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This study assessed pasireotide, a somatostatin-receptor–binding analogue, at two dose levels for the treatment of Cushing's disease. The median urinary free cortisol level decreased by about 50% by month 2 and remained stable in the higher-dose and lower-dose groups. Cushing's disease is a rare disorder of chronic hypercortisolism due to a corticotropin-secreting pituitary adenoma. The disorder is associated with central obesity, osteoporosis, arterial hypertension, insulin resistance, glucose intolerance, diabetes mellitus, dyslipidemia, cardiovascular disease, and increased mortality. 1 – 5 Transsphenoidal surgery is the primary therapy in most patients, with remission rates of 65 to 90% when an expert pituitary surgeon operates. 6 However, remission definitions vary, and relapse occurs in up to 30% of patients. Second-line options include repeat pituitary surgery, radiation therapy, bilateral adrenalectomy, and medical therapy. However, current medical treatments have not been tested in large prospective, randomized trials. Corticotroph . . .

Social-evaluative stressors—experiences in which people feel they could be judged negatively—pose a major threat to adolescent mental health 1 – 3 and can cause young people to disengage from stressful pursuits, resulting in missed opportunities to acquire valuable skills. Here we show that replicable benefits for the stress responses of adolescents can be achieved with a short (around 30-min), scalable 'synergistic mindsets' intervention. This intervention, which is a self-administered online training module, synergistically targets both growth mindsets 4 (the idea that intelligence can be developed) and stress-can-be-enhancing mindsets 5 (the idea that one’s physiological stress response can fuel optimal performance). In six double-blind, randomized, controlled experiments that were conducted with secondary and post-secondary students in the United States, the synergistic mindsets intervention improved stress-related cognitions (study 1, n  = 2,717; study 2, n  = 755), cardiovascular reactivity (study 3, n  = 160; study 4, n  = 200), daily cortisol levels (study 5, n  = 118 students, n  = 1,213 observations), psychological well-being (studies 4 and 5), academic success (study 5) and anxiety symptoms during the 2020 COVID-19 lockdowns (study 6, n  = 341). Heterogeneity analyses (studies 3, 5 and 6) and a four-cell experiment (study 4) showed that the benefits of the intervention depended on addressing both mindsets—growth and stress—synergistically. Confidence in these conclusions comes from a conservative, Bayesian machine-learning statistical method for detecting heterogeneous effects 6 . Thus, our research has identified a treatment for adolescent stress that could, in principle, be scaled nationally at low cost. An online training module that synergistically targets two different mindsets can reduce stress levels in adolescents in the context of social-evaluative stressors—stressful experiences in which individuals fear that others are judging them negatively.

Background Hypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function. Methods In a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water. Results In human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five ( P  < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated ( P  < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis ( P  < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice ( P  < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo ( P  < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo ( P  < 0.05). Conclusions Glucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass. Graphical abstract

Rationale5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce.ObjectivesThe first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1β), as well as the acute psychedelic experience.MethodsAssessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA).Results5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment.ConclusionInhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

Corticosteroids are potent modulators of human higher cognitive function. They are released in response to stress, and are thought to be involved in the modulation of cognitive function by inducing distinct rapid nongenomic, and slow genomic changes, affecting neural plasticity throughout the brain. However, their exact effects on the neural correlates of higher-order cognitive function as performed by the prefrontal cortex at the human brain system level remain to be elucidated. Here, we targeted these time-dependent effects of corticosteroids on prefrontal cortex processing in humans using a working memory (WM) paradigm during functional MRI scanning. Implementing a randomized, double-blind, placebo-controlled design, 72 young, healthy men received 10 mg hydrocortisone either 30 min (rapid corticosteroid effects) or 240 min (slow corticosteroid effects), or placebo before a numerical n-back task with differential load (0- to 3-back). Corticosteroids' slow effects appeared to improve working memory performance and increased neuronal activity during WM performance in the dorsolateral prefrontal cortex depending on WM load, whereas no effects of corticosteroids' rapid actions were observed. Thereby, the slow actions of corticosteroids seem to facilitate adequate higher-order cognitive functioning, which may support recovery in the aftermath of stress exposure.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition often persisting into adulthood, characterized by inattention, impulsivity, and hyperactivity. Emerging research suggests a connection between ADHD and gut microbiota, highlighting probiotics as potential therapeutic agents. This study involved a double-blind, randomized controlled trial where college students with ADHD received either a multi-strain probiotic supplement or a placebo daily for three months. ADHD symptoms were evaluated using a computerized performance test (MOXO) and the MATAL questionnaire. Academic records provided performance data. Additionally, eating and sleeping habits, gastrointestinal symptoms, and anthropometrics were assessed through questionnaires before and after the intervention. Fingernail cortisol concentrations (FCC) measured the long-term activity of the hypothalamic–pituitary–adrenal axis. The findings indicated that the probiotic significantly decreased hyperactivity, improved gastrointestinal symptoms, and enhanced academic performance. A multivariate analysis identified age as a significant predictor, with younger participants experiencing greater overall benefits from the intervention. There was also a negative correlation between FCC and symptoms of attention and impulsivity. Furthermore, higher academic grades were associated with lower levels of hyperactivity and impulsivity. These results suggest a beneficial impact of probiotics on ADHD symptoms and lay the groundwork for further studies to evaluate the effects of various probiotic strains on clinical outcomes in ADHD.

The main hypothesis of this study in older adults is that repeated walks in a forest but not an urban environment for one month lead to reduced chronic stress compared to the previous month without any intervention. This was achieved by the measurement of cumulative cortisol concentrations in hair. Older adults of both sexes ( n  = 54; 71 ± 6.2 years) participated in a randomised, parallel-group trial. They were randomly assigned to a forest or an urban walking group. They completed two 40-minute walking sessions per week over one month. Hair samples and morning, as well as afternoon salivary samples, were collected at baseline and following one month of walking interventions. A significant reduction in cumulative hair cortisol was observed during the month of repeated forest but not urban walking compared to the previous month, indicating decreased chronic stress. Salivary cortisol concentrations decreased in the forest group only. No differences in salivary alpha-amylase activity were noticed. Walking activities had no negative impact on the diurnal rhythmicity of stress markers. Quality of life measures showed improvements in emotional well-being in the forest group. A negative correlation was found between hair cortisol and certain quality of life dimensions in urban but not forest groups. Repeated forest walks affect objective measures of chronic stress in older adults, evidenced by lower cumulative hair cortisol concentrations and improved emotional well-being. These findings encourage incorporating forest-based interventions into mental health programs for older adults aimed at enhancing well-being, stress coping, and cognitive functions.

Perceived ethnic discrimination is a stressor that negatively affects mental and physical health. To address this issue, we tested the feasibility and preliminary effectiveness of an ecological momentary music intervention for stress reduction in everyday life in Turkish immigrant women perceiving chronic ethnic discrimination. Following an intra-individual randomized design, we combined subjective assessments and biological measures (salivary cortisol and alpha-amylase). Using a smartphone-based app, twenty participants responded to stress- and discrimination-related items four times a day for 35 days, and additionally reported each stressful/discriminatory event they perceived. Participants were then randomly instructed to listen to music or not. At each measurement time point, participants provided saliva samples. The feasibility of the ecological momentary music intervention was indicated by high usage rates of the app and participants’ positive self-reports. We found immediate (post 1: b  =  − 14.64, p  = .045, post 2: b  =  − 14.62, p  = .047) and intermediate ( b  =  − 0.81, p  < .001) effects of music listening on subjective stress levels but not on biological stress levels. Our study provides valuable insights into the potential of music listening for stress reduction in the everyday life of Turkish immigrant women perceiving chronic ethnic discrimination.

Gastrointestinal (GI) symptoms are common and can affect children’s social lives. This study investigated the effects of exposure to a rich natural environment on GI symptoms, salivary cortisol levels, salivary amylase levels, and the gut microbiota in young children. Children aged 5–6 years from four kindergartens in Japan were randomly assigned to two groups: a nature childcare group and a regular childcare group. The children were exposed to their respective conditions once weekly for one month. Before and after the intervention, GI symptoms were detected using the Children’s Somatization Inventory to calculate a ‘GI score’ and categorize participants into GI and control groups (primary outcome measure). Fecal examinations were performed for gut microbiota using 16 S-rRNA analysis, salivary cortisol and amylase levels were quantified, and the Child Behavior Checklist was administered. The two groups had similar GI symptoms, salivary cortisol and amylase levels, and behavioral characteristics. Following the intervention, significant differences in the GI score, abdominal pain, constipation, Shannon index value, and salivary cortisol and amylase levels ( p  < 0.05) were observed between the two childcare groups. Spending free and abundant time in nature during early childhood could help maintain digestive system homeostasis, increase gut microbiota diversity, and reduce cortisol levels.

Substantial evidence supports the efficacy of cognitive bias modification (CBM) for attention and interpretation. However, CBM targeting memory bias (CBM-M) remains underexplored despite its clinical relevance. This study examines the effectiveness and neurobiological mechanisms of CBM-M. Fifty-eight individuals with elevated anxious and depressive personality traits (>1 SD) were randomly assigned to either CBM-M or sham training (n = 29 per group) in a parallel, double-blind, randomized controlled trial. The intervention involved eight sessions over 1 month. CBM-M aimed to enhance positive autobiographical memory (AM) recall by focusing on positive and negative words, whereas sham training lacked this enhancement module. Anxiety and depressive traits and symptoms, explicit and implicit memory biases, and AM specificity were assessed. Additionally, intrinsic functional connectivity was measured via functional magnetic resonance imaging, and cortisol levels were assayed via saliva collected at 10 time points across 2 days before and after the intervention. Both groups showed reduced anxiety and depressive traits from pre- to post-intervention. Compared with sham training, CBM-M specifically reduced stress vulnerability, negative explicit memory bias, and daytime cortisol levels, with a large effect size. Improvement in memory bias correlated with stress vulnerability and cortisol reductions. CBM-M also enhanced amygdala functional connectivity with the anteromedial orbitofrontal cortex in comparison with sham training from pre- to post-intervention. CBM-M reduced stress vulnerability and elicited neural changes in amygdala-anteromedial orbitofrontal cortex interactions, which were involved in social reward and AM recall. Future research should identify the most responsive populations and elucidate underlying mechanisms.