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Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ 9 -THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood-brain barrier (BBB) effectively. Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ 9 -THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions.

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.

The endocannabinoid system (ECS), initially identified for its role in maintaining homeostasis, particularly in regulating brain function, has evolved into a complex orchestrator influencing various physiological processes beyond its original association with the nervous system. Notably, an expanding body of evidence emphasizes the ECS's crucial involvement in regulating immune responses. While the specific role of the ECS in bacterial infections remains under ongoing investigation, compelling indications suggest its active participation in host-pathogen interactions. Incorporating the ECS into the framework of bacterial pathogen infections introduces a layer of complexity to our understanding of its functions. While some studies propose the potential of cannabinoids to modulate bacterial function and immune responses, the outcomes inherently hinge on the specific infection and cannabinoid under consideration. Moreover, the bidirectional relationship between the ECS and the gut microbiota underscores the intricate interplay among diverse physiological processes. The ECS extends its influence far beyond its initial discovery, emerging as a promising therapeutic target across a spectrum of medical conditions, encompassing bacterial infections, dysbiosis, and sepsis. This review comprehensively explores the complex roles of the ECS in the modulation of bacteria, the host's response to bacterial infections, and the dynamics of the microbiome. Special emphasis is placed on the roles of cannabinoid receptor types 1 and 2, whose signaling intricately influences immune cell function in microbe-host interactions., Competing Interests: The authors declare no conflict of interest.

Yeast expression of human G-protein-coupled receptors (GPCRs) can be used as a biosensor platform for the detection of pharmaceuticals. Cannabinoid receptor type 1 (CB1R) is of particular interest, given the cornucopia of natural and synthetic cannabinoids being explored as therapeutics. We show for the first time that engineering the N-terminus of CB1R allows for efficient signal transduction in yeast, and that engineering the sterol composition of the yeast membrane modulates its performance. Using an engineered cannabinoid biosensor, we demonstrate that large libraries of synthetic cannabinoids and terpenes can be quickly screened to elucidate known and novel structure-activity relationships. The biosensor strains offer a ready platform for evaluating the activity of new synthetic cannabinoids, monitoring drugs of abuse, and developing therapeutic molecules.

Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses. This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways. The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.

Cannabis use has increased sharply in the last 20 y among adults, including reproductive-aged women. Its recent widespread legalization is associated with a decrease in risk perception of cannabis use during breastfeeding. However, the effect of cannabis use (if any) on milk production and milk composition is not known. This narrative review summarizes current knowledge related to maternal cannabis use during breastfeeding and provides an overview of possible pathways whereby cannabis might affect milk composition and production. Several studies have demonstrated that cannabinoids and their metabolites are detectable in human milk produced by mothers who use cannabis. Due to their physicochemical properties, cannabinoids are stored in adipose tissue, can easily reach the mammary gland, and can be secreted in milk. Moreover, cannabinoid receptors are present in adipocytes and mammary epithelial cells. The activation of these receptors directly modulates fatty acid metabolism, potentially causing changes in milk fatty acid profiles. Additionally, the endocannabinoid system is intimately connected to the endocrine system. As such, it is probable that interactions of exogenous cannabinoids with the endocannabinoid system might modify release of critical hormones (e.g., prolactin and dopamine) that regulate milk production and secretion. Nonetheless, few studies have investigated effects of cannabis use (including on milk production and composition) in lactating women. Additional research utilizing robust methodologies are needed to elucidate whether and how cannabis use affects human milk production and composition., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We studied whether the function of presynaptic inhibitory cannabinoid CB 1 receptors on the sympathetic nerve fibres innervating resistance vessels is increased in spontaneously hypertensive rats (SHR) like in deoxycorticosterone (DOCA)-salt hypertension. An increase in diastolic blood pressure (DBP) was induced by electrical stimulation of the preganglionic sympathetic neurons or by phenylephrine injection in pithed SHR and normotensive Wistar-Kyoto rats (WKY). The electrically (but not the phenylephrine) induced increase in DBP was inhibited by the cannabinoid receptor agonist CP55940, similarly in both groups, and by the endocannabinoid reuptake inhibitor AM404 in SHR only. The effect of CP55940 was abolished/reduced by the CB 1 receptor antagonist AM251 (in both groups) and in WKY by endocannabinoid degradation blockade, i.e., the monoacylglycerol lipase (MAGL) inhibitor MJN110 and the dual fatty acid amide hydrolase (FAAH)/MAGL inhibitor JZL195 but not the FAAH inhibitor URB597. MJN110 and JZL195 tended to enhance the effect of CP55940 in SHR. In conclusion, the function of presynaptic inhibitory CB 1 receptors depends on the hypertension model. Although no differences occurred between SHR and WKY under basal experimental conditions, the CB 1 receptor function was better preserved in SHR when the endocannabinoid tone was increased by the inhibition of MAGL or the endocannabinoid transporter.

The Endocannabinoid System (ECS) is a well-studied system that influences a variety of physiological activities. It is evident that the ECS plays a significant role in metabolic activities and also has some neuroprotective properties. In this review, we emphasize several plant-derived cannabinoids such as β-caryophyllene (BCP), Cannabichromene (CBC), Cannabigerol (CBG), Cannabidiol (CBD), and Cannabinol (CBN), which are known to have distinctive modulation abilities of ECS. In Alzheimer's disease (AD), the activation of ECS may provide neuroprotection by modulating certain neuronal circuitry pathways through complex molecular cascades. The present article also discusses the implications of cannabinoid receptors (CB1 and CB2) as well as cannabinoid enzymes (FAAH and MAGL) modulators in AD. Specifically, CBR1 or CB2R modulations result in reduced inflammatory cytokines such as IL-2 and IL-6, as well as a reduction in microglial activation, which contribute to an inflammatory response in neurons. Furthermore, naturally occurring cannabinoid metabolic enzymes (FAAH and MAGL) inhibit the NLRP3 inflammasome complex, which may offer significant neuroprotection. In this review, we explored the multi-targeted neuroprotective properties of phytocannabinoids and their possible modulations, which could offer significant benefits in limiting AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The synthetic forms of delta-9-tetrahydrocannabinol (Δ 9 -THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ 9 -THC. Here, we utilized drug discrimination methods to compare the interoceptive effects of CB ligands that vary in potency, efficacy, and selectivity at the CB receptors, including two ligands, AM411 and AM4089, that show CB 1 partial agonist-like actions in vitro. Male rats were trained to discriminate 0.1 mg/kg AM2201 from saline under a fixed-ratio (FR) 10 response schedule of food reinforcement. After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB 1 antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB 1 full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ 9 -THC), and non-cannabinoids (fentanyl, atropine) were compared. The CBs either fully (AM2201, CP-55,940, JWH-018, AM8936, Δ 9 -THC) or partially (AM411, AM4089) substituted for AM2201, whereas fentanyl and atropine did not produce AM2201-like effects. All CB drugs were more potent than Δ 9 -THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB 1 but not CB 2 receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ 9 -THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally mediated via CB 1 receptors., Competing Interests: Declaration of competing interest The authors have no other financial disclosures or potential conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this review article, we embark on a thorough exploration of cannabinoids, compounds that have garnered considerable attention for their potential therapeutic applications. Initially, this article delves into the fundamental background of cannabinoids, emphasizing the role of endogenous cannabinoids in the human body and outlining their significance in studying neurodegenerative diseases and cancer. Building on this foundation, this article categorizes cannabinoids into three main types: phytocannabinoids (plant-derived cannabinoids), endocannabinoids (naturally occurring in the body), and synthetic cannabinoids (laboratory-produced cannabinoids). The intricate mechanisms through which these compounds interact with cannabinoid receptors and signaling pathways are elucidated. A comprehensive overview of cannabinoid pharmacology follows, highlighting their absorption, distribution, metabolism, and excretion, as well as their pharmacokinetic and pharmacodynamic properties. Special emphasis is placed on the role of cannabinoids in neurodegenerative diseases, showcasing their potential benefits in conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. The potential antitumor properties of cannabinoids are also investigated, exploring their potential therapeutic applications in cancer treatment and the mechanisms underlying their anticancer effects. Clinical aspects are thoroughly discussed, from the viability of cannabinoids as therapeutic agents to current clinical trials, safety considerations, and the adverse effects observed. This review culminates in a discussion of promising future research avenues and the broader implications for cannabinoid-based therapies, concluding with a reflection on the immense potential of cannabinoids in modern medicine.

Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects. Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality. Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis. However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC. This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development of small molecules that selectively target the cannabinoid receptor subtype 2 (CB2R) is emerging as an intriguing therapeutic strategy to treat neurodegeneration, as well as to contrast the onset and progression of cancer. In this context, in-silico tools able to predict CB2R affinity and selectivity with respect to the subtype 1 (CB1R), whose modulation is responsible for undesired psychotropic effects, are highly desirable. In this work, we developed a series of machine learning classifiers trained on high-quality bioactivity data of small molecules acting on CB2R and/or CB1R extracted from ChEMBL v30. Our classifiers showed strong predictive power in accurately determining CB2R affinity, CB1R affinity, and CB2R/CB1R selectivity. Among the built models, those obtained using random forest as algorithm proved to be the top-performing ones (AUC in validation ≥0.96) and were made freely accessible through a user-friendly web platform developed ad hoc and called ALPACA (https://www.ba.ic.cnr.it/softwareic/alpaca/). Due to its user-friendly interface and robust predictive power, ALPACA can be a valuable tool in saving both time and resources involved in the design of selective CB2R modulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: This study established the in vitro anti-lymphoma pharmacodynamic actions of the endocannabinoids (anandamide-AEA and 2-arachidonoylglycerol-2AG) on canine non-Hodgkin lymphoma (NHL) and human NHL cells., Main Methods: The expression of cannabinoid (CB 1 and CB 2 ) receptors in various canine NHL cells {1771, CLBL-1, CLL-1, peripheral blood mononuclear cells (PBMCs)} was studied using Quantitative real-time PCR (RT-qPCR). Anti-lymphoma cell viability assay was performed to assess the effect of endocannabinoids on various canine and human NHL cells (1771, CLBL-1, CLL-1, Ramos cells). The spectrophotometric and fluorometric procedures evaluated oxidative stress, inflammation, apoptosis, and mitochondrial function markers. SAS® and Prism-V La Jolla, CA, USA, were used for statistical analysis., Key Findings: The current study validated the presence of CB 1 and CB 2 receptors in the canine NHL cells. There was a significantly higher expression of CB 1 and CB 2 receptors in B-cell lymphoma (BCL) cells (1771, CLBL-1, Ramos) compared to canine T-cell lymphoma (TCL) cells (CL-1). AEA and 2AG dose and time-dependently exhibited significant but differential anti-lymphoma effects on canine and human NHL cells. Anti-lymphoma pharmacodynamic actions of the endocannabinoids in the canine 1771 NHL cells revealed a significant alteration in the markers of oxidative stress, inflammation, and a decrease in mitochondrial function without altering the apoptotic markers., Significance: Establishing the anti-lymphoma pharmacodynamic actions of endocannabinoids may provide new therapeutic interventions and expedite cannabinoid research., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Since ancient times, Cannabis and its preparations have found various applications such as for medical, recreational and industrial purposes. Subsequently the 1930s, legislation in many countries has restricted its use due to its psychotropic properties. More recently, the discovery of endocannabinoid system, including new receptors, ligands, and mediators, its role in maintaining the homeostasis of the human body and the possible implication in various physiological and pathophysiological processes has also been understood. Based on this evidence, researchers were able to develop new therapeutic targets for the treatment of various pathological disorders. For this purpose, Cannabis and cannabinoids were subjected for the evaluation of their pharmacological activities. The renewed interest in the medical use of cannabis for its potential therapeutic application has prompted legislators to take action to regulate the safe use of cannabis and products containing cannabinoids. However, each country has an enormous heterogeneity in the regulation of laws. Here, we are pleased to show a general and prevailing overview of the findings regarding cannabinoids and the multiple research fields such as chemistry, phytochemistry, pharmacology and analytics in which they are involved., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Despite the successful introduction of combined antiretroviral therapy, the prevalence of mild to moderate forms of HIV-associated neurocognitive disorders (HAND) remains high. It has been demonstrated that neuronal injury caused by HIV is excitotoxic and inflammatory, and it correlates with neurocognitive decline in HAND. Endocannabinoid system (ECS) protects the body from excitotoxicity and neuroinflammation on demand and presents a promising therapeutic target for treating HAND. Here, we firstly discuss the potential pathogenesis of HAND. We secondly discuss the structural and functional changes in the ECS that are currently known among HAND patients. We thirdly discuss current clinical and preclinical findings concerning the neuroprotective and anti-inflammatory properties of the ECS among HAND patients. Fourth, we will discuss the interactions between the ECS and neuroendocrine systems, including the hypothalamic-pituitary-adrenocortical (HPA) and hypothalamic-pituitary-gonadal (HPG) axes under the HAND conditions. Materials and Methods: We have carried out a review of the literature using PubMed to summarize the current state of knowledge on the association between ECS and HAND. Results: The ECS may be ideally suited for modulation of HAND pathophysiology. Direct activation of presynaptic cannabinoid receptor 1 or reduction of cannabinoid metabolism attenuates HAND excitotoxicity. Chronic neuroinflammation associated with HAND can be reduced by activating cannabinoid receptor 2 on immune cells. The sensitivity of the ECS to HIV may be enhanced by increased cannabinoid receptor expression in HAND. In addition, indirect regulation of the ECS through modulation of hormone-related receptors may be a potential strategy to influence the ECS and also alleviate the progression of HAND due to the reciprocal inhibition of the ECS by the HPA and HPG axes. Conclusions: Taken together, targeting the ECS may be a promising strategy to alleviate the inflammation and neurodegeneration caused by HIV-1 infection. Further studies are required to clarify the role of endocannabinoid signaling in HIV neurotoxicity. Strategies promoting endocannabinoid signaling may slow down cognitive decline of HAND are proposed.

Cannabinoid receptors (CBs), including CB1 and CB2, are the key components of a lipid signaling endocannabinoid system (ECS). Development of synthetic cannabinoids has been attractive to modulate ECS functions. CB1 and CB2 are structurally closely related subtypes but with distinct functions. While most efforts focus on the development of selective ligands for single subtype to circumvent the undesired off-target effect, Yin-Yang ligands with opposite pharmacological activities simultaneously on two subtypes, offer unique therapeutic potential. Herein we report the development of a new Yin-Yang ligand which functions as an antagonist for CB1 and concurrently an agonist for CB2. We found that in the pyrazole-cored scaffold, the arm of N1-phenyl group could be a switch, modification of which yielded various ligands with distinct activities. As such, the ortho-morpholine substitution exerted the desired Yin-Yang bifunctionality which, based on the docking study and molecular dynamic simulation, was proposed to be resulted from the hydrogen bonding with S173 and S285 in CB1 and CB2, respectively. Our results demonstrated the feasibility of structure guided ligand evolution for challenging Yin-Yang ligand., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

3,3'-Diindolylmethane (DIM), a natural product-derived compound formed upon ingestion of cruciferous vegetables, was recently described to act as a partial agonist of the anti-inflammatory cannabinoid (CB) receptor subtype CB 2 . In the present study, we synthesized and evaluated a series of DIM derivatives and determined their affinities for human CB receptor subtypes in radioligand binding studies. Potent compounds were additionally evaluated in functional cAMP accumulation and β-arrestin recruitment assays. Small substituents in the 4-position of both indole rings of DIM were beneficial for high CB 2 receptor affinity and efficacy. Di-(4-cyano-1H-indol-3-yl)methane (46, PSB-19837, EC 50 : cAMP, 0.0144 µM, 95% efficacy compared to the full standard agonist CP55,940; β-arrestin, 0.0149 µM, 67% efficacy) was the most potent CB 2 receptor agonist of the present series. Di-(4-bromo-1H-indol-3-yl)methane (44, PSB-19571) showed higher potency in β-arrestin (EC 50 0.0450 µM, 61% efficacy) than in cAMP accumulation assays (EC 50 0.509 µM, 85% efficacy) while 3-((1H-indol-3-yl)methyl)-4-methyl-1H-indole (149, PSB-18691) displayed a 19-fold bias for the G protein pathway (EC 50 : cAMP, 0.0652 µM; β-arrestin, 1.08 µM). DIM and its analogs act as allosteric CB 2 receptor agonists. These potent CB 2 receptor agonists have potential as novel drugs for the treatment of inflammatory diseases., (© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

There is growing need to increase the knowledge on the cannabinoid ligands in the treatment of overactive bladder. Among potential candidates, arachidonyl-2'-chloroethylamide (ACEA), a selective cannabinoid CB1 receptor agonist is proposed. The aim of this paper was to determine if ACEA, a selective cannabinoid CB1 receptor agonist, could reverse the effects of corticosterone (CORT), characteristic of depressive and bladder overactivity potential. The animals (48 female rats) were divided into four groups: I-control, II-received CORT, III-received ACEA, and IV-received the combination of CORT and ACEA. The conscious cystometry, forced swim test (FST), and locomotor activity measurements were performed 3 days after the last dose of ACEA, followed by ELISA measurements. In group IV, ACEA restored urodynamic parameters that were altered by CORT. CORT prolonged the immobility time in FST and the values were lowered by ACEA. ACEA normalized the expression of c-Fos in all the analyzed central micturition centers (group IV vs. group II). ACEA restored the CORT-induced changes in the biomarkers in urine (BDNF, NGF), bladder detrusor (VAChT, Rho kinase), bladder urothelium (CGRP, ATP, CRF, OCT-3, TRPV1), and hippocampus (TNF-α, IL-1β and Il-6, CRF, IL-10, BDNF, NGF). In conclusion, ACEA was proven to reverse CORT-induced changes in both cystometric and biochemical parameters that are determinants of OAB/depression, which represents an example of an existing link between OAB and depression via cannabinoid receptors., Competing Interests: The authors declare no conflict of interest.

Parkinson's disease is a neurodegenerative disorder which is characterised mostly by loss of dopaminergic nerve cells throughout the nigral area mainly as a consequence of oxidative stress. Muscle stiffness, disorganised bodily responses, disturbed sleep, weariness, amnesia, and voice impairment are all symptoms of dopaminergic neuron degeneration and existing symptomatic treatments are important to arrest additional neuronal death. Some cannabinoids have recently been demonstrated as robust antioxidants that might protect the nerve cells from degeneration even when cannabinoid receptors are not triggered. Cannabinoids are likely to have property to slow or presumably cease the steady deterioration of the brain's dopaminergic systems, a condition for which there is now no treatment. The use of cannabinoids in combination with currently available drugs has the potential to introduce a radically new paradigm for treatment of Parkinson's disease, making it immensely useful in the treatment of such a debilitating illness., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors' expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.

Cannabinoid receptors are widely distributed in many cells in Rheumatoid arthritis RA and strengthening factor to boost the development of RA diseases. Here, the hollow mesoporous copper sulfide (CuS) was used as the carrier skeleton and the cannabinoid type 2 (CB2) receptor agonist JWH133 was efficiently loaded inside of CuS through adsorption, then the outer layer was modified with hyaluronic acid (HA) to prevent the leakage of internal drugs. After the CuS-JWH133@HA nano carrier reached the target area, HA responsive cracked under RA microenvironment to realize the first step of accurate drug delivery of JWH133, and the thermally responsive CuS under near-infrared (NIR) promoted the release of internal drugs. Then, JWH133 specifically combined CB2 receptors on the surface of macrophage, synovial cells and osteoblasts to realize the second step of drug delivery. The inflammatory factors secreted by cells are significantly inhibited, and the activity of osteoblasts was significantly enhanced. Therapeutic effect by CuS-JWH133@HA of RA was well verified by decreasing levels of inflammation in vivo and improvement of inflamed and swollen joints of mice. The CuS-JWH133@HA nanocomposite showed satisfactory multidimensional therapeutic effect of RA in vitro and in vivo, which provided a novel idea for RA treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Cannabinoids play critical roles in human pathophysiology through the cannabinoid (CB) receptors and non-CB receptors on variety of cells, tissues, and organs. Microvasculature with the inside bloodstream containing the plasmatic and cellular components exerts multiple functions in maintaining tissue and organ physiology through microcirculation. This review focusses on the impact of cannabinoids on the microvasculature, including mechanisms mediated by both CB receptor-related pathways and CB receptor-independent pathways.

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mitochondria play a critical role in the regulation of several biological processes (e.g., programmed cell death, inflammation, neurotransmission, cell differentiation). In recent years, accumulating findings have evidenced that cannabinoids, a group of endogenous and exogenous (synthetic and plant-derived) psychoactive compounds that bind to cannabinoid receptors, may modulate mitochondrial function and dynamics. As such, mitochondria have gained increasing interest as central mediators in cannabinoids' pharmacological and toxicological signatures. Here, we review the mechanisms underlying the cannabinoids' modulation of mitochondrial activity and dynamics, as well as the potential implications of such mitochondrial processes' disruption on cell homeostasis and disease. Interestingly, cannabinoids may target different mitochondrial processes (e.g., regulation of intracellular calcium levels, bioenergetic metabolism, apoptosis, and mitochondrial dynamics, including mitochondrial fission and fusion, transport, mitophagy, and biogenesis), by modulating multiple and complex signaling pathways. Of note, the outcome may depend on the experimental models used, as well as the chemical structure, concentration, and exposure settings to the cannabinoid, originating equivocal data. Notably, this interaction seems to represent not only an important feature of cannabinoids' toxicological signatures, with potential implications for the onset of distinct pathological conditions (e.g., cancer, neurodegenerative diseases, metabolic syndromes), but also an opportunity to develop novel therapeutic strategies for such pathologies, which is also discussed in this review., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The existence of a formal Endocannabinoid System in C. elegans has been questioned due to data showing the absence of typical cannabinoid receptors in the worm; however, the presence of a full metabolism for endocannabinoids, alternative ligands, and receptors for these agents and a considerable number of orthologous and homologous genes regulating physiological cannabinoid-like signals and responses - several of which are similar to those of mammals - demonstrates a well-structured and functional complex system in nematodes. In this review, we describe and compare similarities and differences between the Endocannabinoid System in mammals and nematodes, highlighting the basis for the integral study of this novel system in the worm., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin's immune response. In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases.

The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cannabinoid type 1 (hCB1) and type 2 (hCB2) receptors are pleiotropic and crucial targets whose signaling contributes to physiological homeostasis and its restoration after injury. Being predominantly expressed in peripheral tissues, hCB2R represents a safer therapeutic target than hCB1R, which is highly expressed in the brain, where it regulates processes related to cognition, memory, and motor control. The development of hCB2R ligands represents a therapeutic opportunity for treating diseases such as pain, inflammation and cancer. Identifying new selective scaffolds for cannabinoids and determining the structural determinants responsible for agonism and antagonism are priorities in drug design. In this work, a series of N -[1,3-dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulfonamides is designed and synthesized and their affinity for human hCB1R and hCB2R is determined. Starting with a scaffold selected from the NIH Psychoactive Drug Screening Program Repository, through a combination of molecular modeling and structure-activity relationship studies, we were able to identify the chemical features leading to finely tuned hCB2R selectivity. In addition, an in silico model capable of predicting the functional activity of hCB2R ligands was proposed and validated. The proposed receptor activation/deactivation model enabled the identification of four pure hCB2R-selective agonists that can be used as a starting point for the development of more potent ligands.

In the present study the interaction of cannabinoid, PhAR-DBH-Me [( R , Z )-18-((1 S ,4 S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-ylphenyl-acetate] and tramadol in two neuropathy models, as well as their possible toxic effects, was analyzed. The anti-allodynic effect of PhAR-DBH-Me, tramadol, or their combination, were evaluated in neuropathic rats. Furthermore, the effective dose 35 (as the 35 % of the anti allodynic effect) was calculated from the maximum effect of each drug. Moreover, the isobolographic analysis was performed to determine the type of interaction between the drugs. A plasma acute toxicity study was carried out to assess the hepatic, renal, and heart functions after an individual or combined administration of the drugs, as well as histology using the hematoxylin-eosin or Masson-trichome method. PhAR-DBH-Me, tramadol, and their combination produced an antiallodynic effect on spinal nerve ligation (SNL) and cisplatin-induced neuropathic pain in rats. Moreover, PhAR-DBH-Me and tramadol combination showed a synergistic interaction in neuropathic pain rats induced by SNL but not for cisplatin-induced neuropathy. On the other hand, changes in renal and hepatic functions were not observed. Likewise, analysis of liver, kidney and heart histology showed no alterations compared with controls. Results show that the combination of PhAR-DBH-Me and tramadol attenuates the allodynia in SNL rats; the acute toxicology analysis suggests that this combination could be considered safe in administered doses., (© 2022 Geovanna Nallely Quiñonez-Bastidas et al., published by Sciendo.)

The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The central nervous system produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that a moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because eCBs are biosynthesized from PUFAs. The primary eCB metabolites are derived from arachidonic acid, a 20:4n-6 (ω-6) PUFA, and the n-3 (ω-3) PUFAs, EPA and DHA. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulating appetite, influencing energy metabolism, supporting the immune system, and facilitating neuroplasticity. A diet containing different essential n-6 and n-3 PUFAs will dominate the formation of specific eCBs, and subsequently their actions as ligands for CB1 and CB2. The eCBs also function as substrates for cyclooxygenase enzymes, including potential substrates for the oxylipins (OxLs), which can be proinflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications for exercise responses via synthesis of eCBs and their effects on neuroinflammation. Neurotrophins also participate in interactions between diet and the eCBs, specifically brain-derived neurotrophic factor (BDNF). BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will describe the role of PUFAs in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence for exercise effects on eCBs, and describe eCB and BDNF actions on neuroplasticity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The cannabinoid system is ubiquitously present and is classically considered to engage in neural and immunity processes. Yet, the role of the cannabinoid system in the whole body and tissue metabolism via central and peripheral mechanisms is increasingly recognized. The present review provides insights in (i) how cannabinoid signaling is regulated via receptor-independent and -dependent mechanisms and (ii) how these signaling cascades (might) affect skeletal muscle plasticity and physiology. Receptor-independent mechanisms include endocannabinoid metabolism to eicosanoids and the regulation of ion channels. Alternatively, endocannabinoids can act as ligands for different classic (cannabinoid receptor 1 [CB 1 ], CB 2 ) and/or alternative (e.g., TRPV1, GPR55) cannabinoid receptors with a unique affinity, specificity, and intracellular signaling cascade (often tissue-specific). Antagonism of CB 1 might hold clues to improve oxidative (mitochondrial) metabolism, insulin sensitivity, satellite cell growth, and muscle anabolism, whereas CB 2 agonism might be a promising way to stimulate muscle metabolism and muscle cell growth. Besides, CB 2 ameliorates muscle regeneration via macrophage polarization toward an anti-inflammatory phenotype, induction of MyoD and myogenin expression and antifibrotic mechanisms. Also TRPV1 and GPR55 contribute to the regulation of muscle growth and metabolism. Future studies should reveal how the cannabinoid system can be targeted to improve muscle quantity and/or quality in conditions such as ageing, disease, disuse, and metabolic dysregulation, taking into account challenges that are inherent to modulation of the cannabinoid system, such as central and peripheral side effects., (© 2022 Wiley Periodicals LLC.)

Despite the very large number of phytocannabinoids isolated from Cannabis ( Cannabis sativa L.), bioactivity studies have long remained focused on the so called "Big Four" [Δ 9 -THC ( 1 ), CBD ( 2 ), CBG ( 3 ) and CBC ( 4 )] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as "minor phytocannabinoids", is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the "dark cannabinome", into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs.

Background: The endocannabinoid system (ECS) is composed of cannabinoid receptors type 1 (CBR1) and type 2 (CBR2), cannabinoid-based ligands (endogenous chemically synthesized phytocannabinoids), and endogenous enzymes controlling their concentrations. Cannabinoid receptors (CBRs) have been identified in invertebrates and in almost all vertebrate species in the central and peripheral nervous system as well as in immune cells, where they control neuroimmune homeostasis. In humans, rodents, dogs, and cats, CBRs expression has been confirmed in the skin, and their expression and tissue distribution become disordered in pathological conditions. Cannabinoid receptors may be a possible therapeutic target in skin diseases., Objectives: To characterize the distribution and cellular expression of CBRs in the skin of horses under normal conditions., Animals: Fifteen healthy horses., Methods: Using full-thickness skin punch biopsy samples, skin-derived primary epidermal keratinocytes and dermal-derived cells, we performed analysis of Cnr1 and Cnr2 genes using real-time PCR and CBR1 and CBR2 protein expression by confocal microscopy and Western blotting., Results: Normal equine skin, including equine epidermal keratinocytes and dermal fibroblast-like cells, all exhibited constant gene and protein expression of CBRs., Conclusions and Clinical Importance: Our results represent a starting point for developing and translating new veterinary medicine-based pharmacotherapies using ECS as a possible target., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa . Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.

Cannabinoids exert anti-cancer actions; however, the underlying cytotoxic mechanisms and the cannabinoid receptors (CBRs) involved remain unclear. In this study, CBRs were characterized in several cancer cell lines. Radioligand binding screens surprisingly revealed specific binding only for the non-selective cannabinoid [ 3 H]WIN-55,212-2, and not [ 3 H]CP-55,940, indicating that the expressed CBRs exhibit atypical binding properties. Furthermore, [ 3 H]WIN-55,212-2 bound to a single site in all cancer cells with high affinity and varying densities. CBR characteristics were next compared between human prostate cancer cell lines expressing low (PC-3) and high (DU-145) CBR density. Although mRNA for canonical CBRs was detected in both cell lines, only 5 out of 15 compounds with known high affinity for canonical CBRs displaced [ 3 H]WIN-55,212-2 binding. Functional assays further established that CBRs in prostate cancer cells exhibit distinct signaling properties relative to canonical G i /G o -coupled CBRs. Prostate cancer cells chronically exposed to both CBR agonists and antagonists/inverse agonists produced receptor downregulation, inconsistent with actions at canonical CBRs. Treatment of DU-145 cells with CBR ligands increased LDH-release, decreased ATP-dependent cell viability, and produced mitochondrial membrane potential depolarization. In summary, several cancer cell lines express CBRs with binding and signaling profiles dissimilar to canonical CBRs. Drugs selectively targeting these atypical CBRs might exhibit improved anti-cancer properties.

Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches.

Introduction: Cannabis (also known as marijuana) is the most frequently used psychoactive substance in the world. The role of cannabis in medicine is rapidly evolving, and advances in the understanding of its pharmacology have led to numerous proposed uses of these drugs., State of the Art: Cannabis contains Δ9-tetrahydrocannabinol and cannabidiol as the primary constituents responsible for pharmacological activity. It is now known that there are at least two types of cannabinoid receptors. CB1 receptors are found mainly in the CNS, and their primary role is to inhibit the release of neurotransmitters. CB2 receptors' leading role is to modulate cytokine release and immune cell migration. Colocalisation of cannabinoid receptors with other types of nervous system receptors allows them to interact with many other transmitters such as dopamine, noradrenaline, acetylcholine, gamma-aminobutyric acid, serotonin, and glutamic and aspartic acids., Clinical Implications: The rapidly expanding understanding regarding cannabinoids led to initial attempts to treat selected diseases with cannabinoid receptor agonists and antagonists. The most promising of these was the potential possibility of treating diseases for which current therapy is unsatisfactory, such as neurological diseases including multiple sclerosis, spastic muscular tension, extrapyramidal system diseases, neurodegenerative diseases and cerebral ischaemia. Attempts to treat psychiatric diseases (e.g. psychoses, neuroses, mood disorders, and alcohol dependence syndrome) with cannabinoids are much less advanced., Future Directions: Cannabis and cannabinoids can be widely used to treat several diseases or alleviate symptoms, but their efficacy for specific indications is not always apparent. Further exploration is needed to understand whether the enhanced sensitivity to the cognitive effects of Δ9-THC depends on brain cannabinoid receptor dysfunction, and how these changes contribute to the cognitive deterioration and core pathophysiology symptoms associated with schizophrenia or other neurological and somatoform disorders.

Introduction: Recent investigations have indicated the potential therapeutic role of cannabinoid type 2 (CB2) receptors in various inflammatory-related disorders. However, the role of these receptors has not been studied in skin flap models to date. In this study, we aimed to evaluate the possible involvement of CB2 receptors in the anti-inflammatory effects of sumatriptan, improving the random-pattern skin flap survival in rats., Methods: In a controlled experimental study, 36 male Wistar rats were randomly divided into 6 study groups (n = 6 per group). Two doses of sumatriptan (0.1 and 0.3 mg/kg) were administered intraperitoneally 30 min before harvesting the flap tissue. In a separate group, SR144528 (a selective CB2 receptor inverse agonist) was injected before the most effective dose of sumatriptan to determine the possible involvement of CB2 receptors in its action. Histopathological examinations, the expression level of CB2 receptors (Western blot analysis), and IL-1β and TNF-α concentrations (ELISA) were explored in the skin flap sampled tissues., Results: Sumatriptan 0.3 mg/kg remarkably enhanced the skin flap survival in all macroscopic and microscopic investigations compared to the control group (p < 0.001). IL-1β and TNF-α levels were significantly attenuated (p < 0.001), and the expression of CB2 receptors in skin cells was amplified in rats treated with sumatriptan 0.3 mg/kg (p < 0.05) compared to the control group. However, the administration of SR144528 (2 mg/kg) nullified all the protective effects of sumatriptan 0.3 mg/kg., Conclusion: We discovered that CB2 receptors play a crucial role in the favorable effects of sumatriptan on skin flap survival as a novel mechanism of action. So, targeting these receptors seems to be a dependable method in skin flap surgeries to ensure its survival and prevent tissue necrosis. Further experimental and clinical investigations are needed to ensure the safe clinical application of this method., (© 2021 S. Karger AG, Basel.)

Aims: Characterizing cannabinoid receptors (CBRs) expressed in Ewing sarcoma (EWS) cell lines as potential targets for anti-cancer drug development., Main Methods: CBR affinity and function were examined by competitive binding and G-protein activation, respectively. Cannabinoid-mediated cytotoxicity and cell viability were evaluated by LDH, and trypan blue assays, respectively., Key Findings: qRT-PCR detected CB1 (CB1R) and CB2 receptor (CB2R) mRNA in TC-71 cells. However, binding screens revealed that CBRs expressed exhibit atypical properties relative to canonical receptors, because specific binding in TC-71 could only be demonstrated by the established non-selective CB1/CB2R radioligand [ 3 H]WIN-55,212-2, but not CB1/CB2R radioligand [ 3 H]CP-55,940. Homologous receptor binding demonstrated that [ 3 H]WIN-55,212-2 binds to a single site with nanomolar affinity, expressed at high density. Further support for non-canonical CBRs expression is provided by subsequent binding screens, revealing that only 9 out of 28 well-characterized cannabinoids with high affinity for canonical CB1 and/or CB2Rs were able to displace [ 3 H]WIN-55,212-2, whereas two ligands enhanced [ 3 H]WIN-55,212-2 binding. Five cannabinoids producing the greatest [ 3 H]WIN-55,212-2 displacement exhibited high nanomolar affinity (K i ) for expressed receptors. G-protein modulation and adenylyl cyclase assays further indicate that these CBRs exhibit distinct signaling/functional profiles compared to canonical CBRs. Importantly, cannabinoids with the highest affinity for non-canonical CBRs reduced TC-71 viability and induced cytotoxicity in a time-dependent manner. Studies in a second EWS cell line (A-673) showed similar atypical binding properties of expressed CBRs, and cannabinoid treatment produced cytotoxicity., Significance: Cannabinoids induce cytotoxicity in EWS cell lines via non-canonical CBRs, which might be a potential therapeutic target to treat EWS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review., (© 2021. The Author(s).)

Introduction: Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. There is a growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties., Method: A database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types., Results: Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (-)-trans-Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB 1 and CB 2 , but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2., Conclusion: Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology. There is a need for further studies to characterise its mode of action at the molecular level and to delineate efficacious dosage and route of administration in addition to synergistic regimes., (© 2021. The Author(s).)

Since the Act on the medical use of cannabis, at which cannabis-based medicines and cannabinoids became law, there has been an exponential increase in prescriptions for the acquisition of cannabis for medical purposes. The aim of this leading article is to compile and assess the currently available relevant clinical evidence for the use of cannabis and cannabinoids for treatment of acute and chronic pain. Based on the systematic literature review "Cannabis-Potential and risks (CAPRIS)" commissioned by the German Federal Ministry of Health and the recently published recommendations of the European Pain Federation EFIC, this article aims to give an orientation aid for the decision-making process in the clinical routine.

Natural products make up a large proportion of medicine available today. Cannabinoids from the plant Cannabis sativa is one unique class of meroterpenoids that have shown a wide range of bioactivities and recently seen significant developments in their status as therapeutic agents for various indications. Their complex chemical structures make it difficult to chemically synthesize them in efficient yields. Synthetic biology has presented a solution to this through metabolic engineering in heterologous hosts. Through genetic manipulation, rare phytocannabinoids that are produced in low yields in the plant can now be synthesized in larger quantities for therapeutic and commercial use. Additionally, an exciting avenue of exploring new chemical spaces is made available as novel derivatized compounds can be produced and investigated for their bioactivities. In this review, we summarized the biosynthetic pathways of phytocannabinoids and synthetic biology efforts in producing them in heterologous hosts. Detailed mechanistic insights are discussed in each part of the pathway in order to explore strategies for creating novel cannabinoids. Lastly, we discussed studies conducted on biological targets such as CB1, CB2 and orphan receptors along with their affinities to these cannabinoid ligands with a view to inform upstream diversification efforts.

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Paland, Pechkovsky, Aswad, Hamza, Popov, Shahar and Louria-Hayon.)

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.

The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified. There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified. Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder. This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.

Derivatives of the plant Cannabis sativa have been used for centuries for both medical and recreational purposes, as well as industrial. The first proof of its medicinal use comes from ancient China, although there is evidence of its earlier utilization in Europe and Asia. In the 19th century, European practitioners started to employ cannabis extracts to treat tetanus, convulsions, and mental diseases and, in 1851, cannabis made its appearance in the Pharmacopoeia of the United States as an analgesic, hypnotic and anticonvulsant. It was only in 1937 that the Marijuana Tax Act prohibited the use of this drug in the USA. The general term Cannabis is commonly used by the scientific and scholar community to indicate derivatives of the plant Cannabis sativa. The word cannabinoid is a term describing chemical compounds that are either derivate of Cannabis (phytocannabinoids) or artificial analogues (synthetic) or are produced endogenously by the body (endocannabinoids). A more casual term "marijuana" or "weed", a compound derived from dried Cannabis flower tops and leaves, has progressively superseded the term cannabis when referred to its recreational use. The 2018 World health organisation (WHO) data suggest that nearly 2.5% of the global population (147 million) uses marijuana and some countries, such as Canada and Uruguay, have already legalised it. Due to its controversial history, the medicinal use of cannabinoids has always been a centre of debate. The isolation and characterisation of Δ 9 tetrahydrocannabinol (THC), the major psychoactive component of cannabis and the detection of two human cannabinoid receptor (CBRs) molecules renewed interest in the medical use of cannabinoids, boosting research and commercial heed in this sector. Some cannabinoid-based drugs have been approved as medications, mainly as antiemetic, antianorexic, anti-seizure remedies and in cancer and multiple sclerosis patients' palliative care. Nevertheless, due to the stigma commonly associated with these compounds, cannabinoids' potential in the treatment of conditions such as cancer is still largely unknown and therefore underestimated., (Copyright © 2020. Published by Elsevier Ltd.)