Adrian Lopresti

Background and Objectives
Bacopa monnieri is a plant used in Ayurvedic medicine with traditional uses for memory and cognitive function. The objective of this study was to examine the effects of supplementation with a Bacopa monnieri extract (Bacumen®) on cognitive function, stress, and fatigue in adults with self-reported memory and attention problems.

Study Design
Two-arm, 12-week, parallel-group, randomized, double-blind, placebo-controlled trial.

Methods
Overall, 101 volunteers aged 40–70 years with self-reported memory and attention problems were supplemented with 300 mg daily of a Bacopa monnieri extract (Bacumen®) (n = 50) or a placebo (n = 51). Outcome measures included several computer and researcher-administered cognitive tasks assessing verbal learning, attention and working memory (primary outcome measures) and self-report measures assessing memory, mood, and fatigue (secondary outcome measures). Changes in blood concentrations of brain-derived neurotrophic factor, malondialdehyde, and acetylcholine esterase activity were also examined. Cognitive assessments, blood collections and self-reported questionnaires were completed in person on day 0 and week 12. Moreover, self-report questionnaires were completed online at weeks 4 and 8. Participants, researchers and the statistician were blinded until all data was collected and a blind review was completed.

Results
Of the 101 participants randomized, 87 participants completed the study, 47 in the placebo group and 40 in the Bacopa monnieri group. On the basis of complete data collected from 87 participants, there were no between-group differences in changes in the primary outcome measures comprising verbal learning (p = 0.391), attention (p = 0.713), and working memory (p = 0.610). However, in the Bacopa-supplemented participants, there were greater reductions in overall self-reported stress reactivity (p = 0.03); and fatigue and stress levels after exposure to a cognitive-demanding computer task (secondary outcome measures). There were no group differences in changes in blood concentrations of measured markers. Bacopa monnieri supplementation was generally well-tolerated, with no serious adverse reactions, although there was a greater frequency of self-reported adverse reactions in the Bacopa monnieri group (p = 0.024), primarily comprising digestive complaints and headaches.

Conclusions
The results from this study indicate that compared with the placebo, Bacopa monnieri supplementation for 12 weeks did not result in greater improvements in cognitive performance. However, stress reduction and anti-fatigue effects were identified, which requires investigation in future trials.

Clinical Trials Registration Number
Australian New Zealand Clinical Trials Registry (ANZCTR)—ACTRN12623000475640.

Background/objectives: Tocotrienols are a form of vitamin E that may have neuroprotective effects. However, there have been no studies examining its effects on cognitive function when delivered as a stand-alone intervention. The purpose of this two-arm, 12-week, randomised, double-blind, placebo-controlled trial was to examine the effects of supplementation with tocotrienols derived from rice bran (TheraPrimE® rice) on memory and sleep in adults with subjective memory complaints.

Methods: Ninety-one adults aged 40–80 were supplemented with a placebo or 100 mg of tocotrienols daily. Outcome measures included the Test of Memory and Learning (version 2), and self-report questionnaires assessing executive function and sleep quality. Moreover, changes in blood markers associated with inflammation, oxidative stress, and neurotropic activity were examined.

Results: Compared to the placebo, tocotrienol supplementation was associated with greater improvements in general memory (p = 0.045, 95% CI: 0.34, 32.21). Memory changes were primarily due to improvements in non-verbal memory (p = 0.039, 95% CI: 0.68, 26.63). However, there were no group differences in changes in verbal memory. Moreover, there were no group differences in changes in self-reported executive function, although there were greater improvements in sleep disturbance in the tocotrienols group (p = 0.015, 95% CI: −4.80, −0.55). An examination of blood markers revealed a statistically significant larger increase in Tumour Necrosis Factor-α in the placebo group (p = 0.043) and a larger increase in C-reactive protein (p = 0.039) in the tocotrienols group. Tocotrienols were not associated with any serious adverse reactions.

Conclusion: This is the first controlled study demonstrating the cognitive-enhancing and sleep-promoting effects of stand-alone supplementation with tocotrienols. However, future research is required to substantiate this study’s results and examine the potential mechanisms of action.

Purpose: To assess the effects of magnesium bisglycinate supplementation on insomnia symptoms in healthy adults reporting poor sleep quality.
Patients and Methods: This randomized, double-blind, placebo-controlled trial enrolled 155 adults aged 18– 65 years with self-reported poor sleep quality. Participants were randomly assigned to either magnesium bisglycinate supplementation (250 mg elemental magnesium, daily) or placebo capsules. Sleep quality was assessed using the Insomnia Severity Index (ISI) and additional psychological questionnaires at baseline and multiple time points throughout the study. Generalized linear mixed models (GLMM) adjusted for baseline ISI scores, age, sex, body mass index, and occupation were applied.

Results: The magnesium bisglycinate group showed a significantly greater reduction in ISI scores compared to the placebo group from baseline to Week 4 (− 3.9 [95% CI: − 5.8 to − 2.0] vs − 2.3 [95% CI: − 4.1 to − 0.4], respectively; p = 0.049). The effect size was small (Cohen’s d = 0.2), indicating a modest benefit. Exploratory analyses suggested notably greater improvements among participants reporting lower baseline dietary magnesium intake, potentially indicating a subgroup of high responders. No significant differences were observed in other psychological outcomes.

Conclusion: Magnesium bisglycinate supplementation modestly improved insomnia severity in adults reporting poor sleep quality. Future research should include objective sleep assessments, longer intervention periods, and better characterization of potential high responders by systematically assessing baseline dietary magnesium intake and status.
Clinical Trial Registration Name: Effect of magnesium bisglycinate supplementation on sleep and fatigue parameters in healthy adults reporting poor sleep quality; https://drks.de/search/en/trial/DRKS00031494 DRKS-ID: DRKS00031494.

Background
Saffron, derived from the stigmas of the Crocus sativus flower, has been shown in previous trials to have antidepressant effects in clinically diagnosed adults. However, the recruitment of small sample sizes, short treatment periods, and variability in the quality of studies have negatively impacted the strength of conclusions.

Objectives
The purpose of this 2-arm, 12-wk, parallel-group, randomized, double-blind, placebo-controlled trial was to examine the effects of supplementation with a saffron extract (Affron) on mood and sleep in adults experiencing subclinical depressive symptoms.

Methods
Two hundred and two adults aged 18–70 with depressive symptoms were supplemented with 28 mg saffron daily or a placebo. Outcome measures included the Depression, Anxiety, and Stress Scale – 21, Sleep Disturbance and Sleep-Related Impairment Scale, World Health Organization–Five Well-Being Scale, and daily depression, stress, and anxiety ratings.

Results
On the primary outcome measure, compared to the placebo, saffron was associated with greater improvements in the Depression, Anxiety, and Stress scale – 21 depression score (β: –2.92 points; 95% confidence interval: –5.13, –0.71 points; Cohen’s d = 0.39), with 72.3% of participants in the saffron group achieving a clinically significant change (a reduction of ≥ 7 points) compared to 54.3% of participants in the placebo group (P = 0.010). However, in the other secondary outcomes, there was no evidence of between-group differences. In exploratory analyses across various strata and assumptions, improvements in sleep disturbances (β: –2.72 points; 95% confidence interval: –4.99, –0.46 points; Cohen’s d = 0.44) were identified in a subset of participants with a greater severity of sleep disturbance. There were no serious adverse reactions reported.

Conclusions
This study, the largest conducted to date on saffron, provides evidence supporting the beneficial effects of 3 mo of saffron supplementation on depressive symptoms in adults. Large placebo responses were evident in this study, which require consideration in future trials.
This trial was registered at Australian and New Zealand clinical trials registry as ACTRN12623001358639.

In traditional medicine, Khaya senegalensis has been used to treat menstrual pain, dysmenorrhea, and digestive pain and discomfort. However, there are no human clinical trials examining its safety and efficacy for the treatment of menstrual distress. Therefore, the purpose of this two-arm, parallel-group, randomized, double-blind, placebo-controlled trial was to examine the safety and efficacy of supplementation with a Khaya senegalensis preparation (Khapregesic
) on menstrual pain and menstrual distress in menstruating women.
Eighty-four women experiencing menstrual pain and distress were supplemented 3g daily with this Khaya senegalensis preparation or a placebo for one menstrual cycle. Changes in menstrual pain and other symptoms of menstrual distress were examined through daily ratings and validated self-report questionnaires. Moreover, changes in the use of rescue medications, C-reactive protein, and safety blood measures were examined.
Compared to the placebo, this Khaya senegalensis preparation was associated with greater reductions in daily menstrual pain ratings (p=0.033) and reductions in overall menstrual distress (p=0.042). Improvements in emotional wellbeing were also identified, along with reductions in the use of rescue medications, although this latter finding requires confirmation in future trials. No changes in C-reactive protein were identified. This Khaya senegalensis preparation was well-tolerated and there were no significant changes in safety blood markers.
This study provides evidence supporting the safety and efficacy of a Khaya senegalensis preparation on menstrual pain and menstrual distress in women. Further investigations will be important to confirm and expand on the current findings and to help identify its potential mechanisms of action.
ANZCTR, ACTRN12624000731594p. Registered 14 June 2024, https://www.anzctr.org.au/ACTRN12624000731594p.aspx.

Background: Lutein and zeaxanthin are fat-soluble antioxidant nutrients that have evidence of beneficial effects on vision and eye health.

Purpose: Examine the effects of supplementation with lutein and zeaxanthin isomers (Lute-gen®) on eye health, eye strain, sleep quality, and attention in high electronic screen users.

Study design: Two-arm, 6-month, parallel-group, randomized, double-blind, placebo-controlled trial.

Methods: Seventy volunteers aged 18 to 65 who used electronic screens for more than 6 h daily were supplemented with 10 mg of lutein and 2 mg of zeaxanthin-isomers or a placebo. Outcome measures included several ophthalmic examinations comprising the Schirmer tear test, photo-stress recovery time, contrast sensitivity, tear film break-up time, and self-report measures of visual fatigue, computer vision, sleep quality and attention.

Results: Compared to the placebo, lutein and zeaxanthin supplementation was associated with greater improvements in the Schirmer tear test, photo-stress recovery time, and tear film break-up time. However, there were no between-group differences in the change in self-report measures or contrast sensitivity. Lutein and zeaxanthin supplementation was well-tolerated, with no reports of serious adverse reactions or clinically significant changes in safety blood measures, including liver function, renal function, blood lipids, and full blood examination.

Conclusion: The results from this study provide support for the beneficial effects of 6 months of lutein and zeaxanthin supplementation on regular users of electronic screens. Compared to the placebo, there were improvements in several ophthalmic examinations for dry eyes and visual health. However, these findings were not corroborated by group differences in the administered self-report measures. Lutein and zeaxanthin were well tolerated, with no serious adverse effects or significant changes in vital signs or blood safety measures.

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.

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.

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).

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.