Divergent synthesis of fractionated Cannabis sativa extract led to multiple cannabinoids C-&O-glycosides with anti-proliferative/anti-metastatic properties.

Here, we present an interesting, previously unreported method for fractionating a particular class of cannabinoids from the crude leaf extract of Cannabis sativa using HP-20 resins. In this study, we report a novel method of divergent synthesis of fractionated Cannabis sativa extract, which allows the generation of multiple cannabinoids C- and O-glycosides which react with the glycosyl donor 2,3,4,6-tetra-O-acetyl-d-mannosyl trichloroacetimidate (TAMTA) to create eight C- and O-ß-d-cannabinoids glycosides (COCG), which are separated by HPLC and whose structures are characterized by 1D, 2D NMR, and mass spectrometry. These glycosides exhibit improved anti-proliferative and anti-metastatic effects against numerous cancer cell lines in vitro and are more water-soluble and stable than their parent cannabinoids. The in vitro testing of the pure cannabinoids (1-4) and their C- & O-glycosides (1a-4a) and 1b-4b exhibited anti-proliferative and anti-metastatic activities against a panel of eight human cancer cell lines in contrast to their respective parent molecules. Different cancer cell lines' IC50 values varied significantly when their cell viability was compared. In addition to the others, compounds 2a, 3a, 4a, and 2b, 3b were highly potent, with IC50values ranging from 0.74 µM (3a) to 51.40 µM (4a).Although2a(1.42 µM) and3a(0.74 µM) exhibited lower IC50values in the MiaPaca-2 cell line than4a(2.58 µM). But, in addition to the comparable anti-clonogenic activity of4ain MiaPaca-2 and Panc-1 cells, it manifested remarkable anti-invasive activity than either 2a or 3a.In contrast to 2a, 2b, 3a, and 3b and their respective parent compounds,4ahad substantial anti-invasive/anti-metastatic capabilities and possessed anti-proliferative activity.The effects of 4a treatment on MiaPaca-2 and Panc-1 cells include a dose-dependent increase in the expression of E-cadherin and a significant decrease in the expression of Zeb-1, Vimentin, and Snail1. Our results demonstrate that divergent synthesis of fractionated Cannabis sativa extract is a feasible and efficient strategy to produce a library of novel cannabinoid glycosides with improved pharmacological properties and potential anticancer benefits.

The putative cannabinoid-secreting trichome of Trema micrantha (L.) Blume (Cannabaceae).

Trema, a genus of the popularly known Cannabaceae, has recently been the subject of cannabinoid bioprospection. T. micrantha is a tree with pharmacological potential widely used in folk medicine. It has two types of glandular trichomes, bulbous and filiform, spread throughout the plant body. Considering the proximity of this species to Cannabis sativa and Trema orientalis, species containing cannabinoids, the glandular trichomes of T. micrantha are also expected to be related to the secretion of these compounds. Thus, this study aims to detail the morphology of secretory trichomes during the synthesis, storing and release of metabolites in T. micrantha. We tested the proposition that they could be a putative type of cannabinoid-secreting gland. Pistillate and staminate flowers and leaves were collected and processed for ontogenic, histochemical, and ultrastructural analyses. Both types of glandular trichomes originate from a protodermal cell. They are putative cannabinoid-secreting sites because: (1) terpene-phenols and, more specifically, cannabinoids were detected in situ; (2) their secretory subcellular apparatus is consistent with that found in C. sativa: modified plastids, polyribosomes, an extensive rough endoplasmic reticulum, and a moniliform smooth endoplasmic reticulum. Plastids and smooth endoplasmic reticulum are involved in the synthesis of terpenes, while the rough endoplasmic reticulum acts in the phenolic synthesis. These substances cross the plasma membrane by exocytosis and are released outside the trichome through cuticle pores. The study of the cell biology of the putative cannabinoid glands can promote the advancement of prospecting for natural products in plants.

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.

The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ9-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS)-made of receptors, metabolic enzymes, and transporters-that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of the ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here a critical review of our knowledge of the goods and bads of the ECS as a therapeutic target is presented to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. SIGNIFICANCE STATEMENT: The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like cannabinoid receptors 1 and 2) and metabolic enzymes (like fatty acid amide hydrolase and monoacylglycerol lipase), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels, providing new opportunities to treat patients.

Twice-daily oral administration of a cannabidiol and cannabidiolic acid-rich hemp extract was well tolerated in orange-winged Amazon parrots (Amazona amazonica) and has a favorable pharmacokinetic profile.

OBJECTIVE: To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects. ANIMALS: 12 birds. PROCEDURES: Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated. RESULTS: Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol. CLINICAL RELEVANCE: Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.

Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy.

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.

Novel insights into the antibacterial activities of cannabinoid biosynthetic intermediate, olivetolic acid, and its alkyl-chain derivatives.

Investigations of antibacterial activities revealed that the incorporation of longer alkyl chains to the C-6 position in resorcylic acid conferred antibacterial properties against Staphylococcus aureus and Bacillus subtilis. The resultant olivetolic acid (OA) derivatives with n-undecyl and n-tridecyl side-chains, even those lacking the hydrophobic geranyl moiety from their C-3 positions, exhibited strong antibacterial activities against B. subtilis at a MIC value of 2.5 µM. Furthermore, the study demonstrated that the n-heptyl alkyl-chain modification at C-6 of cannabigerolic acid (CBGA) effectively enhanced the activity against B. subtilis, demonstrating the importance of the alkyl side-chain in modulating the bioactivity. Overall, the findings in this study provided insight into further evaluations of the antibacterial activities, as well as other various biological activities of OA and CBGA derivatives, especially with optimized hydrophobicities at both the alkyl and prenyl side-chain positions of the core skeleton for the discovery of novel drug seeds.

Harnessing the advances of genetic engineering in microalgae for the production of cannabinoids.

Cannabis is widely recognized as a medicinal plant owing to bioactive cannabinoids. However, it is still considered a narcotic plant, making it hard to be accessed. Since the biosynthetic pathway of cannabinoids is disclosed, biotechnological methods can be employed to produce cannabinoids in heterologous systems. This would pave the way toward biosynthesizing any cannabinoid compound of interest, especially minor substances that are less produced by a plant but have a high medicinal value. In this context, microalgae have attracted increasing scientific interest given their unique potential for biopharmaceutical production. In the present review, the current knowledge on cannabinoid production in different hosts is summarized and the biotechnological potential of microalgae as an emerging platform for synthetic production is put in perspective. A critical survey of genetic requirements and various transformation approaches are also discussed.

Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.

The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.

The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.

A new UHPLC-MS/MS method for cannabinoids determination in human plasma: A clinical tool for therapeutic drug monitoring.

Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-Nor-9carboxy-Δ9-tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.

Dietary PUFAs and Exercise Dynamic Actions on Endocannabinoids in Brain: Consequences for Neural Plasticity and Neuroinflammation.

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 Role of Nutritional Status, Gastrointestinal Peptides, and Endocannabinoids in the Prognosis and Treatment of Children with Cancer.

Neoplastic diseases in children are the second most frequent cause of death among the young. It is estimated that 400,000 children worldwide will be diagnosed with cancer each year. The nutritional status at diagnosis is a prognostic indicator and influences the treatment tolerance. Both malnutrition and obesity increase the risk of mortality and complications during treatment. It is necessary to constantly search for new factors that impair the nutritional status. The endocannabinoid system (ECS) is a signaling system whose best-known function is regulating energy balance and food intake, but it also plays a role in pain control, embryogenesis, neurogenesis, learning, and the regulation of lipid and glucose metabolism. Its action is multidirectional, and its role is being discovered in an increasing number of diseases. In adults, cannabinoids have been shown to have anti-cancer properties against breast and pancreatic cancer, melanoma, lymphoma, and brain tumors. Data on the importance of both the endocannabinoid system and synthetic cannabinoids are lacking in children with cancer. This review highlights the role of nutritional status in the oncological treatment process, and describes the role of ECS and gastrointestinal peptides in regulating appetite. We also point to the need for research to evaluate the role of the endocannabinoid system in children with cancer, together with a prospective assessment of nutritional status during oncological treatment.

Maternal hypercaloric diet affects factors involved in lipid metabolism and the endogenous cannabinoid systems in the hypothalamus of adult offspring: sex-specific response of astrocytes to palmitic acid and anandamide.

Aim: We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes.Methods: We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide.Results: Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation (Tnfa and Il6) and gliosis (Gfap, vimentin and Iba1) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (vimentin), fatty acid oxidation (Cpt1a) and monounsaturated fatty acid synthesis (Scd1). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor (Cnr1) and Nape-pld, an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme Faah in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism.Conclusion: These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.

Activity of THC, CBD, and CBN on Human ACE2 and SARS-CoV1/2 Main Protease to Understand Antiviral Defense Mechanism.

THC, CBD, and CBN were reported as promising candidates against SARS-CoV2 infection, but the mechanism of action of these three cannabinoids is not understood. This study aims to determine the mechanism of action of THC, CBD, and CBN by selecting two essential targets that directly affect the coronavirus infections as viral main proteases and human angiotensin-converting enzyme2. Tested THC and CBD presented a dual-action action against both selected targets. Only CBD acted as a potent viral main protease inhibitor at the IC50 value of 1.86 ± 0.04 µM and exhibited only moderate activity against human angiotensin-converting enzyme2 at the IC50 value of 14.65 ± 0.47 µM. THC acted as a moderate inhibitor against both viral main protease and human angiotensin-converting enzymes2 at the IC50 value of 16.23 ± 1.71 µM and 11.47 ± 3.60 µM, respectively. Here, we discuss cannabinoid-associated antiviral activity mechanisms based on in silico docking studies and in vitro receptor binding studies.

Periprandial response of central cannabinoid system to different feeding conditions in rainbow trout Oncorhynchus mykiss.

BACKGROUND: The mechanisms that regulate food intake are very complex since they comprise several neuroendocrine and metabolic signals responding to energetic or reward requirements. Previous studies in mammals indicate that cannabinoid system is implicated in homeostatic and hedonic regulation of food intake. In fish, several studies describe the components of this system, but only a little information is available regarding their role in food intake and energy balance regulation. OBJECTIVES: The objective of this study was to evaluate the main components of cannabinoid system related to feeding conditions in fish. METHODS: Samples of blood and different brain areas (telencephalon and hypothalamus) were taken from rainbow trout under different nutritional status (fasted, fed and refed) at different periprandial times (-30, 0, +30 and +180 min). RESULTS: Changes in AEA and 2-AG levels were observed in plasma related to the nutritional status and the sampling times assessed. At central levels, changes in endocannabinoids levels were observed in hypothalamus and in mRNA abundance of cnr1 and tprv1 in telencephalon and faah, gpr55 and fos in both brain areas. DISCUSSION: The results obtained suggest a role of endocannabinoid system in the regulation of food intake in fish at central level but further studies are required to fully elucidate the mechanisms involved.

Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice.

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body's metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

Cannabinoids and sleep-wake cycle: The potential role of serotonin.

Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.

Therapeutic Potential for Cannabinoids in Sports Medicine: Current Literature Review.

ABSTRACT: Cannabidiol and other cannabinoids are being used more frequently for sports medicine-related conditions. This review will help sports medicine clinicians answer questions that their athletes and active patients have about the potential effectiveness of cannabinoids on common sports medicine conditions. In the article, the authors compare cannabidiol and delta-9-tetrahydrocannabinol effects, noting the difference on the endocannabinoid and nonendocannabinoid receptors. The theoretical benefits of these two compounds and the current legality in the United States surrounding cannabidiol and delta-9-tetrahydrocannabinol use also are addressed.

Effects of cannabinoid (CBD) on blood brain barrier permeability after brain injury in rats.

Cannabidiol is a natural herbal medicine known to protect the brain from traumatic brain injury (TBI). Here, a TBI rat model was established, with cannabidiol administered intraperitoneally at doses of 5, 10, or 20 mg/kg, 30 min before surgery and 6 h after surgery until sacrifice. Brain water content, body weight, and modified neurological severity scores were determined, and enzyme-linked immunosorbent assay, immunofluorescence staining, hematoxylin and eosin staining, Nissl staining, Evans-blue dye extravasation, and western blotting were performed. Results showed that cannabidiol decreased the number of aquaporin-4-positive and glial fibrillary acidic protein-positive cells. Cannabidiol also significantly reduced the protein levels of proinflammatory cytokines (TNF-α and IL-1ß) and significantly increased the expression of tight junction proteins (claudin-5 and occludin). Moreover, cannabidiol administration significantly mitigated water content in the brain after TBI and blood-brain barrier disruption and ameliorated the neurological deficit score after TBI. Cannabidiol administration improved the integrity and permeability of the blood-brain barrier and reduced edema in the brain after TBI.

Endocannabinoid System and Its Regulation by Polyunsaturated Fatty Acids and Full Spectrum Hemp Oils.

The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.