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While psychotherapeutic treatments for posttraumatic stress disorder (PTSD) show in general good responses in affected individuals, 30–40% of patients show limited improvement. On a biological level, the endocannabinoid system of the body may play a role in the aftermath of trauma, in PTSD, and in extinction processes. This study is a secondary analysis of a randomized-controlled trial including patients with PTSD over the course of trauma-focused inpatient treatment. It aimed to investigate whether endocannabinoid system alterations are associated with symptom severity and treatment response. Fifty-four female inpatients with PTSD provided hair samples and completed psychometric questionnaires at pre-treatment, post-treatment, and 3-month follow-up. Endocannabinoid (EC: AEA, 1-AG/2-AG) and N -acylethanolamine (NAE: SEA, PEA, OEA) concentrations were measured in scalp-near 3-cm hair segments, reflecting cumulative concentrations in the 3 months prior to sampling. At pre-treatment, higher depressive and anxiety symptoms were significantly associated with lower hair AEA levels, whereas higher PTSD symptoms (when controlling for depressive symptoms) and more traumatic experiences were significantly associated with higher hair AEA and NAE levels respectively. PTSD symptoms improved across treatment, remaining stable at 3-month follow-up, but were predicted neither by pre-treatment hair ECs/NAEs nor their changes across treatment and follow-up, which was confirmed in subgroup analyses. Our findings suggest that hair ECs/NAEs may be distinctly linked with trauma-related and affective and anxiety symptoms, however, do not predict treatment response in PTSD. This challenges expectations and highlights the complexity of endocannabinoid system alterations in stress-related psychopathology. Given the study’s limitations, including a female-only sample and lack of a control group, larger studies with control groups and multiple biomarkers are needed to identify intervention-related biomarkers in PTSD. Highlights Hair endocannabinoids and N -acylethanolamines at pre-treatment and their change were unrelated to PTSD symptoms across treatment and follow-up At pre-treatment, hair AEA associated negatively with pre-treatment depressive and anxiety symptoms At pre-treatment, hair AEA associated positively with PTSD symptoms after controlling for depressive symptoms At pre-treatment, more traumatic experiences were related to higher hair SEA, PEA, and OEA levels in female inpatients with PTSD

Pediatric major depressive disorder (MDD) represents a leading cause of disability worldwide in children and adolescents, while its underlying pathophysiology remains largely elusive. The endocannabinoid system (ECS) and the hypothalamus-pituitary-adrenal (HPA) axis are considered intertwined regulatory systems crucially implicated in the pathophysiology of depressive disorders. This study explores the cross-sectional and longitudinal association between the ECS, specifically anandamide (AEA), and the HPA axis with its main effector cortisol and MDD status and severity in children and adolescents. Utilizing data from the omega-3-pMDD trial, a phase III Randomized Clinical Trial assessing the efficacy and safety of omega-3 fatty acid supplementation in pediatric MDD, we examined hair AEA and cortisol concentrations in 110 children and adolescents aged 8-17 years, with MDD. Associations between MDD, symptom severity and hair AEA and cortisol concentrations were explored across four measurement time points (baseline, week 6, 24 and 36). Additionally, 127 healthy children and adolescents were examined once to enable cross-sectional comparisons between MDD cases and healthy controls. Baseline comparisons for the 237 children and adolescents showed lower cortisol and AEA levels in hair of children and adolescents with MDD compared to healthy controls. Longitudinal multi-level analysis over all time-points further corroborated negative longitudinal associations between hair cortisol and depressive symptoms in children and adolescents with MDD. Taken together, reduced baseline AEA and cortisol levels emerge as robust biomarker in depressed youth, while the negative longitudinal association between hair cortisol and depression symptoms might provide useful for therapy monitoring purposes. These results hold implications for early detection, diagnosis, and therapeutic response prediction in pediatric MDD.

IntroductionObesity is a major health concern in postmenopausal women, and chronic low-grade inflammation contributes to the development of obesity. Cellular studies and high-fat-diet-induced obese mouse model mimicking obesity show the antiobesity effect of annatto-extracted tocotrienols (TT) with antioxidant capability. We aim to assess the safety and efficacy of TT consumption for lipid-related parameters in obese postmenopausal women.Methods and analysisEligible obese postmenopausal women will be randomly assigned to placebo group (430 mg olive oil) and TT group (DeltaGold Tocotrienol 70%) for 24 weeks. In the present study, the primary outcome is total/regional fat mass and visceral adipose tissue. The secondary outcomes include lipid profile in serum, mRNA expression of fatty acid synthase and carnitine palmitoyltransferase 1A in fat tissue, oxylipins and endocannabinoids in plasma and adipose tissue, abundance and composition of intestinal microbiome in faeces, high-sensitivity C-reactive protein (hs-CRP) in serum and leptin in serum. Every participant will be evaluated at 0 (prior to starting intervention) and 24 weeks of intervention, except for serum lipid profile and hs-CRP at 0, 12 and 24 weeks. ‘Intent-to-treat’ principle is employed for data analysis. Hierarchical linear modelling is used to estimate the effects of dietary TT supplementation while properly accounting for dependency of data and identified covariates. To our knowledge, this is the first randomised, placebo-controlled, double-blinded study to determine dietary TT supplementation on an obese population. If successful, this study will guide the future efficacy TT interventions and TT can be implemented as an alternative for obese population in antiobesity management.Ethics and disseminationThis study has been approved by the Bioethics Committee of the Texas Tech University Health Sciences Center, Lubbock. An informed consent form will be signed by a participant before enrolling in the study. The results from this trial will be actively disseminated through academic conference presentation and peer-reviewed journals.Trial registration numberNCT03705845.

Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.

The endocannabinoid system and its extension, the endocannabinoidome (eCBome), are involved in numerous biological processes, notably energy homeostasis, across virtually all tissues. While the circulating eCBome mediator profile is associated with dietary intakes and metabolic status, an important knowledge gap resides in the identification of the precise determinants of these mediators in the gut lumen. We aimed at establishing the profile of eCBome mediators in human feces and investigating their association with circulating eCBome mediators, dietary intakes, metabolic status, and gut microbiota composition. N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2-MAGs) were profiled by liquid chromatography coupled to tandem mass spectrometry in plasma and feces of a cross-sectional cohort (n = 195) and a short-term dietary intervention trial (n = 21) with comprehensive dietary intakes and gut microbiota measures. Six NAEs and 7 2-MAGs were identified in fecal samples, but some, especially omega-3-derived mediators, were undetectable in the majority of samples. Fecal NAEs, and to a lower extent 2-MAGs, were positively albeit weakly correlated with the circulating levels of eCBome mediators. Fecal 2-arachidonoyl-glycerol, N-palmitoyl-ethanolamine, and N-docosahexaenoyl-ethanolamine levels were positively associated with visceral adiposity and with some parameters of the metabolic profile. Dietary intakes of foods rich in fibers were associated with lower fecal levels of several eCBome mediators, while intakes of unsaturated fatty acids were associated with fecal 2-oleoyl-glycerol and 2-linoleoyl-glycerol. Interestingly, gut microbiota diversity and composition were a strong correlate of the fecal eCBome profile. The fecal eCBome profile is associated with gut microbiota composition and dietary intakes, more than with the circulating profile. These results strengthen the hypothesis of an interrelation between the gut microbiome and eCBome signaling involved in the regulation of numerous host biological processes.

Analysis of endocannabinoids (ECs) and N -acylethanolamines (NAEs) in hair is assumed to retrospectively assess long-term EC/NAE concentrations. To inform their use, this study investigated stability of EC/NAE hair concentrations in mothers, fathers, and their children across the perinatal period as well as associations between family members. In a prospective cohort study, EC (AEA, 1-AG/2-AG) and NAE (SEA, PEA, OEA) levels were quantified in hair samples taken four times in mothers ( n  = 336) and their partners ( n  = 225) from pregnancy to two years postpartum and in offspring ( n  = 319) from shortly after birth to two years postpartum. Across the perinatal period, maternal and paternal hair ECs/NAEs showed poor multiple-test consistency (16–36%) and variable relative stability, as well as inconsistent absolute stability for mothers. Regarding children, hair ECs/NAEs evidenced poor multiple-test consistency (4–19%), no absolute stability, and either no or variable relative stability. Hair ECs/NAEs showed small to medium significant associations across the perinatal period within couples and parent–child dyads. Findings suggest hair ECs/NAEs during the perinatal period possess variable stability in adults, albeit more stability in fathers than mothers in this time. This highlights the need to further investigate factors associated with changes in hair ECs/NAEs across time. The first two years of life may be a dynamic phase for the endocannabinoid system in children, potentially characterized by complex within-family correspondence that requires further systematic investigation.

Background/Objectives: Endocannabinoids are endogenous bioactive lipids that promote neurodevelopment and positive energy balance. Increased levels of endocannabinoids are associated with obesity, but the effect of maternal obesity on breast milk endocannabinoids across lactation is mostly unknown. Methods: Women from Rio de Janeiro (Brazil) (n = 92) were followed from the third trimester of pregnancy to 119 days postpartum, and milk samples were analyzed in the postpartum days 2–8 (T1), 28–47 (T2), and 88–119 (T3). We assessed the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) by high-performance liquid chromatography–mass spectrometry, leptin and insulin by immunoassay, and macronutrients by colorimetric assays in milk samples. Results: Milk AEA concentration was higher in T2 compared with T1 or T3, while 2-AG levels were higher in T2 and T3 compared with T1. Milk endocannabinoids were directly correlated with pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and milk triglycerides. Triglyceride and leptin levels were higher in mature milk (T2 and T3) of women with BMI > 25 or excessive GWG. Adjusted linear regression models showed a positive association between excessive GWG and milk 2-AG (β = 1629; 95% CI: 467–2792; p = 0.008). Conclusions: The endocannabinoid levels are higher in mature milk from women with obesity or excessive GWG, which may impact offspring development and metabolism.

In this study, a novel approach was developed to quantify endocannabinoids (eCBs), and was based on the liquid biosensor BIONOTE. This device is composed of a probe that can be immersed in a solution, and an electronic interface that can record a current related to the oxy-reductive reactions occurring in the sample. The two most representative members of eCBs have been analysed in vitro by BIONOTE: anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Bovine serum albumin was used to functionalize the probe and improve the sensibility of the whole analytical system. We show that BIONOTE is able to detect both AEA and 2-AG at concentrations in the low nanomolar range, and to discriminate between these eCBs and their moieties arachidonic acid, ethanolamine and glycerol. Notably, BIONOTE distinguished these five different molecules, and it was also able to quantify AEA in human plasma. Although this is just a proof-of-concept study, we suggest BIONOTE as a cheap and user-friendly prototype sensor for high throughput quantitation of eCB content in biological matrices, with an apparent diagnostic potential for tomorrow’s medicine.

A common method to quantify chronic stress is the analysis of stress markers in keratinized matrices such as hair or nail. In this study, we aimed to validate a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the combined quantification of steroid hormones and endocannabinoids (eCBs) in the keratinized matrix nail. Furthermore, we aimed to investigate the suitability of the nail matrix for the detection of these stress markers in a pilot study. An LC–MS/MS method was used for the simultaneous identification and quantification of four eCBs (2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA)) and five steroid hormones (cortisol, cortisone, androstenedione, progesterone, testosterone) in human nails using a surrogate analyte method for each analyte. The method was validated in terms of selectivity, response factor, linearity, limit of quantification (LOQ), precision, accuracy, matrix effect, recovery, robustness, and autosampler stability. Nail samples were extracted for 1 h with methanol following a clean-up with a fully automated supported liquid extraction (SLE). The influence of nail weight on the quantification was investigated by using 0.5–20 mg of nail sample. As a proof of concept, nail samples (N = 57) were analyzed from a cohort representing newborns (1 month old), children (between 1 and 10 years), and adults (up to 43 years). It could be shown that the established workflow using a 1 hour extraction and clean-up by SLE was very robust and resulted in a short sample preparation time. The LC–MS/MS method was successfully validated. Matrix effects with ion enhancement occurred mainly for 2-AG. Sample weights below 5 mg showed variations in quantification for some analytes. Certain analytes such as PEA and progesterone could be accurately quantified at a sample weight lower than 5 mg. This is the first study where steroids and eCBs could be simultaneously detected and quantified in infant and adult nails. These results show that nails may serve as an alternative keratinized matrix (compared to hair) for the retrospective monitoring of cumulative eCB and steroid hormone levels. The combined assessment of eCBs and steroids from nails could provide a new approach to gain new insights into stress exposure in newborns and adults.

N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are lipid signalling molecules within the endocannabinoid system, which regulates numerous physiological processes and is implicated in diverse pathological conditions. Given the limited feasibility of obtaining human tissue samples, quantifying AEA and 2-AG in biological matrices is essential for understanding the endocannabinoid system in humans. While many studies have used blood samples for this purpose, the collection of this matrix typically requires invasive venipuncture, which limits the scalability and practicality of endocannabinoid research. This study validated extraction and LC–MS/MS methods for quantifying AEA and 2-AG (co-quantified with its isomer 1-AG) in minimally invasive matrices, including saliva and finger-prick blood microsamples, with acceptable linearity, recovery, reproducibility, and matrix effects. The assay additionally enabled exploratory quantification of arachidonic acid, oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and selected steroid hormones, supporting multiplexed assessment from a single sample. Analyte concentrations measured in blood microsamples did not directly correspond to plasma concentrations, indicating that microsampling is suited for assessing relative within-study changes rather than absolute plasma equivalence. Application of the method demonstrated that venipuncture did not significantly alter salivary AEA or 2-AG concentrations. Overall, this method provides a minimally invasive and accessible approach for investigating endocannabinoid dynamics alongside other physiological biomarkers.