The effect of Polygonum minus extract on cognitive and psychosocial parameters according to mood status among middle-aged women: a randomized, double-blind, placebo-controlled study
Received 10 April 2015
Accepted for publication 10 June 2015
Published 22 September 2015 Volume 2015:10 Pages 1505—1520
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Richard Walker
This paper has been retracted
Suzana Shahar,1 Ainor Farahin Aziz,2 Siti Nur Arina Ismail,2 Hanis Mastura Yahya,2 Normah Che Din,3 Zahara Abdul Manaf,1 Manal M Badrasawi1
1Dietetics Programme, 2Nutritional Sciences Programme, 3Health Psychology Programme, School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
Background: Polygonum minus (PM) or locally known in Malaysia, as “kesum” is rich in micronutrients and natural antioxidants. However, its beneficial effect on outcome associates with oxidative stress including cognitive function is yet to be discovered. We assessed the efficacy of PM extract (LineMinus™) on cognitive function and psychosocial status among middle-aged women in Klang Valley of Malaysia.
Methods: A randomized, double-blind, placebo-controlled trial among 35 healthy middle-aged women was performed, and subjects were randomized to receive either 250 mg PM or placebo of 100 mg maltodextrin each were taken twice daily for 6 weeks. Subjects were assessed for neuropsychological test, psychosocial status, and anthropometric at baseline, week 3, and week 6. Biomarkers were also determined at baseline and week 6.
Results: The supplementation of PM showed significant intervention effect on Digit Span test (P<0.05) social functioning domain of 36-Item Short Form Health Survey (P<0.05) among subjects with mood disturbance. While, among subjects with good mood, PM supplementation improved Wechsler Abbreviated Scale of Intelligence (WASI) for IQ verbal (P=0.016) and Full Scale IQ of WASI (P=0.004). There were no adverse effects reported for the supplementation as indicated using biomarkers, including liver function and clinical symptoms.
Conclusion: Supplementation of PM is safe to be consumed for 6 weeks, with potential benefits to attention, short-term memory, improved quality of life, and mood, as well as IQ.
Keywords: cognitive function, P. minus, psychosocial, women, phytochemicals, quality of life
Polygonum minus (PM) or locally known in Malaysia, as “kesum” has been proven to be a potent natural source of antioxidant due to its high antioxidant activity.1,2 The PM leaves are used to treat dandruff,3 and to warm up the body, and were believed to be good for blood circulation.4 Nutritionally, PM is rich in antioxidant vitamins such as carotenes, retinol equivalents, and vitamin C, α-tocopherol (vitamin E), and minerals such as calcium, phosphorus, iron, sodium, potassium, magnesium, copper, and zinc.5 Several studies have reported positive effect of such micronutrients and herbs on mood and cognitive function. For example, a placebo-controlled trial among 300 healthy adults involving 4 weeks administration of a vitamin B complex with vitamin C and minerals (Berocca Calmag®) reported that the supplementation improved subjective ratings of stress, anxiety, and psychological well-being.6 Similarly, a study was carried out to assess the effects of a similar supplement for 4 weeks among 80 healthy men also reported significant attenuated subjective stress and anxiety.7 In addition, antioxidant-rich natural herbs such as pine bark extract supplementation for 5 weeks have also been reported to improve cognitive function among middle-aged men, as assessed using spatial working memory and immediate recognition tasks.8
Recently, SuperUlam, containing several natural herbs including PM, has been reported to improve cognitive function and mood.9 However, little is known about the beneficial effect of a single extract of PM. Furthermore, the former study9 excluded those with poor mood status. According to the World Health Organization (WHO), 12% of Global Disease Burden in 2000 was due to mental and behavioral disorders and it is predicted to increase to 15% by 2020, and indeed, depression causes the largest amount of years lived with disability (YLDs).10 Thus, this study aimed to determine the effect of natural herbs, ie, PM supplementation on cognitive function and psychosocial parameters among healthy middle-aged working women according to mood status, either poor or good mood. The working middle-aged women were chosen to be the study population, because many studies and cohort stated that women had more anxiety and mood disorders than men11–13 and double prevalence of depression compared with men,14,15 and this trend can persist until 54 years.16 Among working adults, a study has reported that the stress score and mood disturbances were higher among middle-aged adults compared with young and older adults.17 In addition, one study reported that the women have higher job stresses and higher risk of depression compared with men in a 6-year cohort study.18 Generally, mental health problems were shown to increase with age, and there are significant sex differences affecting this increase.19 Generally, all the subjects were below the mean age of menopause of 51 years old, in Malaysia.20 For these reasons, the study subjects were chosen from middle-aged, working females.
Materials and methods
A randomized, placebo-controlled trial was conducted among 35 healthy middle-aged women recruited from three schools and a governmental organization in Klang Valley, central Malaysia. The inclusion criteria included women, aged 35–55 years and body mass index (BMI) <40.0 kg/m2. Subjects with medical conditions (eg, uncontrolled diabetes and kidney problem), had a history of substance or alcohol abuse, smoking, history of major depression, bipolar disorder, pregnant, or lactating, were excluded. Subjects were randomized to either intervention group receiving PM (250 mg of PM) or placebo group (100 mg maltodextrin) twice daily. The study protocol was approved by the Medical Research Ethics Committee of the Universiti Kebangsaan Malaysia, and informed consent was obtained from each subject in accordance with the principles suggested in the Declaration of Helsinki,21 and Good Clinical Practice Guidelines.
Intervention (herbal product) and placebo
The supplements capsule containing 250 mg of PM extract (LineMinus™ Biotropics Malaysia Berhad, Selangor, Malaysia), of which the structural formula for the extract standardized based on quercetin 3-glucuronide and quercitrin (Table 1). The standardized extract was prepared by a water extraction with dried leaves of PM to plant extract ratio (1:20) using the unique best-available method of aqueous extraction technology.22,23 The product was obtained from a manufacturer with good manufacturing practice, free from Salmonella, Escherichia coli, and Staphylococcus aureus. The levels of heavy metals of lead, arsenic, cadmium, and mercury contents were less than 1.0, 1.0, 0.2, and 0.05 ppm and within the regulated limits of 10.0, 5.0, 0.3, and 0.5 ppm, respectively. Every bottle was closed with inner seal white caps to ensure its safety, prior to consuming.
Table 1 Energy, nutrient, and bioactive profile of kesum (Polygonum minus) and placebo capsules
Subjects were provided with two bottles containing 60 capsules throughout the intervention period of 6 weeks. The placebo used was a sensory-identical capsule. The energy, carbohydrate content, and appearance of the placebo were designed to be similar as the PM. Both groups were required to take two capsules once daily after breakfast, lunch, or dinner. The dosage of two capsules (ie, 500 mg/day) was determined based on a toxicity study on Wistar rats of which no-observed-adverse-effect level of PM extract, at more than 1,000 mg/kg body weight, following oral administration for 8 days.23
Data collection, outcome measures, and follow-up
A preliminary health screening is performed through a self-administered questionnaire, and a collection of 20 mL fasting venous blood to determine biomarkers including HbA1C, serum lipid, renal profile, liver function, and blood pressure was conducted on 63 subjects. Forty-three subjects were eligible and consented and further assessed for measuring primary outcomes including a neuropsychological tests by using Digit Span,24 Rey Auditory Verbal Learning Test (RAVLT),25 Comprehensive Trail Making Test (CTMT),26 Wechsler Abbreviated Scale of Intelligence (WASI),27 and CNS Vital Sign (CNSVS),28 psychosocial test by using Profile of Mood States (POMS),29 and quality of life using 36-Item Short Form Health Survey (SF-36).30
Their anthropometric measurements including body weight were measured using TANITA digital lithium scale HD319 to the nearest 0.1 kg (Tanita Corporation, Tokyo, Japan); height using SECA Leicester Portable Height Measure (SECA, Hamburg, Germany); and blood pressure was also measured using an automated monitor (Omron HEM 7321-E, OMRON Healthcare Co., Ltd, Kyoto, Japan). These measurements were taken at baseline, week 3, and week 6. Blood investigations were conducted again at week 6 to determine the same biomarkers as stated previously. On the testing days, subjects were advised to limit their consumption of caffeinated drinks not more than two cups daily. Subjects were then randomly allocated to either intervention or placebo-controlled group. Subjects were asked to refrain from taking any vitamins, other herbal supplements throughout the study period. The supplements were provided to the subjects with instructions for consumption listed on the label. Compliance was checked regularly, and 98.3% of the capsules given were consumed by the subjects. A list of symptoms or any side effects experienced by the participant were recorded by the research assistants at each visit.
Compliance was assessed by performing capsule count at the end of week 3 and week 6. Subjects were reminded by the researcher to take the capsule through a daily phone call or short message service. Subjects were required to record the time of consumption in a dose diary provided.
All analyses were performed using SPSS software (v 20.0; IBM Corporation, Armonk, NY, USA). The Shapiro–Wilk test was used to determine data normality. The results were expressed as the mean ± standard deviation (SD) or frequency and percentage, with 95% confidence interval. A two-way repeated measures ANOVA with adjustment of confounders including age, year of education, household income, BMI, and polyphenol intake was conducted according to two stratifications, ie, good mood (POMS ≤15) and mood disturbance (POMS >15).8 All tests were two-tailed at a probability level of 0.05. Statistical analysis was performed under a double-blind protocol, meaning the treatment code was revealed to the researchers only after analysis of all study outcomes completed.
A total of 35 subjects, from initially 43 recruited, completed the study (response rate 87.5%). Three subjects were dropped due to health problems, and two subjects were lost to follow-up (Figure 1). The mean age of subjects was 45±5.9 and 45±5.5 years, respectively, for both placebo (group A) and PM (group B). All the subjects were Malays, and both groups showed no significant difference with respect to socio-demographic profile (Table 2).
Figure 1 Study recruitment and flow chart.
Table 2 Baseline characteristics of subjects
At baseline, there were no significant differences between groups on cognitive and psychosocial status. There was an interaction effect for Digit Span scale score (P<0.05) among subjects with mood disturbance, of which the mean of Digit Span scale improved among subjects intervention group when compared with placebo (Table 3). The mean of Digit Span scale increased among subjects in PM supplemented group from 9±2.2 at baseline to 10±1.5 at week 3 and maintained at 10±1.9 at week 6. While, among the placebo group, the value increased from 7±1.4 at baseline to 7±1.4 at week 3, but reduced to 9±2.9 at week 6 (Figure 2A). Furthermore, percentage of change of Digit Span continuously increased among the PM supplemented group, but it increased then decreased in the placebo group within subjects with mood disturbance (Figure 2B). Among those with good mood, there was a significant interaction effect for Verbal IQ (P<0.05) and Full Scale IQ of WASI (P<0.05) (Table 3). As shown in Figure 3A, within those with good, subjects supplemented with PM, the mean score of Verbal IQ improved from 107±4.4 at baseline to 110±8.6 at week 3 and slightly reduced to 109±6.7 at week 6, but the later value still higher than baseline (Figure 3A and B). Such increment was not notably seen in the placebo group. With respect to the Full Scale IQ of WASI, the mean score increased sharply from 105±10.4 at baseline in PM supplemented group to 115±9.4 at week 3 but slightly reduced to 115±9.4 at week 6, but the later value still higher than baseline. However, such a sharp rise was not noted in the placebo group (Figure 4A). Thus, the percentage of change increased by 9% at 3 week and slightly reduced to 7.2% at week 6 in the PM supplemented group, when compared with a slight of increment only between 1% and 2% in the placebo group (Figure 4B). The difference in percentage of change between groups at week 3 was significantly differed.
The time effect was noted in CTMT composite index (P<0.05) among subjects with mood disturbance and CTMT (Trail 3) (P<0.05) for subjects with good mood.
With respect to psychosocial, there was a significant interaction effect for SF-36 subscale, ie, social functioning (P<0.05), of which there was an increased in the mean score among intervention group with mood disturbance from 74±19.4 (baseline) to 89±10.0 (week 3), and 90±9.1 (week 6), when compared with the decrease in placebo group (Table 4 and Figure 5A). Thus, the percentage of change in the PM supplemented group increased by 30% at week 3 and reduced to 15% at week 6, when compared with a reduction by 3% in the placebo group (Figure 5B). However, a significant interaction and time effect was also observed with subjects with mood disturbance in control group showed an improvement in vigor (subscale in POMS), when compared with intervention group (P<0.05 for both) (Table 3). The mean score of vigor decreased from 91±15.7 at baseline in the placebo group to 89±19.7 at week 3 and 88±12.5 at week 6. However, an increment was noted in the intervention group (Figure 6A and B). Among subjects with good mood, only a significant time effect in anger subscale of POMS was found (P<0.05).
There were no significant interaction effects on anthropometric parameters and blood biomarkers in Tables 5 and 6, respectively. However, there was a significant time effect for weight, BMI, and diastolic blood pressure; sodium, uric acid, creatinine, total protein, globulin, total cholesterol/high density lipoprotein, and HbA1C (P<0.05) for all parameters. No significant adverse effects were reported in both placebo and intervention groups.
To the best of our knowledge, this is the first clinical trial to evaluate the cognitive and psychosocial effects of PM in human specifically in middle-aged women, with its safety as evidenced by blood biomarkers have also been proven. Recently, interest in products aimed at improving cognitive performance and mood is steadily increasing. However, those products were not supported by scientific evidence. There is a trend that most individuals preferred a natural option for improving cognitive function and mood rather than pharmaceutical agents which have been reported to have some side effects.31 In one study, Laditka et al found that most of adults used supplements to treat or cure their cognitive problems rather than to prevent them.32 Hence, this study provides scientific evidence of beneficial effect of natural herbs, ie, PM extract in improving cognitive function and psychosocial parameter.
In this study, PM supplementation exerts positive effect on IQ, by 2.1% for verbal and 7.3% for Full Scale IQ of WASI, for subgroup with good mood (POMS ≤15). PM is a natural herb rich in phytochemicals particularly flavonoid (ie, flavonols, myricetin quercetin, methyl flavonol, and flavones),33 higher than total flavonoid when compared with other indigenous plants.34 In addition, PM water extract had higher antioxidant activity when comparing with ginger (Zingiber officinale) and turmeric (Curcuma longa), measured by the total phenolic content, 2,2-diphenyl-11-picrylhydrazyl free radical and ferric reducing antioxidant power.34,35 These phytochemicals have strong antioxidant capacities play an important role in delaying or preventing degenerative diseases caused by oxidative damage of living cell components and its free radical scavenging properties may help to reduce oxidative stress and lipid peroxidation in neuronal membrane, further results in positive effect on memory, cognition, and improved cerebrovascular blood flow.36
Flavonoids and their metabolites are shown to modulate neuronal signaling through tyrosine kinase, phosphoinositide 3-kinase, protein kinase C, and mitogen-activated protein kinase pathways.36 These signaling cascades are also critical for the control of inflammatory processes in the brain, including the activation of microglia in response to cytokines and the induction of inducible nitric oxide synthase and nitric oxide production.37 By affecting such pathways, flavonoids can be seen as innovative dietary strategies for reducing the effects of neuroinflammation in the brain. In addition, its attribution can also have a direct impact on memory acquisition (learning), consolidation (storage of labile table memory), and storage process through the induction of new protein synthesis in neurons. Moreover, flavonoids may induce increases in cerebral blood flow which eventually give an impact on acute cognitive performance, or may lead to an increase in hippocampal vascularization capable of inducing new neuronal growth.38 Thus, PM has the ability to improve cognition including attention and short-term memory, indicated by an improvement in Digit Span by 14.7% as being seen in this study, among individuals with poor mood or having some degree of mood disturbance. Similar findings were observed in other studies involving natural herbs as neuroprotective supplementations in improving cognitive functions.8,9
In this study, the ability of PM supplementation in improving cognition among those with mood disturbance will further improve general well-being such as the social functioning in SF-36. Stress is a risk factor for low physical strength lead to poor well-being. PM composed of quercetin and quercetin-3-glucuronide as its bioactive chemical act as anti-depression agent.39 Moreover, those flavones including hyperin and isoquercitrin had a potential structure for anti-depression.40 Quercetin and quercetin-3-glucuronide were reported to impact the gamma-aminobutyric acid receptors producing sedation, anxiolytic, or anticonvulsive effects.41 Animal studies showed that quercetin dose dependently increases social interaction, decreases immobility time, and minimizes changes in behavior in animal experiments, such as the swim test or forced immobilization which designed to create anxiety and behavioral despair.42,43 Thus, it might explain the ability of quercetin in improving social functioning (extent or frequency of physical health and emotions problem interacting with normal social activities) in SF-36. Further, in vivo studies showed that quercetin reduced stress-induced brain corticotropin-releasing factor (CRF) expression (CRF has been implicated in anxiety and depression).42,44 It also attenuates stress-induced increases of plasma corticosterone and adrenocorticotropic hormone.44
In this study, only one of eight domains in POMS, ie, vigor showed significant intervention effect upon supplementation of PM. This beneficial effect was seen in placebo group with mood disturbance. This might be due to differences in subject measurements. Different individuals may have different ways of experiencing emotion. Moods can easily fluctuate and constantly change over period of time and this makes mood changes difficult to measure. Mood can affect by a number of environmental or external factors (ie, social interactions or stressful life events) and internal factors (ie, circadian rhythms or menstrual cycle in women).45 The six distinct mood states in POMS are not claim to capture the entire content domain of mood.46 The use of more objective measurements such as eye-tracking method to monitor emotions based on pupil dilations,47 or by using BioM-10 Mood Panel,48 a peripheral biomarker set of low vs high mood states are recommended for future studies.
As this is the first study, to the best of our knowledge, to assess the effects of PM extract on cognitive function and psychosocial status, only few comparisons can be made with the existing research in improving cognitive with herbs supplementation. Curcuma longa or turmeric is commonly used to make curries in Asia, has been portrayed as having antioxidant and has the effect of neuron.49 Flavonoid and polyphenols have been long studied for their strong antioxidant capacities, and as scavenging agents for reactive oxygen species thus it have potential role in preventing aging and oxidative stress-related diseases.50,51 American ginseng (Panax quinquefolius) has been found to improve working memory performance.52 Recently, the product known as SuperUlam has been reported to improve cognitive function and mood after 3 weeks supplementation among middle-aged healthy individuals. SuperUlam is a mixture of several natural plant extracts including PM extract.9 In an animal study, the potent antioxidant in PM extract was capable of entering into and protecting cells from oxidative damage, and produce favorable effects of cognitive function, because the brain has a high level of metabolism and required a high amount of oxygen to do its function which is prone to oxidation by the free radicals.22 Thus, PM extract, along with other natural herbs, has shown to have a neuroprotective effect in human as noted in this study.
The PM extract was safe to use as indicated by no significant changes in liver function, kidney function, and other blood indices in the study subjects, these findings were supported by findings from a recent study which also reported the safety of supplement contains a mixture of herbs, including PM extract on liver and kidney function.53 However, in a retrospective review study on the risk assessment of using Polygonum multiflorum, on liver function, liver damage was reported in some cases. The safety of this herb may be affected by the type of the species, type of extract, dose, and duration of the intervention. It should be noted that this study documented the safety of another species of Polygonum which is PM aqueous extraction using a specific dose of 500 mg/day and 6 weeks intervention period.
This research has some strengths, including the use of randomized, placebo-controlled, double-blind study design, a full 6 weeks of supplementation, blood monitoring at baseline and post-treatment, and multiple assessments of many cognitive functions. However, this study also has several limitations. For example, although the cognitive tests completed by the subjects were objective, standardized tests based on well-known, validated measures of neuropsychological functioning, several of the subtests on the CNS Vital Signs battery are relatively brief and may not be sensitive enough to detect very subtle changes in neuropsychological functioning.28 Future research may wish to include objective assessments of cognitive function such as magnetic resonance imaging.
The cognitive measures in this study were administered 3 weeks apart, thus it is possible that improvements in performance due to practice or learned effects may have obscured the ability to detect any direct effects of study products on cognitive functioning. Future studies using alternative research designs with longer study duration may help to clarify this concern. In addition to this, we attribute the lack of statistical significance in our study due to small sample size and short duration of study. Thus, a future higher-powered study is needed to investigate an appropriate number of individuals to generate further statistically significant results with a wide range of population that include different sex and races. Overall, the findings of this study were the first to demonstrate the cognitive function and psychosocial status following supplementation of water extract of PM (LineMinus™) for 6 weeks with no adverse effect on blood biomarkers including liver and renal function and also blood sugar and fasting serum lipid. However, the results have to be taken with caution, because not all components of cognitive functions and psychosocial status were shown to be statistically significant. Further research is required to assess the neurocognitive effects of PM in other populations (eg, older individuals and those with cognitive problems).
This study showed that PM supplementation (LineMinus™) improved both attention and short-term memory and quality of life for social functioning domain among women with mood disturbance in this study. Analysis in a subgroup with good mood indicated that the supplementation improved the IQ of the women in this study. Supplement given at a dosage of 500 mg/day was also proved to be safe with no adverse or toxicity effect on health has assessed using several biomarkers. There is a need to further investigate the beneficial effect of the supplementation among other vulnerable groups such as older adults, for a longer period of study and involving objective measures and biomarkers associated with cognition.
This study was funded by Biotropics Malaysia Berhad. The authors thank all participating schools and institution who gave their utmost cooperation in completing the study. The authors also thank all the fieldworkers involved during the data collection period.
SS had access to all data and was involved in the overall study design, interpretation of the data, and revising the manuscript. AFA was involved in interpretation of data, drafting, and revising the manuscript. NCD, ZAM, and MMB made substantial contributions to conception and study design. Both NCD and MMB were also involved in the planning of statistical analyses and revising the manuscript. HMY contributed in conception of the study, supervising the fieldwork, and revising the manuscript. SNAI performed statistical analyses, interpreted the data, and revised the manuscript. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.
The authors report no conflicts of interest in this work.
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