![Patient distribution into the different classes of four ISI components (3 subcomponents 1a, b, c) at V1 and V2 (ITT population; n ¼ 35 at V1, n ¼ 28 at V2; % [n]).](https://www.researchgate.net/publication/331484243/figure/fig3/AS:863643956682753@1582920173152/Patient-distribution-into-the-different-classes-of-four-ISI-components-3-subcomponents_Q320.jpg)
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A combination of Eschscholtzia californica Cham. and Valeriana
officinalis L. extracts for adjustment insomnia: A prospective
observational study
Samira Ait Abdellah
a
,Aur
elie Berlin
a
, Claude Blondeau
a
,
*
, Isabelle Guinobert
a
,
Ang
ele Guilbot
a
, Marc Beck
b
, François Duforez
c
a
Groupe PiLeJe, 37 quai de Grenelle, 75015, Paris Cedex 15, France
b
1 avenue Cornaudric, 31240, L’Union, France
c
Hotel-Dieu de Paris, Centre du Sommeil et de la Vigilance, 1 Place du parvis Notre-Dame, 75181, Paris Cedex, France
article info
Article history:
Received 23 March 2018
Received in revised form
15 February 2019
Accepted 24 February 2019
Available online xxx
Keywords:
Valerian
Eschscholtzia
Insomnia disorders
Adjustment insomnia
abstract
Eschscholtzia californica Cham. and Valeriana officinalis L. have long been used for the management of
sleep disorders and anxiety. Use of a fixed combination of these two plant extracts (Phytostandard
®
d’Eschscholtzia et de Val
eriane, PiLeJe Laboratoire, France) was investigated in an observational study.
Adults with adjustment insomnia according to the criteria of the International Classification of Sleep
Disorders and with an insomnia severity index (ISI) score >7 enrolled by GPs took a maximum of four
tablets of the eschscholtzia and valerian combination every night for four weeks. Within one month, ISI
score decreased by approximately 30% (from 16.09 ±3.67 at inclusion (V1) to 11.32 ±4.78 at 4 weeks
(V2); p <0.0001). Night sleep duration significantly increased between the first and the fourth week of
supplement intake, sleep efficiency increasing from 78.4% ±12.5 to 84.6% ±10.2 (p ¼0.002). There was
no improvement in sleep latency. The number of awakenings decreased by approximately 25% and their
total duration by approximately 25 min. Anxiety score significantly decreased by 50% from 13.9 ±7.3 a t
V1 to 6.7 ±6.3 at V2 (p <0.0001). The supplement was well tolerated. These results suggest that the
tested combination of eschscholtzia and valerian extracts could be beneficial for the management of
insomnia in adults and deserves further investigation.
©2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier
Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
1. Introduction
Insomnia is defined as difficulty in initiating or maintaining
sleep that is associated with daytime consequences and is not
attributable to environmental circumstances or inadequate op-
portunity for sleep.
1,2
In the International Classification of Sleep
Disorders, insomnia is considered as chronic when it has persisted
for at least three months at a frequency of at least three times per
week; it is defined as short-term insomnia, also called adjustment
insomnia, acute insomnia or anxiety-related insomnia, when it
meets the symptom criteria but has persisted for less than three
months.
1
The definition of chronicity is variable, but a minimum
duration of one month is stipulated by the International Classifi-
cation of Diseases.
3
Adjustment insomnia is a remarkably common problem, most
adults experiencing insomnia or sleeplessness at one time or
another in their lives. According to epidemiological studies, about
one-third of the general population suffers from at least one
insomnia symptom (difficulty in initiating or in maintaining sleep,
or non-restorative sleep).
4,5
One study specifically focusing on
acute insomnia reported a prevalence of 7.9% in a UK sample, with
an annual incidence of 36.6%.
6
Adjustment insomnia is triggered by
a stressor dsuch as interpersonal conflicts, stress at work, a
temporary change of schedule or location, a new situation requiring
adjustment, or temporary abuse of a licit or illicit stimulating
*Corresponding author. PiLeJe Laboratoire, 37 Quai de Grenelle, 75015, Paris
cedex 15, France.
E-mail addresses: s.aitabdellah@pileje.com (S.A. Abdellah), a.berlin@pileje.com
(A. Berlin), c.blondeau@pileje.com (C. Blondeau), i.guinobert@pileje.com
(I. Guinobert), angele.guilbot@gmail.com (A. Guilbot), marc@beck31.net (M. Beck),
fduforez@europeansleepcenter.fr (F. Duforez).
Peer review under responsibility of The Center for Food and Biomolecules,
National Taiwan University.
Contents lists available at ScienceDirect
Journal of Traditional and Complementary Medicine
journal homepage: http://www.elsevier.com/locate/jtcme
https://doi.org/10.1016/j.jtcme.2019.02.003
2225-4110/©2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Journal of Traditional and Complementary Medicine xxx (xxxx) xxx
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
substance dand is generally relieved once that stressor is no
longer present.
2,7
In view of the transient nature of adjustment
insomnia, individuals generally do not seek medical treatment and
often turn to nonpharmacological or over-the-counter remedies,
4,8
herbal medicines representing one of the most frequently used
types of complementary or alternative treatment for insomnia.
8,9
Among herbal medicines, valerian has long been used to aid
sleep and relieve anxiety and is also among those most extensively
studied. The effects of valerian have been attributed to interactions
of valepotriates, valerenic acid, and other components with the
GABAergic system, GABA being a key sleep-promoting neuro-
transmitter.
10,11
It has also been suggested that its effects could be
induced by the GABA contained in the extracts tested. However,
whether exogenous GABA can cross the blood-brain barrier is far
from clear.
10,12 e14
Overall, the results of in vitro and in vivo studies
suggest both a sedative and an anxiolytic effect of valerian, medi-
ated by various interacting components which might promote
sleep and improve nervous state.
The effects on sleep of valerian alone or in combination with
hops have been studied in many clinical trials that vary in their
conclusions. Reviews and meta-analyses either found no difference
in sleep outcomes between valerian and placebo,
4,9
or concluded
that valerian may improve sleep quality, but that methodological
problems limit the ability to draw firm conclusions.
15,16
Most of the
clinical studies included in these analyses were considered to be of
poor quality with regard to their design, the diagnosis of the pa-
tients included and/or sample size.
4,9
In addition, a wide range of
preparations, doses and treatment durations were tested in these
clinical studies, and it is well known that the method of extraction
can affect the active components, and thus the efficacy of prepa-
rations. On the other hand, in its assessment of Valeriana officinalis
L., radix, the Herbal Medicinal Products Committee of the European
Medicines Agency (HPMC/EMA) concluded that the herbal sub-
stance and derived preparations of this plant have a positive risk/
benefit ratio in view of their minimal adverse events in relation to
their efficacy. The committee consequently considered as well
established the use of one specific extract of Valeriana officinalis L.,
radix for the relief of mild nervous tension and sleep disorders and
as traditional the use of a dozen other extracts for the relief of mild
symptoms of mental stress and to aid sleep.
17
This assessment was
based on the analysis of a large body of evidence that may serve as a
proof of efficacy and safety (derived not only from clinical trials but
also from experimental, post-marketing, epidemiological studies,
etc.) and notably took into account the type of preparation used (in
contrast to published meta-analyses).
The HMPC/EMA also recognizes the traditional use of extracts of
the aerial parts of Eschscholtzia californica Cham., herba for the relief
of mild symptoms of mental stress and sleep aid on the basis of
their long-standing use.
18
The sedative and anxiolytic properties of
E. californica (California poppy) extracts have been demonstrated in
several preclinical studies.
18e21
In particular, prolongation of
sleeping time and reduced locomotor activity were observed in
mice and rats receiving various doses of E. californica extracts.
19,20
In contrast, clinical data on eschscholtzia are very scarce.
22,23
The
effects of E. californica result from its chemical composition and in
particular the presence of specific alkaloids, such as californidine
and eschscholtzine.
18
Eschscholtzia would act by binding to
benzodiazepine receptors.
24,25
We hypothesized that use of a supplement combining Valeriana
officinalis L. and Eschscholtzia californica Cham. might be of benefit
for patients with adjustment insomnia. We therefore conducted an
observational study to evaluate one-month use of a supplement
comprising a fixed combination of eschscholtzia and valerian ex-
tracts in adults diagnosed with adjustment insomnia. The study
was conducted in the primary care setting as general practitioners
(GPs) are consulted for insomnia in the first instance, this disorder
constituting a frequent reason for consultation in primary care.
2
2. Materials and methods
2.1. Study design and ethics statement
This was an open-label, observational, longitudinal study per-
formed in France between September 2016 and January 2017. The
study was conducted in a routine practice context without any
additional or unusual procedure as regards diagnosis, monitoring
or supplement use. The study was conducted by GPs who habitually
recommended the dietary supplement to patients suffering from
insomnia, so patients would have received the combination
regardless of whether they were enrolled in the study. The study
was approved by the Advisory Committee on Information Pro-
cessing in Material Research in the Field of Health (agreement no.
15.859) and the National Commission on Computerization and
Freedom. The study was performed in accordance with the ethical
standards laid down in the Declaration of Helsinki and the
Strengthening the Reporting of Observational studies in Epidemi-
ology (STROBE) guidelines. It was registered on the ClinicalTrials.
gov site in November 2016 (identifier: NCT02981238).
2.2. Participants and recruitment
Patients aged 18e65 years of either sex were recruited by GPs.
Patients had to meet both of the following inclusion criteria: (1)
current presence of adjustment insomnia and/or history of this
disorder within the last 3 months. The diagnosis of insomnia was
based on the patient’s complaint: sleep perceived by the patient as
difficult to achieve, insufficient or non-restorative
1
; (2) deteriora-
tion of sleep within the previous month resulting in a score strictly
greater than 7 on the insomnia severity index (ISI).
26
Exclusion criteria were: (1) an anxiety score on the Hamilton
anxiety rating scale (HAM-A) 30; (2) a score on the Epworth
sleepiness scale >10; (3) symptoms suggestive of sleep apnoea or
restless leg syndrome; (4) chronic pain syndrome requiring daily
intake of analgesics; and (5) ongoing psychotropic (neuroleptic,
anxiolytic, antidepressant or hypnotic) treatment or under treat-
ment that might adversely affect the waking state (antihistamines,
beta-blockers, cough syrups, etc.). Patients with illnesses and/or
undergoing treatments liable to interfere with sleep disorders were
not eligible for this study. All patients received written information
about the study and gave their written consent before participating
in it.
2.3. Supplement
The dietary supplement was a combination of eschscholtzia and
valerian extracts (Phytostandard
®
d’Eschscholtzia et de Val
eriane,
PiLeJe Laboratoire, France) marketed in France since 2010. One
tablet contains 80 mg of eschscholtzia extract (Eschscholtzia cal-
ifornica Cham.,flowering aerial parts) and 32 mg of valerian extract
(Valeriana officinalis L., roots). Patients were instructed to take a
maximum of four tablets of the supplement every night for one
month.
2.4. Procedure
The procedure complied with routine practice and official rec-
ommendations for the management of sleep disorders.
2
On the first visit (V1), patient eligibility was verified. GPs had to
complete an electronic inclusion form including the patient’s socio-
demographic (age and sex) and anthropometric (height and
S.A. Abdellah et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx2
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
weight) characteristics, their medical and sleep disorder history,
and information on sleep, associated symptoms, concomitant ill-
nesses and treatments (Fig. 1). Anxiety status (HAM-A), daytime
sleepiness (Epworth sleepiness scale) and severity of insomnia (ISI)
were assessed. Patients also evaluated the intensity of insomnia
(from no impact to high impact on their life), quality of sleep (from
excellent to bad) and quality of waking state (from daytime som-
nolence to good waking state) on a 10 cm visual analogue scale
(VAS).
During the first week (W1) and the last week (W4) of supple-
ment intake, patients had to report sleep characteristics in an
electronic sleep diary to estimate sleep latency (interval between
going to bed and sleep onset); total sleep duration ([time of falling
asleep to time of waking] - total duration of awakenings in the
night); number and duration of awakenings; and index of sleep
efficiency ([total sleep time/time spent in bed] x 100).
On the second visit (V2; Day 28e35), after one month of sup-
plement intake, GPs had to collect information on adverse events
and concomitant treatments. Anxiety (HAM-A scale), insomnia
severity (ISI), and insomnia intensity and quality of sleep and
waking state (VAS) were re-assessed. Information provided in the
electronic sleep diary and compliance with supplement intake
were also checked.
2.5. Main evaluation scales
The Epworth sleepiness scale rates on a 4-point scale (from 0 to
3) the patient’s usual likelihood of dozing off or falling asleep while
engaged in eight different activities differing widely in their som-
nificity.
27
The sum of the eight individual scores gives an estimate
of the person’s‘average sleep propensity’across a wide range of
activities in their everyday life.
The HAM-A anxiety scale grades the severity of 14 symptoms
from 0 ¼absent to 4 ¼maximum/disabling giving a total score
ranging from 0 to 56. The severity of anxiety was classified as mild
(scores 0e17), mild to moderate (scores 18e24) or moderate to
severe (scores 25e30). Patients with a score 30 were not
included.
28
The ISI is a self-assessment questionnaire evaluating the nature,
severity, and impact of insomnia.
26,29
The usual recall period
comprises the past month. The ISI components are: 1) sleep dis-
order severity (subcomponents: difficulty falling asleep, difficulty
staying asleep, early morning awakening), 2) sleep satisfaction, 3)
interference of sleep difficulties with daytime functioning, 4)
extent to which the patient’s sleep problems are noticed by others,
and 5) the patient’s concern about his/her sleep disorder. A 5-point
Likert scale is used to rate each item (from 0 ¼no problem to
4¼very severe problem) yielding a total score ranging from 0 to 28.
The total score is interpreted as follows: absence of insomnia
(scores 0e7); sub-threshold insomnia (scores 8e14); moderate
insomnia (scores 15e21); and severe insomnia (scores 22e28).
2.6. Evaluation endpoints
The primary endpoint was change in total ISI score (components
1 to 5) between V1 and V2.
26,30
Secondary endpoints comprised
changes in each of the seven ISI components and subcomponents,
anxiety score (HAM-A scale), intensity of insomnia, quality of sleep
and waking state (VAS) between V1 and V2; evolution of sleep
latency, sleep duration (nap and night sleep separately and
cumulated), number and duration of awakenings and index of sleep
efficiency between W1 and W4 (means for the entire week, for
working days and for the weekend). Patient satisfaction, safety and
compliance were also assessed.
2.7. Statistical analysis
For the calculation of sample size, we postulated a 4-point dif-
ference in total ISI score between V1 and V2, with a standard de-
viation (SD) of 6 points.
30e32
Based on Student’s t-test for paired
data, a bilateral test, a power of 80% and an error probability of 0.05,
the number of participants required to observe a significant dif-
ference was estimated to be 40.
Continuous variables are presented as means ±SD, categorical
variables being presented as percentages. The chi-squared test was
used to assess differences between categorical variables. The
Shapiro-Wilk test was used to test each variable for normality.
Student’s t-test or the Mann-Whitney Utest was used depending
on the normality or non-normality of the data distribution. In all
tests, p values <0.05 were considered statistically significant. The
principal analysis was performed on the intention to treat (ITT)
population (i.e. all included patients).
33
A second confirmatory
analysis was performed in the per protocol (PP) population (i.e.
patients with no major protocol deviation).
33
The safety analysis
was performed on all subjects who had received at least one dose of
treatment.
Before the multivariate analysis, several univariate analyses
were conducted by the addition of a single covariate (age, gender,
menopausal status, physical activity, shift work, lifestyle recom-
mendations [diet and behaviour], allopathic treatment in addition
to supplement intake, concomitant pathology, and tea, coffee and
alcohol consumption) in the statistical model of the primary
endpoint. A covariate was considered as a candidate for the
multivariate analysis if the p value of this covariate was below the
Use of valerian and eschscholtzia supplement
scales scales
Fig. 1. Study design.
S.A. Abdellah et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx 3
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
20% significance threshold (p <0.20). The ISI score was then ana-
lysed using a mixed linear model (to account for repeated mea-
surements in the same subject) using the backward method and
forcing the “Visit”variable in the model. Significant covariates at
the 5% threshold (p <0.05) were retained in the final statistical
model of the primary endpoint. The difference in ISI score between
V2 and V1 was calculated. All statistical analyses were performed
using SAS 9.3 (SAS Institute Inc, Cary, NC, US).
3. Results
A total of 39 patients were screened by 18 GPs between
September 2016 and January 2017 (Fig. 2). Three patients were
excluded because they did not meet the inclusion criteria, so finally
36 patients (Safety Population and ITT Population) started to take
the supplement at V1. Ten (27.8%) of these patients terminated the
study prematurely (1 included by error, 3 lost to follow up and 6
who failed to attend V2), 26 patients completing the study. Four of
these latter patients were excluded from the analysis, two on the
grounds of a medical history (menopause and migraine, respec-
tively) and two because they were receiving a concomitant treat-
ment (a
b
-blocker for chronic hypertension in both cases) that
might have had an impact on efficacy criteria. Twenty-two patients
were included in the PP population.
3.1. Baseline characteristics (ITT population)
The patients enrolled comprised mainly women (77.8%, 28/36
patients; ITT population). Mean age at inclusion was 49.6 ±11. 3
years.
Mean ISI score was 16.1 ±3.7 (n ¼35). Among the 21 patients
who provided information on their sleep disorder in their sleep
diary, 7 patients (43.8%, 7/16 with available data) reported sleep-
onset insomnia, 16 patients (84.2%, 16/19) sleep-maintenance
insomnia, 6 patients (31.6%, 6/19) early morning awakening and
10 patients (55.6%, 10/18) sleep dissatisfaction (patients might have
declared several insomnia characteristics).
At V1, 4 patients in the ITT population (18.2%, 4/22 who provided
information) declared having hypertension, 2 patients (9.1%, 2/22) a
respiratory disorder, 1 patient (4.5%, 1/22) a neuropsychological
disorder and 3 patients (14.3%, 3/22) thyroid problems, a further 7
patients (31.8%, 7/22) being treated for other (unspecified) diseases.
3.2. Primary endpoint: ISI score
A significant decrease in the mean ISI score was observed after
one month of use of the supplement combining eschscholtzia and
valerian extracts. The mean ISI score decreased by approximately
30% from 16.09 ±3.67 (n ¼35) at V1 to 11.32 ±4.78 (n ¼28) at V2
(4.93 ±4.83 [n ¼28]; p <0.0001, difference V2-V1
[CI
95%
]¼¡4.82 [6.58; 3.07]). The median score was 16.0 (range:
10.0e24.0) at V1 and 12.0 (range: 3.0e21.0) at V2.
Patient distribution between the four ISI classes at V2 was
significantly different from that observed at V1 (p <0.0001, OR
[CI
95%
]¼0.13 [0.06; 0.29]; Fig. 3). At V2, 7 patients (25.0%, 7/28) no
longer suffered from insomnia. None of the patients had severe
insomnia at V2 compared to 3 (8.6%, 3/35) at V1.
The multivariate analysis confirmed the significant decrease in
the ISI score between V1 and V2.
3.3. Secondary endpoints
3.3.1. ISI component scores
At V2, patient distribution into the different classes of four of the
five ISI components was significantly different from that reported
at V1 (Fig. 4). After one month of supplement intake (V2), patients
were less likely to have difficulties in falling asleep (p <0.01, OR
[CI
95%
]¼0.43 [0.23; 0.80]), staying asleep (p <0.001, OR
[CI
95%
]¼0.21 [0.09; 0.52]), and were less likely to experience early
morning awakenings (p <0.005, OR [CI
95%
]¼0.29 [0.13; 0.61]).
Overall, their sleep disorders interfered less with daytime func-
tioning (p <0.005, OR [CI
95%
]¼0.23 [0.09; 0.60]). In addition,
Population
screened (n=39)
No major deviation from protocol
1 with an Epworth scale score = 10
1 under psychotropic medication or
treatment affecting sleep state
Fig. 2. Flow diagram.
S.A. Abdellah et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx4
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
patients were more satisfied with their sleep (p <0.0001, OR
[CI
95%
]¼14.78 [5.14; 42.47]) and less concerned about their sleep
disorder (p <0.05, OR [CI
95%
]¼0.40 [0.19; 0.84]). The proportions of
patients in the “none”and “mild”classes were higher for these ISI
components and subcomponents.
There was no significant change in the fifth component “noti-
ceability of sleep problems to others in terms of impairing patient
quality of life”(data not shown).
3.3.2. Sleep diary
Analysis of the data recorded in patients’sleep diaries revealed
that total sleep duration (during an entire week) significantly
increased between W1 and W4 by about half an hour (p¼0.016,
difference W1-W4 [CI
95%
]¼0.56 [0.12; 1.00]; Table 1). There was
similarly a significant increase in night sleep duration of about half
an hour (p ¼0.009, difference W1-W4 [CI
95%
]¼0.57 [0.16; 0.98]),
but no change in the mean duration of naps. Total sleep duration
was significantly improved during working days (p ¼0.01, differ-
ence W1-W4 [CI
95%
]¼0.61 [0.16; 1.07]) whereas there was no
significant difference on weekends.
A significant improvement in sleep efficiency was observed
between the first and last study week as a whole, including both
working days and weekends (Table 1). With respect to each of these
weeks as a whole, sleep efficiency increased from 78.4% ±12.5 for
W1 to 84.6% ±10.2 for W4 (p ¼0.002, difference W1-W4
[CI
95%
]¼6.16 [2.68; 9.65]).
There was no improvement of sleep latency: patients needed
35.8 ±20 min in W1 and 31.6 ±21.2 min in W4 to fall asleep, the
difference not being statistically significant (Table 1).
A significant decrease was observed in both the number and
duration of nocturnal awakenings during the entire week,
including both working days and the weekend (but not in the
number of awakenings during weekends; Table 1). Comparison of
the entire first and last study weeks showed a decrease of
approximately 25% in the number of awakenings (p ¼0.001, dif-
ference W1-W4 [CI
95%
]¼0.25 [-0.39; 0.11]) and a decrease of
approximately 25 min in their total duration (p ¼0.001, difference
W1-W4 [CI
95%
]¼¡25.03 [-38.82; ¡11.25]).
3.3.3. Intensity of insomnia, quality of sleep and quality of daytime
waking state
Both a decrease in insomnia intensity (impact of insomnia on
the patient’s life) and an improvement in quality of life were
observed. The VAS score of insomnia intensity significantly
decreased by 44.8% from 70.8 ±18.5 (n ¼24) at V1 to 39.1 ±21.5
(n ¼18) at V2 (p <0.0001), the quality of sleep score decreasing by
42.7% from 76.5 ±16.0 (n ¼24) at V1 to 43.8 ±26.7 (n ¼18) at V2
Fig. 3. Patient distribution into ISI classes at V1 and V2.
Fig. 4. Patient distribution into the different classes of four ISI components (3 subcomponents 1a, b, c) at V1 and V2 (ITT population; n ¼35 at V1, n ¼28 at V2; % [n]).
S.A. Abdellah et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx 5
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
(p <0.0001). No significant improvement in the quality of daytime
waking state was observed between V1 and V2.
3.3.4. Anxiety score
The HAM-A score significantly decreased after one month of
supplement use, from 13.9 ±7.3 (n ¼36) at V1 to 6.7 ±6.3 (n ¼26)
at V2 (¡6.7 ±6.2 [n ¼26]; p <0.0001; difference V2-V1
[CI
95%
]¼¡6.87 [-9.33;-4.41]). The median score was 12.5 (range:
4.0e29.0) at V1 and 5.0 (range: 0.0e23.0) at V2.
There was a significant difference in patient distribution into the
different HAM-A classes between V1 and V2 (p ¼0.016, OR
[CI
95%
]¼0.27 [0.10; 0.79]; Fig. 5). At V2, most patients (88.5%, 23/
26) presented mild anxiety (score <17). Three patients (11.5%, 3/26)
showed mild to moderate anxiety at V2. No patient manifested
moderate to severe anxiety at V2 compared to 5 patients (13.9%, 5/
36) at V1.
3.3.5. Compliance
According to data collected by GPs for 27 patients, the mean
total number of supplement tablets taken during the study period
was 49.2 ±32.7, the median number being 54 (range: 0e96).
3.3.6. Safety
The supplement was well tolerated. One patient out of 36 (safety
population) experienced an adverse event comprising nocturnal
pollakiuria. This adverse event was mild and did not lead to
discontinuation of supplement use. No serious adverse events were
reported.
All statistically significant results reported for the ITT population
were also observed in the PP population except for sleep efficiency
at night during weekends (p ¼0.06).
4. Discussion
In this study performed with recognised and validated criteria
and measurement scales for the diagnosis and assessment of
insomnia and anxiety, use of a supplement combining eschscholt-
zia and valerian extracts was associated with a significant decrease
in the severity of adjustment insomnia as assessed by the ISI score.
Mean ISI score decreased by approximately 30% (approximately 5
points) between the first visit and the last visit four weeks later.
Similar decreases in the overall ISI score have been previously re-
ported with other herbal medicines and also psychological/
behavioural interventions. For instance, in a double-blind, ran-
domized, controlled trial, the efficacy of a polyherbal medicine
containing valerian (valerian, passion flower and hop combination)
was compared to that of zolpidem in patients with primary
insomnia (fewer than 6 h of sleep per night, ISI score >7).
34
A two-
week treatment induced an ISI decrease of approximately 5.5
points, an effect that did not differ from that observed with zolpi-
dem. A similar decrease was reported in another study performed
in patients with cancer-related sleep disturbance who received
Gamiguibi-tang, a traditional herbal formula, for two weeks.
35
In a
single-blind, randomized, controlled study performed in adults
with chronic insomnia, mindfulness-based cognitive therapy
induced a 4-point decrease in ISI score at 2 months.
36
Similarly, a
6e8 point decrease in ISI score was reported after 8e9weeksof
cognitive behavioural therapy in two controlled studies enrolling
adults with insomnia.
37,38
In our study, patients were also less likely to have difficulties in
falling asleep (one of the ISI components) one month after starting
to use a supplement combining eschscholtzia and valerian extracts.
In contrast, according to data from sleep diaries there was no
improvement in sleep latency. However, the time of falling asleep
was certainly not appropriately recorded in sleep diaries. Sleep
latency should therefore also be measured objectively by actig-
raphy and its evaluation should not be based solely on the patient’s
subjective assessment. Similar results on sleep maintenance and
duration of sleep were nevertheless observed with regard to ISI
scores and sleep diary data. ISI scores revealed that patients were
less likely to have difficulties staying asleep and were also less
likely to wake up too early. The analysis of information collected in
sleep diaries showed a significant increase in night sleep duration
(of approximately 36 min) between the first and the fourth week of
supplement use. This improvement in the duration of sleep had a
significant impact on sleep efficiency. Sleep efficiency was nearly
85% at the end of the one-month study period, which is the
generally accepted cut-off for “normal”sleep efficiency.
39
In
Table 1
Changes in sleep latency, duration and number of awakenings, and sleep efficiency between W1 and W4 in the ITT population.
Working days Weekends Entire week
W1 (n ¼20* or 21) W4 (n ¼21) p value W1 (n ¼20* or 21) W4 (n ¼21) p value W1 (n ¼20* or 21) W4 (n ¼21) p value
Mean ±SD Mean ±SD Mean ±SD Mean ±SD Mean ±SD Mean ±SD
Total sleep duration (h) 6.8 ±1.1* 7.4 ±1.3 0.01 7.4 ±1.7* 7.8 ±1.5 0.29 6.9 ±1.22* 7.5 ±1.20 0.016
Night sleep duration (h) 6.7 ±1.1 7.3 ±1.2 0.008 7.2 ±1.6 7.7 ±1.2 0.19 6.8±1.15 7.4 ±1.08 0.009
Nap sleep duration (h) 0.1 ±0.24* 0.1 ±0.20 0.48 0.1 ±0.34* 0.1 ±0.32 0.71 0.1 ±0.24* 0.1 ±0.22 0.33
Sleep efficiency (%) 77.5 ±11.6 83.9 ±12.0 0.003 80.6 ±16.0 86.8 ±7.0 0.04 78.4 ±12.5 84.6 ±10.2 0.002
Sleep latency (min) 36.5 ±21.9 31.2 ±22.7 0.3 32.5 ±23.7 30.1 ±26.7 0.7 35.8 ±20 31.6 ±21.2 0.4
Duration of awakenings (min) 58.5 ±46.2 34.1 ±34.2 0.001 43.6 ±50.8 15.8 ±20 0.02 53.8 ±44.8 28.8 ±27.0 0.001
Number of awakenings 1.1 ±0.69 0.8 ±0.64 0.0004 0.9 ±0.71 0.7 ±0.73 0.1 1.0 ±0.66 0.8 ±0.64 0.001
Fig. 5. Patient distribution into HAM-A classes at V1 and V2.
S.A. Abdellah et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx6
Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
addition, a 25% decrease in the number of awakenings was
observed, associated with a 25-min reduction in their duration.
According to ISI scores, there was also a lesser impact of sleep
disorders on daytime functioning at the end of the study period.
Patients were more satisfied with their sleep and less concerned
about their sleep disorder. VAS scores confirmed the improvement
in quality of life.
In addition to the improvement in sleep characteristics, a
reduction in the level of anxiety was observed. Mean HAM-A score
was significantly decreased by more than 50% (approximately 7
points) after one month of supplement use. This suggests that the
combination tested could benefit sleep by inducing a general state
of relaxation. Valerian has well-known beneficial effects on anxi-
ety.
17
We previously showed that a valerian extract had a relaxant
effect on skeletal muscle
40
and it is well known that muscle
relaxation facilitates sleep.
41,42
The main limitation of our observational study is obviously the
absence of a control group. Due to the placebo effect, sometimes
high in the context of insomnia treatment,
2,7
the effect of the
combination tested might be overestimated. It is also worth noting
that the majority of the patients included were women of meno-
pause age, but the multivariate analysis showed that this covariate
had no impact on the results.
The management of insomnia disorders includes both phar-
macological and non-pharmacological approaches. Cognitive
behavioural therapy (CBT) is a first-line therapeutic approach for
insomnia based on sleep hygiene measures and changes in mal-
adaptive behaviour patterns.
11
The goals of this approach are to
control the patient’s environment, restrict the amount of time
spent in bed, reduce outside stimuli, promote relaxation and
mindfulness, limit caffeine and alcohol, and avoid daytime napping
and exercise close to bedtime. The benefits of CBT are generally not
evident straight away and their impact is not immediate.
11
In
addition, treatment access is poor since qualified CBT-therapists are
rare and expensive. Hypnotic drugs are regularly used for insomnia
and other sleep disorders, over 95% of insomniac patients being
prescribed hypnotics in some countries.
43
When prescribed, hyp-
notic medication should be continued for the shortest period of
time as hypnotics and sedatives, such as benzodiazepines and
barbiturates, are associated with undesirable effects, including
adaptation, dependency, hang-over effects, increased sleep, apnoea
and anterograde amnesia.
17
There is an obvious need for treatments
that are better tolerated and easier to implement.
17
Adjustment
insomnia is transient by definition and generally resolves once the
triggering stressor disappears.
2,7
It is therefore acknowledged that,
in contrary to chronic insomnia, adjustment insomnia does not
always require treatment. The recent European guideline for the
diagnosis and treatment of insomnia states that “acute insomnia
does not need a specific treatment in all cases”.
7
The French
guidelines recommend in the case of adjustment insomnia “first to
take the drama out of the situation and provide psychological
support; if needed, pharmacological treatment, whether sedative,
anxiolytic or hypnotic, should be as light (phytotherapy) and brief
as possible”.
2
It is nevertheless important to keep in mind that
adjustment insomnia can also be recurrent and may become
chronic.
2
Certain mechanisms inducing chronicity can be at work
from the first month of insomnia. Therapeutic options capable of
preventing the development of chronic insomnia
17
and limiting its
repercussions on health should therefore be available to patients.
Herbal medicines with relaxing and soothing properties could
help the practitioner to manage insomnia, especially when the risk/
benefit ratio of hypnotic drug prescription is likely to be unfav-
ourable. For instance, elderly people are more sensitive to the po-
tential adverse effects of drugs, and the risks generally outweigh
any marginal benefits of hypnotics in this population.
43
The usual
adverse effects of benzodiazepines occur more frequently in the
elderly, increasing in particular the risk of falls or driving acci-
dents.
2
Herbal medicines may offer an alternative treatment option
that is both effective and devoid of the typical undesirable effects
observed with conventional treatments. In our study, the combi-
nation tested was well tolerated with only one undesirable effect
reported. Valerian is generally well tolerated.
4,15,44
Minor adverse
effects have been reported with chronic use of valerian extracts,
including headaches, excitability, uneasiness, and insomnia.
45
Very
large doses may cause bradycardia and arrhythmias, and decrease
intestinal motility. Data on the safety of eschscholtzia extracts are
scarce; nonetheless, due to their opioid-like effects, they should not
be used in patients manifesting sleep apnoea.
5. Conclusion
The results of this observational study performed in the primary
care context suggest that the tested proprietary supplement con-
taining eschscholtzia and valerian extracts could be of interest for
the management of insomnia. An improvement in sleep quality and
quantity, with a decrease in insomnia-induced daytime impair-
ments were seen, all these factors constituting insomnia treatment
goals.
7
Whether this combination could be an effective alternative
to conventional treatments for insomnia would need to be further
investigated in a double-blind placebo-controlled study including
actigraphy and polysomnography as objective measurements.
Conflicts of interest
AG was the Scientific Department Manager at Pileje Laboratoire
at the time of the study; IG is Research Project Manager, AB and CB
are Scientific and Medical Writers and SAA is Clinical Project
Manager at PiLeJe Laboratoire. FD and MB are consultants for PiLeJe
Laboratoire and gave advice on the study design.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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Please cite this article as: Abdellah SA et al., A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment
insomnia: A prospective observational study, Journal of Traditional and Complementary Medicine, https://doi.org/10.1016/j.jtcme.2019.02.003
