Marijuana has been used by humans for thousands of years for both medicinal and recreational purposes. This included the treatment of pain, inflammation, seizures, and nausea. In the 1960s, the structure of the principal psychoactive ingredient Δ9-tetrahydrocannabinol was determined, and over the next few decades, two cannabinoid receptors were characterized along with the human endocannabinoid system and what it affects. This includes metabolism, the cardiovascular and reproductive systems, and it is involved in such conditions as inflammation, cancer, glaucoma, and liver and musculoskeletal disorders. In the central nervous system, the endocannabinoid system has been linked to appetite, learning, memory, and conditions such as depression, anxiety, schizophrenia, stroke, multiple sclerosis, neurodegeneration, addiction, and epilepsy. It was the profound effectiveness of cannabidiol, a non-psychoactive ingredient of marijuana, to relieve the symptoms of Dravet syndrome, a severe form of childhood epilepsy, that recently helped spur marijuana research. This has helped substantially to change society\'s attitude towards this potential source of useful drugs. However, research has also revealed that the actions of endocannabinoids, such as anandamide and 2-arachidonoylglycerol, and the phytocannabinoids, tetrahydrocannabinol and cannabidiol, were not just due to interactions with the two cannabinoid receptors but by acting directly on many other targets including various G-protein receptors and cation channels, such as the transient receptor potential channels for example. This mini-review attempts to survey the effects of these 4 important cannabinoids on these currently identified targets.

The endocannabinoid system (ECS) regulates neurotransmission linked to synaptic plasticity, cognition, and emotion. While it has been demonstrated that dysregulation of the ECS in adulthood is relevant not only to central nervous system (CNS) disorders such as autism spectrum disorder, cognitive dysfunction, and depression but also to brain function, there are few studies on how dysregulation of the ECS in the neonatal period affects the manifestation and pathophysiology of CNS disorders later in life. In this study, DO34, a diacylglycerol lipase alpha (DAGLα) inhibitor affecting endocannabinoid 2-AG production, was injected into C57BL/6N male mice from postnatal day (PND) 7 to PND 10, inducing dysregulation of the ECS in the neonatal period. Subsequently, we examined whether it affects neuronal function in adulthood through electrophysiological and behavioral evaluation. DO34-injected mice showed significantly decreased cognitive functions, attributed to impairment of hippocampal synaptic plasticity. The findings suggest that regulation of ECS activity in the neonatal period may induce enduring effects on adult brain function.

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been reported to exhibit anticancer effects, including against colorectal cancer (CRC); however, the detailed mechanisms have not been clarified. Herein, we demonstrated that 2-AG suppressed cyclooxygenase-2 (COX-2) expression induced by prostaglandin E2 in human colon cancer HCA-7 cells. The suppression of COX-2 expression by 2-AG was through the acceleration of processing body (P-body) formation followed by COX-2 mRNA degradation. These effects were restored by TAK-715, a specific inhibitor of p38 MAPK. Therefore, the effect of 2-AG on COX-2 may be distinct from conventional non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the function of COX-2, whereas 2-AG suppresses the protein expression of COX-2. Recently, the cardiovascular risks of NSAIDs were reported by the Food and Drug Administration in the United States. Therefore, elucidation of the effect of 2-AG is expected to contribute to the development of an alternative and novel therapeutic option that would have no or fewer risks regarding cardiovascular events.

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.

Fentanyl has become the leading driver of opioid overdoses in the United States. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigated the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity measured via actigraphy was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. We found that female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl administration increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24-h of withdrawal. On withdrawal day 2, only females showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.

Background: Dysregulation of the endocannabinoid (eCB) system is implicated in various stress-related neuropsychiatric disorders (SRDs), including anxiety, depression, and post-traumatic stress disorder (PTSD). In this systematic review and meta-analysis, our objectives were to characterize circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations at rest and in response to acute laboratory-based psychosocial stress in individuals with SRDs and without (controls). Our primary aims were to assess the effects of acute psychosocial stress on eCB concentrations in controls (Aim 1), compare baseline (prestress) eCB concentrations between individuals with SRDs and controls (Aim 2), and explore differential eCB responses to acute psychosocial stress in individuals with SRDs compared with controls (Aim 3). Methods: On June 8, 2023, a comprehensive review of the MEDLINE (PubMed) database was conducted to identify original articles meeting inclusion criteria. A total of 1072, 1341, and 400 articles were screened for inclusion in Aims 1, 2, and 3, respectively. Results: Aim 1, comprised of seven studies in controls, revealed that most studies reported stress-related increases in AEA (86%, with 43% reporting statistical significance) and 2-AG (83%, though none were statistically significant except for one study in saliva). However, meta-analyses did not support these patterns (p\'s>0.05). Aim 2, with 20 studies, revealed that most studies reported higher baseline concentrations of both AEA (63%, with 16% reporting statistical significance) and 2-AG (60%, with 10% reporting statistical significance) in individuals with SRDs compared with controls. Meta-analyses confirmed these findings (p\'s<0.05). Aim 3, which included three studies, had only one study that reported statistically different stress-related changes in 2-AG (but not AEA) between individuals with PTSD (decrease) and controls (increase), which was supported by the meta-analysis (p<0.001). Meta-analyses showed heterogeneity across studies and aims (I2=14-97%). Conclusion: Despite substantial heterogeneity in study characteristics, samples, and methodologies, consistent patterns emerged, including elevated baseline AEA and 2-AG in individuals with SRDs compared with controls, as well as smaller stress-related increases in 2-AG in individuals with SRDs compared with controls. To consider eCBs as reliable biomarkers and potential intervention targets for SRDs, standardized research approaches are needed to clarify the complex relationships between eCBs, SRDs, and psychosocial stress.

OBJECTIVE: To compare the levels of endocannabinoids (EC) in plasma, aqueous humor and tears, cortisol in plasma and aqueous, in primary angle closure glaucoma (PACG) and controls, while comparing the quality of life in both groups.
METHODS: A total of 60 patients, ≥40years of age, with a diagnosis of PACG or cataract, 30 in each group were recruited. They were subjected to a detailed ophthalmic evaluation, a WHO Quality of Life Brief Version (WHOQOL-BREF) questionnaire answering and collection of tear, aqueous and blood samples. The levels of endocannabinoids-anandamide (AEA), 2-arachidonoylglycerol (2AG) in plasma, aqueous humor and tears; cortisol in plasma and aqueous humor; and WHO-QOL score in each group were noted.
RESULTS: Plasma AEA (p = 0.01) and plasma 2-AG, (p = 0.002) levels were significantly higher in the control group as compared to the PACG group. WHO-QOL score was better in controls (p < 0.001). The EC were in undetectable levels in aqueous. Plasma and aqueous cortisol were significantly higher in PACG and both had the highest Area under the receiver operating characteristics (AUROC) curve value for differentiating PACG from controls. Tear 2AG and tear AEA had a moderately strong positive correlation with plasma 2-AG. Females had insignificantly higher levels of plasma and tear endocannabinoids.
CONCLUSIONS: Tear endocannabinoids were determined for the first time in PACG and normal with no difference between the two groups. Plasma and aqueous cortisol levels are a differentiating factor between normal and glaucoma patients with plasma endocannabinoids being remarkably higher in normals. Quality of life in glaucoma patients with high cortisol levels is poorer.

Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.

UNASSIGNED: Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice.
UNASSIGNED: Tat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxiety-like behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex.
UNASSIGNED: Tat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression.
UNASSIGNED: Findings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system.

Microglia and macrophages can influence the evolution of myelin lesions through the production of extracellular vesicles (EVs). While microglial EVs promote in vitro differentiation of oligodendrocyte precursor cells (OPCs), whether EVs derived from macrophages aid or limit OPC maturation is unknown.
Immunofluorescence analysis for the myelin protein MBP was employed to evaluate the impact of EVs from primary rat macrophages on cultured OPC differentiation. Raman spectroscopy and liquid chromatography-mass spectrometry was used to define the promyelinating lipid components of myelin EVs obtained in vitro and isolated from human plasma.
Here we show that macrophage-derived EVs do not promote OPC differentiation, and those released from macrophages polarized towards an inflammatory state inhibit OPC maturation. However, their lipid cargo promotes OPC maturation in a similar manner to microglial EVs. We identify the promyelinating endocannabinoids anandamide and 2-arachidonoylglycerol in EVs released by both macrophages and microglia in vitro and circulating in human plasma. Analysis of OPC differentiation in the presence of the endocannabinoid receptor antagonists SR141716A and AM630 reveals a key role of vesicular endocannabinoids in OPC maturation. From this study, EV-associated endocannabinoids emerge as important mediators in microglia/macrophage-oligodendrocyte crosstalk, which may be exploited to enhance myelin repair.