Purpose: Insufficient sleep is common and under-reported, linked to increased health risks. Many individuals seek alternatives to conventional medications, which often have adverse side effects. Patients and Methods: This monocentric, single-arm, open-label exploratory study (Reg. No: NCT05748574) evaluated a granulate formulation containing 75 mg extract of the fresh herb of Lactuca sativa, 190 mg Melissa officinalis,120 mg L-Tryptophan, and 60 mg Magnesium in healthy adults with sleep disturbances. Conducted in Germany in 2023, 50 subjects consumed the formula nightly for 14 days. Outcomes were assessed via diaries, questionnaires, cognitive tests, wearables, saliva samples, and polysomnography (PSG) in a 10-subject subgroup. Statistical analysis compared pre- and post-treatment differences. Results: Nightly awakenings reduced by 31% (p < 0.001) and early morning awakenings by 16% (p < 0.001). PSG data indicated a 28% increase in deep sleep (N3&N4, p > 0.05), a 70% rise in stage N4 (p = 0.042) and an 18% reduction in REM sleep (p > 0.05). The Apnea-Hypopnea index decreased by 26% (p = 0.11). Sleep quality ("Sleep questionnaire" SF-B/R index, primary outcome) improved by 14% (p = 0.003), with a 37% improvement in highly anxious individuals (p <= 0.001). Restedness increased by 22% in week 1 and 28% in week 2 (p <= 0.001). Psychological tension dropped by 21% and up to 29% (p <= 0.001). Daytime performance indicators included a 13% reduction in sleepiness and a 23% improvement in mood (p <= 0.014). Executive function showed a 13% improvement (p <= 0.001) on computerized tests (COMPASS). Findings from wearables, sleep quantity, and salivary biomarkers yielded an inconsistent picture. Adherence was high, with no serious adverse events reported. Conclusion: The formulation was associated with observed improvements in subjective sleep quality-particularly among anxious individuals-as well as well-being and daytime function. Further confirmation through randomized placebo-controlled studies is warranted to further prove causality.

Background & aims: Sleep disturbances are widespread in modern societies and linked to a variety of diseases, creating an urgent need for the development of products that help combat sleep difficulties. One suitable nutritional supplement may be a fish hydrolysate composed of low molecular weight peptides. Methods: This two -arm, double-blind, randomized, placebo -controlled crossover study investigated the effect of a 4 -week fish hydrolysate intervention on sleep in a healthy German population reporting poor sleep quality, assessed with the Pittsburgh Sleep Quality Index (PSQI). Further sleep parameters were measured using an online diary and a wrist wearable device. Additionally, questionnaires related to stress, anxiety, depression, and well-being were evaluated and salivary cortisol and product satisfaction were assessed. Results: The 4 -week fish hydrolysate supplementation significantly improved subjective sleep quality measured with the PSQI-score (p = .002). Moreover, individuals reported improvements in sleep efficacy and a reduction in sleep disturbances and daytime sleepiness during fish hydrolysate intake (p = .013, p = .046, p = .004 respectively), but not during placebo phase (all p > .05). No significant intra-individual differences were found between fish hydrolysate and placebo supplementation (p > .05). Conclusions: Although no significant intra-individual differences were found between fish hydrolysate and placebo supplementation, the significant improvement in subjective sleep quality from baseline to treatment phase suggests that fish hydrolysate is a safe nutritional supplement to support individuals with self -reported sleep problems. Clinical trial registration: The study is registered at ClinicalTrials.gov with the Identifier NCT04 983355. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Acute stress is a contributing factor to mood and anxiety disorders, but few treatments safely address physiological stress. Allopregnanolone is an endogenous neurosteroid GABAA positive allosteric modulator (PAM) with anti-depressant and anxiolytic activity but low oral bioavailability. LYT-300, an oral prodrug of allopregnanolone that uses the Glyph™ technology platform, has enhanced oral bioavailability. We tested the potential for LYT-300 to blunt stress reactivity in a randomized, double-blinded, placebo-controlled study of healthy participants using the Trier Social Stress Test (TSST), a validated clinical model of anxiety.

ObjectiveThis Phase IV placebo-controlled clinical trial was designed to demonstrate the efficacy and safety of the product Neurodoron (Kalium phosporicum comp., KPC) in patients with neurasthenia.MethodsThis monocenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (registration number: DRKS00003261) was conducted in an outpatient German trial site. Women and men aged 18 and above were randomized to receive either KPC or placebo if they reported typical symptoms of neurasthenia and a severe psychiatric disorder could be excluded. The primary objectives were a reduction in characteristic symptoms of nervous exhaustion and perceived stress as well as improvement in general health status after 6 weeks of treatment.ResultsIn total, 204 patients underwent screening, 78 were randomized in each treatment group, and 77 patients each received treatment (intention-to-treat (ITT) population = 154 patients). For none of the primary efficacy variables, an advantage in favor of KPC could be demonstrated in the pre-specified analysis (p-values between 0.505-0.773, Student's t-test). In a post-hoc analysis of intra-individual differences after 6 weeks treatment, a significant advantage of KPC vs. placebo was shown for characteristic symptoms of nervous exhaustion (irritability (p = 0.020); nervousness (p = 0.045), Student's t-test). Adverse event (AE) rates were similar between treatment groups, in both groups six AEs were assessed as causally related to treatment (severity mild or moderate). No AE resulted in discontinuation of treatment.ConclusionsTrial treatment was well tolerated with only a few and minor AEs reported, confirming the markedly good safety of KPC. A significant improvement of neurasthenia was seen for the total study population at the end of the treatment period. Superiority of KPC vs. placebo could not be demonstrated with the pre-specified analysis with regards to a sum score of 12 typical symptoms, perceived stress, or general health status. However, the explorative post-hoc analysis revealed that KPC is superior to placebo in the characteristic symptoms irritability and nervousness. KPC could therefore be a beneficial treatment option for symptomatic relief of neurasthenia.

1 Abstract Introduction The term neurasthenia has been introduced in the late 19th century. Stress was indicated as one of the main triggers. Many treatment options are available to reduce the associated symptoms. Complementary and alternative medicine (CAM) is widely used due to its long tradition and positive safety profile. This Phase IV placebo-controlled clinical trial was designed to demonstrate efficacy and safety of the CAM-product Neurodoron® in patients with neurasthenia. Methods This monocentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted in a dedicated outpatient German trial site. Women and men aged 18 and above were randomized to receive either Neurodoron® or matching placebo if they reported typical symptoms of neurasthenia and a severe psychiatric disorder could be excluded. The primary objectives were a reduction in characteristic symptoms of nervous exhaustion and perceived stress as well as improvement in general health status after 6 weeks of treatment. Results 204 patients underwent screening, 78 were randomized in each treatment group, and 77 patients each received treatment (intention-to-treat (ITT) population = 154 patients). For none of the primary efficacy variables, an advantage in favor of Neurodoron® could be demonstrated in the pre-specified analysis (p-values between 0.505 to 0.773, Student’s t-test). In a post-hoc analysis of intra-individual differences after 6 weeks treatment, a significant advantage of Neurodoron® vs. placebo was shown for characteristic symptoms of nervous exhaustion (irritability (p = 0.020); nervousness (p = 0.045), Student’s t-test). Adverse Event (AE) rates were similar between treatment groups, in both groups 6 AEs were assessed as causally related to treatment (severity mild or moderate). No AE resulted in discontinuation of treatment. Conclusion A significant improvement of neurasthenia was seen for the total study population at the end of the treatment period. Superiority of Neurodoron® vs. placebo could not be demonstrated with the pre-specified analysis. However, the post-hoc analysis suggests Neurodoron® as a beneficial option over placebo for the treatment of neurasthenia, especially given its confirmed markedly good safety.

Introduction . Stress is associated with a multitude of physical and psychological health impairments. To tackle these health disorders, over-the-counter (OTC) products like Neurodoron® are popular since they are considered safe and tolerable. Experience reports and first studies indicate that Neurodoron® is efficient in the treatment of stress-associated health symptoms. To confirm this, a non-interventional study (NIS) with pharmacies was conducted. Methods . The NIS was planned to enroll female and male patients who suffered from nervous exhaustion with symptoms caused by acute and/or chronic stress. The main outcome measures were characteristic stress symptoms, stress burden, and perceived stress. Further outcome measures included perceived efficacy and tolerability of the product as assessed by the patients and collection of adverse drug reactions (ADRs). A study duration of about 21 days with a recommended daily dose of 3–4 tablets was set. Results . 279 patients were enrolled at 74 German pharmacies. The analyzed set (AS) included 272 patients (mean age 44.8 ± 14.4 years, 73.9% female). 175 patients of the AS completed the NIS. During the study, all stress symptoms declined significantly (total score 18.1 vs. 12.1 (of max. 39 points), p  < 0.0001). Furthermore, a reduction of stress burden (relative difference in stress burden, VAS = −29.1%, p  < 0.0001) was observed. For most patients, perceived stress was reduced at the study end (PSQ total score decreased in 70.9% of the patients). 75.9% of the study population rated the product efficacy as “good” or “very good” and 96.6% rated its tolerability as “good” or “very good.” One uncritical ADR was reported. Discussion/Conclusion . This study adds information on the beneficial effects of Neurodoron® in self-medication. The results from this NIS showed a marked reduction in stress burden and perceived stress, along with an excellent safety profile of the medicinal product (MP) Neurodoron®. Further trials are required to confirm these results.

AbstractBackgroundCognitive health is a major concern for many people, and with potential benefits to academic and professional life, maximising cognitive performance is of interest far beyond the older demographics. Several natural products have been suggested as nootropics, including the herb sage. Previous assessments of various Salvia species have reported a range of effects on cognitive performance and mood in both older adult and younger adult populations. This study was conducted with Sibelius™: Sage, an aqueous-ethanol extract of S. officinalis, to assess for the beneficial effects on cognitive performance in adolescents (12-14 year olds) and young adults (18-25 year olds).Methods and FindingsAn acute, double-blind, placebo-controlled study was conducted with two single doses of Sibelius™: Sage (150 mg and 300 mg). Cognitive performance was evaluated using CogTrack™, which probes aspects of cognitive performance covering attention, working memory and episodic/declarative memory through a series of computer-based tasks. Consistent with previous study of Sibelius™: Sage a significant effect was seen on the Immediate Word Recall task in young adults; suggesting acute treatment benefits to verbal episodic/declarative memory performance. Physiological effects of the treatment on salivary cortisol and oxytocin levels, as well as blood pressure and heart rate were also assessed, with limited evidence of an effect on these factors. No adverse events or side-effects linked to the study product intake was observed. The study was registered at the German Clinical Trials Register (DRKS-ID: DRKS00015716).ConclusionsA significant improvement due to the Sage extract was shown for a task assessing short-term episodic memory (Immediate Word Recall), supporting beneficial effects on cognitive performance in young adults that are consistent with previous reports in healthy older adults. These findings suggest that further investigation of the effects observed in this study in larger, long-term human volunteer studies could be beneficial to pursue.

Chronic stress is a risk-factor for the development of mood and stress-related disorders. Clinical evidence indicates that probiotics can influence the stress response and mood. The Sisu study investigated whether Lacticaseibacillus paracasei Lpc-37® (Lpc-37®) could modulate stress, mood and well-being. Prior to a two-week run-in period, 120 healthy adults (18-45 y) were stratified for sex and chronic stress and randomized to either 1.75 × 1010 colony forming units (CFU) of Lpc-37 or placebo (1:1) per day for 5 weeks. The primary objective was the effect of Lpc-37 on heart rate (HR) in response to the Trier Social Stress Test (TSST). Secondary objectives were assessed by biomarkers and self-report scales over the study. The primary hypothesis was not met in either the Intention-to-Treat (ITT) or Per Protocol (PP) population, but Lpc-37 reduced the increase in HR in participants with low chronic stress (LCS) and increased HR in participants with high chronic stress (HCS) during the TSST. Supporting significant efficacy in the PP population (n = 113), Lpc-37 reduced perceived stress following intervention. More significant effects were identified within the subgroups where Lpc-37 reduced exhaustion during the TSST and normalized cortisol levels at 8pm in participants with LCS, reduced perceived stress also in females, and increased perceived health and sleep-related recovery in participants with HCS. Adverse events (AEs) were similar between groups, there were no severe AEs, and vital signs remained unchanged. Overall, Lpc-37 reduced perceived stress compared to placebo. Other beneficial effects within biomarkers related to stress indicate that the effects of Lpc-37 may be differentially dependent on sex and chronic stress. (ClinicalTrials.gov: NCT03494725).

neuropattern: a translational tool to reduce stress in the workplace Objectives: The study assesses the usefulness of a novel translational tool, neuropattern, in the prevention of stress-related disorders by means of personalised diagnostics and treatment measures derived therefrom. It took the form of a pilot study with a wait list control group. Methods: 70 employees of the Forestry Department Rhineland-Palatinate in Germany were assigned to an experimental group or a wait list control group by means of block randomisation and underwent neuropattern diagnostics either immediately at the start of the study or after a waiting period of three months. After the diagnostic assessment, all study participants received an explanatory disease model and access to individualised online self-help, whilst their physicians were provided with a diagnostic report and treatment recommendations. Questionnaires on health (SF-12), stress perception (PSS), emotional exhaustion (MBI), work-related stress (ERI), work ability (WAI) and health behaviour were used at the start of the study and after three months in order to assess possible beneficial effects of neuropattern. Results: Compared to the control group, the application of neuropattern in the experimental group resulted in a greater improvement in mental health, a significant increase in sporting activity and a significantly higher reduction in perceived stress, emotional exhaustion, overexertion and burnout in the workplace. No significant differences were found with regard to the development of physical health, current work ability, work-related reward, effort-reward ratio and practice of relaxation methods. Contrary to expectations, it was possible to observe growing pessimism about future work ability and a higher increase in sick leave in the experimental group as compared to the control group. Conclusions: The present study delivers initial findings on the usefulness of neuropattern diagnostics in a non-clinical population. However, further research is required to determine the best operating conditions. Keywords: work-related stress – burnout – prevention – conceptual endophenotypes – personalised medicine – neuropattern

Changing working conditions demand adaptation, resulting in higher stress levels in employees. In consequence, decreased productivity, increasing rates of sick leave, and cases of early retirement result in higher direct, indirect, and intangible costs. The aim of the study was to test the usefulness of a novel translational tool, Neuropattern, for early detection, prevention, and personalized treatment of stress-related disorders. The trial was designed as a pilot study with a wait list control group. In this study, 70 employees of the Forestry Department Rhineland-Palatinate, Germany were block-randomized and either underwent Neuropattern immediately, or after a waiting period of three months. After the diagnostic assessment, they received an explanatory disease model and individualized online counseling while their physicians were provided with diagnostic results and treatment recommendations. In order to assess possible beneficial effects of Neuropattern, questionnaires regarding health (SF-12), stress perception (PSS), emotional exhaustion (MBI), work stress (ERI) and work ability (WAI) as well as questions on health behavior were included at several time points. The application of Neuropattern resulted in significantly higher increase in measures of mental health and sporting activity and a significantly stronger decrease in perceived stress, emotional exhaustion and overcommitment, as compared to the control group. No such differences were found with regard to subjects’ physical health, current work ability, reward, effort-reward ratio and practice of relaxation methods. In addition, we unexpectedly found that subjects of the experimental group became significantly more pessimistic regarding their future work ability and showed higher rates of sick leave than control subjects did. These changes remained consistent during 3 and 6 months of follow-up. The present study encouraged the application of Neuropattern to early intervention in non-clinical populations. However, further research is required to determine the best operating conditions.

INTRODUCTION:Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress. METHODS:In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs). RESULTS:In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related. CONCLUSIONS:These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.

Background & aims: Many women experience emotional and physical symptoms around the time of ovulation and more so before menstruation interfering with their daily normal life also known as premenstrual syndrome (PMS). Recent observational data suggest that supplementation with Lipogen's phosphatidylserine (PS) and phosphatidic acid (PA) complex (PAS) alleviates these PMS symptoms. The aim of this study was to confirm these observations on the effects of PAS on PMS symptom severity within a controlled clinical trial setting. Methods: Forty women aged 18-45 years with a diagnosis of PMS were assigned to either take PAS (containing 400 mg PS & 400 mg PA per day) or a matching placebo. The study comprised 5 on-site visits including 1 baseline menstrual cycle followed by 3 treatment cycles. Treatment intake was controlled for by using an electronic device, the Medication Event Monitoring System (MEMS (R)). Primary outcome of the study was the PMS symptoms severity as assessed by using the Daily Record of Severity of Problems (DRSP). Further, SIPS questionnaire (a German version of the Premenstrual Symptoms Screening Tool (PSST)), salivary hormone levels (cortisol awakening response (CAR) and evening cortisol levels) as well as serum levels (cortisol, estradiol, progesterone and corticosteroid binding globulin (CBG)) were assessed. Results: PMS symptoms as assessed by the DRSP Total score showed a significantly better improvement (p = 0.001) over a 3 cycles PAS intake as compared to placebo. In addition, PAS treated women reported a greater improvement in physical (p = 0.002) and depressive symptoms (p = 0.068). They also reported a lower reduction of productivity (p = 0.052) and a stronger decrease in interference with relationships with others (p = 0.099) compared to the placebo group. No other DRSP scale or item showed significant results. Likewise, the reduction in the number of subjects fulfilling PMS or premenstrual dysphoric disorder (PMDD) criteria as classified by the SIPS did not differ between the PAS and the placebo group. For the biomarkers, the salivary cortisol percentage increase of the CAR was significantly less pronounced in the follicular phase of cycle 4 than in the follicular phase of cycle 1 for subjects taking PAS when compared to subjects taking placebo (p = 0.018). Furthermore, the change of serum cortisol levels between visit 1 and visit 5 differed significantly between groups (p = 0.043). While serum cortisol levels of PAS treated females slightly decreased between visit 1 and visit 5, cortisol levels of females treated with placebo increased. For all other biomarkers, no treatment effects were observed over the 4 cycles study period. Overall, this study confirms that a daily intake of PAS, containing 400 mg PS and 400 mg PA, can be considered as safe. Conclusions: Results substantiate the efficacy of PAS in reducing symptoms of PMS. In view of the recent inclusion of severe PMS symptoms (PMDD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the positive results of this clinical study merits consideration of developing the PAS complex as a botanical drug for treatment of PMDD. Clinical trial registration: The study is registered at Deutsches Register Klinischer Studien with the registration number DRKS00009005. (c) 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

Intranasal oxytocin (OXT) application is emerging as a potential treatment for socio-emotional disorders associated with abnormalities in OXT system (re-) activity. The crucial identification of patients with such abnormalities could be streamlined by the assessment of basal and stimulus-induced OXT concentrations in saliva, using a simple, stress-free sampling procedure (i.e. an OXT challenge test). We therefore established the Regensburg Oxytocin Challenge (ROC) test to further validate salivary OXT concentrations as a practical, reliable and sensitive biomarker.OXT concentrations were quantified by radioimmunoassay in samples collected at home by healthy adult male and female volunteers before and after running ("Run") or sexual self-stimulation ("Sex"). In lactating women, salivary OXT concentrations were quantified before, during and after breastfeeding. Salivary OXT along with salivary cortisol and heart rate were monitored in healthy adult participants undergoing the Trier Social Stress Test (TSST).The home-based "Run" and "Sex" challenges as well as the laboratory-based TSST caused quantifiable, rapid, and consistent increases in salivary OXT (approximately 2.5-fold after 10-15 min), which were similar for men and women. Breastfeeding did not result in measurably increased salivary OXT levels, probably because the short pulses of OXT release characteristic for lactation were missed.Taken together, ROC tests reliably assess the responsiveness of the OXT system (i.e., the increase in salivary OXT concentrations as compared to basal levels) to challenges such as "Run" and "Sex" at home or psychosocial stress (TSST) in the laboratory. Further studies with larger sample numbers are essentially needed in order to reveal individual differences in ROC test outcomes depending on, for example, genetic or environmental factors. (C) 2015 Elsevier Ltd. All rights reserved.

BACKGROUND:Supplementation with a phosphatidylserine and phosphatidylserine/ phosphatidic acid complex (PAS) has been observed to normalize stress induced dysregulations of the hypothalamus-pituitary-adrenal axis (HPAA). Prolonged stress first induces a hyper-activation of the HPAA, which then can be followed by a state of hypo-activation.The aim of this study was to examine effects of an oral supplementation with 400 mg PS & 400 mg PA (PAS 400) per day on the endocrine stress response (ACTH, saliva and serum cortisol) to a psychosocial stressor. A special focus was to analyze subgroups of low versus high chronically stressed subjects as well as to test efficacy of 200 mg PS & 200 mg PA (PAS 200).METHODS:75 healthy male volunteers were enrolled for this double-blind, placebo-controlled study, stratified by chronic stress level, and randomly allocated to one of three study arms (placebo, PAS 200 and PAS 400 per day, respectively). Study supplementation was administered for 42 days for each participant. Chronic stress was measured with the Trier Inventory for Chronic Stress (TICS), and subgroups of high and low chronic stress were differentiated by median values as provided by the TICS authors. A six week period of supplementation was followed by an acute stress test (Trier Social Stress Test - TSST).RESULTS:Chronic stress levels and other baseline measures did not differ between treatment groups (all p>0.05). Acute stress was successfully induced by the TSST and resulted in a hyper-responsivity of the HPAA in chronically stressed subjects. Compared to placebo, a supplementation with a daily dose of PAS 400 was effective in normalizing the ACTH (p=0.010), salivary (p=0.043) and serum cortisol responses (p=0.035) to the TSST in chronically high but not in low stressed subjects (all p>0.05). Compared to placebo, supplementation with PAS 200 did not result in any significant differences in these variables (all p>0.05). There were no significant effects of supplementation with PAS on heart rate, pulse transit time, or psychological stress response (all p>0.05).CONCLUSION:In chronically stressed subjects, a supplementation with PAS 400 (MemreePlus™) can normalize the hyper-responsivity of the HPAA to an acute stressor.TRIAL REGISTRATION:TRIAL REGISTRATION:DRKS-ID: DRKS00005125.

Although the mechanisms of sweating due to thermoregulation vs. stress are distinct, the antiperspirant industry focuses primarily on perspiration due to heat as their method of efficacy testing. To better understand the overall protection afforded by a ‘Clinical Strength’ over‐the‐counter antiperspirant product, we compare results from a standard hot‐room study with results from two studies using the Trier Social Stress Test (TSST).