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.

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.

RCT Entities:   Population Interventions Outcomes

Introduction

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

Study design

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

Constituents (per 100 g)	Placebo	Polygonum minus
Energya
kJ	386	305
kcal	1,621	1,281
Macronutrientsa
Fat (g)	0	0
Carbohydrate (g)	94	67.6
Protein (g)	2.6	8.6
Micronutrientsb,c
Calcium (mg)	6.3	38.5
Iron (mg)	0.4	1.4
Vitamin A (µg)	0	0
l-Ascorbic acid (mg)	10.6	27.0
α-Tocopherol (mg)	0	0
Bioactive content (%)c
Quercetin-3-glucuronide	–	0.4
Quercitrin	–	0.1

Notes:

Determined by Method of Analysis for Nutritional Labeling, AOAC, 1993.54

Determined by US Environmental Protection Agency (EPA) method revision 2, 1995.55

Determined by high performance liquid chromatography.

Abbreviation: AOAC, Association of Official Agricultural Chemists.

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 checking

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.

Statistical analysis

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.

Results

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

Baseline characteristics	Group A (n=18)	Group B (n=17)	P-value
Age (years), mean ± SD	46±6.1	45±4.6	0.829a
Anthropometric status, mean ± SD
Weight (kg)	67±9.7	67±11.7	0.929a
Height (cm)	156±5.0	154±5.5	0.412a
BMI (kg/m2)	27.7±3.9	28.2±5.0	0.734a
Marital status, n (%)
Married	18 (100.0)	16 (94.1)	0.296b
Single	0 (0.0)	1 (5.9)
Level of education, n (%)
Secondary school	8 (44.4)	4 (23.5)	0.362b
Certificate/diploma	2 (11.1)	4 (23.5)
Degree	8 (44.4)	9 (52.9)
Occupation, n (%)
Teacher	8 (44.4)	9 (52.9)	0.615b
Non-teacher	10 (55.6)	8 (47.1)
Household income per month (RM), mean ± SD	7,591±3,904.2	8,251±5,125.1	0.670a

Notes:

Independent t-test;

chi-squared test.

Abbreviations: BMI, body mass index; RM, Ringgit Malaysia; SD, standard deviation.

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.

Table 3

Cognitive function at baseline, week 3, and week 6 according to mood status (mean ± SD)

Scale	Mood disturbance		Group effect		Time effect		Intervention effect		Good mood		Group effect		Time effect		Intervention effect
	A (n=7), mean ± SD	B (n=13), mean ± SD	P-value	ηp2	P-value	ηp2	P-value	ηp2	A (n=11), mean ± SD	B (n=4), mean ± SD	P-value	ηp2	P-value	ηp2	P-value	ηp2
Digit Spana scale score
Baseline	7±1.4	9±2.2	0.470	0.041	0.080	0.177	0.037*	0.224	9±1.8	9±3.7	0.572	0.042	0.701	0.043	0.886	0.015
Week 3	11±3.6	10±1.5							9±3.1	9±1.4
Week 6	9±2.9	10±1.9							10±2.1	10±2.5
RAVLTb
Baseline	53±5.4	50±7.8	0.411	0.053	0.603	0.030	0.313	0.083	48±11.7	58±8.9	0.965	0.00	0.430	0.086	0.294	0.139
Week 3	55±7.4	48±10.1							46±12.1	54±5.4
Week 6	52±5.4	51±7.6							48±10.6	54±4.3
Recall
Baseline	38±6.4	41±6.9	0.839	0.003	0.071	0.185	0.701	0.027	47±11.6	53±6.2	0.975	0.00	0.104	0.246	0.394	0.110
Week 3	50±5.8	48±6.1							48±10.9	53±8.2
Week 6	52±5.4	50±7.8							47±12.2	51±8.5
CTMTc
Trail 1
Baseline	38±6.4	41±6.9	0.839	0.003	0.071	0.185	0.701	0.027	39±11.2	37±7.1	0.431	0.079	0.777	0.031	0.946	0.007
Week 3	50±5.8	48±6.1							48±7.7	47±7.6
Week 6	52±5.4	50±7.8							52±12.4	48±10.0
Trail 2
Baseline	42±5.7	45±8.4	0.751	0.008	0.961	0.003	0.149	0.136	46±10.1	39±4.1	0.301	0.132	0.207	0.179	0.235	0.165
Week 3	54±14.6	45±4.7							50±9.1	37±5.4
Week 6	51±11.6	52±12.1							53±12.4	43±6.4
Trail 3
Baseline	41±7.7	42±10.1	0.736	0.009	0.158	0.132	0.168	0.128	42±11.9	43±8.3	0.416	0.084	0.029*	0.358	0.236	0.165
Week 3	46±7.4	49±10.5							47±11.6	43±8.9
Week 6	49±11.0	46±7.2							50±10.6	47±8.8
Trail 4
Baseline	39±7.8	40±6.8	0.818	0.004	0.321	0.084	0.349	0.078	42±10.6	38±1.3	0.554	0.046	0.149	0.212	0.276	0.149
Week 3	43±12.9	44±8.1							44±10.2	39±5.3
Week 6	40±9.4	46±8.6							47±7.6	43±4.8
Trail 5
Baseline	46±6.5	45±6.0	0.612	0.020	0.582	0.041	0.917	0.007	40±8.4	42±4.3	0.429	0.080	0.757	0.034	0.062	0.293
Week 3	48±11.7	45±8.0							46±9.6	43±6.9
Week 6	51±9.8	50±6.4							51±7.3	44±10.1
Composite index
Baseline	40±5.4	41±7.0	0.947	0.00	0.026*	0.246	0.619	0.036	41±9.8	39±5.1	0.382	0.097	0.206	0.179	0.284	0.146
Week 3	48±8.1	45±6.1							46±9.4	40±6.6
Week 6	48±8.4	48±7.0							50±9.8	44±6.8
WASId IQ verbal
Baseline	104±9.8	109±11.7	0.241	0.104	0.918	0.007	0.568	0.043	114±11.4	107±4.4	0.260	0.177	0.179	0.218	0.016*	0.447
Week 3	107±8.5	106±6.7							110±4.3	110±8.6
Week 6	108±6.8	109±5.7							110±5.5	109±6.7
WASIe IQ performance
Baseline	107±11.8	108±9.7	0.288	0.086	0.425	0.064	0.390	0.070	113±8.5	104±18.5	0.426	0.093	0.082	0.301	0.891	0.016
Week 3	112±12.2	115±6.0							120±8.3	116±10.3
Week 6	114±6.8	121±6.0							120±3.7	114±13.6
WASIf IQ full
Baseline	106±10.4	110±10.1	0.198	0.124	0.794	0.018	0.957	0.003	115±6.9	105±10.4	0.176	0.245	0.514	0.091	0.004*	0.542
Week 3	110±10.4	111±5.9							117±5.2	115±9.4
Week 6	113±5.7	116±5.0							116±4.3	113±9.0
CNSVS
Visual memoryg
Baseline	90±20.1	85±8.4	0.591	0.023	0.498	0.052	0.383	0.071	80±17.4	97±21.0	0.691	0.021	0.642	0.054	0.440	0.097
Week 3	83±15.0	88±14.5							78±14.6	88±9.4
Week 6	80±22.2	84±18.1							85±21.2	93±5.3
Psychomotor speedh
Baseline	97±11.0	100±15.0	0.286	0.087	0.451	0.059	0.292	0.090	84±26.1	97±9.3	0.938	0.001	0.551	0.072	0.492	0.085
Week 3	94±10.9	99±14.9							88±19.5	97±14.5
Week 6	93±15.6	104±17.6							97±13.8	102±15.0
Reaction timei
Baseline	94±15.6	81±18.7	0.969	0.000	0.133	0.144	0.520	0.049	91±17.4	94±11.4	0.631	0.030	0.266	0.153	0.324	0.131
Week 3	95±19.0	89±15.7							96±13.4	98±4.9
Week 6	97±12.3	91±11.6							98±11.1	90±14.6
Cognitive flexibilityj
Baseline	103±15.1	92±12.1	0.322	0.075	0.581	0.041	0.746	0.022	93±14.0	101±9.4	0.905	0.002	0.973	0.003	0.937	0.008
Week 3	105±16.4	101±12.0							103±16.4	105±16.5
Week 6	109±12.8	107±11.6							108±6.8	106±12.0
Processing speedk
Baseline	107±17.3	99±13.8	0.741	0.009	0.591	0.040	0.577	0.041	98±13.0	116±7.7	0.290	0.138	0.126	0.228	0.765	0.033
Week 3	110±16.7	104±15.7							104±15.1	117±20.3
Week 6	110±21.0	112±24.5							109±12.8	125±25.1
Executive functionl
Baseline	105±15.3	93±11.7	0.339	0.070	0.655	0.032	0.701	0.027	97±13.2	101±9.7	0.848	0.005	0.923	0.010	0.903	0.013
Week 3	105±17.1	101±12.4							105±11.1	106±15.7
Week 6	109±13.1	107±12.2							107±7.0	107±11.6
Motor speedm
Baseline	92±14.9	100±13.7	0.123	0.173	0.834	0.014	0.614	0.037	81±29.7	86±11.8	0.598	0.036	0.744	0.036	0.682	0.047
Week 3									81±22.5	86±8.1
Week 6									89±12.1	87±5.2

Notes:

P<0.05 significant using ANCOVA with age, year of education, household income, BMI, and polyphenol intake as covariates. A, placebo group; B, Polygonum minus group. Mood disturbance = POMS >15; good mood = POMS ≤15. Higher score represents –

good short term memory;

good learning ability and memory;

higher executive function;

higher IQ verbal;

higher IQ performance;

higher score overall IQ;

higher visual memory;

higher psychometer speed;

longer reaction time;

higher level of functioning;

longer processing speed;

higher level of executive functioning; and

higher level of motor speed.

Abbreviations: ANCOVA, analysis of covariance; BMI, body mass index; CNSVS, CNS Vital Sign; CTMT, Comprehensive Trail Making Test; , partial eta squared; POMS, Profile of Mood States; RAVLT, Rey Auditory Verbal Learning Test; SD, standard deviation; WASI, Wechsler Abbreviated Scale of Intelligence.

Figure 2

(A) The mean score of Digit Span at baseline, week 3, and week 6 among subjects with mood disturbance according to study groups. (B) The percentage of mean change for Digit Span from baseline to week 3 and week 6 among subjects with mood disturbance according to study groups.

Notes: A, placebo group; B, Polygonum minus group. Mood disturbance = POMS >15. *P<0.05 independent t-test.

Abbreviation: POMS, Profile of Mood States.

Figure 3

(A) The mean score of Verbal IQ of WASI at baseline, week 3, and week 6 among subjects with good mood according to study groups. (B) The percentage of mean change for Verbal IQ from baseline to week 3 and week 6 among subjects with mood disturbance according to study groups.

Notes: A, placebo group; B, Polygonum minus group. Good mood = POMS ≤15. Non-significant independent t-test.

Abbreviations: POMS, Profile of Mood States; WASI, Wechsler Abbreviated Scale of Intelligence.

Figure 4

(A) The mean score of Full IQ of WASI at baseline, week 3, and week 6 among subjects with good mood according to study groups. (B) The percentage of mean change for Full IQ of WASI from baseline to week 3 and week 6 among subjects with mood disturbance according to study groups.

Notes: A, placebo group; B, Polygonum minus group. Good mood = POMS ≤15. *P<0.05 independent t-test.

Abbreviations: POMS, Profile of Mood States; WASI, Wechsler Abbreviated Scale of Intelligence.

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).

Table 4

Psychosocial status at baseline, week 3, and week 6 of intervention according to mood status (mean ± SD)

Scale	Mood disturbance		Group effect		Time effect		Intervention effect		Good mood		Group effect		Time effect		Intervention effect
	A (n=7), mean ± SD	B (n=13), mean ± SD	P-value	ηp2	P-value	ηp2	P-value	ηp2	A (n=11), mean ± SD	B (n=4), mean ± SD	P-value	ηp2	P-value	ηp2	P-value	ηp2
POMSa tension
Baseline	11±4.5	12±3.8	0.763	0.007	0.921	0.006	0.831	0.014	7±2.0	6±3.5	0.843	0.005	0.290	0.143	0.917	0.011
Week 3	8±6.0	8±5.3							11±6.1	9±7.4
Week 6	10±3.3	9±5.5							7±6.3	6±1.8
Depression
Baseline	9±4.9	15±4.4	0.702	0.012	0.939	0.005	0.809	0.016	3±2.2	3±2.4	0.533	0.050	0.266	0.152	0.621	0.058
Week 3	6±10.1	7±8.1							11±10.5	12±13.5
Week 6	9±9.2	10±8.6							6±11.5	2.5±2.6
Anger
Baseline	13±4.6	13±3.9	0.733	0.009	0.724	0.016	0.606	0.028	5±3.9	6±3.6	0.958	0.000	0.029*	0.375	0.861	0.019
Week 3	6±4.2	9±4.7							11±9.0	11±11.6
Week 6	12±6.5	10±6.6							7±3.7	5±1.3
Vigor
Baseline	19±7.2	19±5.0	0.834	0.004	0.003*	0.357	0.027*	0.244	20±7.4	21±6.7	0.159	0.232	0.173	0.197	0.864	0.018
Week 3	17±5.2	17±6.0							20±4.7	19±1.7
Week 6	21±5.0	18±3.9							19±6.2	22±5.5
Fatigue
Baseline	9±2.1	10±3.7	0.270	0.093	0.554	0.044	0.800	0.017	4±2.5	5±2.9	0.249	0.162	0.239	0.164	0.918	0.011
Week 3	5±3.4	7±5.2							9±6.4	10±5.7
Week 6	8±4.5	8±4.6							6±6.3	5±4.2
Confuse
Baseline	7±2.7	9±1.9	0.194	0.126	0.753	0.022	0.788	0.018	5±1.4	4±1.0	0.662	0.025	0.373	0.116	0.885	0.015
Week 3	6±3.9	7±2.9							8±3.9	7±4.4
Week 6	7±3.4	7±3.5							6±4.5	5±1.4
TMD
Baseline	30±10.8	41±17.2	0.807	0.005	0.648	0.023	0.594	0.030	4±9.0	4±3.8	0.332	0.118	0.766	0.033	0.877	0.016
Week 3	19±27.9	20±28.7							29±31.5	26±41.7
Week 6	26±24.9	26±25.3							13±32.1	2±13.2
SF-36b physical functioning
Baseline	95±6.5	79±19.6	0.356	0.071	0.634	0.024	0.606	0.028	87±12.9	94±4.8	0.958	0.000	0.589	0.064	0.379	0.114
Week 3	91±11.0	85±14.5							88±12.9	93±5.0
Week 6	94±6.1	84±13.8							90±11.4	96±4.8
Role limitation due to physical health
Baseline	82±37.4	75±32.3	0.732	0.009	0.269	0.096	0.474	0.056	70±35.0	94±12.5	0.429	0.080	0.762	0.033	0.236	0.165
Week 3	82±31.3	77±33.0							68±37.2	69±47.3
Week 6	89±28.3	85±37.6							61±42.4	100±0.0
Role limitation due to emotional problems
Baseline	90±25.2	72±40.5	0.510	0.034	0.710	0.018	0.396	0.063	88±30.8	100±0.0	0.771	0.011	0.796	0.014	0.384	0.103
Week 3	95±12.6	82±32.2							100±0.0	83±33.3
Week 6	90±25.2	95±18.5							91±30.2	83±33.3
Energy/fatigue
Baseline	59±8.4	58±13.9	0.111	0.183	0.685	0.029	0.842	0.013	73±16.0	76±15.5	0.500	0.059	0.541	0.054	0.815	0.010
Week 3	69±7.5	68±13.5							75±17.5	75±14.7
Week 6	65±13.5	65±12.7							74±21.7	79±12.5
Emotional well-being
Baseline	75±9.4	70±13.2	0.261	0.096	0.671	0.030	0.391	0.070	80±11.0	84±9.8	0.377	0.098	0.799	0.028	0.588	0.064
Week 3	77±5.0	76±13.2							86±9.7	84±14.2
Week 6	71±19.4	73±12.4							81±15.6	85±9.5
Social functioning
Baseline	91±15.7	74±19.4	0.356	0.066	0.571	0.042	0.024*	0.249	80±21.1	97±6.3	0.335	0.116	0.741	0.037	0.265	0.153
Week 3	89±19.7	89±10.0							89±13.1	94±12.5
Week 6	88±12.5	90±9.1							84±16.9	97±6.3
Pain
Baseline	80±19.5	63±12.0	0.069	0.232	0.685	0.029	0.828	0.014	78±19.4	92±16.3	0.680	0.022	0.697	0.044	0.245	0.161
Week 3	84±13.8	77±15.5							83±14.8	84±14.2
Week 6	85±19.9	70±6.0							82±20.7	87±10.3
General health
Baseline	68±12.5	62±15.9	0.534	0.030	0.606	0.038	0.278	0.094	72±21.1	78±15.5	0.476	0.065	0.684	0.046	0.654	0.052
Week 3	69±17.0	71±15.7							78±17.5	75±13.5
Week 6	69±17.4	69±14.4							73±22.6	80±10.8

Notes:

P<0.05 significant using ANCOVA with age, year of education, household income, BMI, and polyphenol intake as covariates. A, placebo group; B, Polygonum minus group. Mood disturbance = POMS >15; good mood = POMS ≤15.

Score 0–4, higher score indicates anxiety, emotional suppression, and psychological distress.

Score 0–100, with higher scores reflecting better quality of life, except for physical pain, which is reversed.

Abbreviations: ANCOVA, analysis of covariance; BMI, body mass index; , partial eta squared; POMS, Profile of Mood States; SD, standard deviation; SF-36, 36-Item Short Form Health Survey; TMD, total mood disturbance.

Figure 5

(A) The mean score of social functioning of SF-36 at baseline, week 3, and week 6 among subjects with mood disturbance according to study groups. (B) The percentage of mean change for social functioning of SF-36 from baseline to week 3 and week 6 among subjects with mood disturbance according to study groups.

Notes: A, placebo group; B, Polygonum minus group. Mood disturbance = POMS >15. Non-significant independent t-test.

Abbreviations: POMS, Profile of Mood States; SF-36, 36-Item Short Form Health Survey.

Figure 6

(A) The mean score of vigor at baseline, week 3, and week 6 among subjects with mood disturbance according to study groups. (B) The percentage of mean change for vigor from baseline to week 3 and week 6 among subjects with mood disturbance according to study groups.

Notes: A, placebo group; B, Polygonum minus group. Mood disturbance = POMS >15. Non-significant independent t-test.

Abbreviation: POMS, Profile of Mood States.

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.

Table 5

Profile of anthropometric parameters at baseline, week 3, and week 6 according to mood status (mean ± SD)

Parameter	Group A (n=18), mean ± SD	Group B (n=17), mean ± SD	Group effect			Time effect			Intervention effect
			P-value	ηp2	Power	P-value	ηp2	Power	P-value	ηp2	Power
Weight (kg)
Baseline	67.3±9.7	66.9±11.7	0.933	0.000	0.051	0.046*	0.089	0.598	0.611	0.015	0.128
Week 3	67.6±9.7	67.4±11.7
Week 6	67.5±9.8	67.1±11.5
BMI (kg/m2)
Baseline	27.7±3.9	28.2±5.0	0.728	0.004	0.063	0.045*	0.090	0.601	0.589	0.016	0.134
Week 3	27.8±3.8	28.4±5.0
Week 6	27.8±3.9	28.2±5.0
Fat percentage
Baseline	37.8±5.0	37.3±4.9	0.789	0.002	0.058	0.253	0.041	0.291	0.991	0.000	0.051
Week 3	38.2±4.8	37.7±5.3
Week 6	38.1±4.5	37.7±4.7
Systolic (mmHg)
Baseline	118±20.6	117±17.9	0.812	0.002	0.056	0.880	0.004	0.069	0.878	0.004	0.069
Week 3	119±16.1	117±15.0
Week 6	117±12.3	117±13.6
Diastolic (mmHg)
Baseline	75±14.7	72±13.7	0.630	0.007	0.076	0.016*	0.117	0.739	0.627	0.014	0.124
Week 3	70±11.2	67±8.3
Week 6	69±10.4	69±9.3

Notes:

Significant at P<0.05 using two-way repeated measures ANOVA. A, placebo group; B, Polygonum minus group.

Abbreviations: ANOVA, analysis of variance; BMI, body mass index; , partial eta squared; SD, standard deviation.

Table 6

Profile of biochemical at baseline and week 6 according to mood status (mean ± SD)

Parameter	Group A (n=18), mean ± SD	Group B (n=17), mean ± SD	Group effect			Time effect			Intervention effect
			P-value	ηp2	Power	P-value	ηp2	Power	P-value	ηp2	Power
Sodium (mmol/L)
Baseline	141±1.6	141±2.1	0.353	0.026	0.150	0.000*	0.323	0.971	0.072	0.095	0.437
Week 6	143±1.9	141±2.6
Potassium (mmol/L)
Baseline	4.2±0.2	4.3±0.4	0.762	0.003	0.060	0.045*	0.116	0.525	0.083	0.088	0.410
Week 6	4.5±0.5	4.4±0.4
Urea (mmol/L)
Baseline	3.7±1.1	3.7±0.8	0.830	0.001	0.055	0.323	0.030	0.164	0.210	0.047	0.237
Week 6	3.7±0.9	3.5±1.0
Uric acid (µmol/L)
Baseline	302±65.4	303±71.3	0.658	0.006	0.072	0.009*	0.189	0.767	0.206	0.048	0.240
Week 6	291±69.5	271±57.2
Creatinine (µmol/L)
Baseline	60±7.6	61±9.1	0.596	0.009	0.081	0.000*	0.511	1.000	0.991	0.000	0.050
Week 6	65±8.8	67±9.9
eGFR (mL/min/1.73 m2)
Baseline	96±15.5	95±19.9	0.856	0.001	0.054	0.000*	0.516	1.000	0.999	0.000	0.050
Week 6	87±13.0	86±18.2
Total protein (g/L)
Baseline	78±3.4	79±3.3	0.354	0.026	0.150	0.015*	0.166	0.701	0.616	0.008	0.078
Week 6	77±3.0	78±4.6
Albumin (g/L)
Baseline	45±2.1	45±2.9	0.953	0.000	0.050	0.112	0.075	0.355	0.605	0.008	0.080
Week 6	45±1.9	44±3.3
Globulin (g/L)
Baseline	33±3.7	35±3.5	0.403	0.020	0.131	0.071	0.095	0.441	0.640	0.007	0.074
Week 6	33±2.9	33±4.5
Bilirubin (µmol/L)
Baseline	11±5.9	11±4.9	0.702	0.004	0.066	0.083	0.088	0.411	0.330	0.029	0.161
Week 6	10±6.5	9±3.4
Alkaline phosphatase (U/L)
Baseline	74±20.2	73±14.7	0.709	0.004	0.066	0.407	0.021	0.129	0.395	0.022	0.133
Week 6	74±19.7	77±23.5
GGT (U/L)
Baseline	27±21.1	29±12.9	0.565	0.010	0.087	0.437	0.018	0.119	0.491	0.014	0.104
Week 6	27±20.0	35±41.2
Aspartate transferase (U/L)
Baseline	23±7.1	21±6.7	0.422	0.020	0.124	0.093	0.083	0.389	0.191	0.051	0.254
Week 6	24±11.4	32±30.4
Alanine transaminase (U/L)
Baseline	22±11.9	20±14.5	0.354	0.026	0.150	0.222	0.045	0.227	0.092	0.084	0.393
Week 6	20±9.8	33±40.6
Total cholesterol (mmol/L)
Baseline	5.4±0.9	5.3±1.2	0.942	0.000	0.051	0.654	0.006	0.072	0.500	0.014	0.102
Week 6	5.4±0.9	5.4±1.3
Triglycerides (mmol/L)
Baseline	0.9±0.4	0.9±0.2	0.672	0.005	0.070	0.200	0.049	0.246	0.462	0.017	0.112
Week 6	0.9±0.3	1.0±0.5
HDL (mmol/L)
Baseline	1.5±0.3	1.7±0.4	0.112	0.075	0.354	0.128	0.069	0.328	0.362	0.025	0.146
Week 6	1.5±0.3	1.7±0.5
LDL (mmol/L)
Baseline	3.5±0.9	3.2±1.0	0.429	0.019	0.121	0.545	0.011	0.091	0.872	0.001	0.053
Week 6	3.5±0.8	3.3±1.0
Total cholesterol/HDL (mmol/L)
Baseline	3.7±1.1	3.2±0.7	0.142	0.064	0.309	0.019*	0.156	0.670	0.460	0.017	0.112
Week 6	3.8±1.0	3.4±0.9
HbA1C (%)
Baseline	5.9±0.8	5.7±0.4	0.325	0.029	0.163	0.000*	0.559	1.000	0.285	0.035	0.184
Week 6	5.6±0.7	5.4±0.3

Notes: Significant at

P<0.05 using two-way repeated measures ANOVA. A, placebo group; B, Polygonum minus group.

Abbreviations: ANOVA, analysis of variance; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyl transferase; HbA1C, hemoglobin A1C; HDL, high density lipoprotein; LDL, low density lipoprotein; , partial eta squared; SD, standard deviation.

Discussion

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 quer-cetin 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).

Conclusion

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.