Maternal Cannabis Use during Lactation and Potential Effects on Human Milk Composition and Production: A Narrative Review.

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.

Cannabinoids in the treatment of glioblastoma.

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM. Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells. Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology. Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice. The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out. The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs. In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.

Timeframe Analysis of Novel Synthetic Cannabinoids Effects: A Study on Behavioral Response and Endogenous Cannabinoids Disruption.

This study investigates the impact of SCs consumption by assessing the effects of three novel synthetic cannabinoids (SCs); MDMB-CHMINACA, 5F-ADB-PINACA, and APICA post-drug treatment. SCs are known for their rapid onset (<1 min) and prolonged duration (≥5 h). Therefore, this research aimed to assess behavioral responses and their correlation with endocannabinoids (ECs) accumulation in the hippocampus, and EC's metabolic enzymes alteration at different timeframes (1-3-5-h) following drug administration. Different extents of locomotive disruption and sustained anxiety-like symptoms were observed throughout all-encompassing timeframes of drug administration. Notably, MDMB-CHMINACA induced significant memory impairment at 1 and 3 h. Elevated levels of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were detected 1 h post-MDMB-CHMINACA and 5F-ADB-PINACA administration. Reduced mRNA expression levels of fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) (AEA and 2-AG degrading enzymes, respectively), and brain-derived neurotrophic factor (BDNF) occurred at 1 h, with FAAH levels remaining reduced at 3 h. These findings suggest a connection between increased EC content and decreased BDNF expression following SC exposure. Cognitive disruption, particularly motor coordination decline and progressive loss manifested in a time-dependent manner across all the analyzed SCs. Our study highlights the importance of adopting a temporal framework when assessing the effects of SCs.

Toll-like receptor signalling as a cannabinoid target.

Toll-like receptors (TLRs) have become a focus in biomedicine and biomedical research given the roles of this unique family of innate immune proteins in immune activation, infection, and autoimmunity. It is evident that TLR dysregulation, and subsequent alterations in TLR-mediated inflammatory signalling, can contribute to disease pathogenesis, and TLR targeted therapies are in development. This review highlights evidence that cannabinoids are key regulators of TLR signalling. Cannabinoids include component of the plant Cannabis sativa L. (C. sativa), synthetic and endogenous ligands, and overall represent a class of compounds whose therapeutic potential and mechanism of action continues to be elucidated. Cannabinoid-based medicines are in the clinic, and are furthermore under intense investigation for broad clinical development to manage symptoms of a range of disorders. In this review, we present an overview of research evidence that signalling linked to a range of TLRs is targeted by cannabinoids, and such cannabinoid mediated effects represent therapeutic avenues for further investigation. First, we provide an overview of TLRs, adaptors and key signalling events, alongside a summary of evidence that TLRs are linked to disease pathologies. Next, we discuss the cannabinoids system and the development of cannabinoid-based therapeutics. Finally, for the bulk of this review, we systematically outline the evidence that cannabinoids (plant-derived cannabinoids, synthetic cannabinoids, and endogenous cannabinoid ligands) can cross-talk with innate immune signalling governed by TLRs, focusing specifically on each member of the TLR family. Cannabinoids should be considered as key regulators of signalling controlled by TLRs, and such regulation should be a major focus in terms of the anti-inflammatory propensity of the cannabinoid system.

Immune and glial cell alterations in the rat brain after repeated exposure to the synthetic cannabinoid JWH-018.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.

Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice.

OBJECTIVE: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D. METHODS: We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre+ Cnr1fl/fl) mice. We evaluated female NOD RIP Cre+ Cnr1fl/fl mice and their NOD RIP Cre-Cnr1fl/fl and NOD RIP Cre+ Cnr1Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation. RESULTS: Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre+ Cnr1fl/fl mice compared to wild-type littermates. NOD RIP Cre+ Cnr1fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node Treg cells were significantly higher in NOD RIP Cre+ Cnr1fl/flvs NOD RIP Cre-Cnr1fl/fl. CONCLUSIONS: Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D.

Evaluation of cannabimimetic effects of selected minor cannabinoids and Terpenoids in mice.

BACKGROUND: The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. Δ9-Tetrahydrocannabinol (Δ9-THC) is the plant's primary psychoactive constituent. Given the abuse liability of Δ9-THC, assessment of the psychoactive effects of minor cannabinoids and other plant constituents is important, especially for compounds that may be used medicinally. This study sought to evaluate select minor cannabinoids and terpenes for Δ9-THC-like psychoactivity in mouse Δ9-THC drug discrimination and determine their binding affinities at CB1 and CB2 receptors. METHODS: Δ9-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenevarin (CBCV), Δ8-tetrahydrocannabinol (Δ8-THC), (6aR,9R)-Δ10-tetrahydrocannabinol [(6aR,9R)-Δ10-THC], Δ9-tetrahydrocannabinol varin (THCV), ß-caryophyllene (BC), and ß-caryophyllene oxide (BCO) were examined. RESULTS: All minor cannabinoids showed measurable cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor binding, with CBC, CBCV, and CBD, showing the weakest CB1 receptor binding affinity. BC and BCO exhibited negligible affinity for both CB1 and CB2 receptors. In drug discrimination, only Δ8-THC fully substituted for Δ9-THC, while CBN and (6aR,9R)-Δ10-THC partially substituted for Δ9-THC. THCV and BCO did not alter the discriminative stimulus effects of Δ9-THC. CONCLUSION: In summary, only some of myriad cannabinoids and other chemicals found in the cannabis plant bind potently to the identified cannabinoid receptors. Further, only four of the compounds tested herein [Δ9-THC, Δ8-THC, (6aR,9R)-Δ10-THC, and CBN] produced Δ9-THC-like discriminative stimulus effects, suggesting they may possess cannabimimetic subjective effects. Given that the medicinal properties of phytocannabinoids and terpenoids are being investigated scientifically, delineation of their potential adverse effects, including their ability to produce Δ9-THC-like intoxication, is crucial.

Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Dual cytoplasmic-peroxisomal compartmentalization engineering and multiple metabolic engineering strategies for high yield non-psychoactive cannabinoid in Saccharomyces cerevisiae.

CBG (Cannabigerol), a nonpsychoactive cannabinoid, has garnered attention due to its extensive antimicrobial and anti-inflammatory properties. However, the natural content of CBG in Cannabis sativa L. is minimal. In this study, we developed an engineered cell factory for CBG production using Saccharomyces cerevisiae. We introduced the CBGA biosynthetic pathway into S. cerevisiae and employed several strategies to enhance CBGA production. These strategies included dynamically inhibiting the competitive bypass of key metabolic pathways regulated by Erg20p. Additionally, we implemented a dual cytoplasmic-peroxisomal compartmentalization approach to further increase CBGA production. Furthermore, we ensured efficient CBGA production by optimizing NADPH and acetyl-CoA pools. Ultimately, our engineered strain achieved a CBG titer of 138 mg L-1 through fed-batch fermentation in a 5 L bioreactor, facilitated by microwave decarboxylation extraction. These findings underscore the significant potential of yeast cell factories for achieving higher yields in cannabinoid production.

Engineering cannabinoid production in Saccharomyces cerevisiae.

Phytocannabinoids are natural products with highly interesting pharmacological properties mainly produced by plants. The production of cannabinoids in a heterologous host system has gained interest in recent years as a promising alternative to production from plant material. However, the systems reported so far do not achieve industrially relevant titers, highlighting the need for alternative systems. Here, we show the production of the cannabinoids cannabigerolic acid and cannabigerol from glucose and hexanoic acid in a heterologous yeast system using the aromatic prenyltransferase NphB from Streptomyces sp. strain CL190. The production was significantly increased by introducing a fusion protein consisting of ERG20WW and NphB. Furthermore, we improved the production of the precursor olivetolic acid to a titer of 56 mg L-1 . The implementation of the cannabinoid synthase genes enabled the production of Δ9 -tetrahydrocannabinolic acid, cannabidiolic acid as well as cannabichromenic acid, where the heterologous biosynthesis of cannabichromenic acid in a yeast system was demonstrated for the first time. In addition, we found that the product spectrum of the cannabinoid synthases localized to the vacuoles of the yeast cells was highly dependent on extracellular pH, allowing for easy manipulation. Finally, using a fed-batch approach, we showed cannabigerolic acid and olivetolic acid titers of up to 18.2 mg L-1 and 117 mg L-1 , respectively.

Human osteoclasts in vitro are dose dependently both inhibited and stimulated by cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

Legalized use of cannabis for medical or recreational use is becoming more and more common. With respect to potential side-effects on bone health only few clinical trials have been conducted - and with opposing results. Therefore, it seems that there is a need for more knowledge on the potential effects of cannabinoids on human bone cells. We studied the effect of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) (dose range from 0.3 to 30 µM) on human osteoclasts in mono- as well as in co-cultures with human osteoblast lineage cells. We have used CD14+ monocytes from anonymous blood donors to differentiate into osteoclasts, and human osteoblast lineage cells from outgrowths of human trabecular bone. Our results show that THC and CBD have dose-dependent effects on both human osteoclast fusion and bone resorption. In the lower dose ranges of THC and CBD, osteoclast fusion was unaffected while bone resorption was increased. At higher doses, both osteoclast fusion and bone resorption were inhibited. In co-cultures, both osteoclastic bone resorption and alkaline phosphatase activity of the osteoblast lineage cells were inhibited. Finally, we observed that the cannabinoid receptor CNR2 is more highly expressed than CNR1 in CD14+ monocytes and pre-osteoclasts, but also that differentiation to osteoclasts was coupled to a reduced expression of CNR2, in particular. Interestingly, under co-culture conditions, we only detected the expression of CNR2 but not CNR1 for both osteoclast as well as osteoblast lineage nuclei. In line with the existing literature on the effect of cannabinoids on bone cells, our current study shows both stimulatory and inhibitory effects. This highlights that potential unfavorable effects of cannabinoids on bone cells and bone health is a complex matter. The contradictory and lacking documentation for such potential unfavorable effects on bone health as well as other potential effects, should be taken into consideration when considering the use of cannabinoids for both medical and recreational use.

CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies.

The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1ß. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-ß/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.

Dual Engineering of Olivetolic Acid Cyclase and Tetraketide Synthase for the Formation of Longer Alkyl-Chain Olivetolic Acid Analogs and Their Antibacterial Activities.

Among presently used pharmaceuticals, about 60% were developed from natural products with unique chemical diversity and biological activities. Hence, the discovery of new bioactive compounds from natural products is still important for further drug development. In addition, breakthroughs in synthetic biology have also begun to produce many useful compounds through manipulations of the biosynthetic genes for secondary metabolites. Theoretically, this approach can also be exploited to generate new unnatural compounds by intermixing the genes from different biosynthetic pathways and/or engineering the secondary metabolite enzyme(s) with expanded substrate and product specificities. Δ9-Tetrahydrocannabinol (Δ9-THC), the heat-decarboxylated tetrahydrocannabinolic acid (Δ9-THCA) produced by Cannabis sativa, is the most important therapeutic cannabinoid due to its useful pharmacological features, such as analgesic, anti-emetic, anti-inflammatory, and anti-epileptic activities. In the structures of cannabinoids, the resorcinyl alkyl chain is a critical pharmacophore, and the therapeutic effects of Δ9-THC can be enhanced by converting the pentyl (C5) moiety at C-3 to other acyl moieties. Thus, the expansion of unnatural cannabinoids with different C-3 alkyl moiety analogs might establish an excellent platform for the further development of therapeutically beneficial cannabinoids. This article reviews the structure-based dual engineering of both enzymes responsible for the formation of the resorcinyl core of Δ9-THC and describes the effect of C-6 alkyl-length extension of olivetolic acid, along with related analogs, on the antibacterial activities against Bacillus subtilis and Staphylococcus aureus.

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathways.

Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of PINK1, PARKIN and BNIP3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathway.

Foldseek reveals a CBGA prenylating enzyme GlyMa_02G168000 from Glycine max.

The present research provides an application for an aromatic prenyltransferase from Glycine max for use in heterologous microorganism expression to generate cannabinoids. The known cannabinoid prenyltransferase CsPT04 was queried in FoldSeek. An enzyme derived from Glycine max known as GLYMA_02G168000, which is a predicted homogentisate solanyltransferase, was identified and found to have affinity for the prenylation of geranyldiphosphate (GPP) and olivetolic acid (OA) to produce cannabigerolic acid (CBGA) and cannabigerol (CBG). The in vitro production of CBGA was accomplished through the heterologous expression of this prenyltransferase in Saccharomyces cerevisiae. After growing the yeast cells, a purified microsomal fraction was harvested, which was rich in the membrane-bound prenyltransferase GlyMa_02G168000. Addition of purified microsomal fraction to a reaction matrix facilitated the successful prenylation of externally supplied OA with GPP, culminating in the production of CBGA. Structural comparisons revealed a notably closer similarity between GLYMA_02G168000 and CsPT04, compared to the similarity of other cannabinoid prenyltransferases with CsPT04. Herein, a novel application for a homogentisate solanyltransferase has been established towards the production of cannabinoids.

Syntheses of Cannabinoid Metabolites: Ajulemic Acid and HU-210.

Cannabinoid metabolites have been reported to be more potent than their parent compounds. Among them, ajulemic acid (AJA) is a side-chain analog of Δ9-THC-11-oic acid, which would be a good template structure for the discovery of more potent analogues. Herein, we optimized the key allylic oxidation step to introduce the C-11 hydroxy group with a high yield. A series of compounds was prepared with this condition applied including HU-210, 11-nor-Δ8-tetrahydrocannabinol (THC)-carboxylic acid and Δ9-THC-carboxylic acid.

The synthetic cannabinoids menace: a review of health risks and toxicity.

Synthetic cannabinoids (SCs) are chemically classified as psychoactive substances that target the endocannabinoid system in many body organs. SCs can initiate pathophysiological changes in many tissues which can be severe enough to damage the normal functionality of our body systems. The majority of SCs-related side effects are mediated by activating Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). The activation of these receptors can enkindle many downstream signalling pathways, including oxidative stress, inflammation, and apoptosis that ultimately can produce deleterious changes in many organs. Besides activating the cannabinoid receptors, SCs can act on non-cannabinoid targets, such as the orphan G protein receptors GPR55 and GPR18, the Peroxisome Proliferator-activated Receptors (PPARs), and the Transient receptor potential vanilloid 1 (TRPV1), which are broadly expressed in the brain and the heart and their activation mediates many pharmacological effects of SCs. In this review, we shed light on the multisystem complications found in SCs abusers, particularly discussing their neurologic, cardiovascular, renal, and hepatic effects, as well as highlighting the mechanisms that intermediate SCs-related pharmacological and toxicological consequences to provide comprehensive understanding of their short and long-term systemic effects.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.

Involvement of Cannabinoid Receptors and Adenosine A2B Receptor in Enhanced Migration of Lung Cancer A549 Cells Induced by γ-Ray Irradiation.

Residual cancer cells after radiation therapy may acquire malignant phenotypes such as enhanced motility and migration ability, and therefore it is important to identify targets for preventing radiation-induced malignancy in order to increase the effectiveness of radiotherapy. G-Protein-coupled receptors (GPCRs) such as adenosine A2B receptor and cannabinoid receptors (CB1, CB2, and GPR55) may be involved, as they are known to have roles in proliferation, invasion, migration and tumor growth. In this study, we investigated the involvement of A2B and cannabinoid receptors in γ-radiation-induced enhancement of cell migration and actin remodeling, as well as the involvement of cannabinoid receptors in cell migration enhancement via activation of A2B receptor in human lung cancer A549 cells. Antagonists or knockdown of A2B, CB1, CB2, or GPR55 receptor suppressed γ-radiation-induced cell migration and actin remodeling. Furthermore, BAY60-6583 (an A2B receptor-specific agonist) enhanced cell migration and actin remodeling in A549 cells, and this enhancement was suppressed by antagonists or knockdown of CB2 or GPR55, though not CB1 receptor. Our results indicate that A2B receptors and cannabinoid CB1, CB2, and GPR55 receptors all contribute to γ-radiation-induced acquisition of malignant phenotypes, and in particular that interactions of A2B receptor and cannabinoid CB2 and GPR55 receptors play a role in promoting cell migration and actin remodeling. A2B receptor-cannabinoid receptor pathways may be promising targets for blocking the appearance of malignant phenotypes during radiotherapy of lung cancer.

Feeding spent hemp biomass to lactating dairy cows: Effects on performance, milk components and quality, blood parameters, and nitrogen metabolism.

The legalization of industrial hemp by the 2018 Farm Bill in the United States has driven a sharp increase in its cultivation, including for cannabinoid extraction. Spent hemp biomass (SHB), produced from the extraction of cannabinoids, can potentially be used as feed for dairy cows; however, it is still illegal to do so in the United States, according to the US Food and Drug Administration Center for Veterinary Medicine, due to the presence of cannabinoids and the lack of data on the effect on animals. To assess the safety of this byproduct as feed for dairy cows, late-lactation Jersey cows (245 ± 37 d in milk; 483 ± 38 kg body weight; 10 multiparous and 8 primiparous) received a basal total mixed ration (TMR) diet plus 13% alfalfa pellet (CON) or 13% pelleted SHB for 4 wk (intervention period [IP]) followed by 4 wk of withdrawal period (WP), where all cows received only the basal TMR during WP. The dry matter intake (DMI), body weight, body condition score, milk yield, milk components, and fatty acid profile, blood parameters, N metabolism, methane emission, and activity were measured. Results indicated that feeding SHB decreased DMI mainly due to the low palatability of the SHB pellet, as the cows consumed only 7.4% of the total TMR with 13.0% SHB pellet offered in the ration. However, milk yield was not affected during the IP and was higher than CON during the WP, leading to higher milk yield/DMI. Milk components were not affected, except for a tendency in decreased fat percentage. Milk fat produced by cows fed SHB had a higher proportion of oleate and bacteria-derived fatty acids than CON. The activity of the cows was not affected, except for a shorter overall lying time in SHB versus CON cows during the IP. Blood parameters related to immune function were not affected. Compared with CON, cows fed SHB had a lower cholesterol concentration during the whole experiment and higher ß-hydroxybutyric acid during the WP, while a likely low-grade inflammation during the IP was indicated by higher ceruloplasmin and reactive oxidative metabolites. Other parameters related to liver health and inflammatory response were unaffected, except for a tendency for higher activity of alkaline phosphatase during IP and a lower activity of gamma-glutamyl transferase during WP in the SHB group versus CON. The bilirubin concentration was increased in cows fed SHB, suggesting a possible decrease in the clearance ability of the liver. Digestibility of the dry matter and protein and methane emission were not affected by feeding SHB. The urea, purine derivatives, and creatinine concentration in urine was unaffected, but cows fed SHB had higher N use efficiency and lower urine volume. Altogether, our data revealed a relatively low palatability of SHB affecting DMI with minimal biological effects, except for a likely low-grade inflammation, a higher N use efficiency, and a possible decrease in liver clearance. Overall, the data support the use of SHB as a safe feed ingredient for lactating dairy cows.