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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

Objective/background To validate and extend on previous positive findings of the sleep-enhancing effects of saffron supplementation in adults with unsatisfactory sleep. Patients/methods In this 28-day, 3-arm, parallel-group, double-blind, randomised controlled trial, 120 adults with unsatisfactory sleep received either a placebo, 14 mg, or 28 mg of a standardised saffron extract (affron®), 1 h before bed. Outcome measures included the Pittsburgh Sleep Diary (with sleep quality ratings as the primary outcome measure), Insomnia Symptom Questionnaire (ISQ), Profile of Mood States, Restorative Sleep Questionnaire, the Functional Outcomes of Sleep Questionnaire, and evening salivary melatonin and cortisol concentrations. Results Compared to the placebo, saffron supplementation was associated with greater improvements in sleep quality ratings (primary outcome measure), mood ratings after awakening, the ISQ total score, and ISQ-insomnia classifications. However, there were no significant differences between the saffron and placebo groups in other questionnaire and sleep diary outcome measures. Sleep improvements were similar for the two administered saffron doses. Compared to the placebo, saffron supplementation was associated with increases in evening melatonin concentrations but did not affect evening cortisol. Saffron supplementation was well-tolerated with no reported significant adverse effects. Conclusions These results provide further validation of the sleep-enhancing effects of 28-days of saffron supplementation in adults with unsatisfactory sleep. Further research is required to examine the efficacy and safety of saffron supplementation using objective sleep measures, over a longer duration, in people presenting with a diagnosed insomnia disorder and other psychogenic and demographic characteristics, and into its potential sleep-enhancing mechanisms of action.

BackgroundThere is preliminary evidence to suggest curcumin can alleviate digestive symptoms in adults with self-reported digestive complaints and irritable bowel syndrome. However, in all these trials, curcumin was used as a component of a multi-herbal combination and there were consistent concerns associated with risk of bias in most studies. The goal of this study was to investigate the effects of a curcumin extract (Curcugen™) on gastrointestinal symptoms, mood, and overall quality of life in adults presenting with self-reported digestive complaints. Moreover, to determine the potential therapeutic mechanisms of action associated with curcumin, its effects on intestinal microbiota and small intestinal bowel overgrowth (SIBO) were examined.MethodsIn this 8-week, parallel-group, double-blind, randomised controlled trial, 79 adults with self-reported digestive complaints were recruited and randomised to receive either a placebo or 500 mg of the curcumin extract, Curcugen™. Outcome measures included the Gastrointestinal Symptom Rating Scale (GSRS), intestinal microbial profile (16S rRNA), Depression, Anxiety, and Stress Scale – 21 (DASS-21), Short Form-36 (SF-36), and SIBO breath test.ResultsBased on self-report data collected from 77 participants, curcumin was associated with a significantly greater reduction in the GSRS total score compared to the placebo. There was also a greater reduction in the DASS-21 anxiety score. No other significant between-group changes in self-report data were identified. An examination of changes in the intestinal microbial profile and SIBO test revealed curcumin had no significant effect on these parameters. Curcumin was well-tolerated with no significant adverse events.ConclusionsThe curcumin extract, Curcugen™, administered for 8 weeks at a dose of 500 mg once daily was associated with greater improvements in digestive complaints and anxiety levels in adults with self-reported digestive complaints. Compared to the placebo, there were no significant changes in intestinal microbiota or SIBO; however, further research using larger samples and testing methods that allow more detailed microbial analyses will be important. An investigation into other potential mechanisms associated with curcumin’s gastrointestinal-relieving effects will also be important such as examining its influence on the intestinal barrier function, inflammation, neurotransmitter activity, and visceral sensitivity.Trial registrationAustralian New Zealand Clinical Trials Registry, Trial ID.ACTRN12619001236189. Registered 6 September 2019.

Heart rate variability (HRV) is a measure of the variation between consecutive heartbeats. It provides a marker of the interplay between the parasympathetic and sympathetic nervous systems, and there is an increasing body of evidence confirming an increased HRV is associated with better mental and physical health. HRV may be a useful marker of stress as it represents the ability of the heart to respond to a variety of physiological and environmental stimuli. HRV tends to decrease as we age and is positively associated with physical activity, fitness, and healthier lifestyles. The relation between HRV and micronutrients (vitamins and minerals) has also received some attention in the research literature. In this review, cross-sectional and interventional studies on human populations examining the relation between HRV and micronutrients are appraised. Micronutrients identified and examined in this review include vitamins D, B-12, C, and E; the minerals magnesium, iron, zinc, and coenzyme Q10; and a multivitamin-mineral formula. Due to the paucity of research and significant heterogeneity in studies, definitive conclusions about the effects of these micronutrients on HRV cannot be made at this time. However, there is accumulating evidence suggesting deficiencies in vitamins D and B-12 are associated with reduced HRV, and zinc supplementation during pregnancy can have positive effects on HRV in offspring up until the age of 5 y. To further elucidate the relation between micronutrients and HRV, additional robustly designed and adequately powered studies are required.

Stress is the nonspecific response of the body to any demand for change. Excess or chronic psychological or environmental stress is associated with an increased risk of mental and physical diseases, with several mechanisms theorized to be associated with its detrimental effects. One underappreciated potential mechanism relates to the effects of psychological and environmental stress on micronutrient concentrations. Micronutrients (vitamins and minerals) are essential for optimal physical and mental function, with deficiencies associated with an array of diseases. In this article, animal and human studies investigating the effects of various psychological and environmental stressors on micronutrient concentrations are reviewed. In particular, the effects of psychological stress, sleep deprivation, and physical exercise on micronutrient concentrations and micronutrient excretion are summarized. Micronutrients identified in this review include magnesium, zinc, calcium, iron, and niacin. Overall, the bulk of evidence suggests stress can affect micronutrient concentrations, often leading to micronutrient depletion. However, before definitive conclusions about the effects of stress can be made, the impact of different stressors, stress severity, and acute versus chronic stress on micronutrient concentrations requires investigation. Moreover, the impact of stress on micronutrients in different populations varying in age, gender, and premorbid health status and the durability of changes after a stressor is resolved require examination. The medical, physical, and psychological implications of nutrient changes caused by a stressor also remain to be determined.

Context Saffron (Crocus sativus L.) has gained interest as a potential treatment in psychiatry. Objective This systematic review and meta-analysis sought to investigate the effect of saffron supplementation, as both an adjunctive therapy and monotherapy, on symptoms of depression and anxiety in clinical and general populations compared with pharmacotherapy or placebo. Data sources Using the PRISMA guidelines, a systematic literature review of randomized controlled trials was conducted. Data extraction A meta-analysis was conducted to determine treatment effect. Risk of bias was assessed using the Jadad scale. Results Twenty-three studies were included. Saffron had a large positive effect size when compared with placebo for depressive symptoms (g = 0.99, P < 0.001) and anxiety symptoms (g = 0.95, P < 0.006). Saffron also had a large positive effect size when used as an adjunct to antidepressants for depressive symptoms (g = 1.23, P = 0.028). Egger’s regression test found evidence of publication bias. Conclusions Saffron could be an effective intervention for symptoms of depression and anxiety; however, due to evidence of publication bias and lack of regional diversity, further trials are required. PROSPERO registration CRD42017070060.

Psychological and pharmacological interventions are the most common treatments for adult depression. While these interventions have robust evidence supporting their efficacy, there remain up to 60 percent of individuals who do not respond to treatment, or only partially respond. Unfortunately, efforts at improving outcome rates from new or modified versions of psychological or pharmacological interventions have been disappointing. It is argued that increased treatment efficacy for depression may be achieved by utilising integrative or adjunctive treatments. As depression is influenced by an array of psychological, biological, social, environmental, dietary, and lifestyle factors, it is hypothesised that treatment outcomes will only be improved when integrative interventions are utilised. The research supporting the potential of several of these factors are reviewed in this article including those associated with diet, exercise, sleep, sunshine/light, nature, herbs and nutraceuticals, social connections, meditation, religion/spirituality, and alcohol and nicotine use. It is argued that increased efforts should be directed at investigating integrative or adjunctive interventions, rather than stand-alone treatments, to enhance outcomes for depression.

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.

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.

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.

Testosterone concentrations in males tend to decline with advancing age. Low testosterone, also known as androgen deficiency (AD), is associated with an increased risk of morbidity and mortality. Currently, the primary treatment for AD is testosterone replacement therapy (TRT), which may exacerbate pre-existing medical conditions. Therefore, the use of alternative options, such as herbs, spices, plants, or their extracts, has been explored as a potential treatment option for AD. The aim of this systematic review was to summarize and critically evaluate randomized controlled trials published on the efficacy of single herbal ingredients on testosterone concentrations, in addition to its fractions or binding proteins, in men (≥18 y). From the 4 databases searched, there were 13 herbs identified in 32 studies, published between 2001 and 2019. The main findings of this review indicate that 2 herbal extracts, fenugreek seed extracts and ashwagandha root and root/leaf extracts, have positive effects on testosterone concentrations in men. Also, some evidence exists for another herb and herbal extract, Asian red ginseng and forskohlii root extract. Overall, 9 out of 32 studies demonstrated statistically significant increases in testosterone concentrations. Moreover, 6 studies out of 32 were judged as having a low risk of bias. Current evidence is largely based on young, nonclinical populations, with 16 out of 32 studies using men

The aim of this study was to investigate the efficacy and suitability of a brief integrative intervention, Personalized Integrative Therapy (PI Therapy), for the treatment of adult depression and/or anxiety. In this 6-week, 3-arm, parallel-group, randomized trial, PI Therapy delivered alone or with nutritional supplements (PI Therapy + Supps) was compared to cognitive behavior therapy (CBT) in 48 adults with depression and/or anxiety. All treatments were delivered as a 1-day workshop plus 6 weeks of reminder phone text messages to reinforce topics and skills covered in the workshop. Affective symptoms decreased significantly and to the same extent in all 3 conditions. At the end of treatment, 33% to 58% of participants reported levels of depressive symptoms in the normal range, and 50% to 58% reported nonclinical levels of anxiety. Compared to CBT and PI Therapy, PI Therapy + Supps was associated with significantly greater improvements in sleep quality. These findings suggest that a brief integrative intervention with or without supplements was comparable to CBT in reducing affective symptoms in adults with depression and/or anxiety. However, sleep quality improved only in the PI Therapy + Supps condition. These findings will require replication with a larger cohort.

STUDY OBJECTIVES: Herbal medicines are frequently used by adults with sleep difficulties. However, evidence of their efficacy is limited. Therefore, the goal of this study was to examine the sleep-enhancing effects of a standardized saffron extract (affron). METHODS: This was a 28-day, parallel-group, double-blind, randomized controlled trial. Sixty-three healthy adults aged 18–70 with self-reported sleep problems were recruited and randomized to receive either saffron extract (affron; 14 mg twice daily) or a placebo. Outcome measures included the Insomnia Severity Index (ISI; primary outcome measure) collected at baseline and days 7, 14, 21, and 28 and the Restorative Sleep Questionnaire (RSQ) and the Pittsburgh Sleep Diary (PSD) collected on days −1, 0, 3, 7, 14, 27, and 28. RESULTS: Based on data collected from 55 participants, saffron was associated with greater improvements in ISI total score (P = .017), RSQ total score (P = .029), and PSD sleep quality ratings (P = .014) than the placebo. Saffron intake was well tolerated with no reported adverse effects. CONCLUSIONS: Saffron intake was associated with improvements in sleep quality in adults with self-reported sleep complaints. Further studies using larger samples sizes, treatment periods, objective outcome measures, and volunteers with varying demographic and psychographic characteristics are required to replicate and extend these findings. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Effects of Saffron on Sleep Quality in Healthy Adults with Self-Reported Unsatisfactory Sleep; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377781; Identifier: ACTRN12619000863134. CITATION: Lopresti AL, Smith SJ, Metse AP, Drummond PD. Effects of saffron on sleep quality in healthy adults with self-reported poor sleep: a randomized, double-blind, placebo-controlled trial. J Clin Sleep Med. 2020;16(6):937–947.

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.

Curcumin, a phytochemical from the spice turmeric, has anti-inflammatory properties and has been shown to have pain-relieving effects. In this 8-week, randomised, double-blind, placebo-controlled study, 101 adults with knee osteoarthritis received either 500 mg twice daily of a standardised curcumin extract (Curcugen®) or placebo. Outcome measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS), knee pain ratings, Japanese Orthopaedic Association Score for Osteoarthritic Knees (JOA), PROMIS–29, and performance-based testing comprising the 40-m fast-paced walk test, 6-min walk test, timed up-and-go test, and 30-s chair stand test. Compared to the placebo, curcumin significantly reduced the KOOS knee pain score (p = 0.009) and numeric knee pain ratings (p = 0.001). Curcumin was also associated with greater improvements (p ≤ 0.05) than the placebo on the timed up-and-go test, 6-min walk test, and the JOA total score; but not the 30-s chair stand test or 40-m fast-paced walk test. Pain-relieving medication was reduced in 37% of participants on curcumin compared to 13% on placebo. The findings support the potential efficacy of curcumin for the treatment of osteoarthritis of the knee but studies of longer duration, varying treatment doses, differing curcumin extracts, and the use of other objective outcome measures will be helpful to expand on these findings.

In this 28-day, randomised, double-blind, placebo-controlled trial, 100 adults with self-reported poor sleep received either a placebo or a standardised Bacopa monnieri extract (150 mg twice daily). Outcome measures included the Bergen Insomnia Scale (primary outcome measure), Functional Outcomes of Sleep Questionnaire, Pittsburgh Sleep Diary, Short Form-36 Health Survey, and the Depression, Anxiety, and Stress Scale. Changes in salivary concentrations of cortisol, dehydroepiandrosterone sulfate, immunoglobulin A (sIgA), α-amylase (sAA), C-reactive protein, melatonin, and the fatigue biomarker index were also assessed. Based on the Bergen Insomnia Scale, Bacopa monnieri did not improve sleep patterns more than the placebo; however, it was associated with greater improvements in emotional wellbeing, general health, and pain-related symptoms. Bacopa monnieri was also associated with greater reductions in sIgA and sAA compared to the placebo. Future clinical trials using varying doses, treatment periods, and objective outcome measures will be important to validate these findings.

Ashwagandha is a medicinal plant that has been used in Ayurvedic and indigenous medicine for over 3000 years. Because interest and the popularity of ashwagandha has increased in several Western countries, there are an increasing number of human trials evaluating its efficacy across a range of conditions. Based on the PRISMA guidelines, human trials assessing the effects of ashwagandha on mental and/or physical conditions, and/or human performance, used as a stand-alone or adjunct intervention, and delivered as a single ingredient, were eligible for inclusion in this systematic review. Forty-one studies were identified examining the effects of ashwagandha on stress and anxiety, sexual function and fertility, athletic performance, cognitive performance, pain, fatigue, thyroid function, schizophrenia, diabetes, obsessive-compulsive disorder, insomnia, hypercholesterolemia, and tuberculosis. Results from most of these studies indicated positive effects from ashwagandha intake, although treatment dose, duration, and extract types varied significantly. Moreover, trials often comprised of small sample sizes and were primarily conducted in India (32 studies). Overall, the strongest evidence for therapeutic efficacy of ashwagandha is the alleviation of stress and anxiety symptoms. The results from this systematic review suggest ashwagandha has a potentially large array of therapeutic applications. However, while promising, the significant heterogeneity across studies and the limited number of investigations means further research utilising robust and adequately-powered study designs are required.

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.

Background: Ashwagandha (Withania somnifera (L.) Dunal) is a herb traditionally used to reduce stress and enhance wellbeing. The aim of this study was to investigate its anxiolytic effects on adults with self-reported high stress and to examine potential mechanisms associated with its therapeutic effects. Methods: In this 60-day, randomized, double-blind, placebo-controlled study the stress-relieving and pharmacological activity of an ashwagandha extract was investigated in stressed, healthy adults. Sixty adults were randomly allocated to take either a placebo or 240 mg of a standardized ashwagandha extract (Shoden) once daily. Outcomes were measured using the Hamilton Anxiety Rating Scale (HAM-A), Depression, Anxiety, and Stress Scale -21 (DASS-21), and hormonal changes in cortisol, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. Results: All participants completed the trial with no adverse events reported. In comparison with the placebo, ashwagandha supplementation was associated with a statistically significant reduction in the HAM-A (P = .040) and a near-significant reduction in the DASS-21 (P = .096). Ashwagandha intake was also associated with greater reductions in morning cortisol (P

Background:As a stand-alone intervention, saffron has efficacy for the treatment of mild-to-moderate depression. However, research as an adjunct agent is limited.Aims:The effects of saffron as an adjunct to pharmaceutical antidepressants in adults with persistent depression was investigated.Methods:In this eight-week, randomised, double-blind, placebo-controlled study, adults with persistent depression, currently taking a pharmaceutical antidepressant were given a placebo or a saffron extract (affron®, 14 mg b.i.d.). Primary outcome measures included the clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) and self-rated MADRS (MADRS-S). Secondary outcome measures included the Antidepressant Side-Effect Checklist (ASEC) and Short Form-36 Health Survey (SF-36).Results:Of the 160 participants enrolled, 139 provided usable data. Based on the MADRS, depressive symptoms decreased more in participants taking saffron compared with a placebo, with reductions of 41 and 21%, respectively ( p = 0.001). However, scores on the MADRS-S decreased 27 and 26% in the saffron and placebo conditions, respectively ( p = 0.831). Saffron was associated with a greater reduction in adverse effects of antidepressants ( p = 0.019), although this was non-significant after covarying for baseline values ( p = 0.449). Quality of life improved in both groups with no significant between-group differences ( p = 0.638).Conclusion:Adjunctive administration of a standardised saffron extract (affron®) for eight weeks was associated with a greater improvement in depressive symptoms as measured by the clinician-rated MADRS but not the self-report MADRS-S. Given the conflicting results, further research is needed to clarify the clinical benefits of saffron as an adjunctive treatment for adults with persistent depressive symptoms despite antidepressant drug treatment.

Diet, sleep, and exercise are lifestyle factors important for the prevention and treatment of psychiatric disorders, including major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. These lifestyle factors can contribute to dysregulation in important physiological mechanisms associated with psychiatric disorders and influence neuroprogression. We review research highlighting the important role of these lifestyle factors for different psychiatric conditions, and examine the potential mechanisms behind their therapeutic effects, with a particular emphasis on how they may each influence neuroprogression.

Increasing evidence suggests that major depressive disorder is associated with mitochondrial dysfunction, and consequently, increased oxidative stress. In this chapter, the role of mitochondria and how they potentially influence physiological processes associated with depression are reviewed. Research on mitochondrial disturbances in adults with depression is also summarized and possible causes for these disturbances are presented. In particular, a focus is placed on lifestyle, environmental, nutritional, and biological influences on mitochondrial function. More specifically, the role of stress, hypothalamus-pituitary-adrenal axis activity, sleep disturbances, diet, nutrients, exercise, gut microbiota, and pharmaceutical medications on mitochondrial activity are discussed. Many of these areas are problematic in people with depression and present as plausible options to improve both depression and mitochondrial function.

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.

[Background]: Saffron has antidepressant and anxiolytic effects in adults with mild-to-moderate depression. However, this is the first study examining its mood-related effects in teenagers. [Methods]: In this 8-week, randomised, double-blind, placebo-controlled study, youth aged 12–16 years, with mild-to-moderate anxiety or depressive symptoms were given tablets containing placebo or a saffron extract (affron, 14 mg b.i.d). The youth and parent versions of the Revised Child Anxiety and Depression Scale (RCADS) were used as outcome measures. [Results]: 80 participants were enrolled and 68 completed the study. Based on youth self-reports, affron was associated with greater improvements in overall internalising symptoms (p = 0.049), separation anxiety (p = 0.003), social phobia (p = 0.023), and depression (p = 0.016). Total internalising scores decreased by an average of 33% compared to 17% in the placebo group (p = 0.029). However, parental reports of improvements were inconsistent as mean improvements in RCADS scores were greater in the saffron group (40% vs 26%) (p = 0.026), although no other significant differences were identified. affron was well-tolerated and there was a trend of reduced headaches in participants on the active treatment. [Limitations]: The use of a self-report instrument, limited study duration, single treatment dose, and non-clinical sample used in this study limit the generalisability of study findings. [Conclusion]: The administration of a standardised saffron extract (affron) for 8 weeks improved anxiety and depressive symptoms in youth with mild-to-moderate symptoms, at least from the perspective of the adolescent. However, these beneficial effects were inconsistently corroborated by parents., This study was funded by Pharmactive Biotech Products SL. The authors gratefully acknowledge Pharmactive Biotech Products SL Company for funding the project.

Curcumin, from the spice turmeric, exhibits anti-inflammatory, antioxidant, anticancer, antiviral, and neurotrophic activity and therefore holds promise as a therapeutic agent to prevent and treat several disorders. However, a major barrier to curcumin's clinical efficacy is its poor bioavailability. Efforts have therefore been dedicated to developing curcumin formulations with greater bioavailability and systemic tissue distribution. However, it is proposed in this review that curcumin's potential as a therapeutic agent may not solely rely on its bioavailability, but rather its medicinal benefits may also arise from its positive influence on gastrointestinal health and function. In this review, in vitro, animal, and human studies investigating the effects of curcumin on intestinal microbiota, intestinal permeability, gut inflammation and oxidative stress, anaphylactic response, and bacterial, parasitic, and fungal infections are summarized. It is argued that positive changes in these areas can have wide-ranging influences on both intestinal and extraintestinal diseases, and therefore presents as a possible mechanism behind curcumin's therapeutic efficacy.

A recent randomised, double-blind, placebo controlled study conducted by our research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500 mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p

Saffron has antidepressant and anxiolytic effects in adults with mild-to-moderate depression. However, this is the first study examining its mood-related effects in teenagers.In this 8-week, randomised, double-blind, placebo-controlled study, youth aged 12-16 years, with mild-to-moderate anxiety or depressive symptoms were given tablets containing placebo or a saffron extract (affron80 participants were enrolled and 68 completed the study. Based on youth self-reports, affronThe use of a self-report instrument, limited study duration, single treatment dose, and non-clinical sample used in this study limit the generalisability of study findings.The administration of a standardised saffron extract (affron

Turmeric has been used in traditional medicine for centuries to treat a range of ailments. Its primary active constituent curcumin, can influence an array of biological activities. Many of these, such as its anti-inflammatory, antioxidant, neuroprotective, and monoaminergic effects are dysregulated in several neuropsychiatric disorders. In this systematic review, in vitro, animal, and human studies investigating the potential of curcumin as a treatment for neuropsychiatric disorders such as major depressive disorder, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorder, psychotic disorders, and autism are reviewed, and directions for future research are proposed. It is concluded that curcumin is a promising, natural agent for many of these conditions, however, further research utilising robust, clinical designs are essential. The problem associated with the poor oral bioavailability of standard curcumin also requires consideration. Currently the greatest support for the efficacy of curcumin is for the treatment of major depressive disorder.

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.

Ashwagandha ( Withania somnifera) is a herb commonly used in Ayurvedic medicine to promote youthful vigor, enhance muscle strength and endurance, and improve overall health. In this 16-week, randomized, double-blind, placebo-controlled, crossover study, its effects on fatigue, vigor, and steroid hormones in aging men were investigated. Overweight men aged 40–70 years, with mild fatigue, were given a placebo or an ashwagandha extract (Shoden beads, delivering 21 mg of withanolide glycosides a day) for 8 weeks. Outcome measures included the Profile of Mood States, Short Form (POMS-SF), Aging Males’ Symptoms (AMS) questionnaire, and salivary levels of DHEA-S, testosterone, cortisol, and estradiol. Fifty-seven participants were enrolled, with 50 people completing the first 8-week period of the trial and 43 completing all 16 weeks. Improvements in fatigue, vigor, and sexual and psychological well-being were reported over time, with no statistically significant between-group differences. Ashwagandha intake was associated with an 18% greater increase in DHEA-S ( p = .005) and 14.7% greater increase in testosterone ( p = .010) compared to the placebo. There were no significant between-group differences in cortisol and estradiol. In conclusion, the intake of a standardized ashwagandha extract (Shoden beads) for 8 weeks was associated with increased levels of DHEA-S and testosterone, although no significant between-group differences were found in cortisol, estradiol, fatigue, vigor, or sexual well-being. Further studies with larger sample sizes are required to substantiate the current findings.

Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus-pituitary-adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined.

Genus Salvia, commonly known as sage, is the largest genus in the Lamiaceae family. It comprises many species traditionally used as brain-enhancing tonics. In vitro and animal studies have confirmed that several Salvia species contain a large array of active compounds that may enhance cognitive activity and protect against neurodegenerative disease. In this review, the active constituents in plants belonging to the genus Salvia are summarised, and their influence on pharmacodynamics pertinent to cognitive activity are detailed. In particular, the effects of plants belonging to the genus Salvia and their constituents on cognitive skills including memory, attention and learning are detailed. Their potential effects in dementia, including Alzheimer’s disease, are also examined. Completed human trials are summarised, and factors influencing the potency of Salvia plants are covered. Finally, directions for future research are proposed to enhance our understanding of the potential health benefits of Salvia plants.

It is well accepted that diet quality has an important role in the prevention and treatment of several physical diseases. However, its influence on mental health has received far less attention, although there is increasing evidence to support a relationship with depression. In this narrative review, investigations into the relationship between diet and bipolar disorder are examined and the potential implications in the management and treatment of bipolar disorder are reviewed.The authors provide a narrative review of the relevant information.Research is limited, although there are preliminary findings to suggest a relationship between diet and bipolar disorder. Findings from cross-sectional research suggest that people with bipolar disorder consume an unhealthier dietary pattern. This has significant treatment implications as bipolar disorder has a high comorbidity with several physical diseases. In addition, diet also influences several biological processes that are dysregulated in bipolar disorder, namely monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression.The role of diet in bipolar disorder requires further attention in research as it presents as a factor that may contribute to the worsening course of this condition and may potentially enhance current treatment outcomes.

Major depression is a debilitating condition affecting approximately 10% of the population. While primary treatments comprise pharmaceutical and/or psychological interventions, efficacy rates are far from ideal, reaching treatment remission rates of only 20-40%. Diet and exercise are two lifestyle factors that are commonly associated with major depression and have the potential to increase treatment efficacy. In this chapter, epidemiological and interventional studies on diet and exercise in major depression will be reviewed with a particular emphasis on their role in the prevention and treatment of this disorder. The influence of diet and exercise on dysregulated biological pathways associated with depression will also be summarized, namely, their impact on neurotransmitter balance, oxidative stress, inflammation, neurogenesis, and hypothalamus-adrenal-pituitary (HPA) axis regulation.

Attention deficit hyperactivity disorder (ADHD) has a complex aetiology although theories associated with disturbances in dopaminergic and noradrenergic activity are most commonly cited. The importance of these catecholamines in ADHD is supported by its effective treatment utilising stimulant and non-stimulant medications that modify their activity. Recently, there has been interest in oxidative and nitrosative stress (O&NS) in ADHD and its potential to contribute to this condition. In this article, research investigating O&NS in ADHD is reviewed and its impact on catecholaminergic activity and neurological structure is discussed. Lifestyle, environmental, psychological and nutritional influences on O&NS in people with ADHD are reviewed, and evidence for the therapeutic efficacy of antioxidant-related therapies is assessed. A selection of interventions with antioxidant mechanisms is presented as potential options for the treatment of ADHD. However, further research is required to help elucidate the role of O&NS and antioxidants for the prevention and management of ADHD.

Paediatric depression is estimated to affect 15–20% of youths prior to adulthood and is associated with significant social, educational and physical impairment. Current treatments comprise moderately efficacious psychological therapies and pharmaceutical antidepressants. However, nutritional therapies are also available and are regularly sought by people with depressive illnesses and parents of depressed youths. In this narrative review, studies examining the antidepressant effects of individual nutritional supplements in child and adolescent populations are appraised. Epidemiological studies examining the relationship between nutritional status and paediatric depression, or depressive symptoms are also reviewed. Nutrients covered in this article include: omega-3 polyunsaturated fatty acids, s-adenosylmethionine, vitamin C, vitamin D, zinc, iron and B-vitamins. Although several of these nutrients present as promising treatments for paediatric depression, there is a lack of high-quality studies examining the antidepressant effects of all the aforementioned ingredients. Before nutritional treatments are accepted as validated treatments for paediatric depression, further high-quality studies are required.

Background Curcumin, the principal curcuminoid derived from the spice turmeric, influences several biological mechanisms associated with major depression, namely those associated with monoaminergic activity, immune-inflammatory and oxidative and nitrosative stress pathways, hypothalamus-pituitary-adrenal (HPA) axis activity and neuroprogression. We hypothesised that curcumin would be effective for the treatment of depressive symptoms in individuals with major depressive disorder. Methods In a randomised, double-blind, placebo-controlled study, 56 individuals with major depressive disorder were treated with curcumin (500 mg twice daily) or placebo for 8 weeks. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI). Results From baseline to week 4, both curcumin and placebo were associated with improvements in IDS-SR30 total score and most secondary outcome measures. From weeks 4 to 8, curcumin was significantly more effective than placebo in improving several mood-related symptoms, demonstrated by a significant group x time interaction for IDS-SR30 total score (F1, 53=4.22, p=.045) and IDS-SR30 mood score (F1, 53=6.51, p=.014), and a non-significant trend for STAI trait score (F1, 48=2.86, p=.097). Greater efficacy from curcumin treatment was identified in a subgroup of individuals with atypical depression. Conclusions Partial support is provided for the antidepressant effects of curcumin in people with major depressive disorder, evidenced by benefits occurring 4 to 8 weeks after treatment. Limitations Investigations with larger sample sizes, over extended treatment periods, and with varying curcumin dosages are required.

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.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.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.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.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.

Biomarkers are regularly used in medicine to provide objective indicators of normal biological processes, pathogenic processes or pharmacological responses to therapeutic interventions, and have proved invaluable in expanding our understanding and treatment of medical diseases. In the field of psychiatry, assessment and treatment has, however, primarily relied on patient interviews and questionnaires for diagnostic and treatment purposes. Biomarkers in psychiatry present a promising addition to advance the diagnosis, treatment and prevention of psychiatric diseases. This review provides a summary on the potential of peripheral biomarkers in major depression with a specific emphasis on those related to inflammatory/immune and oxidative stress/antioxidant defences. The complexities associated with biomarker assessment are reviewed specifically around their collection, analysis and interpretation. Focus is placed on the potential of peripheral biomarkers to aid diagnosis, predict treatment response, enhance treatment-matching, and prevent the onset or relapse of major depression.

Curcumin is the principal curcuminoid of the popular Indian spice turmeric and has attracted increasing attention for the treatment of a range of conditions. Research into its potential as a treatment for depression is still in its infancy, although several potential antidepressant mechanisms of action have been identified. Research completed to date on the multiple effects of curcumin is reviewed in this paper, with a specific emphasis on the biological systems that are compromised in depression. The antidepressant effects of curcumin in animal models of depression are summarised, and its influence on neurotransmitters such as serotonin and dopamine is detailed. The effects of curcumin in moderating hypothalamus–pituitary–adrenal disturbances, lowering inflammation and protecting against oxidative stress, mitochondrial damage, neuroprogression and intestinal hyperpermeability, all of which are compromised in major depressive disorder, are also summarised. With increasing interest in natural treatments for depression, and efforts to enhance current treatment outcomes, curcumin is presented as a promising novel, adjunctive or stand-alone natural antidepressant.