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Effects of a hops (Humulus lupulus l.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: A randomized, placebo-controlled, double-blind, crossover pilot study


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Objective: The Humulus lupulus L. plant (hops) is used as a herbal medicinal product for anxiety/mood disorders. Our aim was to study the effects of a hops dry extract on self-reported depression, anxiety and stress levels in young adults. Design: Apparently healthy young adults from our university completed the Depression Anxiety Stress Scale-21 (DASS-21) and those reporting at least mild depression, anxiety and stress were invited to complete the study intervention. This followed a randomized (1:1), placebo-controlled, double-blind, crossover design with two 4-week intervention periods (hops or placebo; two 0.2 gr capsules once daily) separated by a 2-week wash-out. Anthropometric measurements, DASS-21 assessments and measurements of morning cortisol plasma levels were performed at the beginning and the end of the 4-week treatment periods. Results: 36 participants (Females/Males: 31/5; age: 24.7±0.5 years) completed the study intervention (attrition: 6/42). No significant changes in body weight and composition or morning circulating cortisol were noted with the hops or placebo. Significantly decreased DASS-21 anxiety, depression and stress scores were documented with hops (9.2±7.3 vs. 5.1±5.9, 11.9±7.9 vs. 9.2±7.4, and 19.1±8.1 vs. 11.6±8.1; all p values <0.05), which were significantly greater compared to those caused by the placebo (all p values <0.05). Conclusion: In otherwise healthy young adults reporting at least mild depression, anxietyand stress symptoms, daily supplementation with a hops dry extract can significantly improve all these symptoms over a 4-week period. These beneficial effects agree with the indication of hops for anxiety/mood disorders and restlessness, as approved by the German Commission E.
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Effects of a hops (Humulus lupulus L.) dry extract
supplement on self-reported depression, anxiety and stress
levels in apparently healthy young adults: a randomized,
placebo-controlled, double-blind, crossover pilot study
Ioannis Kyrou,1,2,3,4 Aimilia Christou,1 Demosthenes Panagiotakos,1
Charikleia Stefanaki,5 Katerina Skenderi,1 Konstantina Katsana,1 Constantine Tsigos1
1Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece,
2Aston Medical Research Institute, Aston Medical School, Aston University, B4 7ET, Birmingham, UK, 3Translational &
Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, CV4 7AL,
Coventry, UK,
WISDEM, University Hospitals Coventry and Warwickshire NHS Trust, CV2 2DX, Coventry, UK,
Research Laboratory, 1
Department of Pediatrics, Athens University Medical School, National and Kapodistrian
University of Athens, Athens, Greece
OBJECTIVE: The Humulus lupulus L. plant (hops) is used as a herbal medicinal product for
anxiety/mood disorders. Our aim was to study the effects of a hops dry extract on self-reported
depression, anxiety and stress levels in young adults. DESIGN: Apparently healthy young
adults from our university completed the Depression Anxiety Stress Scale-21 (DASS-21) and
those reporting at least mild depression, anxiety and stress were invited to complete the study
intervention. This followed a randomized (1:1), placebo-controlled, double-blind, crossover
design with two 4-week intervention periods (hops or placebo; two 0.2 gr capsules once daily)
separated by a 2-week wash-out. Anthropometric measurements, DASS-21 assessments and
measurements of morning cortisol plasma levels were performed at the beginning and the
end of the 4-week treatment periods. RESULTS: 36 participants (Females/Males: 31/5; age:
24.7±0.5 years) completed the study intervention (attrition: 6/42). No significant changes in body
weight and composition or morning circulating cortisol were noted with the hops or placebo.
Significantly decreased DASS-21 anxiety, depression and stress scores were documented with
hops (9.2±7.3 vs. 5.1±5.9, 11.9±7.9 vs. 9.2±7.4, and 19.1±8.1 vs. 11.6±8.1; all p values <0.05),
which were significantly greater compared to those caused by the placebo (all p values <0.05).
CONCLUSION: In otherwise healthy young adults reporting at least mild depression, anxiety
HORMONES 2017, 16(2):171-180
Address for correspondence:
Constantine Tsigos MD, PhD, Professor of Endocrinology, Nutrition and Metabolism, Department of Nutrition and Dietetics, School
of Health Science and Education, Harokopio University, 70 El. Venizelou Str., 17671 Athens, Greece; Tel.: +30 210 9549180,
Received: 30-05-2017, Accepted: 19-06-2017
Research paper
Chronic stress is frequently manifested with anxiety
and/or depressive symptomatology, which progres-
sively may lead to a spectrum of behavioral and/or
somatic disorders.
Currently, anxiety and mood
disorders constitute the most prevalent mental health
problems in the general population, which often coexist
particularly in primary care settings and the commu-
nity.5-7 Indeed, the lifetime prevalence of any mood
disorder is estimated to average 12%, whilst large
population-based studies show that up to 33.7% of
individuals in the general population are affected by
an anxiety disorder in their lifetime.5,6 Moreover, as
these stress-related disorders frequently affect young
individuals during their most active years, there is
also a significant impact on their quality of life and
productivity, with the World Health Organization
(WHO) recognizing depression as the leading cause
of disability worldwide.8
In addition, anxiety disorders and depression have
been traditionally amongst the most prominent reasons
for using complementary therapies.9-11 Of note, such
therapies are more common in patients reporting
mental health-related problems than in the rest of the
population, and they are also used more frequently
compared to conventional therapies by individu-
als with self-defined anxiety disorders and severe
depression.9 Thus, it is not surprising that most of
the patients visiting mental health care providers for
anxiety and/or mood disorders report the use of com-
plementary therapies, with herbal medicinal products
being used more frequently.
Interestingly, the use
of these therapies is increasing, not only because of
dissatisfaction with conventional medicine, but also
due to a holistic orientation to health, particularly
regarding options to reduce stress/anxiety, and to a
broader attitude towards seeking non-prescription and
non-pharmacological treatments with fewer adverse
Amongst the plants used for medicinal purposes,
the plant named Humulus lupulus L (Family: Can-
nabaceae) has a long-standing tradition of medici-
nal use in Europe.
Hops is the common name of
the strobiles (cones) of the female inflorescences
of the Humulus lupulus L. plant and is widely used
as a bittering agent in the beer brewing industry, as
well as a herbal medicinal product mostly for sleep
disturbances.15 Thus, hops in the form of herbal tea,
infusions, liquid/alcoholic extracts, tinctures and
powdered herbal substances have traditionally been
used for the relief of insomnia, excitability and restless-
ness associated with tension headaches and nervous
tension.14,15 Indeed, the German Commission E has
approved the use of hops for sleep disturbances and
mood disorders, such as anxiety and restlessness.16
Data from in vivo studies in rats have shown that a
hops extract and its fraction containing alpha-bitter
acids (humulones) exert significant sedative and
antidepressant effects, whilst hops beta-acids (lupu-
lones) appear to also exhibit antidepressant activity
with fewer sedative effects, probably by affecting
gamma-aminobutyric acid (GABA) neurotransmission
activity.17,18 Moreover, in vitro binding experiments
on selected central nervous system (CNS) receptors
using a fixed combination valerian-hops extract and its
individual components have shown that hops interact
with certain serotonin (5-HT6) and melatonin (ML1)
receptor subtypes, which are involved in various
CNS functions related to stress activity, relaxation,
circadian rhythms and sleep.19
Despite the popularity of hops, particularly in
central Europe, as a sedative and mood-enhancing
herbal medicinal product, there is a marked paucity
of high-quality, placebo-controlled clinical studies on
the efficacy of hops in reducing stress-related symp-
tomatology. Therefore, the aim of the present study
was to explore the effects of a commercially available
hops dry extract on self-reported depression, anxiety
and stress levels in apparently healthy young adults.
and stress symptoms, daily supplementation with a hops dry extract can significantly improve
all these symptoms over a 4-week period. These beneficial effects agree with the indication of
hops for anxiety/mood disorders and restlessness, as approved by the German Commission E.
Key words: Anxiety, Depression, Hops supplement, Humulus lupulus L, Stress
Hops effects on depression, anxiety and stress 173
Study protocol - Design
The study was approved by the Institutional Review
Board of Harokopio University, Athens, Greece, and
was conducted in accordance with the principles and
recommendations of the Declaration of Helsinki.
study protocol had a randomized, placebo-controlled,
double-blind, crossover design with two 4-week in-
tervention periods separated by a 2-week wash-out
period. Study participants were allocated to start the
intervention with either placebo or hops dry extract
capsules (two 0.2 g capsules once daily in the evening,
which is the recommended daily dose for this hops
supplement) according to a pre-established computer
generated randomization schedule (randomization ratio:
1:1). Placebo and hops (0.2 g hops extract; Melcalin
HOPs, Biotekna Srl., Venice, Italy) capsules for the
study treatment were kindly provided by Biotekna
Srl. (Biotekna Srl., Venice, Italy). In the context of
this study, placebo and hops capsules were provided
in sealed, identical containers/bottles, each covering a
4-week treatment period. Each of these containers was
coded as either “I” or “II” in order to blind both study
investigators and participants to the randomization/
treatment until the study was completed. Each study
participant was provided with one capsule container
at the beginning of each intervention period, whilst all
capsule containers were collected at the end of each
4-week period in order to count any unused capsules
as a measure of compliance with the study treatment.
For a 2-week period prior to the study initiation and
throughout the total duration of the study, all par-
ticipants were asked to abstain from hops-containing
products (e.g. beer) and other supplements/vitamins
(e.g. valerian or St. John’s wort). In addition, all study
subjects were asked to refrain from significant changes
to their dietary habits and maintain their usual activity
levels throughout the study duration. Moreover, all
participants were also instructed to keep a record of
any symptoms/signs of adverse events and/or illnesses,
as well as any use of medications for the duration of
the study, and these records were checked by the study
investigators at the end of both experimental periods.
Study participants
The cohort of this study was recruited from young
Caucasian adults (age >18 years) attending Haroko-
pio University, Athens, Greece at an under- or post-
graduate level. The study exclusion criteria included
any systemic disease (e.g. neurological or psychiatric
disorders, including clinically diagnosed anxiety
disorders and depression) or treatment (e.g. sedative
or antidepressant medications and relevant supple-
ments/preparations) which could interfere with the
study objectives so that only apparently healthy adults
were recruited into the study. Furthermore, individuals
with recent (within the past two months) significant
changes in body weight (>3% of total body weight)
and/or physical activity levels as well as subjects
with known drug and/or alcohol use disorders were
excluded from recruitment. All study participants
completed a psychological profile assessment via
the validated, self-reported study questionnaire (i.e.,
the Depression Anxiety Stress Scale-21, as detailed
in the following section) and volunteers with scores
indicating at least mild depression, anxiety and stress
levels were further invited to participate in the inter-
vention part of the study. All study procedures were
completed during an exam-free period to avoid bias
relating to exam-related stress. Each participant was
fully informed about the study aims, design and ex-
perimental procedures and provided written informed
consent before participating in the study.
Study protocol assessments
Anthropometric measurements were performed
for all study subjects at the beginning and the end
of the two 4-week treatment periods. Body weight
and height were measured at our university research
unit in participants without shoes or heavy clothing.
Body weight (BW) was measured to the nearest 0.5
kg and height to the nearest 1 cm. Body mass index
(BMI) was calculated as body weight in kilograms
divided by the square of the height in meters. Body
composition analyses, including body fat mass (FM:
%BW), total body water (TBW: %BW) and extracel-
lular water (ECW: %BW), were also performed at
the same time-points using a calibrated, standardized,
dual frequency bioelectrical impedance analysis (BIA)
instrument (BIA-ACC device, Biotekna Srl., Venice,
Italy), as previously described.21
Assessments of self-reported depression,
anxiety and stress symptomatology
Depression, anxiety and stress symptomatology was
assessed in all study participants using the validated
Greek translation of the Depression Anxiety Stress
Scale-21 (DASS-21), which has been shown to be
reliable in the Greek adult general population with
psychometric properties similar to those reported in
the international literature.
The DASS-21 is a well-
established, validated, self-rating scale which measures
the magnitude of three negative emotional states,
i.e. depression, anxiety and stress. This instrument
is considered both sensitive and accurate and thus
is widely applied in research. Briefly, the DASS-21
consists of 21 self-reporting items with seven items
in each of the three subscales (depression, anxiety,
and stress, respectively), documenting the relevant
symptomatology over the past week.
Each item
comprises a statement and four ordinal responses,
which are rated as: (i) “Did not apply to me at all
- NEVER”; (ii) “Applied to me to some degree, or
some of the time - SOMETIMES”; (iii) “Applied to
me to a considerable degree, or a good part of the
time - OFTEN”; and (iv) “Applied to me very much,
or most of the time - ALMOST ALWAYS”, and are
assigned a score of 0, 1, 2 and 3, respectively. Scores
from the seven items in each subscale are summed up
to yield a single subscale score. Each of these subscale
scores is further multiplied by two (subscale score
range: 0-42) in order to compare it with the normative
data of the long form of the DASS instrument which
has 42 items (DASS-42). Notably, the DASS-21 has
the same factor structure and yields similar results
to the DASS-42, while it requires half the time to be
administered (5-10 mins). Subscale scores equal or
higher than 10, 8 and 15 indicate the presence of at
least mild depression, anxiety and stress symptoma-
tology, respectively. Higher scores in each subscale
indicate even greater severity of the corresponding
depression, anxiety and stress symptoms.23
Cortisol plasma levels measurements
Blood sampling for measurements of morning
cortisol plasma levels was performed in all study
participants at the beginning and the end of the two
4-week intervention periods, as per study protocol.
All venous blood samples were collected between
0800 and 0900 hours, after overnight fasting (10 hours
of overnight fasting without food or drink intake,
except for water). All plasma cortisol measurements
were carried out on an ΑΙΑ-600ΙΙ analyzer (TOSOH
Bioscience, Inc., South San Francisco, CA, USA)
using a competitive fluorescence enzyme immunoas-
say based on individual test cups, according to the
manufacturer’s instructions (ST AIA-PACK CORT,
TOSOH Bioscience, Inc., South San Francisco, CA,
USA; assay range: 0.2-60 µg/dL; intra- and inter-assay
coefficient of variation <5.0%).
Statistical analysis
Normally distributed variables are presented as
means ± standard error (SEM), unless otherwise
stated. Categorical variables are presented as frequen-
cies. Differences between and within groups were
evaluated using two-way (group X time) analysis of
variance (ANOVA) and Repeated-Measures ANOVA,
as appropriate. The Shapiro-Wilk test was used to
evaluate the normality of the distribution of quan-
titative variables. Correlations between continuous
variables with skewed distributions were tested by
the Spearman’s rank correlation coefficient. Associa-
tions between continuous and categorical variables
were evaluated using the Pearson chi-square test and
the Mann-Whitney test, where appropriate. Statisti-
cal significance was considered with a two-sided p
value of <0.05. The Statistical Package for the Social
Sciences, SPSS, version 18.0 (SPSS Inc., Chicago,
IL, USA) was used to analyze data.
Of the 126 adults who completed the DASS-21
questionnaire, 42 individuals (Females/Males: 38/4;
age: 25±3.9 years) were eligible based on the study
inclusion/exclusion criteria and consented to participate
in the intervention part of the study. Figure 1 pres-
ents the CONSORT flow diagram of all participants
throughout the study stages. Six of the study subjects
who entered the intervention part of the study failed
to complete the first intervention arm as per protocol
and were excluded from further analyses (Figure 1;
study attrition rate: 14.2%). None of the study par-
ticipants experienced adverse/side effects from the
study treatment (hops extract or placebo).
Hops effects on depression, anxiety and stress 175
The key baseline characteristics of the study par-
ticipants (N= 36) who completed the two 4-week
intervention periods (placebo and hops) of this double-
blind, randomized, crossover study are presented in
Table 1. The study participants exhibited no significant
changes in body weight, BMI and body composition
parameters (FM; TBW; ECW) with the two study
treatments (data not shown; all corresponding p values
Figure 1. Flow diagram of all participants throughout the study stages.
>0.05). Similarly, neither the hops nor the placebo
induced significant changes in the morning cortisol
plasma levels in the study cohort (17.7±5.8 μg/dL vs.
17.6±6.3 μg/dL and 18.5±5.9 μg/dL vs. 18.9±4.8 μg/
dL, respectively; both p values >0.05).
A significant decrease in the DASS-21 anxi-
ety score was noted with both the hops (9.2±7.3
vs. 5.1±5.9; p=0.003) and the placebo (8.3±7.1 vs.
6.2±5.6; p=0.041), which was significantly greater
with the hops compared to the placebo (p=0.009)
(Figure 2). In addition, the DASS-21 depression
score decreased significantly after the hops (11.9±7.9
vs. 9.2±7.4; p <0.001) and the placebo (11.8±9.2 vs.
10.7±8.6; p=0.005), with a significantly more potent
effect following the hops treatment compared to pla-
cebo (p=0.001) (Figure 3). Moreover, the DASS-21
stress scores were also significantly reduced with
the hops and the placebo study treatments (19.1±8.1
vs. 11.6±8.1; p=0.003, and 17.8±9.9 vs. 15.1±8.8;
p=0.022, respectively), with hops again inducing a
significantly greater effect than the placebo (p=0.009)
(Figure 4).
Finally, no correlations were identified between
any of the three DASS-21 subscale scores and base-
line or post-treatment study variables, including body
weight, BMI, body composition parameters (FM;
TBW; ECW) and morning cortisol plasma levels
(data not shown).
The primary objective of this study was to explore
potential effects of a commercially available hops dry
extract on self-reported depression, anxiety and stress
symptomatology in apparently healthy young adults.
Table 1. Selected baseline characteristics of the study participants
(N= 36) who completed both the two 4-week intervention periods
(placebo and hops) of this double-blind, randomized, crossover study
Baseline variable Study cohort (N= 36)
Gender (Females/Males) 31/5
Age (years) 24.7 ± 0.5
Body Weight (kg) 62.1 ± 1.3
BMI (kg/m2)22.7 ± 0.4
Fat Mass (% BW) 23.8 ± 0.8
Total Body Water (% BW) 49.9 ± 0.5
Extra Cellular Water (% BW) 47.1 ± 0.4
DASS-21 Depression Score 11.9 ± 1.0
DASS-21 Anxiety Score 8.8 ± 0.8
DASS-21 Stress Score 18.4 ± 1.1
Morning Plasma Cortisol (μg/dL) 18.1 ± 0.7
BMI: body mass index; BW: body weight; DASS-21: Depression
anxiety stress scale-21; Data presented as means ± standard error.
Figure 2. Depression anxiety stress scale-21 (DASS-21) anxiety
scores at baseline and after hops and placebo 4-week treatment.
Data are presented as means ± standard error. *: p=0.041 be-
fore vs. after placebo treatment; #: p=0.003 before vs. after hops
treatment; §: p=0.009 hops treatment vs. placebo treatment.
Figure 3. Depression anxiety stress scale-21 (DASS-21) de-
pression scores at baseline and after hops and placebo 4-week
treatment. Data are presented as means ± standard error.
*: p=0.005 before vs. after placebo treatment; #: p <0.001 before
vs. after hops treatment; §: p=0.001 hops treatment vs. placebo
Hops effects on depression, anxiety and stress 177
als suffering from depression because of the known
sedative effects of hops, which may accentuate de-
pressive symptoms and potentiate the sedative effects
of existing therapy.
In regard to this point, our
study findings suggest that hops may have an overall
beneficial mood-enhancing effect without significant
adverse/side effects in treatment-naïve individuals
presenting with symptoms of both depression and
anxiety/stress. Of note, this presence of depressive/
anxiety comorbidity is a frequent problem in everyday
clinical practice, since anxiety and mood disorders
often coexist, particularly in individuals in the general
population.7 Additional clinical studies are required
to further explore potential effects (beneficial and
adverse/side effects) of hops in patients with depres-
sion not associated with increased anxiety/stress and
in cases of anergic or atypical depression.
The pathophysiologic relationship between chronic
stress and clinical manifestations of depression and/
or anxiety is complex, with melancholic depression
representing a typical example of dysregulated stress
response and hyperactivation of the stress system.1-4
Indeed, the stress system consists of a highly in-
terconnected neuroendocrine infrastructure, which
is located both in the CNS and the periphery. The
central control stations of this system are positioned
in the hypothalamus and the brain stem, including
primarily the parvocellular corticotropin-releasing
hormone (CRH) and arginine-vasopressin (AVP)
neurons of the paraventricular hypothalamic nuclei,
as well as the locus coeruleus/norepinephrine system.
Furthermore, the hypothalamic-pituitary-adrenal (HPA)
axis and the efferent sympathetic/adrenomedullary
system constitute the main effector limbs via which
the CNS regulates the adaptive stress responses.1
Based on the documented effects induced by the hops
treatment in our study, it is plausible that hops may
affect one or more of these stress system centers/com-
ponents, thereby reducing the chronic stress-related
over-activity and resulting in improvement of the
manifested depression/anxiety symptoms. However,
our study results showed no significant changes in
the morning plasma levels of cortisol, which is the
final hormonal effector of the HPA axis.1-4 This may
suggest either that hops has no significant impact on
basal circulating cortisol levels or that it may have
more subtle effects on the circadian rhythm of the
Applying a randomized, placebo-controlled, double-
blind, crossover study design, our findings in a cohort
of otherwise healthy young adults with at least mild
self-reported depression, anxiety and stress symptoms
revealed a significant reduction in the levels of all
these symptoms with hops which was significantly
greater compared to placebo (Figures 2 to 4). These
results are in accord with the traditional use and the
indication of hops for mood disorders, anxiety and
restlessness, as approved by the German Commis-
sion E.14,16 To date, most of the clinical data on the
effects of hops in humans are from studies utilizing
hops as part of a combination preparation, typically
with valerian,14 and hence it is not feasible to draw
safe conclusions regarding direct mood-enhancing
effects of hops based on these studies. To the best of
our knowledge, this is the first placebo-controlled
clinical study showing that a hops extract alone can
significantly improve symptoms relating to both de-
pression and increased anxiety/stress, thus revealing
these hops-specific beneficial effects.
Interestingly, it has been suggested in the literature
that hops should be taken with caution by individu-
Figure 4. Depression anxiety stress scale-21 (DASS-21) stress
scores at baseline and after hops and placebo 4-week treatment.
Data are presented as means ± standard error. *: p=0.022 be-
fore vs. after placebo treatment; #: p=0.003 before vs. after hops
treatment; §: p=0.009 hops treatment vs. placebo treatment.
HPA axis and the diurnal variation of circulating
cortisol. To identify such potential effects, further
studies with a more complex study design would be
required, utilizing multiple serial sampling of blood
or saliva in order to explore hypothesized changes
in the diurnal variation of cortisol levels.
Further underlying mechanisms may also be impli-
cated in the effects of hops in the central stress system.
Indeed, in vitro data indicate that hops may affect the
GABA synthesis/metabolism and the GABAergic
neurotransmission activity in the CNS.
tantly, GABA is the key inhibitory neurotransmitter
implicated in the regulation of neuronal excitability
and central stress system activity, acting mostly as a
brake on the stimulated neural circuitry during stress.
Not surprisingly, low GABA levels in the CNS are as-
sociated with anxiety, restlessness and depression.
Thus, hops could potentially exert anxiolytic and/or
antidepressant effects by modulating the levels and/
or activity of GABA in the CNS.
the evidence supporting this hypothesis is based on
preliminary data from in vitro experimental studies,
which need to be corroborated by in vivo and clinical
data. Similarly, based on in vitro binding experiments
hops appears to interact with both serotonin (5-HT6)
and melatonin (ML1) receptor subtypes in the CNS,19
hence its anxiolytic and/or antidepressant effects may
also involve the corresponding neural circuits, which
have a well-established role in depression and the
regulation of the central stress system and circadian
Finally, another mechanism that may contribute
to the hops-induced effects noted in our study is
improvement in the sleep pattern/quality due to the
sedative activity of hops.14,15 This has also been sug-
gested in two studies by Franco et al. which used
non-alcoholic beer as a dietary source of hops over
a 2-week period in 30 university students and 17
healthy female nurses, respectively.
Both these
studies reported improvement in night sleep quality
(e.g. reduced sleep latency), with the latter study
suggesting that the effects on sleep quality were also
reflected in decreased self-reported anxiety levels,
as measured by the State-Trait Anxiety Inventory.34
However, these two studies were not conducted in
a blinded manner, lacked a placebo-controlled arm
and had a non-standardized source of hops, thus
limiting the interpretation and implications of the
reported findings, particularly regarding the hops
effects on anxiety levels through improved sleep
quality. In order to explore this hypothesis, well-
designed, placebo-controlled studies with subjective
and objective measures of sleep quality, quantity and
architecture will be required.
A limitation of this study is that the depression,
anxiety and stress symptomatology of the participants
was self-reported. However, the DASS-21 is a well-
validated instrument, which is shown to accurately
capture the underlying symptoms of these emotional
states and is widely applied in this type of research.
Furthermore, complimentary/herbal medicines are
used more frequently by individuals with self-defined
anxiety and mood disorders,9 thus our study cohort
represents a highly relevant population of particular
research interest appropriate for exploring the effects
of a commercially available, non-prescription hops
dry extract supplement on depression and anxiety/
stress symptoms.
In this study, a random sample from the under- and
post-graduate students at our university was recruited.
A recruitment/selection bias may thus have existed
in the recruitment process of our study cohort, as the
study was advertised only to our student body. Such
limitations are relatively common in this type of
research, yet it was also our intention to explore this
specific intervention in young adults with undiagnosed
depression and anxiety/stress symptomatology, as the
consequences of untreated anxiety and mood disorders
in this age group are profound on both quality of life
and productivity. Of note, our study was conducted in
an exam-free period of the academic year, so that our
study cohort can be considered at least to an adequate
degree representative of the Greek general population
of otherwise healthy young adults.
It should also be noted that in our study we
documented a significant effect of the placebo in
decreasing the self-reported depression, anxiety
and stress levels. These placebo effects may be
documented in the context of such interventions
to treat depression and/or anxiety/stress disorders,
especially since anxiety reduction and release of
Hops effects on depression, anxiety and stress 179
endogenous opioids (e.g. dopamine and endorphins)
are considered among the putative mechanisms me-
diating the placebo effect(s).35-38 However, despite
the noted placebo effects, our study findings have
allowed us to identify the significantly greater ef-
fects of the hops dry extract used as compared to
placebo. This further highlights the importance of
blinded, placebo-controlled study designs, particu-
larly in studies focused on anxiety/depression and/
or complementary medicine. Notably, it has been
suggested that a “balanced crossover design” may
be applied in order to further address issues relating
to interactions between drug-specific and unspecific
effects; however, this design has practical disadvan-
tages (i.e. it requires four study groups and thus an
increased number of participants) and raises certain
ethical issues (e.g. in this study design, in addition
to the two typical crossover study groups, one study
group receives the drug twice and another group
receives the placebo twice instead of switching from
the study drug to placebo or vice versa).39,40
Finally, our study assessments included profiling
only of morning cortisol plasma levels which did not
detect significant changes with the study intervention.
In order to further explore potential effects of hops
supplementation on the diurnal variation of stress
system activity, additional studies would be required
with serial sampling of blood and/or saliva to assess
any changes in relevant biomarkers, such as salivary
alpha-amylase (a non-invasive biomarker for the
sympathetic nervous system activity).41
Our study presents novel data showing that daily
supplementation with a commercially available hops
dry extract for a 4-week period in a cohort of otherwise
healthy young adults with at least mild self-reported
depression, anxiety and stress symptoms can signifi-
cantly reduce the levels of all these symptoms. This
finding adds to the existing literature on the hops-
induced effects, since most of the existing clinical
studies have used combinations of hops with other
sedative plant extracts. Longer studies are required
to explore the long-term efficacy and safety of this
intervention, which should be also studied in older
patients with depression and/or anxiety/stress disorders.
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... Hops (Humulus lupulus L.) have been used for anxiety and mood disorders (Borrás et al., 2021). In a clinical trial, Kyrou et al. (2017) report enhanced symptoms in patients with anxiety, stress and depression, and reduced insomnia associated with these effects (Table 3) (Table 6). Deshpande et al. (2020) demonstrated the enhancement of sleep quality in healthy patients (Table 6). ...
The incidence and prevalence of age‐related neurodegenerative dementias have been increasing. There is no curative therapy and conventional drug treatment can cause problems for patients. Medicinal plants traditionally used for problems associated with ageing are emerging as a therapeutic resource. The main aim is to give a proposal for use and future research based on scientific knowledge and tradition. A literature search was conducted in several searchable databases. The keywords used were related to neurodegenerative dementias, ageing and medicinal plants. Boolean operators and filters were used to focus the search. As a result, there is current clinical and preclinical scientific information on 49 species used in traditional medicine for ageing‐related problems, including neurodegenerative dementias. There are preclinical and clinical scientific evidences on their properties against protein aggregates in the central nervous system and their effects on neuroinflammation, apoptosis dysregulation, mitochondrial dysfunction, gabaergic, glutamatergic and dopaminergic systems alterations, monoamine oxidase alterations, serotonin depletion and oestrogenic protection. In conclusion, the potential therapeutic effect of the different medicinal plants depends on the type of neurodegenerative dementia and its stage of development, but more clinical and preclinical research is needed to find better, safer and more effective treatments.
... Among the bioactive components contained in resin are essential oils (β-myrcene, caryophyllene, humulene, β-farnesene, α-and β-selinene), bitter acids (humulone, cohumulone, lupulone, colupulone), polyphenols (catechin, epicatechin, rutin, coumarin, gentisic acid, caffeic acid, ferulic acid, sinapic acid, quercetin, and others), avonoids (xanthohumol, isoxanthohumol) (Bertelli 2018;Farag 2012;Stevens 1997). The studies of bioactivity of hops concerned the sedative, anxiolytic, estrogenic (Shishehgar 2012;Zanoli, 2008;Kyrou 2017), anti-in ammatory (Hall 2008 Isoxanthohumol is formed by the conversion of xanthohumol (the most important prenylated hop chalcone, content up to 1% in dry hop cones) in the process of thermal treatment and an increased pH value during the brewing process (Bartmańska 2009). It was rst isolated and then identi ed as a avanone by Verzele et al. in 1957(Verzele 1957. ...
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Chemometric techniques (principal component analysis, PCA, hierarchical cluster analysis, HCA, partial least squares, PLS) were applied to compare and predict the antioxidant activity of hops based on chromatographic fingerprints. Besides, isoxanthohumol (IXH) was quantified in order to compare its content in hop extracts. Reversed phase-high performance liquid chromatography with diode array detection (RP-HPLC-DAD) was used to obtain chromatographic fingerprints. Isoxanthohumol was used as fingerprint marker and validation (linearity, accuracy, precision, robustness, limit of detection (LOD), limit of quantification (LOQ)) of HPLC was performed. The chemical similarity between samples was evaluated using PCA and HCA. The total phenolics was determined by Folin-Ciocalteu (F-C) test and the antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). The highest antioxidant activity (DPPH and FRAP) was observed for Cascade , the highest phenolic content was for Callista and Halertauer Tradition . The high antioxidant activity by FRAP test was obtained for Cascade and Magnum . The fingerprints combined with the antioxidant activity were evaluated using the PLS.
... Humulus lupulus (Hops) contains numerous dietary phytochemicals potent biological and pharmacological properties (Kyrou et al. 2017;Lin et al. 2019). In hop plants subjected to drought stress, leaf proteomic mass fingerprinting identified 28 DEPs. ...
Medicinal plants are the richest sources of a diverse range of phytochemicals which can be validated for their efficacy to develop new therapeutic molecules against a spectrum of human diseases. Despite the fact that these phytochemicals are present at low concentrations, their abundance is influenced by the dynamic metabolic pathways which are modulated at the genome and proteome level. A variety of environmental factors including biotic (e.g., pathogen infection and herbivore attack) and abiotic factors (e.g., light, temperature, drought, salinity, heavy metals and other toxic chemicals) influence these metabolic pathways and other cellular processes, often posing a threat to the yield of crops including medicinal plants crops. Emerging omics technologies have gained interest in the recent years to provide insights on the underlying stress tolerance molecular mechanisms exhibited by plants to cope with different environmental stresses at system biology level. Proteomics, bridging the gap between genomics and transcriptomics, offers a useful approach to study and characterize the proteome (the total set of proteins present in a cell). Mass-spectroscopy-based proteomics has been widely used for characterization and quantification of stress effect at protein and subproteome levels to gain insights on the key biomarker proteins and their post translation modification, which subsequently can be used for developing new breeding strategies to modulate the plant stress tolerance. This chapter discusses the medicinal plants’ proteomics in response to a variety of stress factors including light (UV-B and UV-D), temperature (high temperature and low temperature), drought (water deficit), salinity (salt stress) and heavy metals (lead, cadmium, chromium, and Copper).KeywordsMedicinal plantsProteomicsMass spectrometryAbiotic stressTemperature stressSalt stressDrought stressMetal stressUV stress
... The types of herbal preparations were varied, as well. Two studies aimed to investigate the efficacy of H. lupulus preparations in long-term anxiolytic treatment (Franco et al., 2012;Kyrou et al., 2017), the third trial examined preparation of a single compound (β-eudesmol) in the acute stress model (TSST) (Ohara et al., 2018); and the fourth study investigated mainly menopause-related symptoms, with the inclusion of anxiety, depression, and stress measured with Greene Scale (Aghamiri et al., 2016). Three studies were randomized, placebo-controlled, and double-blind. ...
Background: Clinical research in natural product-based psychopharmacology has revealed a variety of promising herbal medicines that may provide benefit in the treatment of mild mood disorders, however failed to unambiguously indicate pharmacologically active constituents. The emerging role of the microbiota-gut-brain axis opens new possibilities in the search for effective methods of treatment and prevention of mood disorders. Purpose: Considering the clinically proven effectiveness juxtaposed with inconsistencies regarding the indication of active principles for many medicinal plants applied in the treatment of anxiety and depression, the aim of the review is to look at their therapeutic properties from the perspective of the microbiota-gut-brain axis. Method: A literature-based survey was performed using Scopus, Pubmed, and Google Scholar databases. The current state of knowledge regarding Hypericum perforatum, Valeriana officinalis, Piper methysticum, Passiflora incarnata, Humulus lupulus, Melissa officinalis, Lavandula officinalis, and Rhodiola rosea in terms of their antimicrobial activity, bioavailability, clinical effectiveness in depression/anxiety and gut microbiota - natural products interaction was summarized and analyzed. Results: Recent studies have provided direct and indirect evidence that herbal extracts and isolated compounds are potent modulators of gut microbiota structure. Additionally, some of the formed postbiotic metabolites exert positive effects and ameliorate depression-related behaviors in animal models of mood disorders. The review underlines the gap in research on natural products - gut microbiota interaction in the context of mood disorders. Conclusion: Modification of microbiota-gut-brain axis by natural products is a plausible explanation of their therapeutic properties. Future studies evaluating the effectiveness of herbal medicine and isolated compounds in treating mild mood disorders should consider the bidirectional interplay between phytoconstituents and the gut microbiota community.
... Interestingly, the authors found no alterations of progesterone and 17ß-estradiol concentrations at the end of the trial. A randomized (1:1), placebo-controlled trial was conducted to evaluate the effect of a hop dry extract (Melcalin ® 400 mg once daily) on depression, anxiety and stress levels in young adults [164], showing a significant reduction in the levels of these self-reported symptoms, with no significant changes in cortisol concentrations over time in either group. Human studies on a phytochemical-based anti-inflammatory product, consisting of a combination of hop iso-alpha rho acid (200-225 mg per tablet), rosemary, and oleanolic acid, have shown a significant decrease in pain in subjects suffering from chronic inflammation (e.g., osteoarthritis, rheumatoid arthritis, or other autoimmune conditions), probably due to its effect on inhibiting inflammatory signal transduction, leading to the reduction of inflammatory cytokines and prostaglandins such as PGE2, while no gastrointestinal or cardiovascular side effects were reported as in the case of traditional cyclooxygenase (COX)-2 inhibitor administration [165]. ...
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The medicinal potential of hop (Humulus lupulus L.) is widely cited in ancient literature and is also allowed in several official pharmacopoeias for the treatment of a variety of ailments, mainly related to anxiety states. This is due to the plethora of phytoconstituents (e.g., bitter acids, polyphenols, prenyl flavonoids) present in the female inflorescences, commonly known as cones or strobili, endowed with anti-inflammatory, antioxidant, antimicrobial, and phytoestrogen activities. Hop has recently attracted the interest of the scientific community due to the presence of xanthohumol, whose strong anti-cancer activity against various types of cancer cells has been well documented, and for the presence of 8-prenyl naringenin, the most potent known phytoestrogen. Studies in the literature have also shown that hop compounds can hinder numerous signalling pathways, including ERK1/2 phosphorylation, regulation of AP-1 activity, PI3K-Akt, and nuclear factor NF-κB, which are the main targets of the antiproliferative action of bitter acids and prenylflavonoids. In light of these considerations, the aim of this review was to provide an up-to-date overview of the main biologically active compounds found in hops, as well as their in vitro and in vivo applications for human health and disease prevention. To this end, a quantitative literature analysis approach was used, using VOSviewer software to extract and process Scopus bibliometric data. In addition, data on the pharmacokinetics of bioactive hop compounds and clinical studies in the literature were analysed. To make the information more complete, studies on the beneficial properties of the other two species belonging to the genus Humulus, H. japonicus and H. yunnanensis, were also reviewed for the first time.
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Background: The emerging research in the literature continues to forecast a drastic and alarming increase in negative mental health and sleep health outcomes among populations, especially after the COVID-19 pandemic, which significantly influenced people's way of life. With mental health pharmaceutical interventions continuing to be stigmatized and inaccessible among populations, natural supplements provide an opportunity for intervention. Objective: This study sought to conduct a systematic review of the literature on the most recent comprehensive evidence for which nutritional supplements have the greatest therapeutic impact on symptoms of anxiety, depression, and insomnia. Methods: A systematic search of the literature, utilizing several databases, including PubMed and Web of Science, was conducted on 29 April 2022. We used developed keywords and MeSH terms for the search. The study eligibility criteria included (1) a randomized control trial; (2) investigating a plant-based therapeutic or natural supplement as the intervention; (3) measuring at least one health outcome of the following: anxiety symptoms, depressive symptoms, or sleep health outcomes; (4) utilizing validated measurement tools to measure the outcome of interest; (5) written in the English language; (6) peer reviewed; and (7) focused on adults and elderly populations. Main results: Following the PRISMA guidelines, 76 studies were included in this review. We used the revised Risk of Bias tool (RoB2) to assess the quality of all included randomized control trials. A qualitative data synthesis was conducted. Overall, we found several valuable insights from the evidence in the literature, including evidence that demonstrates the benefits of probiotics and vitamin B complexes on anxiety symptoms, depressive symptoms, and sleep quality. Implication of Key Findings: This review provides the most updated findings in the literature on the topic, including an abundance of research that was published in the past 5 years. Given the expected rise in negative mental and sleep health outcomes following the pandemic, the supplements and therapeutics identified in this study should be the target of intervention measures to increase their accessibility and affordability and allow them to be incorporated into clinical guidelines of treatment. PROSPERO registration number: CRD42022361130.
Background Anxiety is one of the psychiatric disorders that disturbs routine life including moods and motivation. Excessive anxiety causes mental illnesses or anxiety disorders, which are commonly treated by synthetic medicines. Recently, there is a substantial increase in the studies of phytochemicals as alternatives to first-line conventional anxiolytic drugs. Yet there is insufficient information about the mechanisms of how these bioactive constitutes from plants manage anxiety disorders. This systematic review aims to answer the following research questions: 1) Which plant extracts and phytochemicals have anxiolytic effect? what is the mechanism of action? 2) Have human trials been conducted to confirm their anxiolytic effect? 3) If not, which plants/phytochemicals are recommended for further human trials? Methodology To define and summarize such information, this systematic review consolidated in vitro, preclinical, and clinical studies that examine the anti-anxiety activity of plant extracts via oral administration, conducted through three scientific databases including PubMed, Scopus, and Google Scholar following the PRISMA protocol. Results and conclusion Similar to synthetic drugs, most bioactive phytochemical compounds modulate anxiolytic activity through six main neurotransmitter pathways including acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate, serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These bioactive compounds mainly belong to phenolics, alkaloids, and terpenoids, and they demonstrated effective therapeutic benefits against anxiety symptoms. Four plants, including Aloysia polystachya, Lavandula angustifolia, Matricaria chamomilla L. and Humulus lupulus, have been evaluated in human trials. However, studies on majority plants were performed using animal models, and among them, Tanacetum parthenium L. Schultz-Bip (Asreraceae), demethoxysudachitin, Albizzia julibrissin, Nelumbo nucifera Gaertn. leaves, Zizyphi spinosi semen seed extract, obovatol, Mangifera indica stem barks, Nectandra grandiflora Ness and Lavandula angustifolia, Bupleurum yinchowense roots, Citrus aurantium L. and Foeniculum vulgare exhibited the most significant anxiolytic effect at dosage of 30 mg/kg/day or lower. Further human trials are recommended to validate the efficacy and safety of these plants/plant extracts/phytochemicals in managing psychiatric disorders.
Cynanchum wilfordii and Humulus lupulus L. have been used for their various pharmacological properties in South Korea as a traditional medicine or health functional food, respectively, and their intake may relieve menopausal symptoms. The purpose of current study was to determine the effect of compound of Cynanchum wilfordii and Humulus lupulus L. (CWHL) in menopausal symptoms of ovariectomized (OVX) mice. OVX mice received CWHL or caudatin (an active ingredient of CWHL) once daily for 7 weeks. Values for hypothalamic serotonin (5-HT), dopamine, norepinephrine, estrogen receptor (ER)-β, 5-HT1A, and 5-HT2A were significantly enhanced, while value for hypothalamic monoamine oxidase A was reduced in CWHL and caudatin groups compared with the OVX group. CWHL and caudatin significantly reduced tail skin temperature and rectal temperature of OVX mice through partial recovering of the levels of serum estrogen, nitric oxide, follicle-stimulating hormone, luteinizing hormone, and receptor-activator of the NF-κB ligand (RANKL). Moreover, CWHL and caudatin improved bone mineral density via decreasing levels of serum RANKL, tartrate-resistant acid phosphatase, and collagen type 1 cross-linked N-telopeptide and improving levels of serum alkaline phosphatase, osteoprotegerin, and osteocalcin compared with the OVX group without adverse effects such as dyslipidemia. CWHL increased uterine ER-β levels but did not change uterus and vaginal weights. Taken together, the results indicate that CWHL may relieve menopausal symptoms by controlling depression-, hot flashes-, and osteoporosis-associated biomarkers. Therefore, we propose that CWHL might be a safe and potential candidate for management of menopause as a health functional food.
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Depression, anxiety, stress, and other mental disorders, which are on the rise worldwide, are indications that pharmacological therapy can have serious adverse effects, which is why many patients prefer to use herbal products to treat these symptoms. Here, we reviewed plants and products derived from them that are commonly used for the above indications, focusing on clinical data and safety profiles. While lavender, hops, maypop, lemon balm, and valerian have consistently been shown in clinical trials to relieve mild forms of neurological disorders, particularly depression, anxiety, and stress, currently available data do not fully support the use of peppermint for anxiety disorders and depression. Recent studies support the use of saffron for depression; however, its toxicological profile raises safety concerns. St. John’s wort is effective in alleviating mild to moderate depression; however, careful use is necessary particularly due to possible interactions with other drugs. In conclusion, more studies are needed to validate the mechanism of action so that these plants can be used successfully and safely to alleviate or eliminate various mental disorders.
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Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and separation anxiety disorder, are the most prevalent mental disorders and are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime. Substantial underrecognition and undertreatment of these disorders have been demonstrated. There is no evidence that the prevalence rates of anxiety disorders have changed in the past years. In cross-cultural comparisons, prevalence rates are highly variable. It is more likely that this heterogeneity is due to differences in methodology than to cultural influences. Anxiety disorders follow a chronic course; however, there is a natural decrease in prevalence rates with older age. Anxiety disorders are highly comorbid with other anxiety disorders and other mental disorders.
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Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.
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Sleep deprivation affects the homeostasis of the physiological functions in the human organism. Beer is the only beverage that contains hops, a plant which has a sedative effect. Our objective is to determine the improvement of subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI). The sample was conducted among a population of 30 university students. The study took place during a period of 3 weeks, the first 7 days were used for the Control, and during the following 14 days the students ingested beer (were asked to drink non-alcoholic beer) while having dinner. The results revealed that Subjective Sleep Quality improved in the case of those students who drank one beer during dinner compared to the Control, this is corroborated by the fact that Sleep Latency decreased (p < 0.05) compared to their Control. The overall rating Global Score of Quality of Sleep also improved significantly (p < 0.05). These results confirm that the consumption of non-alcoholic beer at dinner time helps to improve the quality of sleep at night.
Background: Depressive and anxiety disorders commonly occur together in patients presenting in the primary care setting. Although recognition of individual depressive and anxiety disorders has increased substantially in the past decade, recognition of comorbidity still lags. The current report reviews the epidemiology, clinical implications, and management of comorbidity in the primary care setting. Method: Literature was reviewed by 2 methods: (1) a MEDLINE search (1980-2001) using the key words depression, depressive disorders, and anxiety disorders; comorbidity was also searched with individual anxiety diagnoses; and (2) direct search of psychiatry, primary care, and internal medicine journals over the past 5 years. Results: Between 10% and 20% of adults in any given 12-month period will visit their primary care physician during an anxiety or depressive disorder episode (although typically for a nonpsychiatric complaint); more than 50% of these patients suffer from a comorbid second depressive or anxiety disorder. The presence of depressive/anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased rates of recurrence, and greater psychosocial disability. Typically, long-term treatment is indicated, although far less research is available to guide treatment decisions. Selective serotonin reuptake inhibitor antidepressants are the preferred treatment based on efficacy, safety, and tolerability criteria. Knowledge of their differential clinical and pharmacokinetic profiles can assist in optimizing treatment. Conclusion: Increased recognition of the high prevalence and negative psychosocial impact of depression and anxiety disorder comorbidity will lead to more effective treatment. While it is hoped that early and effective intervention will yield long-term benefits, research is needed to confirm this.
This large cross-sectional, multi-center study evaluated the association of body composition measurements by a novel dual frequency bio-impedance device (BIA-ACC) with chronic stress/inflammation biomarkers and presence of Medically Unexplained Symptoms (MUS). Participants were adult Caucasians of both sexes and included 10416 lean subjects with no MUS (Group A), 58710 lean subjects with MUS (Group B) and 30445 overweight/obese subjects with no MUS and excessive Fat Mass (FM) (Group C). Total body extracellular water (ECW) was lower, while intracellular water (ICW) was greater in Group A than both other groups (p<0.01). Group A had significantly lower FM and higher skeletal mass (SK) and phase angle (PA) than Group B and lower circulating high sensitivity (hs)CRP levels than both other groups. hsCRP was higher in Group C than Group A (p<0.01). Salivary cortisol in Group A was higher in the morning and lower in the evening than both other groups (p<0.001), indicating circadian rhythm obliteration or reversal. ECW correlated positively with hsCRP and 8pm cortisol, but negatively with 8am cortisol and PA, while PA correlated positively with 8am and negatively with 8pm cortisol, 8 am hsCRP and 8 am and 8 pm salivary cortisol correlated to presence of MUS and BIA-ACC measurements, including ECW, ICW, FM, SK and PA. MUS is an index of chronic stress and inflammation and BIA-ACC may provide a useful, bloodless and rapid tool in the clinical setting, distinguishing patients with chronic stress/inflammation from healthy subjects and monitoring their response to treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.