Adrian Lopresti

The oral delivery of curcumin has been shown in several studies to have beneficial pain-relieving effects for the treatment of knee osteoarthritis. However, there has been limited investigation into its efficacy and tolerability when delivered topically. The purpose of this two-arm, 28-day, parallel-group, randomised, double-blind, placebo-controlled trial was to determine the effects of a topical curcumin gel (VAS-101) on knee pain and symptoms in adults with knee osteoarthritis.
Sixty adults aged 45-75 with knee osteoarthritis applied a curcumin or placebo gel to their knee, every second day for 28 days. Outcome measures comprised the Knee Injury and Osteoarthritis Outcome Score (KOOS), daily pain ratings, and several performance-based tests. Rescue oral medication intake was also monitored over time.
Compared to the placebo, VAS-101 was associated with greater improvements in the KOOS pain score (primary outcome measure) (β: 5.12; 95% CI: 0.47, 9.77; d = 0.62,
 = 0.041), and mean daily pain ratings (F
 = 4.42; d = 0.55,
 = 0.005). In the VAS-101 group, 39.3% of participants reported feeling either much or very much improved, compared with 13.3% in the placebo group (
 = 0.019). Moreover, 32.1% of participants in the VAS-101 group achieved a Minimal Clinically Important Difference, compared to 13.3% in the placebo group, although this group difference was not statistically significant (
 = 0.086). There were no group differences in changes in other KOOS subscale scores or the performance-based tests. VAS-101 was well-tolerated, with no significant adverse reactions reported. However, skin staining was observed as expected with topical curcumin, which resolved 2-3 days after application ceased.
Conservative dosing of a topically applied curcumin-containing gel (VAS-101), administered every two days for 28 days, is associated with moderate reductions in knee pain in adults with knee osteoarthritis. Further investigations utilising larger sample sizes, longer treatment durations, and alternative treatment regimens will be important to identify how these factors affect treatment adherence, tolerance, and efficacy.

Background/objectives: Magnesium may help support cognition and sleep. The purpose of this two-arm, 6-week, parallel-group, randomised, double-blind, placebo-controlled trial was to examine the effects of magnesium L-threonate (Magtein®) supplementation on cognitive performance, cognitive age, sleep quality, and selected physiological indicators in adults.

Methods: One hundred adults aged 18 to 45 with self-reported dissatisfied sleep were supplemented with 2 g daily of Magtein® or a placebo. Outcome measures comprised the computer-based National Institute for Health (NIH) Cognitive Toolbox and Raven’s Progressive Matrices Version 2 for the assessment of cognitive function, self-report evaluations of sleep quality and emotional wellbeing, a reaction time test, and physiological data obtained from a sleep-tracking wearable device (Oura Ring), including resting heart rate (HR) and heart rate variability (HRV) during sleep.

Results: Compared to the placebo, Magtein® was associated with greater improvements in overall cognitive performance as measured by the NIH Total Cognition Composite (p = 0.043), with larger treatment effects on working and episodic memory. There was also a 7.5-year reduction in estimated brain cognitive age and a greater improvement in reaction time (p = 0.031). However, there were no group differences in changes in the Raven’s test (p = 0.953). Based on self-report measures, there was a greater improvement in sleep-related impairment (p = 0.043), but no group differences in changes in sleep disturbances (p = 0.316), restorative sleep (p = 0.439), or general wellbeing (p = 0.436); although in a subset of participants with more severe sleep-related problems, group differences in sleep-disturbances were identified (p = 0.031). Based on data from the sleep tracking ring, there were no group differences in sleep outcomes, although there was a greater reduction in HR (p = 0.030) and an increase in HRV (p = 0.036), a physiological marker of stress reduction and improved autonomic balance. Magtein® was well-tolerated, and there were no reports of significant adverse reactions.

Conclusion: The results from this study suggest Magtein® supplementation for 6 weeks improves overall cognition, cognitive age, working memory, reaction time, HR, HRV, and some subjective, but not objective measures of sleep in healthy adults with self-reported dissatisfied sleep.

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.

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.

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.