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Efficacy and safety of Eurycoma longifolia (Physta®) water extract plus multivitamins on quality of life, mood and stress: a randomized placebo-controlled and parallel study

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food & nutrition
ORIGINAL ARTICLE
Efcacy and safety of Eurycoma longifolia (Physta®) water
extract plus multivitamins on quality of life, mood and stress:
arandomized placebo-controlled and parallel study
Annie George1,2, Jay Udani3, Nurhayati Zainal Abidin1 and Ashril Yusof4*
1Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia; 2Biotropics Malaysia
Berhad, Lot 21, Jalan U1/19, Section U1, Hicom-Glenmarie Industrial Park, 40150 Shah Alam, Malaysia; 3Agoura Hills,
CA, USA; 4Exercise Science, Sports Centre, University of Malaya, 50603 Kuala Lumpur, Malaysia
Abstract
Background: The use of alternative and complementary medicines to alleviate stress has increased to avoid the
negative effects of pharmaceutical drugs.
Objective: This study investigated the safety and efcacy of Eurycoma longifolia in combination with multivi-
tamins (EL+MV) versus placebo on improving quality of life (QoL), mood and stress in moderately stressed
healthy participants.
Methods: This randomised, double-blind, placebo-controlled 24-week study enrolled 93 participants aged
25–65 years, with a body mass index of 18–30 kg/m2, scoring ≤18 in tension and ≤14 in fatigue subscale of
Proles of Mood Scores (POMS) questionnaire and supplemented with EL+MV or placebo. The primary
endpoints were QoL measured by 12-Item Short Form Health Survey (SF-12) questionnaire and mood mea-
sured by POMS. The secondary endpoint was stress measured by Multi-Modal Stress Questionnaire (MMSQ).
The safety of the intervention product was measured by complete metabolic panel, lipid and renal analysis
including several immune parameters.
Results: While there were no signicant between-group differences, within-group improvements were observed
in the SF-12 QoL, POMS and MMSQ domains. In the SF-12 domain, improvements were seen in role lim-
itation due to emotional health (P = 0.05), mental component domain (P < 0.001), emotional well- being
(P<0.001), social functioning (P=0.002) as well as vitality (P=0.001) at week 12. An increasing trend in
POMS-vigour domain was also observed in the EL+MV group at week 12. A 15% decrease in physical stress
domain (P< 0.05) compared with 0.7% in the placebo group was also observed in MMSQ. When the sub-
jects were subgrouped according to age, 25–45 and 46–65 years of age, for primary outcomes, between-group
signicance was observed in the 25–45 year group in the social functioning domain of SF-12 (P = 0.021)
and POMS-vigour (P= 0.036) in the 46–65 year group. No signicant changes were observed in vital signs
and complete metabolic panel. Regarding immune parameters, the lymphocytes increased signicantly in the
active group (P≤0.05). In total, 13 adverse events were reported: six on placebo and seven on EL+MV.
Conclusion: EL+MV may support the QoL, mood, stress and immune parameters in healthy participants.
Trial registration: This study has been registered at clinicaltrials.gov (NCT02865863).
Key words: Eurycoma longifolia; multivitamins; quality of life; mood; stress
Received: 25 March 2018; Revised: 13 September 2018; Accepted: 18 September 2018; Published: 16 October 2018
Unresolved stress greatly increases the risk of de-
veloping depression, consequently becoming a
topic of public health awareness and therapeutic
interventions. Depression aficts approximately 20–25%
of women and 10–17% of men during their lifetime (1).
While certain drugs like uoxetine (Prozac) and sertraline
(Zoloft) have been used to treat stress and anxiety disor-
ders and, in recent years, the anti-depressant setraline,
there is a concern that one can be addicted to and depen-
dent on drug usage (2). Alternative and complementary
medicines, such as herbal supplements, have emerged as
substitutes to conventional therapeutics for ameliorating
depression and maintaining mental well-being (3–5).
In South East Asia, where traditional/herbal medicine
is popular, supplementation with Eurycoma longifolia Jack,
Simaroubaceae (Tongkat Ali or Malaysian ginseng), has
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Annie George et al.
been shown to be efcacious for alleviating stress (6), as
well as many other ailments including fever, arthritis, high
blood pressure, diabetes, low energy or libido, bacterial
infections and cancer (7–9). Eurycoma longifolia (EL) is a
slender evergreen tree mainly found in Malaysia, Indonesia
and the Philippines. Derivatives of this plant have been used
to restore and enhance energy levels, to improve physical
and mental performance, endurance and stamina (9) and
quality of life (QoL), as evidenced by a decrease in aging
males symptoms score and an increase in serum testoster-
one levels (10). Another related study showed improvement
in QoL and sexual well-being in men, specically in the do-
mains of ‘physical function’ and ‘vitality’(11). The roots
of EL are largely responsible for its biological activity due
to the presence of alkaloids, quassinoids, quassinoid diter-
penoids, eurycomacoside, eurycolactone, laurylcolactone
or eurycomalactone and pasakbumin-B (7) and peptides
(12). It has been demonstrated to reduce stress through
the reduction of cortisol (6) with a concurrent increase
in lymphocytes and natural killer cells (13). These active
ingredients in EL and in other plants, such as mountain
ginseng (Panax ginseng), may be responsible for improving
QoL, as well as combating stress without adverse effects
(11, 14–16). A recent 4-week, randomised clinical study on
moderately stressed participants consuming water extract
from EL reported signicant improvements in mood, ten-
sion, anger and confusion (6). This was accompanied by
a reduction in cortisol and increased testosterone levels.
Another study investigated the effect of EL on the im-
mune status of moderately stressed subjects (13), whereby
a 1-month supplementation of 200 mg EL extract per day
nearly signicantly improved vigour measured by Prole
of Mood States (POMS) while scores for immunological
vigour also improved.
Micronutrient deciencies contribute to stress and de-
pression (5). Indeed, low levels of folic acid may be cor-
related with depressive symptomatology (16) that can be
ameliorated by mineral supplementation (17). Multinutri-
ent formulations have a signicantly greater effect in reduc-
ing stress and anxiety in subjects than single interventions
alone (18). In addition, a recent study demonstrated that
a formulation consisting of multivitamins, minerals and
herbal extracts was more effective than placebo in signi-
cantly reducing the overall score on a depression, anxiety
and stress scale, as well as improving alertness and gen-
eral daily functioning in healthy older men (19). Further-
more, a high dose of vitamin B complex with vitamin C
and minerals led to signicant improvements in ratings on
Perceived Stress Scales, General Health Questionnaire and
the ‘vigour’ subscale of POMS in healthy males (20).
While preclinical and clinical studies lend credence to the
ability of EL to improve mood which was possibly linked
to hormonal balance favouring elevated mood (21), ef-
cacy studies of EL in combination with micronutrients and
conducted in accordance with established standards are
currently lacking. The objective of this study was to inves-
tigate the safety and efcacy of a multivitamin mix in com-
bination with EL water extract on QoL, mood and stress of
moderately stressed but healthy participants.
Materials and methods
This study was conducted in accordance with the
Guidelines for Good Clinical Practice (ICH-6) and the
Declaration of Helsinki. Institutional Review Board
(IRB) approval was obtained from IntegReview Ethical
Review Board, an independent IRB located in Austin,
TX, USA, comprising scientic and non-scientic mem-
bers of mostly medical doctors, on 17 January 2014 prior
to initiation of any study-related activities. The IRB re-
viewed the protocol, medical ethics, informed consent,
advertisement, stipend and compliance to protocol. The
study was conducted at Medicus Research LLC, a clinical
research site located at Agoura Hills, CA, USA. Written
informed consent was obtained from volunteers prior to
all study procedures. The recruitment and follow-up took
place from 7 February 2014 to 13 March 2015.
Study design
This was a randomised, double-blind, placebo-controlled
parallel study with a 12-week efcacy and a 24-week
safety period. The allocation ratio of participants in each
of the comparison groups was 1:1. Efcacy was measured
at 6and 12 weeks, with safety and adverse events at 6,12
and 24 weeks. The participants were required to make
a total of four visits to the clinical trial site at Medicus
Research LLC, Agoura Hills, CA.
At screening/baseline (week 0), inclusion/exclusion
criteria, medical history and concomitant therapies were
reviewed; baseline demographic data were collected;
heart rate, respiratory rate, blood pressure and oral tem-
perature were measured; and body mass index (BMI)
was calculated. Fasting blood samples were obtained for
assessment of complete blood count (CBC), compre-
hensive metabolic panel (CMP) including kidney func-
tion ( estimated glomerular ltration rate, blood urine
nitrogen [BUN], creatinine and bilirubin), liver function
( aspartate aminotransferase, alanine transaminase), lipid
panel (total cholesterol [TC], high-density lipoprotein-
cholesterol [HDL-C], low-density lipoprotein- cholesterol
[LDL-C], and triglycerides), testosterone (free and total)
and urinalysis (leukocyte esterase, amorphous and calcium
oxalate crystals). A urine pregnancy test was conducted
on females with child-bearing potential. Electrocardio-
gram (EKG) was performed and POMS (22), SF-12 QoL
(23), and Multi-Modal Stress Questionnaire (MMSQ)
(24) were administered. Participants were dispensed a
6-week supply of the investigational product, a daily dos-
ing diary and a 3-day food recall. Subjects who met all the
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E. longifolia + multivitamins on quality of life, mood and stress
study inclusion criteria and none of the exclusion criteria
were enrolled in the study. After eligibility was conrmed,
all volunteers received a randomisation number.
Participants returned to the clinic at weeks 6, 12 and 24
after having fasted for 10 h for assessment of medical and
concomitant medication history. Vital signs and anthro-
pometric measures, compliance and adverse events, and
current medical history were reviewed. Fasting blood was
collected for CBC, CMP, lipid panel, testosterone (free
and total) measurements and urinalysis was performed.
EKG was performed at baseline and at week 24.
POMS, SF-12 and MMSQ questionnaires were admin-
istered and a daily dosing diary and a 3-day food recall
were dispensed at baseline, week 6 and week 12 only. At
week 6, participants were dispensed a 6-week supply of
the investigational product and at week 12, a 12-week
supply of the investigational product. Participants main-
tained their daily diary for the duration of the study pe-
riod and were required to record concomitant therapies
and adverse events.
Participants
Study participants were recruited from the general pop-
ulation by online advertising, recruiting and available
clinical trial databases. Inclusion criteria were as follows:
healthy volunteers between 25 and 65 years of age, BMI
18–30 kg/m2 and having self-reported moderate stress.
Moderate stress was dened as a measure of both the
tension and fatigue subscale of the POMS questionnaire.
Participants who scored ≤18 in the tension subscale and
≤14 in the fatigue subscale were considered as having
moderate stress. The tension subscale items are tense,
on edge, uneasy, restless, nervous and helpless. A highest
score (4=extremely) for each of these items will give a
total subscale score of ≤24 in tension and ≤20 in fatigue.
An upper cut-off limit was determined, that is, a scoring
of ≤18 in the tension subscale and ≤14 in the fatigue sub-
scale, to exclude subjects who might fall within extremely
stressed and possibly depressed category that will require
medication and possibly cannot be addressed with health
supplementation of multinutrients. The subjects were
furthermore required to answer a Yes/No questionnaire
in the inclusion/exclusion criteria as to whether they per-
ceived themselves to having mid-level stress at work as a
result of employment and life balance.
Exclusion criteria: participants were excluded if they
were pregnant, lactating, planning to become pregnant
or unwilling to use adequate contraception during the
duration of the study, or had a history of immune sys-
tem disorders, neurological disorders, temporal arthritis,
ulcerative colitis, history of cancer within 2 years prior
to enrolment, any active infection, or infection requir-
ing antibiotics within 30 days of enrolment, signicant
gastrointestinal conditions including, but not limited to,
inammatory bowel disease, eating disorders, untreated
hypothyroidism and use of herbal products containing
androgenic/anxiolytic activity within 30 days prior to
enrolment.
Investigational product
The investigational product (50 mg per tablet) was a pro-
prietary water extract of EL root (Physta® also known as
LJ100 in the USA). The multivitamin mix consisted of
ascorbic acid (50 mg), retinyl acetate (4,000 IU), chole-
calciferol (200 IU), Dl-alpha tocopherol acetate (15IU),
thiamine mononitrate (1.5 mg), riboavin (1.7 mg),
pyridoxine hydrochloride (2 mg), cyanocobalamin
(0.001 mg), folic acid (0.2 mg), niacinamide (20 mg),
D-biotin (0.15mg), copper (2 mg), iron (10 mg), magne-
sium (10 mg), manganese (2.5 mg), selenium (0.005 mg),
zinc (5 mg) and calcium (100 mg). The placebo contained
microcrystalline cellulose, polyvinylpyrrolidone, sodium
starch glycolate, colloidal silicon dioxide and magnesium
stearate. The investigational product was produced under
good manufacturing practices (GMP) requirements by
Unison Nutraceutical Sdn Bhd and stored in a dry place
at room temperature. Participants were instructed to con-
sume either EL+MV or the placebo starting the day fol-
lowing the baseline visit, one tablet daily in the morning
with water for 24 weeks.
Outcome measures
The primary and secondary outcomes measures were
assessed by questionnaires at week 0 (Visit 0), week 6
(Visit1) and 12 (Visit 2). The primary outcome measure for
this study was the assessment of the efcacy of EL+MV
versus placebo on mood and QoL. Mood state was assessed
using the POMS questionnaire, which consisted of the
following: total mood disturbance and its subscales, ten-
sion, depression, anger, fatigue, confusion and vigour. The
POMS rated emotional and physical aspects of mood as
ranging from ‘not at all (1 point)’ to ‘extremely (5 points)’.
A lower score, except for vigour, indicates better mood.
The POMS Iceberg prole, designed for assessing ac-
tive/healthy individuals (25), was also analysed. QoL was
assessed by the SF-12 questionnaire which measured the
following domains: physical component summary, mental
component summary, physical functioning, role limita-
tions due to physical health, role limitations due to emo-
tional health, energy/fatigue ratio (vitality), emotional
well-being, social functioning, pain and general health.
Scores on the SF-12 scales ranged from 0 to 100, with
higher scores indicating better health.
The secondary objective was to assess stress using
MMSQ, which measured the following subscales: total,
behavioural, cognitive and physical. The MMSQ rated
emotional and physical aspects of stress as ranging from
‘never (1 point)’ to ‘constantly (5 points)’.
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Safety and tolerability of the investigational product
were assessed through changes in CBC, CMP, lipid panel,
total and free testosterone, urinalysis and vital signs at all
visits. The study would be temporarily stopped for any of
the following: if WHO Grade 3 toxicity is experienced by
four or more patients or WHO Grade 4 toxicity is experi-
enced by two or more patient(s).
Compliance
The dispensed study product compliance diaries were
returned to the clinic and participants who were non-
compliant with their diaries were reminded of their obli-
gations regarding appropriate study compliance.
Sample size
The sample size was calculated using the G*Power 3.0.10
software based on a reference value proposed by Perazzo
et al. (26), which assessed QoL (SF-12) following treat-
ment of Gerovital (a multivitamin and mineral combined
with Panax ginseng extract) and placebo. In addition, a
between-factor repeated-measure analysis of variance
(ANOVA) with a level of signicance (α) of 0.05 (two
sided) and power of 80% was considered, while the ratio
between trial and control group was set at 1, resulting in 36
subjects per group. A 20% loss to follow-up was considered
relevant, thus resulting in 45 subjects per group.
Randomisation
Stratied randomisation sequences were created with
computer-generated random numbers, which allocated
subjects based on sex (male/female) into two groups.
Demographic stratications based on gender were set
and crossed. Patients were randomly assigned to order
of treatment (placebo or active) using simple randomisa-
tion based on the atmospheric noise method and sequen-
tial assignment was used to determine group allocation
(GraphPad Prism 6). A computer-generated list of ran-
dom numbers was used in order to allocate participants.
The results of these two randomisations were combined
and assigned as the nal randomisation sequence for this
trial. Allocation, enrolment and assignment of partici-
pants to products were performed by the staff of Medicus
Research LLC who did not perform any analyses or clini-
cal procedures. The allocation information was disclosed
to the investigator, subjects and a statistician after all
measurements were completed. The investigational prod-
uct was stored in a sequentially numbered Study Product
Container in a locked cabinet with limited access.
Statistical analysis
The modied per-protocol analysis included subjects
with at least one post-dose completed visit and partici-
pants who completed all visits of the 24-week study and
consumed the product. Subgroup analysis was performed
based on gender for testosterone measurements, domains
within questionnaires and age groups. The safety analysis
was based on all randomised participants known to have
taken at least one dose of the investigational or placebo
products. Subgroup analysis of primary endpoints was
performed for the age groups, 25–45 and 46–65 years, due
to perceived stress from increased responsibilities in the
older age group and potential hormonal variances which
affect QoL in these subgroups.
All evaluations were performed using the software
package R 3.2.2 (R Core Team, 2015). Descriptive
statistics were calculated for each group and statisti-
cal comparisons were performed using the analysis of
covariance (ANCOVA) adjusting for baseline values.
Numerical endpoints that are intractably non-normal
were assessed by the Mann-Whitney U test; in these
instances, only the comparisons of the changes from
baseline were considered in the formal testing between
groups. Statistical comparisons for baseline characteris-
tics, lipid and testosterone levels, and measures of safety
(haematology, blood chemistry, anthropometrics and
vital signs) were performed using ANOVA. For categor-
ical endpoints, the differences in proportions between
groups were formally tested by the Fisher’s exact test.
The Shapiro–Wilk normality test was carried out to
determine data normality when P > 0.05. Within-group
comparisons on numeric endpoints were made using
Student’s paired t-test or, in the case of intractable non-
normality, the Wilcoxon signed rank test. Differences
were considered signicant at P ≤ 0.05. Subgroup analysis
based on gender differences was conducted for testoster-
one measurements only.
Results
Participant baseline characteristics
A total of 120 participants were screened and a total of 93
subjects were enrolled, of which 7 were lost to follow-up
due to the long enrolment period of 6 months (Fig.1).
There were 28 females and 19 males in the EL + multi-
vitamins group (EL+MV), and 20 females and 19 males
in the placebo group. The demographic characteristics of
participants were not signicantly different in terms of
age, BMI, employment and relationship status between
groups at baseline (Table 1).
More than 94% of participants in both groups were
employed and were predominantly Caucasian in eth-
nicity. There were no signicant differences in CBC,
CMP and urinalysis, anthropometric measures and vital
signs between groups at baseline (Table 2). Analysis of
POMS-Tension-Anxiety mood state subscale showed
participants to be moderately stressed.
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E. longifolia + multivitamins on quality of life, mood and stress
Fig. 1. Study owchart. A total of 120 participants were screened, of which 93 were randomised in the study, with 47 in the
EL+MV group and 39 in the placebo group enrolledas the modied per-protocol population in the nal analysis. EL+MV,
E.longifolia + multivitamin.
Primary endpoints
SF-12 questionnaire on QoL
POMS, SF-12 and MMSQ scores obtained by all partici-
pants in the study before and after supplementation with
EL+MV group or placebo are presented in Table 3. There
were no signicant between-group differences reported in
physical component, mental component, physical function-
ing, role limitations due to physical health, role limitations
due to emotional health, vitality, emotional well-being,
social functioning, pain and general health domains as as-
sessed by the SF-12 questionnaire, but several within-group
signicant ndings were observed (Tabl e 3).
Participants supplemented with EL+MV reported sig-
nicant improvements from baseline, with 9.7% improve-
ment in role limitation due to emotional health at week 6
(P=0.003) and 9.2% at week 12 (P=0.05) (Fig. 2a) and
a further 11.3% improvement in vitality (energy/fatigue
ratio) at week 12 (P=0.001) (Fig. 2b). Similar improve-
ments from baseline were not reported by participants in
the placebo group.
Participants supplemented with EL+MV reported a
signicant increase in the mental component domain at
weeks 6 (P=0.001) and 12 (P<0.001), with an increaseof
24.6% in the EL+MV compared to 12.7% in the placebo
group at week 12. The placebo group only had signicant
improvements at week 6 (P = 0.007). In the emotional
well-being domain, signicant improvements were ob-
served in both groups, with a 23% (P<0.001) and 6.9%
(P<0.01) improvement observed at week 12, respectively,
in the EL+MV and placebo groups. The social function-
ing domain for participants supplemented with EL+MV
signicantly improved by 11.3% at week 12 (P=0.002) but
only by 7.5% at week 6 (P=0.01) in the placebo group.
A subgroup analysis of subjects based on age group
25–45 years had n=29 on treatment and n=24 on placebo,
while age subgroup 46–65 years had n=18 on treatment
and n=12 on placebo. Primary and secondary outcome
measures of POMS, SF-12 and MMSQ revealed a 14.4%
increase in the social functioning score within the SF-12
questionnaire in the 25–45-year subgroup of the EL+MV
group, achieving a between-group signicance (P=0.021).
Changes in other domains remained non-signicant.
Prole of mood states questionnaire on mood
There were no signicant between-group differences
reported in total mood disturbance, tension, depression,
anger, fatigue, confusion and vigour assessed by POMS
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Annie George et al.
Table 1. Demographics and anthropometric measures of all 86 participants enrolled in the study.
EL+MV
(n = 47)
Placebo
(n = 36)
P-value§
Age (years)
Mean ± SD
Median (min – max)
40.6 ± 12.3
36 (25 – 62)
41.0 ± 9.9
39.5 (25 – 62)
0.744σ
Gender (n[%])
Female
Male
28 (60%)
19 (40%)
18 (50%)
18 (50%)
0.504
BMI (kg/m2)
Mean ± SD (n)
Median (min – max)
23.9 ± 3.20
23.4 (18.1 – 35)
25.0 ± 3.24
24.8 (18.3 – 31.8)
0.124
Tobacco use (n[%])
Current smoker
Non-smoker
Past smoker
7 (16%)
31 (69%)
7 (16%)
4 (11%)
29 (81%)
3 (8%)
0.505
Alcohol use (n[%])
Current consumer
Non-drinker
Past drinker
31 (67%)
11 (24%)
4 (9%)
22 (61%)
12 (33%)
2 (6%)
0.739
Ethnicity (n[%])
African-American
Asian
Caucasian
Latino/Hispanic
Other
5 (11%)
3 (6%)
32 (68%)
3 (6%)
4 (9%)
4 (11%)
2 (6%)
18 (51%)
7 (20%)
4 (11%)
0.384
Current employment (n[%])
Employed
Not employed
44 (96%)
2 (4%)
33 (94%)
2 (6%)
1.000
Relationship status (n[%])
Divorced
Domestic partnership
Married
Separated
Single
Widowed
4 (9%)
1 (2%)
12 (26%)
0 (0%)
28 (60%)
2 (4%)
3 (8%)
1 (3%)
8 (22%)
4 (11%)
19 (53%)
1 (3%)
0.318
Have children (n[%])
No
Ye s
32 (71%)
13 (29%)
18 (50%)
18 (50%)
0.067
Systolic blood pressure (mmHg)
Mean ± SD (n)
Median (min – max)
117.7 ± 14.3
117 (91 – 154)
118.4 ± 13.5
119 (91 – 150)
0.819
Diastolic blood pressure (mmHg)
Mean ± SD (n)
Median (min – max)
74.5 ± 10.6
73 (50 – 105)
77.0 ± 10.9
75 (60 – 99)
0.296
Heart Rate (beats per minute)
Mean ± SD (n)
Median (min – max)
66.2 ± 10.7
66 (42 – 94)
64.5 ± 9.5
65 (41 – 84)
0.468
Body temperature (°F)
Mean ± SD (n)
Median (min – max)
98.14 ± 0.44
98.2 (97.2 – 99.8)
98.16 ± 0.64
98.1 (96.4 – 99.6)
0.868
Respiratory rate (per minute)
Mean ± SD (n)
Median (min – max)
14.57 ± 1.96
15 (12 – 20)
14.95 ± 1.60
15 (12 – 18)
0.354
σBetween-group comparison was made using the independent Student’s t-test.
§Between-group comparisons were performed using Fisher’s exact test. The variable n indicates the number of
subjects analysed. Demographics data were not available for three participants.
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E. longifolia + multivitamins on quality of life, mood and stress
Table 2. CBC and CMP safety parameters assessed in participants at all visits.
Item Reference value Group Screening
(Week 0)
Week 6 Week 12 Week 24
AST 7 –≤70 U/L EL + MV 24.8 ± 10.1 23.9 ± 7.8 29.3 ± 27.1 21.5 ± 7.9
Placebo 25.2 ± 9.0 23.7 ± 10.2 24.3 ± 11.1 29.1 ± 36.1
ALT 12 – <90 U/L EL + MV 21.5 ± 13.4 21.5 ± 9.4 22.9 ± 14.5 21.2 ± 16.7*
Placebo 23.5 ± 14.9 21.1 ± 12.4*# 22.0 ± 13.5** 22.3 ± 16.2
ALP 39−117 IU/L EL + MV 64.5 ± 19.2 63.7 ± 19.8 63.8 ± 19.1 59.2 ± 20.3
Placebo 66.9 ± 18.9 67.1 ± 18.4 67.5 ± 17.1 66.1 ± 19.7
Total bilirubin ≤25 µmol/L EL + MV 0.62 ± 0.36 0.53 ± 0.32 0.454 ± 0.284 0.463 ± 0.213
Placebo 0.62 ± 0.36 0.53 ± 0.33 0.450 ± 0.244 0.474 ± 0.350
Sodium 133–148 mmol/L EL + MV 141.18 ± 1.85 141.30 ± 2.47 140.8 ± 4.7 138.9 ± 6.5
Placebo 141.17 ± 2.50 141.08 ± 2.20 140.8 ± 4.9 141.0 ± 2.8
Potassium 3.3–5.7 mmol/L EL + MV 4.21 ± 0.35 4.39 ± 1.25 4.24 ± 0.37 4.20 ± 0.37
Placebo 4.17 ± 0.27 4.24 ± 0.32 4.61 ± 1.74* 4.36 ± 0.39*
Chloride 98–115 mmol/L EL + MV 102.48 ± 1.97 102.42 ± 2.29 101.5 ± 3.9 99.2 ± 5.7***
Placebo 103.17 ± 2.66 102.73 ± 1.79 101.9 ± 4.1* 100.9 ± 2.8***
Carbon dioxide 18–29 mmol/L EL + MV 26.98 ± 1.99 28.6 ± 11.3 25.4 ± 3.4* 23.43 ± 2.93***
Placebo 26.64 ± 2.26 24.9 ± 3.9* 24.8 ± 2.8* 23.97 ± 2.65***
Anion gap 3–11 mEq/L EL + MV 12.3 ± 3.5 13.3 ± 5.0 16.6 ± 5.6*** 20.0 ± 3.3***
Placebo 11.7 ± 3.2 14.8 ± 5.7* 17.0 ± 5.3*** 19.8 ± 4.2***
Calcium 8.4–10.4 mg/dL EL + MV 9.61 ± 0.40 9.60 ± 0.40 9.26 ± 1.58 9.04 ± 0.67***
Placebo 9.56 ± 0.41 9.51 ± 0.41 9.47 ± 0.59 9.19 ± 0.45**
Glucose 70–109 mg/dL EL + MV 94.9 ± 8.6 93.5 ± 9.6 95.2 ± 11.4 89.0 ± 11.6**
Placebo 92.2 ± 10.2 93.3 ± 6.4 91.6 ± 10.5 88.5 ± 16.3
Blood urea nitrogen 8.0–20.0 mg/dL EL + MV 13.2 ± 3.1 13.4 ± 4.4 12.8 ± 3.1 14.7 ± 11.3
Placebo 13.4 ± 3.7 12.9 ± 4.0 12.9 ± 5.2 13.1 ± 4.1
Creatinine 0.47–0.79 mg/dL EL + MV 0.795 ± 0.152 0.782 ± 0.147 0.777 ± 0.172 0.770 ± 0.204
Placebo 0.794 ± 0.200 0.768 ± 0.220 0.812 ± 0.247 0.774 ± 0.192
Blood urea nitrogen:
creatinine ratio
10:1 –20:1 EL + MV 17.1 ± 4.7 17.8 ± 5.3 17.1 ± 4.2 17.8 ± 4.8
Placebo 17.6 ± 5.3 17.6 ± 5.9 16.3 ± 5.0 17.4 ± 4.9
Estimated glomerular
ltration rate
50–≥120 mL/min/1.73 m2EL + MV 64.6 ± 13.1 69.2 ± 19.5 78.2 ± 23.2*** 92.1 ± 28.2***
Placebo 62.6 ± 9.5 74.9 ± 32.4**# 83.5 ± 30.9** 93.1 ± 23.6***
Total serum protein 6.7–8.3 g/dL EL + MV 7.13 ± 0.37 7.09 ± 0.41 8.0 ± 6.2 6.72 ± 0.56***#
Placebo 7.13 ± 0.47 7.02 ± 0.45 7.0 ± 0.6 7.09 ± 0.48
Serum albumin 3.5 to 5.5 g/dL EL + MV 4.63 ± 0.29 4.60 ± 0.30 4.59 ± 0.43 4.42 ± 0.48**#
Placebo 4.54 ± 0.34 4.56 ± 0.33 4.56 ± 0.38 4.55 ± 0.31
Globulin 2.6–4.6 g/dL EL + MV 2.493 ± 0.277 2.49 ± 0.30 2.36 ± 0.29* 2.31 ± 0.51***#
Placebo 2.586 ± 0.304 2.46 ± 0.35* 2.45 ± 0.33 2.53 ± 0.32
Albumin : globulin ratio 0.8–2.0 EL + MV 1.877 ± 0.251 1.875 ± 0.260 1.958 ± 0.205 1.99 ± 0.35*
Placebo 1.778 ± 0.251 1.897 ± 0.320*# 1.894 ± 0.269* 1.83 ± 0.30
Total cholesterol 120–219 mg/dL EL + MV 195 ± 46 194 ± 43 192 ± 43 180 ± 36*
Placebo 184 ± 34 184 ± 41 184 ± 40 177 ± 40
Triglycerides 30–149 mg/dL EL + MV 89 ± 52 104 ± 99 111 ± 90 91 ± 54
Placebo 98 ± 75 111 ± 171 118 ± 110 97 ± 53
HDL cholesterol 40–95 mg/dL EL + MV 74.8 ± 22.6 73.7 ± 23.2 72.7 ± 24.9 61.5 ± 17.9***
Placebo 69.3 ± 20.5 67.5 ± 24.3 63.0 ± 20.9** 61.3 ± 18.7&**
LDL cholesterol 65–139 mg/dL EL + MV 102 ± 38 100 ± 41 99 ± 34 103 ± 33
Placebo 95 ± 28 95 ± 29 97 ± 31 99 ± 28
Coronary risk factor
(cholesterol : HDL)
<3.3 EL + MV 2.79 ± 0.99 2.87 ± 1.07 4.3 ± 8.6* 3.26 ± 1.18***
Placebo 2.87 ± 1.03 3.07 ± 1.71 3.1 ± 1.1** 3.15 ± 1.06**
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Table 2. Continued
Item Reference value Group Screening
(Week 0)
Week 6 Week 12 Week 24
VLDL cholesterol 2 to 30 mg/dL EL + MV 17.9 ± 10.4 20.9 ± 19.7 22.1 ± 18.1 18.2 ± 10.9
Placebo 19.5 ± 14.9 22.3 ± 34.3 23.6 ± 22.0 19.4 ± 10.6
White blood cell 3,300–9,000/μL EL + MV 6.06 ± 1.65 5.60 ± 1.55* 5.57 ± 1.47* 5.88 ± 1.41
Placebo 5.93 ± 1.86 6.10 ± 2.07 5.86 ± 1.58 5.43 ± 1.34
Red blood cell 430–570 10^4/mL EL + MV 4.71 ± 0.44 4.69 ± 0.49 4.64 ± 0.42* 4.63 ± 0.45*
Placebo 4.79 ± 0.47 4.70 ± 0.46 4.70 ± 0.42 4.60 ± 0.40***
Haemoglobin M: 13.5–17.5 g/dL EL + MV 14.69 ± 1.29 14.58 ± 1.44 14.38 ± 1.32** 14.30 ± 1.42**
F: 11.5–15.0 g/dL Placebo 14.61 ± 1.45 14.40 ± 1.49 14.44 ± 1.53 13.98 ± 1.36***
Haematocrit M: 39.7–52.4% EL + MV 43.2 ± 3.5 43.3 ± 3.7 43.1 ± 3.4 43.0 ± 3.7
F: 34.8–45.0% Placebo 43.3 ± 3.6 42.8 ± 3.3 43.4 ± 3.8 42.3 ± 3.4*
Blood platelet 14.0–34.0 ×10^3/mm3EL + MV 248 ± 57 255 ± 61# 256 ± 80 277 ± 76**
Placebo 227 ± 57 223 ± 50 239 ± 49* 245 ± 81*
Mean corpuscular volume 85–102  EL + MV 92.1 ± 3.9 92.6 ± 4.4 92.9 ± 4.3* 93.0 ± 4.1*
Placebo 90.7 ± 5.4 91.4 ± 5.2 92.3 ± 4.9* 90.7 ± 11.6
Mean corpuscular
haemoglobin
28.0–34.0 pg EL + MV 31.22 ± 1.38 31.11 ± 1.47 31.00 ± 1.50 30.91 ± 1.14*
Placebo 30.57 ± 2.13 30.67 ± 2.13 30.72 ± 2.10 30.42 ± 2.02*
Mean corpuscular
haemoglobin concentration
30.2–35.1% EL + MV 33.95 ± 0.92 33.61 ± 1.12 33.39 ± 1.22* 33.24 ± 0.99***
Placebo 33.74 ± 1.15 33.57 ± 1.43 33.26 ± 1.24* 33.01 ± 1.19***
Neutrophil count 1.6–8.0 ×10^9/L EL + MV 55.5 ± 10.8 53.5 ± 10.9# 52.2 ± 10.6* 54.9 ± 9.5
Placebo 56.1 ± 10.1 57.3 ± 9.8 55.8 ± 9.0 56.8 ± 7.7
Lymphocyte count 0.8–3.0 ×10^9/L EL + MV 32.5 ± 9.2 34.6 ± 9.8 35.4 ± 9.1*# 33.2 ± 8.4
Placebo 32.6 ± 8.6 32.4 ± 9.5 32.4 ± 6.9 32.9 ± 6.6
Monocyte count 0.1–1.5 × 10^9/L EL + MV 7.33 ± 2.01 8.00 ± 2.32 7.93 ± 1.94 8.09 ± 2.47
Placebo 7.42 ± 1.67 7.27 ± 1.90 8.19 ± 2.72 7.65 ± 1.91
Eosinophil count 0.0–0.7× 10^9/L EL + MV 3.2 ± 4.0 3.08 ± 2.20 3.28 ± 2.47 3.22 ± 2.35
Placebo 2.8 ± 3.3 2.40 ± 1.93 2.45 ± 1.97 2.25 ± 1.20
Basophil count 0.0–0.2× 10^9/L EL + MV 1.56 ± 0.89 1.42 ± 1.32 1.23 ± 1.76** 0.60 ± 0.54***
Placebo 1.29 ± 0.56 1.08 ± 0.59 1.17 ± 2.30** 0.48 ± 0.46***
*P < 0.05, **P < 0.01, ***P < 0.001, signicant within-group differences and #signicant between-group differences in E. longifolia + multivitamins (EL+MV)
group (n = 44–47) and the placebo group (n = 34–36).
questionnaire. Within group, participants supplemented
with EL+MV and placebo reported signicant improve-
ments in several of the POMS domains. An increasing
trend was observed in the vigour domain of the EL+MV
group at week 12.
The POMS Iceberg prole was applied to the POMS
raw scores of healthy, moderately stressed population of
participants in this study. Average baseline proles showed
that participants in both groups had the expected normal
proles. A normal prole consists of a peak in vigour with
tension, depression, anger, fatigue and confusion making
up the trough of the prole (Fig. 3). In the subgroup anal-
ysis of the POMS scores, participants between the ages
of 46 and 65 years showed signicant between-group im-
provement in vigour (P=0.036) by 14.1% in the EL+MV
group, observed by the mean change from weeks 0 to 12.
Secondary outcomes
Multi-modal stress questionnaire on stress
There were no signicant between-group differences in
self-reported total, behavioural, cognitive and physical
stress by participants, as assessed by the MMSQ question-
naire (Tabl e 3).
Signicant within-group effects were observed in sev-
eral domains in both groups, but only for the EL+MV
group, signicant reduction in physical stress was ob-
served at week 12 (P<0.05), as evidenced by a reduc-
tion of 15% compared to 0.7% in the placebo group only
at week 6 (P< 0.05). The decrease in cognitive stress
and total stress in the EL+MV group was signicant
(P< 0.001) compared to the placebo group (P< 0.01)
at week 12.
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E. longifolia + multivitamins on quality of life, mood and stress
Table 3. POMS and SF-12 MMSQ scores in all participants in the study.
Before
supplementation
P-value After
supplementation–week 6 P-value
After
supplementation – week 12
P-value
EL+MV Placebo EL+MV Placebo EL+MV Placebo
POMS
Tension-anxiety 8.3 ± 4.4 9.8 ± 5.7 0.289 6.6 ± 4.0** 6.8 ± 4.2*** 0.909 5.4 ± 2.9 *** 6.4 ± 4.0*** 0.489
Depression-dejection 8.7 ± 9.5 10.6 ± 11.5 0.892 5.7 ± 9.1** 5.6 ± 8.0** 0.821 3.5 ± 5.4*** 5.2 ± 7.7* 0.427
Anger-hostility 5.1 ± 5.1 7.2 ± 8.5 0.682 3.9 ± 6.3 4.5 ± 6.3* 0.976 2.4 ± 3.5** 4.2 ± 5.8 0.162
Vigour-activity 15.0 ± 6.1 16.6 ± 6.1 0.237 15.1 ± 6.6 16.4 ± 6.1 0.453 16.3 ± 5.4 16.5 ± 5.8 0.974
Fatigue-inertia 6.2 ± 5.7 6.7 ± 5.5 0.673 5.2 ± 5.4 5.5 ± 4.7 0.634 4.2 ± 4.6* 3.2 ± 3.9*** 0.268
Confusion-bewilderment 6.0 ± 4.0 7.9 ± 4.9 0.108 4.96 ± 2.88 5.19 ± 2.72** 0.521 4.63 ± 2.03 5.31 ± 3.01* 0.576
Overall mood 19 ± 27 25 ± 36 0.651 11.2 ± 27.3* 11.1 ± 25.3** 0.962 3.8 ± 18.6*** 7.9 ± 23.8** 0.485
SF-12
Physical component 56.2 ± 5.5 54.9 ± 4.8 0.294 54.1 ± 5.8* 55.1 ± 3.2 0.332 53.8 ± 4.6** 53.7 ± 5.3 0.930
Mental component 28.4 ± 11.2 32.0 ± 10.8 0.148 33.4 ± 9.9** 35.8 ± 8.6** 0.266 35.4 ± 9.4*** 36.0 ± 8.9 0.749
Physical functioning 53.4 ± 7.6 52.5 ± 9.4 0.781 52.7 ± 9.3 54.7 ± 5.4 0.413 53.7 ± 6.3 54.0 ± 7.7 0.391
Role limitations-physical 28.43 ± 2.60 28.88 ± 1.98 0.444 28.84 ± 1.93 29.14 ± 1.31 0.517 28.74 ± 2.01 28.62 ± 2.18 0.817
Role limitations-emotional 18.5 ± 4.7 20.5 ± 3.9 0.044 20.3 ± 3.6** 20.9 ± 3.5 0.341 20.2 ± 4.2* 21.6 ± 2.9 0.101
Energy/fatigue 44.7 ± 11.6 48.3 ± 11.7 0.158 47.3 ± 10.6 51.2 ± 10.0 0.081 49.7 ± 10.1** 51.2 ± 10.6 0.465
Emotional well-being 34.6 ± 13.0 40.7 ± 11.6 0.274 37.5 ± 12.7** 42.8 ± 11.7* 0.429 42.7 ± 10.8*** 43.5 ± 11.6** 0.797
Social functioning 46.7 ± 9.9 49.1 ± 8.9 0.284 49.5 ± 8.5 52.8 ± 6.5* 0.066 52.0 ± 6.3** 50.2 ± 8.2 0.446
Pain 54.3 ± 5.2 54.2 ± 5.4 0.966 53.2 ± 7.6 55.4 ± 4.8 0.207 53.0 ± 7.0 54.5 ± 5.3 0.404
General health 56.6 ± 5.6 56.1 ± 5.1 0.487 56.5 ± 5.5 56.1 ± 6.0 0.843 55.9 ± 5.2 54.7 ± 7.9 0.888
MMSQ
Physical stress 47.6 ± 13.6 43.8 ± 13.0 0.198 45.2 ± 13.1 43.5 ± 11.2* 0.071 40.4 ± 9.1* 40.3 ± 9.5 0.277
Behavioural stress 22.1 ± 5.5 21.6 ± 5.0 0.700 20.6 ± 5.2* 19.6 ± 3.4** 0.323 19.6 ± 4.7*** 19.2 ± 4.5*** 0.673
Cognitive stress 16.5 ± 6.0 14.2 ± 5.8 0.094 14.0 ± 5.4*** 12.2 ± 3.9** 0.091 12.4 ± 3.7*** 11.8 ± 4.2** 0.520
Overall stress 86.1 ± 23.0 79.7 ± 21.3 0.209 79.8 ± 21.4* 72.2 ± 14.6** 0.064 75.5 ± 18.0*** 71.3 ± 15.7** 0.181
POMS, SF-12 and MMSQ scores are depicted as mean ± SD.
*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, signicant within-group difference in E. longifolia + multivitamins (EL+MV) (n = 47) and placebo group (n = 36).
Between-group comparisons were made using ANCOVA.
Fig. 2. (a) Changes in role limitation due to emotional health in EL+MV (n = 46) and placebo (n = 35) groups. Participants
consuming E. longifolia + multivitamins displayed a signicant improvement in role limitation due to emotional health at
week 6 (9.7%; P = 0.003) and week 12 (9.2%; P = 0.05) when compared to baseline. Axes represent change in scores that nu-
merically capture domains in the SF-12 questionnaire. Within-group comparisons were made using the paired t-test. Mean ±
SE values. *P ≤ 0.05. (b) Energy/fatigue ratio in EL+MV (n = 46) and placebo (n = 35) groups. Only participants consuming
E.longifolia + multivitamins showed a signicant increase (11.2%, P = 0.001) in their energy/fatigue ratio at week 12 when com-
pared to baseline. Axes represent change in scores that numerically capture domains in the SF-12 questionnaire. Within-group
comparisons were made using the paired t-test. Mean ± SE values. *P ≤ 0.05.
ab
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Compliance
Compliance, which was assessed by counting the re-
turned unused test product at each visit, was calculated
by determining the number of dosage units taken divided
by the number of dosages expected to have been taken
multiplied by 100. The overall mean compliance was
greater than 99% in both EL+MV and placebo groups.
No participants were removed from the study due to low
compliance (less than 80%).
Safety parameters
Anthropometric measures and vital signs (systolic and
diastolic blood pressure, body temperature, respiratory
rate and heart rate) were similar between EL+MV and
placebo groups after 24 weeks of supplementation. Partic-
ipants consuming EL+MV showed incidental differences
in their respiratory rate at week 12 (P= 0.03) and mean
diastolic blood pressure at week 6 (P=0.02) compared to
the placebo, but not at other time points (Table 1). How-
ever, all excursions were within a normal clinical reference
range for the duration of the study.
Reduction in neutrophil count at week 6 (P=0.03) and
an increase in lymphocyte count at week 12 (P = 0.01)
versus placebo were observed (Table 2). Mean platelet
volume increased in the EL+MV at weeks 12 (P<0.001)
and 24 (P< 0.001) and in the placebo group at weeks 6
(P=0.03), 12 (P<0.001) and 24 (P<0.001) compared
to baseline, but all values remained within their normal
laboratory range (Table 2).
Participants in the EL+MV group showed a decrease
in glucose concentration (P=0.005) and TC(P=0.03) at
24 weeks compared to baseline (Tabl e 2). Urinalysis re-
vealed a difference in the presence of leukocyte esterase
at week 6 (P = 0.008), with 25% of participants in the
EL+MV group testing negative (Table 4). Nine per cent
more participants in the placebo group tested positive
Fig. 3. Changes in POMS Iceberg proles in EL+MV
(n=46) and placebo (n = 36) groups. Changes in POMS
Iceberg proles based on the raw POMS mood state sub-
scales were consistent with that of healthy and active indi-
viduals in tension, depression, anger, vigour, fatigue and
confusion in E. longifolia + multivitamins and placebo
groups. Vigour activity in placebo group was reduced com-
pared to an increase in the supplemented group. Axes rep-
resent change in scores that numerically capture domains
in POMS Iceberg prole.
Table 4. Urinalysis of all participants in the study based on the number of subjects (n).
Presence of leukocyte esterase (n) Presence of calcium oxalate crystals (n)
EL+MV Placebo P-value§EL+MV Placebo P-value§
Week 0
(screening)
1+
2+
3+
Negative
Trace
5 (11%)
2 (4%)
1 (2%)
34 (74%)
4 (9%)
1 (3%)
0 (0%)
1 (3%)
32 (94%)
0 (0%)
0.121 Few
None
0 (0%)
44
(100%)
3 (9%)
31
(91%)
0.079
Week 6 1+
2+
3+
Negative
Trace
2 (5%)
0 (0%)
2 (5%)
38 (88%)
1 (2%)
0 (0%)
2 (6%)
0 (0%)
25 (76%)
6 (18%)
0.008 Few
None
3 (9%)
31
(91%)
7 (27%)
19
(73%)
0.085
Week 12 1+
2+
3+
Negative
Trace
3 (7%)
1 (2%)
1 (2%)
35 (85%)
1 (2%)
2 (6%)
1 (3%)
1 (3%)
21 (66%)
7 (22%)
0.108 Few
None
1 (6%)
17
(94%)
2 (17%)
10
(83%)
0.548
Week 24 1+
2+
3+
Negative
Trace
2 (5%)
3 (7%)
0 (0%)
35 (80%)
4 (9%)
0 (0%)
2 (6%)
0 (0%)
28 (88%)
2 (6%)
0.744 Few
None
2 (25%)
6
(75%)
2 (50%)
2 (50%) 0.547
§Between-group analysis was made using the Fisher’s exact test. P≤0.05 is statistically signicant.
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E. longifolia + multivitamins on quality of life, mood and stress
for the presence of calcium oxalate crystals in the urine
compared to EL+MV group (Table 4).
Testosterone levels
There was no between-group signicance; however, a sig-
nicant time effect within group changes in testosterone
levels was observed. Serum total testosterone decreased in
the placebo group at week 6 compared to during screening
(P=0.009) (Fig. 4a). This decrease continued till weeks
12and 24, but was not observed in the EL+MV group. In
contrast, free serum testosterone levels increased in both
groups (P<0.001) (Fig.4b).
However, there was an increase in free testosterone
levels in males supplemented with EL+MV from 1.67 ±
2.35ng/dL at baseline to 11.4 ± 24.9ng/dL, double the
increase seen in the placebo group, from 1.4 ± 12.7ng/dL
to 6.4 ± 2.9ng/dL (Tab le 5). An increase in free testos-
terone levels from 0.15 ± 0.3 ng/dL in the EL+MV and
0.12± 0.4ng/dL in the placebo group at baseline to 1.05±
0.9 ng/dL and 1.3 ± 1.3 ng/dL, respectively, at week 24
was observed in female participants. There were no sig-
nicant between-group differences in free testosterone
levels in both genders.
Adverse events
In this clinical study, there were a total of 13 adverse
events reported by 13 participants: six (urinary tract in-
fection, blood in urine, nasal congestion, nasopharyngitis
[n=2] and migraine) of which were in the placebo group
and 7 (food poisoning, kidney infection, fracture, inu-
enza, vomiting, nausea and urinary tract infection) were
in the EL+MV group.
Discussion
This study evaluated the efcacy and safety of EL+MV
in healthy males and females with moderate stress. The
demographics of the population studied were middle class
and lower middle class individuals who worked hard to
sustain their families and maintain their lifestyles while
juggling work-related requirements. The participants were
employed and experienced self-reported job-related stress
due to work responsibilities, particularly when responsi-
bility and authority were mismatched (27).
Participants on EL+MV reported a signicant im-
provement in their mental component domain, suggesting
they felt ‘calm and peaceful’, emotional well-being and
improvement in energy/fatigue prole after the 12-week
supplementation. This supports the results of the POMS
analysis with regard to the vigour activity domain, which
reported an increasing trend in the EL+MV group. These
results were further supported by the POMS Iceberg pro-
les that showed optimal peaks of vigour activity and
a decrease in the negative mood clusters, contributing
to the trough values of the prole in both EL+MV and
placebo groups. This concept has previously been applied
to assess physical activity and mood among healthy in-
dividuals (28, 29). After the 12-week supplementation,
the POMS Iceberg proles favoured an improvement in
vigour among participants in the EL+MV group. Pre-
vious studies with nutritionally enriched coffee (28) and
adaptation to competitive sports (30) have reported a
similar shift to healthy POMS Iceberg proles, akin to
positive mood states associated with the use of multivi-
tamins and protein supplements in other stressed popu-
lations (31). In another study, a signicant improvement
in mood by a reduction in tension and anxiety domain of
the POMS was found (P=0.054) in stressed subjects with
EL supplementation (13).
Participants on EL+MV reported signicant improve-
ment in role limitation due to emotional health and in
social functioning domains, suggesting an enhancement
in their QoL, social interactions and related activities.
Fig. 4. (a) Serum total testosterone levels in EL+MV (n = 44) and placebo groups (n = 36). Serum total testosterone decreased
signicantly (P = 0.009) in the placebo group at week 6 compared to baseline. Within-group comparisons were made using the
paired t-test. Mean ± SE values.*P ≤ 0.05. (b) Serum free testosterone levels in EL+MV (n = 44) and placebo (n = 36) groups.
Serum free testosterone increased signicantly in both groups (P < 0.001). Larger percentage increases were observed in the
E.longifolia + multivitamins group. Within-group comparisons were made using the paired t-test. Mean ± SE values.*P ≤ 0.05.
ab
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Annie George et al.
Table 5. Mean concentrations of testosterone in female and male participants.
EL+MV Placebo P-value
(t-test)
EL+MV Placebo P-value
(t-test)
Female Male
Mean ± SD (n)
Within Group P-value
Mean ± SD (n)
Within Group P-value
Mean ±SD (n)
Within Group P-value
Mean ± SD (n)
Within Group P-value
Total testosterone concentration (ng/dL)
Week 0 (baseline) 15.9 ± 12.7 (26) 20.5 ± 12.6 (19) 0.270 641 ± 198 (18) 582 ± 177 (17) 0.269
Week 6 18.3 ± 14.2 (26) 17.8 ± 9.6 (20) 0.723 570 ± 193 (18) 468 ± 230 (17) 0.184
21.6 ± 22.0 (23) 29.4 ± 28.6 (17) 0.155 563 ± 189 (16) 458 ± 188 (17) 0.118
Week 24 18.6 ± 13.2 (28) 20.0 ± 13.1 (19) 0.737 573 ± 208 (18) 434 ± 154 (16) 0.070
Change from
weeks 0 to 6
1.9 ± 6.5 (24)
P = 0.223
−2.9 ± 10.2 (19)
P = 0.556
0.271 −64 ± 125 (17)
P = 0.058
−124 ± 156 (15)
P = 0.003
0.246
Change from
weeks 0 to 12
5.3 ± 14.0 (21)
P = 0.203
8.6 ± 33.3 (16)
P = 0.660
0.530 −74 ± 153 (16)
P = 0.094
−130 ± 152 (15)
P = 0.005
0.401
Change from
weeks 0 to 24
1.9 ± 8.1 (26)
P = 0.115
± 8.5 (18)
P = 0.433
0.839 −79 ± 155 (17)
P = 0.049
−127 ± 185 (14)
P = 0.017
0.710
Free testosterone concentration (ng/dL)
Week-0 (baseline) 0.15 ± 0.30 (26) 0.12 ± 0.44 (19) 0.239 1.67 ± 2.35 (18) 1.40 ± 1.27 (17) 0.298
Week-6 0.39 ± 0.62 (26) 0.27 ± 0.50 (20) 0.456 2.04 ± 2.19 (18) 2.95 ± 2.53 (17) 0.276
Week-12 0.85 ± 0.78 (23) 0.68 ± 1.04 (17) 0.175 3.7 ± 4.2 (16) 4.6 ± 3.1 (17) 0.231
Week-24 1.05 ± 0.89 (28) 1.36 ± 1.37 (19) 0.931 11.4 ± 24.9 (18) 6.4 ± 2.9 (16) 0.506
Change from
week-0 to -6
0.16 ± 0.43 (24)
P = 0.132
0.09 ± 0.31 (19)
P = 0.888
0.304 −0.04 ± 1.72 (17)
P = 0.678
1.72 ± 2.51 (15)
P = 0.030
0.086
Change from
week-0 to 12
0.62 ± 0.76 (21)
P < 0.001
0.53 ± 0.99 (16)
P = 0.025
0.249 2.0 ± 4.4 (16)
P = 0.130
3.4 ± 3.0 (15)
P = 0.002
0.151
Change from
week-0 to-24
0.86 ± 0.93 (26)
P < 0.001
1.26 ± 1.34 (18)
P < 0.001
0.519 9.7 ± 25.9 (17)
P = 0.005
5.3 ± 2.9 (14)
P < 0.001
0.218
Within-group analysis was made using the Wilcoxon signed rank test. Signicant within-group difference in E. longifolia + multivitamins (EL+MV) and
placebo groups;
Between-group analysis was made using the t-test. Probability values P ≤ 0.05 are statistically signicant; n = number of subjects.
A signicant between-group improvement in the 25–45
years subgroup in the social functioning domain could be
explained by the higher occurrence of mood and anxiety
disorder generally increasing with age (30), hence the ex-
tract at a low dosage of 50 mg EL/day, not showing an in-
tervention effect in the older subgroup, instead having an
effect in the younger subgroup. In another study, EL with
a dosage of 200 mg/day was reported to improve the QoL
demonstrated by a reduction of 38% in aging males score
(QoL) after 1-month supplementation (10). A higher dos-
age of EL therefore may be required to affect an older and
otherwise healthy population.
The results of this study indicate that the consumption
of EL+MV formulation affected the emotional health
(SF-12) and vigour (POMS) of the participants. Signi-
cant between-group differences favouring the EL group in
the vigour activity domain of POMS for the 46–65 years
age group could be due to the physical tness since the
reduction in muscle strength in the upper and lower limbs,
changes in body fat percentages and endurance increase
with age and poor nutrition (31). Hence, an intervention
effect may have probably arisen from muscle and strength
improvement (32, 33), anti-ageing and enhancement of
vigour (13) properties of EL. In addition, participants
consuming EL+MV showed a signicant decrease in glu-
cose concentrations from baseline to the end of the study,
supporting its previously reported anti-hyperglycaemic
properties invivo (34, 35) which overall may contribute to
well-being of subjects.
Improvement in mood with the highest decrease in cog-
nitive stress subscale in the MMSQ – which is made up of
several questions that include a participant’s perception
of ‘feeling out of control’, ‘inability to concentrate’, ‘feel-
ing no good’ and a general sense of things being ‘really
bad’ and a desire to ‘run away and hide’ – in participants
supplemented with EL+MV is possibly due to the previ-
ously reported calming effect of EL (6), which is corrobo-
rated by animal studies demonstrating the anti-anxiolytic
effects of EL (22). It was observed that there were more
parents with children in the placebo group. It is surpris-
ing however that the mean for MMSQ (stress) at base-
line was lower in all four domains in the placebo group in
Citation: Food & Nutrition Research 2018, 62: 1374 - http://dx. doi.org/10.29219/fnr.v62.1374 13
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E. longifolia + multivitamins on quality of life, mood and stress
spite of them having more children. The POMS, however,
had higher baseline means in individual domains. The
SF-12 had mixed baseline values where either placebo or
treatment group had higher baseline values. There were
no between-group differences in all domains at baseline.
There were also more women in the treatment group,
which may have contributed to higher mean at baseline
in MMSQ compared to placebo since stress was more
prevalent among women (36).
A large placebo effect as well as large standard de-
viations in POMS total mood disturbance and its sub-
scales, however, perhaps contributed to the absence of
between-group signicance in the questionnaires tested.
Furthermore, it is also plausible that the lower dose of EL
(50 mg/day) used in the current formulation may not have
provided the clinical benets achieved with the higher
dose (200 mg/day) used in previous studies which showed
improvements in tension, anger and confusion with EL
supplementation (6). A reduction in negative mood states
mediated by phytochemicals has been demonstrated in
numerous studies, with placebo effects ranging from 1 to
50% (37–41); therefore, the 10–12% placebo effect seen
with SF-12 and MMSQ and nearly 70% in POMS in the
current study is not surprising. Thus, the lower dose of
EL and a substantial placebo effect exacerbated by the
large statistical deviations observed in the current study
may have obscured the efcacy of EL+MV. This is a
challenge in clinical trials conducted on a healthy popu-
lation as the effects of nutrition interventions are subtle,
whereas drug trials compare exposure with no exposure,
and nutrition trials compare higher and lower exposures.
Everyone consumes nutrients in their diet; therefore, sub-
tle differences may be difcult to detect and have long
latency periods. Taken together, these limitations and
considerations mean that it is difcult to demonstrate
statistically signicant benet between groups (42). In
addition, due to the lack of signicant difference between
groups in primary and secondary outcomes, a compari-
son was made in both outcomes across groups and within
groups at multiple time points, and also in subgroup
analyses by sex and age. This could contribute to type II
error, lack of between-group statistical signicance and
false positives. The problem of multiple comparisons to
be counteracted by, for example, Bonferroni analysis,
may be considered.
Within the safety parameters, signicant increase in
lymphocytes similar to earlier reports (15, 43, 44) was
observed. Furthermore, micronutrients contribute to the
body’s natural defences by supporting physical barriers
(skin/mucosa), cellular immunity and antibody produc-
tion. Vitamins A, B6, B12, C, D, E and folic acid and
the trace elements iron, zinc, copper and selenium work
in synergy to support the protective activities of the
immune cells, whereby vitamins A, C, E and zinc assist in
enhancing the skin barrier function (45). Combining EL
with micronutrients thus is anticipated to provide health
benets through hormonal balance and optimal nutri-
tional requirements.
Participants in this study showed a signicant decrease
in neutrophils that degranulate to release proteases dur-
ing pathogenesis and psychological stress (46). Stress
also enhances neutrophilia and neutrophil counts (47)
without concurrent increase in eosinophils or monocytes
(48), which was also noted in this study. Plant extracts are
known to reduce leukocyte esterase (49) and calcium ox-
alate crystals (50) in urine, similar to observations made
in this study, which suggests fewer urinary abnormalities
associated with EL+MV. It can be speculated that EL is a
nutritional adaptogen (51), an agent that rejuvenates the
body through restoration, which may regulate neutrophils
and leukocyte esterase release. It is plausible that the
EL+MV-mediated improvement in emotional health and
vitality may be associated with changes in these immune
parameters.
Importantly, serum total testosterone levels in the
EL+MV group did not alter, while it decreased in the
placebo group. The stress hormone cortisol increases
under stressed states and as a result, the opposite effect
is that the testosterone levels dip. It is possible through
the absence of the hormone modulating effect of EL
and multinutrients, the cortisol levels as a result of stress
may have increased, hence causing the reduction in tes-
tosterone levels (52). However, there was an increase in
free testosterone levels in males in the EL+MV group. In-
crease in free testosterone levels is a measure of bioavail-
able testosterone (53). Our results are in agreement with
other studies showing a 10.3% increase in free testoster-
one with EL in combination of Polygonum minus sup-
plementation compared to 4.3% with the placebo (54),
and EL- mediated enhancement of free testosterone levels
by 46.8% in subjects suffering from hypogonadism (10).
A supplementation with testosterone improves mood,
energy, friendliness and decreased negative mood (55).
Eurypeptides, a bioactive peptide of 4.3 kDa with tes-
tosterone-modulating properties identied in EL (10),
may restore normal testosterone levels by inuencing the
release of free testosterone from its binding hormone,
sex-hormone-binding globulin, which results in improve-
ment in QoL (10, 55). Eurypeptides enhance metabolism
of pregnenolone and progesterone to yield more dehydro-
epiandrosterone and androstenedione (10, 44, 56) by
activating the CYP17 (17α-hydroxylase and 17,20lyase)
enzyme (10). In addition, even though levels of free tes-
tosterone increased signicantly from baseline in females
in both groups, the increase was higher in the placebo
group compared to EL+MV group, rendering it non-
signicant between groups. Therefore, EL+MV and the
adaptogenic nature of EL may be considered safe in
Citation: Food & Nutrition Research 2018, 62: 1374 - http://dx. doi.org/10.29219/fnr.v62.1374
14
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Annie George et al.
women, preventing an increase in free testosterone, which
is related to conditions such as hirsutism and polycystic
ovary syndrome (57).
There were no signicant and sustained changes from
baseline or against placebo in relevant blood, liver and
kidney laboratory tests. This product was well-tolerated
and safe in the population studied, with no serious ad-
verse events reported, which corroborates ndings from
previous randomised and controlled clinical trials evalu-
ating EL (11). This study did not measure cortisol levels,
which perhaps may have provided valuable information to
understand the efcacy of EL+MV on various stress indi-
cators and immunological parameters. This is a limitation
of the study and should be considered when conducting
future clinical studies.
Observational studies and clinical trials evaluating the
efcacy of EL on mood, stress and testosterone levels have
consistently shown favourable changes in these parameters,
thereby providing a rationale for its incorporation into
new formulations of multivitamins. Multivitamin supple-
mentation enhanced mood by 15% and energy levels by
17% (58) and reduced depressive symptoms since inade-
quacy of key micronutrients has been associated with poor
mood states (19). Therefore, it is reasonable to speculate
that EL synergises health benets exerted by multivita-
mins through improvement in mood states, vigour and a
reduction in stress. The effect of intervention on depressed
subjects could be evaluated in the future since the subjects
used in this study were healthy subjects with only mid-level
stress and not in a depressed state. There are differences and
similarities in the way drugs affect a depressed mental state
compared to the product. For example, uoxetine (Prozac)
and sertraline (Zoloft) are newer medicines that act as se-
lective serotonin reuptake inhibitors (SSRIs). The product
in this study appears to affect energy and mood levels most
likely via hormonal modulation ( testosterone) and nutri-
tional supplementation, for example, vitamins B complex
and C, which also affect mood (20). Vitamin B complex
is involved in the metabolism of S- adenosylmethionine
(SAM), a donator of methyl groups, which plays a deci-
sive role in the functioning of the nervous system and in
the formation of neurotransmitters (e.g. serotonin) (59).
The target of the vitamins is similar, whereas the target
of EL is different for this study. There could be a lack of
intervention effect in subjects with chronic stress or de-
pressed state; hence, one needs to be open to a more pre-
scription-based therapy than nutritional supplementation
for beyond everyday moderate stress. With unrealistic ex-
pectations to treat depression or stress related to suffer-
ing from, for example, advanced disease, there is a risk of
dropping traditional medication exacerbated with a fear of
potential interactions between EL and other medications.
It is however noteworthy that recent research on herb–
drug interaction of EL was weak and inconclusive due to
the dissimilaritiesbetween investigated solvent extract and
aqueous extract of EL (60).
Conclusions
This study reports signicant within-group improvements
in QoL, mood and stress of moderately stressed partic-
ipants supplemented with EL+MV for 12 weeks. De-
spite the placebo effects, participants supplemented with
EL+MV reported improvements in vigour, mental com-
ponent, emotional well-being, cognition and testosterone
levels possibly through hormonal balance and nutritional
supplementation. The stress-related changes in neutrophils
and leukocyte esterase suggest the counteracting effect of
EL+MV supplementation; hence, further research is war-
ranted. Signicant between-group improvements in the
social functioning domain of SF-12 observed in the 25–45
years age group and vigour domain of POMS in the 46–65
years age group supplemented with EL+MV indicate the
efcacy of the supplement in particular spheres of inu-
ence, particularly relating to age. EL+MV was found to be
safe and well-tolerated in this 24-week supplementation
study on moderately stressed participants.
Acknowledgements
The authors would like to thank the volunteers for their time and
participation in the study; Ms. Sasikala Chinnappan for assisting in
the data management and Dr. Joseph Antony for the statistics and
editing of the manuscript.
Conict of interest and funding
The study was funded by NKEA Research Grant Scheme
(NRGS) EPP#1 under the Ministry of Agriculture and
Agro Based Industry, Malaysia. Annie George is an em-
ployee of Biotropics Malaysia Berhad. The authors have
no potential conict of interest.
Declarations
Ethics Approval and Consent to Participate
Ethics (IRB) approval was obtained from IntegReview
Ethical Review Board (Austin, TX, USA) on 17 January
2014 prior to initiation of any study-related activities.
Consent to participate in the study was obtained from all
study participants.
Availability of Data and Material
The data supporting the conclusions of this study are pre-
sented in the main text of this article.
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*Dr. Ashril Yusof
Exercise Science, Sports Centre, University of Malaya,
50603 Kuala Lumpur, Malaysia.
Tel.: +603-79674624
Email: ashril@um.edu.my
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