Examining the associations between testosterone and biomarkers as men age.

OBJECTIVES: Testosterone concentrations in men decline with advancing age. However, the cause of the decline is yet to be fully elucidated. Therefore, the aims of this study were to examine the associations between chronic diseases such as obesity and type 2 diabetes mellitus (T2DM) with total testosterone (TT) and sex hormone-binding globulin (SHBG), using a large nationally-representative data set (National Health and Nutrition Examination Survey; NHANES). METHODS: NHANES is a cross-sectional survey, physical examination, and laboratory evaluation of a nationally-representative sample of a non-institutionalized United States population. Male participants aged ≥18 years during the NHANES 2013-2014 and NHANES 2015-2016 survey periods were selected for this analysis. The analysis included the following data: body mass index (BMI), oral glucose tolerance test (OGTT), homeostatic model assessment of insulin resistance (HOMA-IR), insulin, glucose, and age. RESULTS: An overweight or obese condition was significantly inversely associated with TT and SHBG, even after adjusting for other variables. Several variables associated with T2DM (OGTT, HOMA-IR, insulin, and glucose) were also inversely associated with TT; however, only the associations between OGTT and insulin with TT remained significant after adjusting for the other variables. Insulin and HOMA-IR levels were significantly inversely associated with SHBG; however, only the association between SHBG and pre-diabetic HOMA-IR levels remained significant after adjusting for the other variables. OGTT became significantly associated with SHBG after adjusting for the other variables. Age was significantly inversely associated with TT, but positively associated with SHBG, even after adjusting for other variables. CONCLUSION: The results of the present study, which is the largest to date, indicate that a marker of obesity, BMI, and some markers of T2DM are both independently and significantly inversely associated with TT and SHBG.

Modulation of the hypothalamic-pituitary-adrenal (HPA) axis by plants and phytonutrients: a systematic review of human trials.

INTRODUCTION: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response. Plants, herbs, spices, and plant-based nutrients may influence HPA-axis activity. OBJECTIVE: To evaluate randomised controlled, human trials assessing the effects of single plants or phytonutrients on HPA-axis related hormones. METHODS: A systematic review of PubMed, Cochrane library, and the Cumulative Index to Nursing and Allied Health Literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria comprised of human, randomised controlled studies with a control intervention examining the effects of a single herb, spice, plant, or extract on pre- and post-changes in blood, saliva, urine, or hair concentrations of cortisol, cortisone, corticotrophin-releasing hormone, or adrenocorticotropic hormone. Databases were searched from inception until October 2020. RESULTS: Fifty-two studies were identified examining the effects of ashwagandha, Korean ginseng, St John's Wort, cannabidiol, Rhodiola rosea, curcumin, cherry juice, asparagus, Jiaogulan, Black cohosh, Siberian ginseng, Bacopa monnieri, blueberries, green tea, Caralluma fimbriata, cashew apple juice, melon, American ginseng, Ginkgo biloba, grape juice, grapefruit juice, rosella, hops, mangosteen, holy basil, and pomegranate juice. Due to significant variability in study designs, the effect of phytonutrients on HPA-axis activity in humans was unclear. The most consistent finding was a morning, cortisol-lowering effect from ashwagandha supplementation. CONCLUSION: For most phytonutrients, the effects of supplementation on HPA-axis activity in humans is unclear. Before more definitive conclusions about the effects of phytonutrients on the HPA-axis can be made, further research is required.

Plant-based Medicines (Phytoceuticals) in the Treatment of Psychiatric Disorders: A Meta-review of Meta-analyses of Randomized Controlled Trials: Les médicaments à base de plantes (phytoceutiques) dans le traitement des troubles psychiatriques: une méta-revue des méta-analyses d'essais randomisés contrôlés.

OBJECTIVES: Plant-based medicines have had a long-standing history of use in psychiatric disorders. Highly quantified and standardized extracts or isolates may be termed "phytoceuticals," in a similar way that medicinal nutrients are termed as "nutraceuticals." Over the past 2 decades, several meta-analyses have examined the data for a range of plant-based medicines in the treatment of psychiatric disorders. The aim of this international project is to provide a "meta-review" of this top-tier evidence. METHODS: We identified, synthesized, and appraised all available up to date meta-analyses... of randomized controlled trials (RCTs) reporting on the efficacy and effectiveness of individual phytoceuticals across all major psychiatric disorders. RESULTS: Our systematic search identified 9 relevant meta-analyses of RCTs, with primary analyses including outcome data from 5,927 individuals. Supportive meta-analytic evidence was found for St John's wort for major depressive disorder (MDD); curcumin and saffron for MDD or depression symptoms, and ginkgo for total and negative symptoms in schizophrenia. Kava was not effective in treating diagnosed anxiety disorders. We also provide details on 22 traditional Chinese herbal medicine formulas' meta-analyses (primarily for depression studies), all of which revealed highly significant and large effect sizes. Their methodology, reporting, and potential publication bias were, however, of marked concern. The same caveat was noted for the curcumin, ginkgo, and saffron meta-analyses, which may also have significant publication bias. CONCLUSIONS: More rigorous international studies are required to validate the efficacy of these phytoceuticals before treatment recommendations can be made. In conclusion, the breadth of data tentatively supports several phytoceuticals which may be effective for mental disorders alongside pharmaceutical, psychological therapies, and standard lifestyle recommendations.

Herbal treatments for migraine: A systematic review of randomised-controlled studies.

Herbal treatments are often used as a treatment for migraine. Therefore, an evaluation of their safety and efficacy is important. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and Cochrane Collaboration's tool for assessing the risk of bias, a systematic literature review of randomised, controlled human trials assessing the effects of herbal treatments delivered as a single ingredient for the acute or prophylactic treatment of migraine were conducted. Studies were identified through electronic database searches on Medline (Pubmed), Cochrane Library, Scopus, and CINAHL. Nineteen studies were identified examining the effects on migraine of feverfew, butterbur, curcumin, menthol/peppermint oil, coriander, citron, Damask rose, chamomile, and lavender. Overall, findings on the efficacy of feverfew were mixed and there was positive, albeit limited evidence for butterbur. There were positive, preliminary findings on curcumin, citron, and coriander as a prophylactic treatment for migraine, and the use of menthol and chamomile as an acute treatment. However, the risk of bias was high for many studies. The results of this systematic review suggest that several herbal medicines, via their multifactorial physiological influences, present as potential options to enhance the treatment of migraine. However, further high-quality research is essential to examine their efficacy and safety as a treatment for migraine.

A poly-herbal blend (Herbagut®) on adults presenting with gastrointestinal complaints: a randomised, double-blind, placebo-controlled study.

BACKGROUND: To evaluate the efficacy and tolerability of a poly-herbal formulation, Herbagut, for the treatment of gastrointestinal symptoms and its effect on quality of life parameters in patients presenting with self-reported, unsatisfactory bowel habits. METHODS: This was a randomised, double-blind, placebo-controlled trial. Fifty adults with self-reported unsatisfactory bowel habits, primarily characterised by chronic constipation were randomly allocated to take Herbagut or a matching placebo for 28 days. Efficacy of gastrointestinal changes was measured by the completion of a patient daily diary evaluating changes in stool type (Bristol Stool Form Scale), ease of bowel movements, and feeling of complete evacuation; and the Gastrointestinal Symptom Rating Scale (GSRS). Changes in quality of life were also examined using the World Health Organization Quality of Life - abbreviated version (WHOQOL-BREF), and the Patient Assessment of Constipation-Quality of Life (PAC-QOL). RESULTS: All participants completed the 28-day trial with no adverse events reported. Compared to the placebo, weekly bowel movements increased over time (p < .001), as did self-reported, normal bowel motions (76% vs 4%; p < .001). Self-reported incomplete evacuation was also lower in the Herbagut group compared to placebo (24% vs 76%; p = <.001). GSRS domain ratings for abdominal pain, constipation, diarrhoea, indigestion, and reflux also decreased significantly in people taking Herbagut compared to placebo (p < .001, for all domains). Moreover, quality of life significantly improved in the Herbagut group compared to placebo as indicated by significantly greater improvement in WHOQOL-BREF domain ratings for overall quality of life, social relations, environmental health, psychological health, and physical health (p < .001, for all domains); and PAC-QOL domain ratings for physical discomfort, psychosocial discomfort, worries and concerns, and life satisfaction (p < .001, for all domains). The changes were considered clinically meaningful as evidenced by their large effect sizes. CONCLUSION: Herbagut ingestion over a 28-day period resulted in improvements in several gastrointestinal symptoms and overall quality of life. Further investigation utilising larger sample sizes and diverse clinical and cultural populations are needed. TRIAL REGISTRATION: Clinical Trials Registry- India /2016/11/007479 . Registered 24 April 2015 (retrospectively registered).

Cognitive behaviour therapy and inflammation: A systematic review of its relationship and the potential implications for the treatment of depression.

OBJECTIVE: There is growing evidence confirming increased inflammation in a subset of adults with depression. The impact of this relationship has mostly been considered in biologically based interventions; however, it also has potential implications for psychological therapies. Cognitive behaviour therapy is the most commonly used psychological intervention for the treatment of depression with theories around its efficacy primarily based on psychological mechanisms. However, cognitive behaviour therapy may have an effect on, and its efficacy influenced by, physiological processes associated with depression. Accordingly, the purpose of this systematic review was to examine the relationship between cognitive behaviour therapy and inflammation. METHOD: Studies examining the anti-inflammatory effects of cognitive behaviour therapy in people with depression and other medical conditions (e.g. cancer, diabetes and heart disease) were examined. In addition, the relationship between change in inflammatory markers and change in depressive symptoms following cognitive behaviour therapy, and the influence of pre-treatment inflammation on cognitive behaviour therapy treatment response were reviewed. RESULTS: A total of 23 studies investigating the anti-inflammatory effects of cognitive behaviour therapy were identified. In 14 of these studies, at least one reduction in an inflammatory marker was reported, increases were identified in three studies and no change was found in six studies. Three studies examined the relationship between change in inflammation and change in depressive symptoms following cognitive behaviour therapy. In two of these studies, change in depressive symptoms was associated with a change in at least one inflammatory marker. Finally, three studies examined the influence of pre-treatment inflammation on treatment outcome from cognitive behaviour therapy, and all indicated a poorer treatment response in people with higher premorbid inflammation. CONCLUSION: Preliminary evidence suggests inflammation should be considered within the context of cognitive behaviour therapy, although robust studies examining the relationship are sparse, and heterogeneity between studies and populations examined was high. The potential treatment implications of the bi-directional relationship between inflammation and cognitive behaviour therapy are discussed, and recommendations for future research are proposed.

Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action.

BACKGROUND: Saffron, a spice derived from the flower of Crocus sativus, has now undergone several trials examining its antidepressant effects and, in a recent meta-analysis, was confirmed to be effective for the treatment of major depression. OBJECTIVE: To provide an expanded systematic analysis of the completed clinical studies on saffron and depression, detailing dosages, extract sources, standardisations, safety profile and treatment duration; and, through a narrative review, to examine its potential antidepressant mechanisms of action. DESIGN: In the systematic review of clinical trials, electronic databases were searched for high-quality, randomised, double-blind studies, with placebo or antidepressant controls. A narrative review of in vivo and in vitro studies was conducted to examine its potential antidepressant mechanisms of action. RESULTS: In the systematic review, six studies were identified. In the placebo-comparison trials, saffron had large treatment effects and, when compared with antidepressant medications, had similar antidepressant efficacy. Saffron's antidepressant effects potentially are due to its serotonergic, antioxidant, anti-inflammatory, neuro-endocrine and neuroprotective effects. CONCLUSIONS: Research conducted so far provides initial support for the use of saffron for the treatment of mild-to-moderate depression. Further research is required to expand our understanding of the role and actions of saffron in major depression.

An Examination into the Effects of a Nutraceutical Supplement on Cognition, Stress, Eye Health, and Skin Satisfaction in Adults with Self-Reported Cognitive Complaints: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Dietary quality and the consumption of antioxidant-rich foods have been shown to protect against memory decline. Therefore, this double-blind, randomized, placebo-controlled study aimed to investigate the effects of a nutritional supplement on changes in cognitive performance. Methods: In adults aged 40 to 70 years with subjective memory complaints, participants were randomly allocated to take a supplement containing vitamin E, astaxanthin, and grape juice extract daily for 12 weeks or a matching placebo. The primary outcomes comprised changes in cognitive tasks assessing episodic memory, working memory, and verbal memory. Secondary and exploratory measures included changes in the speed of information processing, attention, and self-report measures of memory, stress, and eye and skin health. Moreover, changes in plasma concentrations of brain-derived neurotrophic factor, malondialdehyde, tumor-necrosis factor-α, and interleukin-6 were measured, along with changes in skin carotenoid concentrations. Results: Compared to the placebo, nutritional supplementation was associated with larger improvements in one primary outcome measure comprising episodic memory (p = 0.037), but not for working memory (p = 0.418) or verbal learning (p = 0.841). Findings from secondary and exploratory outcomes demonstrated that the nutraceutical intake was associated with larger improvements in the Everyday Memory Questionnaire (p = 0.022), increased plasma brain-derived neurotrophic factor (p = 0.030), decreased plasma malondialdehyde (p = 0.040), and increased skin carotenoid concentrations (p = 0.006). However, there were no group differences in changes in the remaining outcome measures. Conclusions: Twelve weeks of supplementation with a nutritional supplement was associated with improvements in episodic memory and several biological markers associated with cognitive health. Future research will be essential to extend and validate the current findings.

The effects of alcohol on testosterone synthesis in men: a review.

INTRODUCTION: Testosterone concentrations in men decline with advancing age, with low testosterone concentrations being associated with multiple morbidities, an increased risk of early mortality, and a reduced quality of life. The purpose of this study was to examine the effects of alcohol on testosterone synthesis in men by investigating its effects on each level of the hypothalamic-pituitary-gonadal axis. AREAS COVERED: Acute consumption of a low-to-moderate amount of alcohol increases testosterone concentrations in men, while consumption of a large volume of alcohol is associated with a reduction in serum testosterone concentrations. Elevated testosterone concentrations result from the increased activity of detoxification enzymes in the liver. Conversely, the primary mechanisms of action involved in the reduction of testosterone are increased hypothalamic-pituitary-adrenal axis activity, inflammation, and oxidative stress. When alcohol is consumed in excess, particularly chronically, it negatively affects testosterone production in men. EXPERT OPINION: Since testosterone is an important component of men's health and wellbeing, current levels of alcohol consumption in many countries of the world require urgent attention. Elucidating the relationship between alcohol consumption and testosterone may be useful in identifying strategies to attenuate the testosterone-reducing effects of excessive or chronic alcohol consumption.

Exploring the efficacy and safety of a novel standardized ashwagandha (Withania somnifera) root extract (Witholytin®) in adults experiencing high stress and fatigue in a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Stress is a state of homeostasis in the body being challenged, resulting in a systemic response. It has become more prevalent in recent years and affects mental and physical health. AIMS: Evaluate the effects of ashwagandha on stress, fatigue, and sex hormones in overweight or mildly obese men and women with self-reported stress and fatigue. METHODS: Two-arm, parallel-group, 12-week, randomized, double-blind, placebo-controlled trial on overweight or mildly obese men and women aged 40-75 years, supplementing with 200 mg of an ashwagandha root extract (Witholytin®) twice daily. RESULTS/OUTCOMES: Supplementation with ashwagandha was associated with a significant reduction in stress levels based on the Perceived Stress Scale (primary outcome); however, the improvements were not significantly different to the placebo group (p = 0.867). Based on the Chalder Fatigue Scale, there was a statistically significant reduction in fatigue symptoms in the ashwagandha group compared to the placebo group (p = 0.016), and participants taking ashwagandha also experienced a significant increase in heart rate variability (p = 0.003). However, there were no significant between-group differences in other self-report outcome measures. In the men taking ashwagandha, there was a significant increase in the blood concentrations of free testosterone (p = 0.048) and luteinizing hormone (p = 0.002) compared to the placebo group. CONCLUSIONS/INTERPRETATION: The results of this study suggest that in overweight middle-to-older age adults experiencing high stress and fatigue, compared to the placebo, ashwagandha did not have a significantly greater impact on perceived stress levels. However, based on secondary outcome measures, it may have anti-fatigue effects. This may be via its impact on the autonomic nervous system. However, further research is required to expand on these current findings.

Sleep health of young adults in Western Australia and associations with physical and mental health: A population-level cross-sectional study.

OBJECTIVES: This article aims to report on the sleep health characteristics of a population-level sample of young Australian adults and examine associations with measures of physical and mental health. METHODS: A cross-sectional study using data from the Raine Study. Data from participants (n = 1234) born into the study (Generation 2) at the 22-year follow-up were used, including data from a self-report questionnaire and polysomnography. RESULTS: The highest prevalence of suboptimal sleep health was seen on measures of sleep duration (30%), onset latency (18%), satisfaction (25%) and regularity (60%). Dissatisfaction with sleep (physical health: ß =0.08; mental health: ß =0.34) and impaired daytime alertness (physical health: ß =0.09; mental health: ß =0.08) were significantly associated with poorer physical and mental health and inadequate polysomnography-measured sleep duration was associated poorer mental health (ß =0.07) (all ps<0.05). CONCLUSIONS: Satisfaction with sleep and daytime alertness, both of which are assessed via self-report, are essential aspects of sleep health for young adults. IMPLICATIONS FOR PUBLIC HEALTH: Findings could inform public health interventions, including screening guidelines, to improve the sleep health and, in turn, the physical and mental health of young adults in Australia.

Effects of a polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study.

Background: Polyphenols are naturally occurring organic compounds found in plants. Research suggests that their intake reduces the risk of cognitive decline and related dementias. Grapes and blueberries are polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Purpose: Examine the effects of supplementation with a standardized and patented polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Methods: One hundred and forty-three volunteers aged 60 to 80 years with mild cognitive impairment were supplemented with either 150 mg of Memophenol™, twice daily or a placebo. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function (BRIEF-A), the Cognitive Failures Questionnaire, and the CASP-19. Results: Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing (p = 0.020), visuospatial learning (p = 0.012), and the BRIEF-A global score (p = 0.046). However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires. Memophenol™ supplementation was well-tolerated with no reports of significant adverse reactions. Conclusion: The promising results from this trial suggest that 6-months of supplementation with Memophenol™ may improve aspects of cognitive function in adults with mild cognitive impairment. Further research will be important to expand on the current findings and identify the potential mechanisms of action associated with the intake of this polyphenol-rich extract.

Potential Role of Curcumin for the Treatment of Major Depressive Disorder.

Curcumin is the major biologically active polyphenolic constituent in the turmeric plant (Curcuma longa) that has been shown to have antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects. Interest in curcumin as a treatment for mental health conditions has increased and there is an expanding body of preclinical and clinical research examining its antidepressant and anxiolytic effects. In this narrative review, human trials investigating the effects of curcumin for the treatment of depression or depressive symptoms are summarised. Using findings from in vitro, animal, and human trials, possible biological mechanisms associated with the antidepressant effects of curcumin are also explored. To increase the understanding of curcumin for the treatment of depression, directions for future research are proposed.

An examination into the mental and physical effects of a saffron extract (affron®) in recreationally-active adults: A randomized, double-blind, placebo-controlled study.

Background: Saffron, derived from the stigmas of the Crocus Sativus flower, has been shown in several studies to improve mood and wellbeing in adults experiencing low mood and anxiety. The goals of this study were to examine its mental and physical effects in healthy, recreationally active adults. Methods: In this 6-week, randomized, double-blind, placebo-controlled study, 62 adults engaging in regular exercise were recruited and randomized to receive a placebo or 28 mg daily of a standardized saffron extract (affron®). Self-report outcome measures include the Physical Activity Enjoyment Scale, Profile of Mood States, and Patient-Reported Outcomes Measurement Information System-29. Participants also wore a wrist-worn heart rate, activity, and sleep monitoring device (WHOOP) to measure changes in sleep quality, resting heart rate, and heart rate variability. To help identify mechanisms of action associated with saffron intake, changes in plasma concentrations of brain-derived neurotrophic factor, oxytocin, and neuropeptide Y were also measured. Results: Based on data collected from all participants, there were no statistically significant between-group differences in changes in any of the outcome measures. However, when changes were analyzed by sex, there were statistically significant greater increases in enjoyment associated with exercise (p =.009) and heart rate variability (p =.001) in male participants taking saffron compared to the placebo. No statistically significant between-group differences were identified in females. Conclusions: The results of this trial suggest saffron may have beneficial effects in recreationally active males, as evidenced by increased exercise enjoyment and heart rate variability. However, no such benefits were identified in females. Future research using larger sample sizes, varying treatment periods, and additional outcome measures will be required to validate the results from this study and help clarify the mechanisms of action associated with saffron intake.This study was prospectively registered on 30 October 2020 with the Australian and New Zealand Clinical Trials Registry (Trial ID. ACTRN12621000501842).

The Effects of Lutein and Zeaxanthin Supplementation on Cognitive Function in Adults With Self-Reported Mild Cognitive Complaints: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lutein and zeaxanthin are fat-soluble, dietary carotenoids with high concentrations in human brain tissue. There have been a number studies confirming an association between lutein and zeaxanthin and cognitive function. PURPOSE: Examine the effects of lutein and zeaxanthin supplementation on cognitive function in adults with self-reported cognitive complaints. STUDY DESIGN: Two-arm, parallel-group, 6-month, randomized, double-blind, placebo-controlled trial. METHODS: Ninety volunteers aged 40-75 years received either 10 mg of lutein and 2 mg of zeaxanthin, once daily or a placebo. Outcome measures included computer-based cognitive tasks, the Cognitive Failures Questionnaire, Behavior Rating Inventory of Executive Function, Profile of Mood States, and the Patient-Reported Outcomes Measurement Information System-29. RESULTS: Compared to the placebo, lutein and zeaxanthin supplementation was associated with greater improvements in visual episodic memory (p = 0.005) and visual learning (p = 0.001). However, there were no other statistically-significant differences in performance on the other assessed cognitive tests or self-report questionnaires. Lutein and zeaxanthin supplementation was well-tolerated with no reports of significant adverse effects. CONCLUSION: The results from this trial suggest that 6-months of supplementation with lutein and zeaxanthin may improve visual memory and learning in community-dwelling adults with self-reported cognitive complaints. However, it had no other effect on other computer-based measures of cognitive performance or self-report measures of cognition, memory, mood, or physical function.

Examining the effects of calorie restriction on testosterone concentrations in men: a systematic review and meta-analysis.

CONTEXT: Testosterone concentrations decline with age, and lower testosterone concentrations are associated with several morbidities, including sexual dysfunction, obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. OBJECTIVE: Because dietary habits play a critical role in weight regulation and T2DM management, the aim of this systematic review and meta-analysis was to summarize and critically evaluate the evidence from randomized controlled trials to determine the effects of calorie restriction (CR) on testosterone concentrations in men. DATA SOURCES: A literature search was conducted across 4 databases, from their inception until March 2020. DATA EXTRACTION: The screening and data extraction were completed by 2 authors independently, and in a blinded manner, according to a priori inclusion and exclusion criteria. DATA ANALYSIS: Of the 4198 studies identified from the initial search, 7 randomized controlled trials were included for data extraction. Significant increases in total testosterone concentrations were reported in 3 of 4 studies in which CR was examined with overweight or obese men, compared with the control groups. Significant decreases in total testosterone concentrations were reported in 2 of 3 studies in which the effects of CR were examined with normal-weight, healthy men, compared with the control groups. In all 4 studies that examined the effect of CR on sex hormone-binding globulin concentrations, the intervention significantly increased sex hormone-binding globulin concentrations compared with that of the control groups irrespective of body composition. CONCLUSION: This systematic review and meta-analysis provide some evidence that CR affects testosterone concentrations in men and this effect depends on their body mass index. PROSPERO registration no. CRD42020173102.

A randomized, double-blind, placebo-controlled trial investigating the effects of an Ocimum tenuiflorum (Holy Basil) extract (HolixerTM) on stress, mood, and sleep in adults experiencing stress.

Background: In Ayurveda, Ocimum tenuiflorum (Holy Basil) is referred to as "the elixir of life" and is believed to promote longevity and general wellbeing. Although limited, there are clinical trials to suggest Ocimum tenuiflorum has anti-stress effects. Purpose: Examine the effects of a standardized Ocimum tenuiflorum extract (HolixerTM) on subjective and objective measures of stress and sleep quality in adults experiencing stress. Study design: Two-arm, parallel-group, 8-week, randomized, double-blind, placebo-controlled trial. Australian and New Zealand Clinical Trials Registry trial registration number ACTRN12621000609853. Methods: One hundred volunteers aged 18-65 years received either 125 mg of Ocimum tenuiflorum twice daily or a placebo. Outcome measures included the Perceived Stress Scale (PSS) (primary outcome measure), Profile of Mood States, Athens Insomnia Scale (AIS), Restorative Sleep Questionnaire, and the Patient-Reported Outcomes Measurement Information System-29. Sleep quality was also assessed using a wrist-worn sleep tracker (Fitbit), and stress changes were examined by measuring between-group differences in hair cortisol and stress responses after exposure to an experiment stress procedure known as the Maastricht Acute Stress Test (MAST). Results: Compared to the placebo, Ocimum tenuiflorum supplementation was associated with greater improvements in PSS (p = 0.003) and AIS (p = 0.025) scores; and at week 8, concentrations in hair cortisol were also lower (p = 0.025). Moreover, Ocimum tenuiflorum supplementation was associated with a buffered stress responses after exposure to the MAST as demonstrated by significantly lower concentrations in salivary cortisol (p = 0.001), salivary amylase (p = 0.001), systolic (p = 0.010) and diastolic (p = 0.025) blood pressure, and subjective stress ratings (p < 0.001). Ocimum tenuiflorum supplementation was well-tolerated with no reports of major adverse effects. Conclusion: The results from this trial suggest that 8 weeks of supplementation with an Ocimum tenuiflorum extract (HolixerTM) may reduce objective and subjective measures of stress, and improve subjective measures of sleep quality. However, further research using gold-standard objective sleep measures will be required to substantiate the sleep-related findings. Clinical trial registration: https://www.anzctr.org.au/ACTRN12621000609853p.aspx, identifier: ACTRN12621000609853p.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

An investigation into the anxiety-relieving and mood-enhancing effects of Echinacea angustifolia (EP107™): A randomised, double-blind, placebo-controlled study.

BACKGROUND: The acute anxiolytic effects of the echinacea angustifolia extract (EP107TM) have been demonstrated in two previous human trials. The goals of this study were to examine the anxiolytic and mood-enhancing effects of echinacea angustifolia over a longer duration with a larger sample size. METHODS: In this 6-week, 3-arm, parallel-group, double-blind, randomised controlled trial, 108 adults with mild-to-moderately severe anxiety were recruited and randomised to receive either a placebo, 20 mg, or 40 mg of echinacea angustifolia, twice daily. Outcome measures included the Clinically Useful Anxiety Outcome Scale (CUXOS), Positive and Negative Affect Scale (PANAS), Short Form-36 (SF-36), and Bergen Insomnia Scale (BIS). RESULTS: Based on data collected from 104 participants, both doses of echinacea were associated with overall reductions in anxiety, although improvements were not different from the placebo. However, both doses of echinacea were associated with greater improvements in the PANAS positive and negative affect scores, and SF-36 emotional wellbeing score compared to the placebo. LIMITATIONS: The positive improvements associated with echinacea were only identified via the secondary outcome measures and, therefore, require validation in future trials. CONCLUSIONS: The echinacea angustifolia extract (EP107TM) administered for 6 weeks at a dose of 40 and 80 mg daily was not associated with greater improvements in anxiety in adults with mild-to-moderately severe anxiety compared to the placebo. However, there were greater improvements in positive and negative affect, and emotional wellbeing, suggesting antidepressant effects. Further studies using clearly-defined populations and validated outcome measures will be useful in future trials.

The Effects of a Saffron Extract (affron®) on Menopausal Symptoms in Women during Perimenopause: A Randomised, Double-Blind, Placebo-Controlled Study.

OBJECTIVES: There is preliminary evidence suggesting saffron may effectively treat menopausal symptoms. The aim of this study was to examine the tolerability and efficacy of a standardised saffron extract (affron®) on menopausal complaints in perimenopausal women. METHODS: In this 12-week, parallel-group, double-blind, randomised controlled trial, 86 perimenopausal women experiencing menopausal complaints received either a placebo or 14 mg of a saffron extract (affron®), twice daily. Outcome measures included the Greene Climacteric Scale (GCS), Positive and Negative Affect Schedule (PANAS), and Short Form-36 Health Survey (SF-36). RESULTS: Based on data collected from 82 participants, saffron was associated with greater improvements in mood and psychological symptoms compared to the placebo. Results from the GCS revealed a significantly greater reduction in the GCS psychological score (P = 0.032), characterised by a 33% reduction in anxiety and a 32% reduction in depression scores from baseline to week 12. There was also a significantly greater reduction in the PANAS negative affect score (P = 0.043) compared to the placebo. However, compared to the placebo, saffron was not associated with greater improvements in vasomotor symptoms, somatic symptoms, or other quality of life measures. Saffron intake was well tolerated with no reported major adverse events. CONCLUSIONS: The saffron extract, affron®, administered for 12 weeks at a dose of 14 mg twice daily was associated with greater improvements in psychological symptoms. Further studies in perimenopausal women presenting with varying severity of menopausal symptoms, using different doses of saffron will be useful to examine in future clinical trials.