Liquid chromatography paired with tandem mass spectrometry (LC-MS/MS) is the gold standard in measurement of endocannabinoid concentrations in biomatrices. We conducted a systematic review of literature to identify advances in targeted LC-MS/MS methods in the period 2017-2024. We found that LC-MS/MS methods for endocannabinoid quantification are relatively consistent both across time and across biomatrices. Recent advances have primarily been in three areas: (1) sample preparation techniques, specific to the chosen biomatrix; (2) the range of biomatrices tested, recently favoring blood matrices; and (3) the breadth of endocannabinoid and endocannabinoid-like analytes incorporated into assays. This review provides a summary of the recent literature and a guide for researchers looking to establish the best methods for quantifying endocannabinoids in a range of biomatrices.

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.

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE\'s RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.

Increased circulating endocannabinoids levels are typically associated with aerobic exercise. This phenomenon is associated with a \"runner\'s high,\" a state of euphoria and well-being experienced after a long exercise. We will provide in this review a transparent and standardized methodology following the PRISMA-P and Cochrane Handbook for Systematic Reviews of Interventions for conducting a systematic review and meta-analysis for synthesizing the available evidence about the effects of physical activity on the circulating levels of AEA and 2-AG endocannabinoids in healthy subjects.
A multi-disciplinary team with basic and clinical expertise in exercise science developed this protocol. PubMed, EMBASE, Web of Science, CINAHL, SPORTDiscus, and Scopus will be the databases. A health sciences librarian was consulted in the development of the research. Search strategies will combine MeSH terms and free text words, including \"exercise,\" \"exercise, physical,\" \"exercise training,\" \"physical activity,\" \"endocannabinoids,\" \"2-arachidonoyl-glycerol,\" \"glyceryl 2-arachidonate,\" \"2-AG,\" \"anandamide,\" \"AEA,\" \"n-arachidonoylethanolamide,\" \"adult,\" \"young adult,\" and \"middle-aged.\" We will select experimental or quasi-experimental studies published through December 2021. The selection of studies, data extraction, assessment of the risk of bias, and the quality of evidence will be carried out in a paired and independent manner, and the consistency will be assessed using the statistics of Cohen Kappa. Methodological quality will be assessed using the Revised Cochrane risk of bias tool for randomized trials (RoB 2) and the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) risk tool. We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence, χ2 and I2 tests for heterogeneity, funnel plots, and the Egger test for publication bias. A meta-analysis for each data comparison will be performed whenever possible to determine the effect of physical activity on endocannabinoids\' circulating levels.
This systematic review and meta-analysis will provide an overview of the evidence about physical activity over AEA and 2-AG endocannabinoids, including comparability of variables between studies, critical interpretation of results, and use of accurate statistical techniques. The endocannabinoid is molecules by which muscles communicate with other tissues and organs, mediating the beneficial effects of exercise on health and performance, including increased glucose uptake, improved insulin action, and mitochondrial biogenesis. They are essential to exercise. Thus, this study will review the acute effect of physical exercise on circulating levels of endocannabinoids in healthy individuals. The results of this study will potentially be transferred to doctors, health professionals, and legislators to guide their decision making, as well as will improve future research.
PROSPERO CRD42020202886 .

Individuals with borderline personality disorder (BPD) or antisocial personality disorder (ASPD) are overrepresented in forensic settings. Yet, despite the burden these disorders place on healthcare and criminal justice systems, there remains a lack of evidence-based pharmacological treatments. Epidemiological data have shown that comorbid cannabis use disorders are common in BPD and ASPD. ∆9 -Tetrahydrocannabinol, the primary psychoactive constituent of cannabis, is an exogenous cannabinoid that stimulates the endocannabinoid system (ECS). Hence, an investigation of the ECS in these conditions is warranted. This scoping review screened 105 records and summarized the extant research on the ECS in ASPD (n = 69) and BPD (n = 61) participants. Preliminary results suggest that alterations of the ECS may be present in these disorders. Although research examining the ECS in personality disorders is still in its infancy, more research is warranted given initial positive findings.

Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.

Acetaminophen (APAP) in humans has robust effects with a high therapeutic index in altering postoperative and inflammatory pain states in clinical and experimental pain paradigms with no known abuse potential. This review considers the literature reflecting the preclinical actions of acetaminophen in a variety of pain models. Significant observations arising from this review are as follows: 1) acetaminophen has little effect upon acute nociceptive thresholds; 2) acetaminophen robustly reduces facilitated states as generated by mechanical and thermal hyperalgesic end points in mouse and rat models of carrageenan and complete Freund\'s adjuvant evoked inflammation; 3) an antihyperalgesic effect is observed in models of facilitated processing with minimal inflammation (eg, phase II intraplantar formalin); and 4) potent anti-hyperpathic effects on the thermal hyperalgesia, mechanical and cold allodynia, allodynic thresholds in rat and mouse models of polyneuropathy and mononeuropathies and bone cancer pain. These results reflect a surprisingly robust drug effect upon a variety of facilitated states that clearly translate into a wide range of efficacy in preclinical models and to important end points in human therapy. The specific systems upon which acetaminophen may act based on targeted delivery suggest both a spinal and a supraspinal action. Review of current targets for this molecule excludes a role of cyclooxygenase inhibitor but includes effects that may be mediated through metabolites acting on the TRPV1 channel, or by effect upon cannabinoid and serotonin signaling. These findings suggest that the mode of action of acetaminophen, a drug with a long therapeutic history of utilization, has surprisingly robust effects on a variety of pain states in clinical patients and in preclinical models with a good therapeutic index, but in spite of its extensive use, its mechanisms of action are yet poorly understood.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and patterns of restrictive and repetitive behavior. Although the neurological underpinnings of ASD remain elusive, the endocannabinoid system (ECS) may play a role in modulating social behavior in ASD. Preclinical studies have suggested that alterations in the ECS result in ASD-like phenotypes, but currently no reviews have examined ECS abnormalities in human studies. This scoping review investigated any evidence of ECS alterations in humans with ASD. A comprehensive literature search was conducted and five studies were eligible for review. Three studies reported a significant reduction of anandamide in ASD compared to controls. Other alterations included decreased 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide and elevated diacylglycerol lipase and monoacylglycerol lipase. Some discrepant findings were also noted, which included elevated or reduced CB2 receptor in three studies and elevated or reduced N-acyl phosphatidylethanolamine phospholipase D and fatty acid amide hydrolase in two studies. We conclude from this preliminary investigation that the ECS may be altered in humans with ASD. Potential limitations of the reviewed studies include medication use and psychiatric comorbidities. Further research, such as positron emission tomography studies, are necessary to fully understand the relationship between ECS markers and ASD.

The endocannabinoid system (ECS) is a cell-signaling system present in multiple organ systems and is an integral part of sustaining the microenvironment necessary for early pregnancy success and maintenance. It plays a significant role in embryo development, transport and implantation as well as placentation. The current theory behind the initiation of term labor is that it is a complex, multifactorial process involving sex steroid hormones, prostaglandin production and interplay at the maternal-fetal interface resulting in increased expression of receptors and gap junctions that promote uterine activation. There is increasing evidence that, in addition to early pregnancy events, the ECS plays a regulatory role in pregnancy maintenance and the timing of labor. This review presents an overview of the ECS in pregnancy that focuses on late gestation and parturition.

Studies investigating alterations of the endocannabinoid system (ECS) in Alzheimer\'s disease (AD) in humans have reported inconsistent findings so far. We performed a systematic review of studies examining alterations of the ECS specifically within humans with AD or mild cognitive impairment (MCI), including neuroimaging studies, studies of serum and cerebrospinal fluid biomarkers, and post-mortem studies. We attempted to identify reported changes in the expression and activity of: cannabinoid receptors 1 and 2; anandamide (AEA); 2-arachidonoylglycerol (2-AG); monoacylglycerol lipase (MAGL); fatty acid amide hydrolase (FAAH); and transient receptor potential cation channel V1 (TRPV1). Twenty-two studies were identified for inclusion. Mixed findings were reported for most aspects of the ECS in AD, making it difficult to identify a particular profile of ECS alterations characterising AD. The included studies tended to be small, methodologically heterogeneous, and frequently did not control for important potential confounders, such as pathological progression of AD. Eight studies correlated ECS alterations with neuropsychometric performance measures, though studies infrequently examined behavioural and neuropsychiatric correlates. PROSPERO database identifier: CRD42018096249.