecular details of other changes are largely elusive and are of immense interest to be explored. At this stage, it will be interesting to elucidate the role of CB2R as a neuroprotective strategy in addition to other proteins that are modulated following cannabis administration.

Neuroinflammation, oxidative stress, and disrupted cell organelles, specifically mitochondria, are intimately associated with compelling causative factors for disease progression and are potential therapeutic avenues to explore in neurodegeneration, along with psychological disturbances; therefore, they should be the prime objective for future studies on cannabinoids to develop novel therapeutic chimeric molecules with minimum side effects and maximum benefits.”

https://www.mdpi.com/1422-0067/26/1/152

Medicinal Cannabis and the Intestinal Microbiome

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“Historically, the multiple uses of cannabis as a medicine, food, and for recreational purposes as a psychoactive drug span several centuries.

The various components of the plant (i.e., seeds, roots, leaves and flowers) have been utilized to alleviate symptoms of inflammation and pain (e.g., osteoarthritis, rheumatoid arthritis), mood disorders such as anxiety, and intestinal problems such as nausea, vomiting, abdominal pain and diarrhea.

It has been established that the intestinal microbiota progresses neurological, endocrine, and immunological network effects through the gut-microbiota-brain axis, serving as a bilateral communication pathway between the central and enteric nervous systems.

An expanding body of clinical evidence emphasizes that the endocannabinoid system has a fundamental connection in regulating immune responses. This is exemplified by its pivotal role in intestinal metabolic and immunity equilibrium and intestinal barrier integrity.

This neuromodulator system responds to internal and external environmental signals while also serving as a homeostatic effector system, participating in a reciprocal association with the intestinal microbiota.

We advance an exogenous cannabinoid-intestinal microbiota-endocannabinoid system axis potentiated by the intestinal microbiome and medicinal cannabinoids supporting the mechanism of action of the endocannabinoid system. An integrative medicine model of patient care is advanced that may provide patients with beneficial health outcomes when prescribed medicinal cannabis.”

https://pubmed.ncbi.nlm.nih.gov/39770543/

“Furthermore, other modes of delivery of medicinal cannabis, such as oro-buccal, sublingual and inhaled/smoked alternatives, provide cannabinoids that have rapid access to the systemic circulation, bypassing the intestinal tract.”

https://www.mdpi.com/1424-8247/17/12/1702

The Role of Cannabinoids and the Endocannabinoid System in the Treatment and Regulation of Nausea and Vomiting

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“Despite using the recommended anti-emetic treatments, control of nausea and vomiting is still an unmet need for cancer patients undergoing chemotherapy treatment. Few properly controlled clinical trials have evaluated the potential of exogenously administered cannabinoids or manipulations of the endogenous cannabinoid (eCB) system to treat nausea and vomiting. In this chapter, we explore the pre-clinical and human clinical trial evidence for the potential of exogenous cannabinoids and manipulations of the eCB system to reduce nausea and vomiting. Although there are limited high-quality human clinical trials, pre-clinical evidence suggests that cannabinoids and manipulations of the eCB system have anti-nausea/anti-emetic potential. The pre-clinical anti-nausea/anti-emetic evidence highlights the need for further evaluation of cannabinoids and manipulations of eCBs and other fatty acid amides in clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/39739175/

https://link.springer.com/chapter/10.1007/7854_2024_554

Hemp Extract (Extractum Cannabis) in the Treatment of Gastrointestinal Distress and Dyspepsia: Historical Insights from Barcelona, Spain

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“This study explores the trajectory of interest in and use of Extractum Cannabis (hemp extract, i.e., extract of Cannabis sativa L.) for the symptomatic treatment of minor gastrointestinal distress and dyspepsia in nineteenth- and early twentieth-century Barcelona (Catalonia, Spain) prior to 1939, through a review of primary sources.

The objective of this paper is to present a historical pharmaceutical and applied review of the medical use of the hemp genus (Cannabis L.) prior to its prohibition, thereby contributing to its recognition as a medicinal product.

The information provided demonstrates evidence of the medicinal use of cannabis within the historical context studied. The interactions between this legacy medical use and the contemporary body of pharmacological and toxicological knowledge (on hemp, its constituents, and the endocannabinoid system in gastrointestinal and stomach disorders) are discussed, providing new possible clinical perspectives.

Within its limitations-including the scope, limited accessibility to, and varying quality of archives-this research contributes to a more granular understanding of the historical embeddedness of psychoactive hemp medicines in northeastern Spain, suggesting that medical and pharmaceutical traditions could play a role in informing contemporary approaches to “medical marijuana”.”

https://pubmed.ncbi.nlm.nih.gov/39770428/

https://www.mdpi.com/1424-8247/17/12/1585

Cannabinoid receptor ligands modulate fibrosis and inflammation in idiopathic pulmonary fibrosis: a preliminary study

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“Background/aim: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes.

Materials and methods: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-β1, IL-8, and TNF-α inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA.

Results: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,212-2 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-β1 and TNF-α release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBR-mediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3.

Conclusion: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.”

https://pubmed.ncbi.nlm.nih.gov/39758842/

https://journals.tubitak.gov.tr/biology/vol48/iss6/4/

Cannabis sativa alleviates experimentally acetic acid- induced ulcerative colitis in rats: targeting CB1/SIRT/MAPK signaling pathways

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“Background: Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.

Objective: The aim of this study was to evaluate the therapeutic effect of Cannabis sativa (C. sativa) on the amelioration of acetic acid-induced colitis in rats.

Materials and methods: Group 1: normal control group was intrarectally administered saline solution (0.9%); group 2: acetic acid (AA) group was given AA intra-rectally (2 mL of 4% (v/v) in 0.9% NaCl) once.; group 3&4: This group represented the ulcerative colitis-induced rats that were injected with acetic acid intra-rectally, then s.c. injection with C. sativa (20 and 40 mg/kg daily for 8 days).

Results: Colonic architectural abnormality significantly improved after pretreatment with C. sativa. Additionally, it significantly reduced the MDA level and prevented the depletion of GSH content. Moreover, C. sativa administration showed suppressive activities on pro-inflammatory cytokines, including NF-κB, MAPK, ERK, PI3K, AKT, HIF-1α, and TLR4. Moreover, it significantly upregulated the level of SIRT and CB1 in the colon tissue.

Conclusion: This study provided a novel impact for CB1 receptor activation produced by C. sativa against AA-induced UC in rats through inhibiting the TLR-4 MAPK/ERK, PI3K, and NFκB signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/39721800/

https://www.tandfonline.com/doi/full/10.1080/08923973.2024.2445733