ORIGINAL RESEARCH ARTICLE

CNS Drugs 2010; 24 (3): 207-225

1172-7047/10/0003-0207/$49.95/0

2010 Adis Data Information BV. All rights reserved.

The Efficacy of Hypericum perforatum

(St Johns Wort) for the Treatment of
Premenstrual Syndrome
A Randomized, Double-Blind, Placebo-Controlled Trial
Sarah Canning,1 Mitch Waterman,1 Nic Orsi,2 Julie Ayres,3 Nigel Simpson2 and Louise Dye1
1 Institute of Psychological Sciences, University of Leeds, Leeds, UK
2 Perinatal Research Group, The YCR and Liz Dawn Pathology and Translational Sciences Centre,
Leeds Institute of Molecular Medicine, St Jamess University Hospital, Leeds, UK
3 Rosalind Bolton PMS Clinic, St Jamess University Hospital, Leeds, UK

Abstract

Background: Premenstrual syndrome (PMS) is a common condition. Some of

the most widely prescribed medications are selective serotonin reuptake inhibitors (SSRIs), based on the hypothesized role of serotonin in the production of PMS symptoms. PMS sufferers, especially those experiencing mild to
moderate symptoms, are often reluctant to take this form of medication and
instead buy over-the-counter preparations to treat their symptoms, for which
the evidence base with regard to efficacy is limited. Hypericum perforatum
(St Johns wort) influences the serotonergic system. As such, this widely
available herbal remedy deserves attention as a PMS treatment.
Objective: To investigate the effectiveness of Hypericum perforatum on
symptoms of PMS.
Study design: This randomized, double-blind, placebo-controlled, crossover
study was conducted between November 2005 and June 2007.
Setting: Institute of Psychological Sciences, University of Leeds, Leeds, UK.
Participants: 36 women aged 1845 years with regular menstrual cycles
(2535 days), who were prospectively diagnosed with mild PMS.
Intervention: Women who remained eligible after three screening cycles
(n = 36) underwent a two-cycle placebo run-in phase. They were then randomly
assigned to receive Hypericum perforatum tablets 900 mg/day (standardized
to 0.18% hypericin; 3.38% hyperforin) or identical placebo tablets for two
menstrual cycles. After a placebo-treated washout cycle, the women crossed
over to receive placebo or Hypericum perforatum for two additional cycles.
Main outcome measures: Symptoms were rated daily throughout the trial
using the Daily Symptom Report. Secondary outcome measures were the
State Anxiety Inventory, Beck Depression Inventory, Aggression Questionnaire and Barratt Impulsiveness Scale. Plasma hormone (follicle-stimulating
hormone [FSH], luteinizing hormone [LH], estradiol, progesterone, prolactin

Canning et al.

208

and testosterone) and cytokine (interleukin [IL]-1b, IL-6, IL-8, interferon

[IFN]-g and tumour necrosis factor [TNF]-a) levels were measured in the
follicular and luteal phases during Hypericum perforatum and placebo treatment.
Results: Hypericum perforatum was statistically superior to placebo in improving physical and behavioural symptoms of PMS (p < 0.05). There were
no significant effects of Hypericum perforatum compared with placebo
treatment for mood- and pain-related PMS symptoms (p > 0.05). Plasma
hormone (FSH, LH, estradiol, progesterone, prolactin and testosterone) and
cytokine (IL-1b, IL-6, IL-8, IFNg and TNFa) levels, and weekly reports of
anxiety, depression, aggression and impulsivity, also did not differ significantly during the Hypericum perforatum and placebo cycles (p > 0.05).
Conclusion: Daily treatment with Hypericum perforatum was more effective
than placebo treatment for the most common physical and behavioural
symptoms associated with PMS. As proinflammatory cytokine levels did not
differ significantly between Hypericum perforatum and placebo treatment,
these beneficial effects are unlikely to be produced through this mechanism of
action alone. Further work is needed to determine whether pain- and moodrelated PMS symptoms benefit from longer treatment duration.
Trial registration number (International Standard Randomised Controlled
Trial Number Register) ISRCTN31487459

Background
The premenstrual syndrome (PMS) refers to a
wide range of cyclic and recurrent psychological,
physical and behavioural symptoms that occur in
the 710 days prior to the onset of menstruation
and which are relieved shortly following the onset
of menstruation.[1-3] PMS severity falls along a
continuum.[4,5] Women with particularly severe
symptoms may be diagnosed with premenstrual
dysphoric disorder (PMDD).[6] Epidemiological surveys have estimated that up to 75% of
women experience mild to moderate premenstrual
symptoms,[7,8] while approximately 38% of women
experience symptoms at a severity sufficient to
meet a diagnosis for PMDD.[9,10] The term PMS
is used in this article when discussion is relevant to
all levels of premenstrual symptom severity, and
the term PMDD is used when discussion is relevant only to the severe end of the PMS spectrum.
There is some dispute in the literature surrounding the nature of PMS.[8,11] From a diagnostic
standpoint, retrospective accounts and selfdiagnosis do not always match prospective symptom
2010 Adis Data Information BV. All rights reserved.

reporting.[12-14] PMS diagnostic criteria should differentiate women who experience problematic premenstrual symptoms from women who do not.[13]
However, current diagnostic criteria for PMS do
not consistently differentiate these two groups of
women.[13-16] The conceptualization of PMS is
also problematic and varies across disciplines.[15] For
example, the medical perspective pathologizes
womens distress and positions it as a reproductive
disorder, whereas the socio-cultural perspective rejects this standpoint.[14] These conceptualizations
lead to quite different treatment approaches.
Various biomedical and psychological interventions are available for the treatment of PMS.
While selective serotonin reuptake inhibitors
(SSRIs) are the medical treatment of choice by
many practitioners for women who experience
severe symptoms,[5,17,18] the use of over-the-counter
(OTC) preparations is often advocated for women
with mild to moderate symptoms.[5,19] Although
various dietary supplements and herbal remedies
have been proposed to alleviate PMS symptoms
and are widely consumed, rigorous scientific
studies to test their efficacy are lacking.[20-23] A
CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

variety of psychological interventions, which focus

on changing the way in which women appraise
and cope with their premenstrual changes, are
also available.[8] Cognitive behavioural and narrative therapy,[24,25] coping skills training[26,27]
and relaxation training[28] have all been shown to
effectively reduce moderate to severe PMS. These
different approaches to PMS treatment reflect
the view that the syndrome could have a multifactorial aetiology. A variety of biopsychosocial
models of PMS have been proposed, which posit
that symptoms arise from a complex interaction
between various biological, psychological and
social factors.[29-33]
A range of biological factors have been implicated in the production of PMS symptoms.
These include abnormal steroid hormone function,[34] disturbed prostaglandin metabolism,[35]
calcium dysregulation,[36,37] poor magnesium
status,[38] abnormal fatty acid metabolism,[39] and
an increased sensitivity to[35] and elevated levels
of[40] prolactin. Increasing evidence suggests serotonergic dysfunction plays a role in the production of PMS symptoms.[23,41,42] Women with PMS
have reduced serotonin levels during the luteal
phase and in comparison with women without
PMS.[43-46] Moreover, PMS symptoms, including
aggression,[47,48] depression,[49] anxiety[50] and
irritability,[51] have been linked to serotonergic
dysfunction. Furthermore, SSRIs successfully reduce mood and somatic PMS symptoms.[17,18,23]
The serotonergic system interacts with the cytokine network.[52-58] Cytokine release varies over
the menstrual cycle.[59,60] Serum levels of interleukin (IL)-1[61,62] and IL-6,[63] for example, increase during the luteal phase. These cytokines
have been associated with symptoms characteristic of PMS, including depression,[64,65] anxiety,[66]
fatigue,[67] headaches[68] and sleep disturbances.[69,70]
Endotoxin administration, which causes the production and secretion of tumour necrosis factor
(TNF)-a, IL-1 and IL-6, has been shown to induce anxiety and depression.[71] It is therefore
possible that cytokines contribute to the production of PMS symptoms,[63] through interaction
with the serotonergic system, in a similar manner
to that suggested for the aetiology of depression.[52,72] SSRIs normalize cytokine levels[73-75]
2010 Adis Data Information BV. All rights reserved.

209

and could therefore reduce PMS symptoms through

this mechanism of action. However, no studies
have yet examined individual cytokine levels or
cytokine interactions in women with PMS.
Hypericum perforatum is a herbal remedy that
influences the serotonergic system[76-78] and suppresses proinflammatory cytokine levels.[79,80]
Hypericum perforatum has been demonstrated to
be an effective treatment for mild to moderate
depression,[81-84] presumably because of its action
on these systems.[76,79,80] As some similarities exist between the symptoms of clinical depression
and mood-related PMS symptoms, such as feeling
down, hopeless, easily annoyed and fatigued,[85-87]
the hypothesis that the mood symptoms commonly associated with PMS should respond to
Hypericum perforatum is plausible.
Three previous randomized, double-blind,
placebo-controlled trials have assessed the effectiveness of Hypericum perforatum for PMS.[86,88,89]
Two of these[88,89] found Hypericum perforatum
to significantly benefit physical PMS symptoms.
However, the omission of methodological details
from these articles meant that their quality could
not be assessed. Hicks et al.[86] did not find
Hypericum perforatum (600 mg/day) to significantly reduce PMS symptoms in comparison
with placebo treatment. Combining symptom
scores from both treatment cycles resulted in
Hypericum perforatum appearing more beneficial
than placebo treatment for each symptom subgroup assessed, but these combined effects did not
reach statistical significance. Most research that
has assessed the efficacy of Hypericum perforatum
for depression has employed a higher dosage of
900 mg/day.[90-93] This is also the dosage recommended by most manufacturers of Hypericum perforatum to improve mood. Consequently, the aim
of this study was to investigate whether Hypericum
perforatum 900 mg/day was more beneficial than
placebo treatment in relieving symptoms of PMS.
Method
Ethical and Regulatory Approval

Ethical approval to carry out the study was

granted by the Institute of Psychological Sciences
CNS Drugs 2010; 24 (3)

Canning et al.

210

(16/12/2004) and the Leeds (West) Research

Ethics Committee (23/6/2005). The Medicines
and Healthcare products Regulatory Agency
(MHRA) also granted approval for the clinical
trial (23/9/2005).
Protocol, Design and Objectives

This was a ten-cycle, randomized, double-blind,

crossover, placebo-controlled study, designed to
evaluate the efficacy of Hypericum perforatum for
the management of mild PMS. After three untreated screening cycles (cycles 13) women who
met a prospective PMS diagnosis underwent a
single-blind placebo run-in phase of two menstrual
cycles (cycles 4 and 5). Thereafter, women were
randomized to receive two cycles of double-blind
treatment with Hypericum perforatum extract or
placebo (cycles 6 and 7). Following a single-blind,
placebo-treated washout cycle (cycle 8), women
were crossed over to placebo or Hypericum perforatum for two additional cycles (cycles 9 and 10).
Participants

Women were recruited for the trial between

November 2005 and August 2006. Respondents
to advertisements and publicity in the local media,
which requested volunteers from the Leeds
area experiencing premenstrual symptoms, were
asked to complete a preliminary screening questionnaire. Women aged between 18 and 45 years
who had regular menstrual cycles (2535 days)
and who were able to make frequent study visits
were eligible for the study. Women who were
photosensitive, using hormonal contraception or
treatment, pregnant or breast-feeding, taking
prescribed (e.g. estrogens, progestogens, danazol,
gonadotropin-releasing hormone agonists) or
OTC (e.g. calcium, evening primrose oil, vitamin
B6, Vitex agnus castus) medication for PMS, reporting menstrual cycle irregularity, or taking
prescribed drugs that are known to interact with
Hypericum perforatum were excluded.
Women who met these selection criteria were
invited for their first study visit at the Rosalind
Bolton PMS clinic, Leeds General Infirmary.
During this visit the inclusion and exclusion criteria were checked and women underwent a
2010 Adis Data Information BV. All rights reserved.

clinical interview. Those who were deemed to be

in good physical and psychological health were
asked to provide written informed consent and
were entered onto the screening phase. During
this phase women were required to demonstrate
at least a 30% increase between their follicular
and luteal Daily Symptom Report (DSR)[94] total
scale scores (30% increase criterion) in at least
two of the three cycles to be eligible to continue in
the study.[95] Follicular scores were obtained by
averaging the DSR total scale scores from cycle
days 510, with day 1 being the first day of
menstruation. Luteal scores were obtained by
averaging the DSR total scale scores from the
6 days prior to the onset of menstruation.[96]
To confirm the diagnosis, PMS symptoms
should be limited to the luteal phase.[1,2,6,97,98]
Prospective symptom reports do not always confirm PMS.[5,99,100] Some women meet the criteria
for a psychiatric diagnosis, most commonly anxiety and depression,[1,99-101] but report PMS due
to premenstrual magnification of their symptoms.[5] Women were excluded from this study if
they showed elevated anxiety and depression
levels in their follicular phase. Women who had
an average total score that exceeded the clinical
threshold for caseness for depression (12)[102,103]
on the Beck Depression Inventory (BDI)[104]
and/or an average total score that exceeded the
upper 90% probability limit (1.645 standard deviation [SD] above the mean)[105] for the general
adult population (51)[106] on the Trait scale of
the State-Trait Anxiety Inventory (STAIT)[106]
were excluded from entering the placebo run-in
phase. A letter was sent to the family practitioners of all participants who remained eligible
and willing to continue in the trial.
Intervention

The Hypericum perforatum extract Li160 (80%

methanolic dry extract, drug-to-extract ratio
36 : 1, containing 0.18% hypericin and 3.38%
hyperforin) was supplied by Lichtwer Pharma
AG (Berlin, Germany). The coated active
(Hypericum perforatum 450 mg) and control
(placebo) tablets were identical, yellow and oval in
appearance, and supplied in identical blister packs
CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

of 15 tablets. The blister packs were packaged in

plain boxes containing 75 tablets, which were
clearly labelled with each participants treatment
code and study cycle number (cycles 410). Every
participant was given seven boxes of tablets
throughout the entire study, supplied at regular
intervals. Participants were instructed to begin
the appropriate box of tablets on the first day of
each menstrual cycle and to take two tablets per
day from this box throughout that cycle.
The probability of assignment to treatment
groups was equal. The randomization code was
generated using a random permuted block method.[107] Two permutations were used: (i) Hypericum
perforatum followed by placebo; and (ii) placebo
followed by Hypericum perforatum. The schedule
was produced using a random number table.[107] A
block size of 10 was employed, with the first permutation being represented by numbers 04 and
the second by numbers 59. For every ten participants randomized, five received Hypericum perforatum followed by placebo and five received placebo
followed by Hypericum perforatum. A pharmacist
from Leeds General Infirmary, otherwise not
involved in the trial, performed the randomization and dispensed the medication. The allocation codes were kept from the principal investigator
who had contact with the participants until after
the last participant completed the trial, when these
codes were revealed. The randomization code was
broken for one participant during the trial, as she
became pregnant. However, as random numbers were used to assign women to conditions, this
did not result in the unblinding of the remaining
participants.
Measurements

The primary outcome measure was the DSR, a

checklist of 17 premenstrual symptoms rated
from 0 (not present at all) to 4 (severe: symptom
is overwhelming and/or unable to carry out daily
activity). The DSR comprises four subscales
which describe mood (anxiety, irritability, depression, nervous tension, mood swing, feeling
out of control), behavioural (poor coordination,
insomnia, confusion, headache, crying, fatigue),
pain (aches, cramps, breast tenderness) and phy 2010 Adis Data Information BV. All rights reserved.

211

sical (food craving, swelling) symptoms.[94]

Women were asked to complete DSRs throughout
the duration of the trial and to note down on
these whether they had their period.
Anxiety, depression, aggression and impulsivity are common premenstrual symptoms, which
cause great distress to women with PMS.[1,108-110]
Moreover, these are the symptoms that often
propel women to seek treatment.[15,111] Hence, secondary outcome measures included the State scale
of the State-Trait Anxiety Inventory (STAIS),[106]
BDI,[104] Aggression Questionnaire (BPAQ)[112] and
Barratt Impulsiveness Scale version 11 (BIS-11)[113]
to determine whether Hypericum perforatum
specifically benefited these common and distressing PMS symptoms. Women were asked to
complete these secondary measures weekly throughout the trial. All self-report measures were provided to participants in diary booklets containing
seven copies of the DSR and one copy of the
BDI, STAIS, BPAQ and BIS-11, which were sent
to participants biweekly throughout the trial.
The diary booklets supplied during the screening cycles also contained one copy of the
STAIT[106] for diagnostic purposes (as described
earlier). The DSRs provided between cycles 4
and 10 included a box for women to tick to confirm that they had taken their study medication that day. Women were instructed to begin
a new diary booklet on the first day of each
menstrual cycle, and to complete the weekly
measures from their previous booklet if applicable. They were asked to return each diary
booklet immediately after its completion in one
of the freepost envelopes provided.
In order to assess the effectiveness of Hypericum
perforatum for PMS, each cycle was divided into
four phases: menses, follicular, rest and luteal. These
phases were determined based on the onset of menstruation. DSR total and subscale scores from
cycle days 14 were averaged and identified
menses, days 510 the follicular phase and days
-1 to -6 the luteal phase. The average of the remaining cycle days were referred to as rest (of
cycle).[96,114,115] The secondary measures asked
women to report how they had been feeling over
the previous week. Hence those completed on
cycle day 7 were taken to represent menses, those
CNS Drugs 2010; 24 (3)

Canning et al.

212

on day 14 the follicular phase and those on cycle

day 1 of the next cycle the luteal phase. If two
diaries had been completed during the rest
phase, the one immediately before the luteal
diary was excluded, as this usually overlapped
with days in the luteal diary. In the rare case
where three diaries were completed (i.e. in a cycle
>35 days) the middle diary was used.
Women were required to visit the principal
investigator at the Institute of Psychological Sciences, University of Leeds, during the follicular
and luteal phases of study cycles 3, 5, 7, 8 and 10.
During these visits, blood samples were obtained
by venepuncture to assess hormone (folliclestimulating hormone [FSH], luteinizing hormone
[LH], estradiol, progesterone, prolactin and testosterone) and cytokine (IL-1b, IL-6, IL-8, interferon [IFN]-g and TNFa) levels. Samples were
collected in edetic acid (EDTA) tubes and immediately centrifuged for 10 minutes at 4200 rpm.
Plasma was removed and aliquoted into eight
Eppendorfs, which were stored at -80C in the
Institute of Psychological Sciences, until they
were transferred to Leeds Institute of Molecular
Medicine, St Jamess University Hospital, where
the samples were thawed and analysed. Hormone
levels were detected in vitro from each sample
simultaneously using the automated biochip
array analyser, Evidence (Randox Laboratories,
Crumlin, UK) using the method previously
described by FitzGerald and colleagues.[116]
Cytokine levels were determined by fluid-phase
multiplex immunoassay using custom kits according to manufacturers instructions (Linco
Research Inc., St Charles, MO, USA). Samples
were run on a Luminex-100 cytometer (Luminex Corporation, Austin, TX, USA), equipped with
Bio-Plex software (Bio-Rad, Hemel Hempstead,
Hertfordshire, UK).[117] All samples from each
individual were analysed together to minimize
interassay variability.
Each week women were asked to provide information regarding any adverse events they experienced and/or concomitant medications taken,
on the relevant page in their diary booklet. Adverse events were also assessed at each study visit
through a semi-structured interview. Participants
blood pressure was also recorded at each visit.
2010 Adis Data Information BV. All rights reserved.

Sample Size

When this study was designed, only one pilot

study testing the efficacy of Hypericum perforatum for PMS had been published.[118] This study
used a pre-post test design and did not employ a
placebo group or crossover design. Therefore, in
order to approximate the effect size necessary for
the purpose of sample size estimation in the current study, response to placebo had to be estimated. This was done by calculating the halfway
point between the total DSR score at baseline and
the first treatment cycle. The effect size was
estimated using the formula d = (treatment placebo)/s within, where s within = S within
O(degress of freedom within/number of participants).[119] Sample size was calculated using the
tables provided by Machin and Campbell[120]
using the equation d =|m0-m1|/population SD.
Hence it was estimated that 22 women would be
required to provide the study with 80% power to
detect a treatment difference corresponding to an
effect size of 0.63 (using a two-sided test with
a = 0.05). A similar randomized, controlled trial
that assessed the efficacy of soy isoflavones for
PMS screened 41 women which, following withdrawals, left 23 women completing the study.[114]
On this basis, it was estimated that at least 41
women should enter the screening phase to ensure the required sample size of 22.
Statistical Analysis

All data analysis was carried out according to a

pre-established analysis plan. The primary analysis
used to assess the effectiveness of Hypericum
perforatum for PMS compared the DSR data collected during Hypericum perforatum and placebo
treatment, during four cycle phases (menses, follicular, rest and luteal) of two treatment cycles. DSR
total scale scores were analysed using a univariate repeated measures analysis of variance (RM
ANOVA) model, while subscale scores were analysed using a doubly multivariate ANOVA model.
Prespecified secondary analyses were conducted on
the BPAQ, BIS-11, STAIS and BDI scores to examine whether a treatment effect operated on the
PMS symptoms aggression, impulsivity, anxiety
CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

and depression. The STAIS and BDI scales each

comprise one total scale score and therefore were
analysed in separate univariate analyses. The
BPAQ comprises four subscales and the BIS-11
three. Hence BPAQ and BIS-11 scores were analysed in separate multivariate analyses. The normality of the distribution of the variables studied
was assessed by consulting the Z scores for skewness and the Kolmogorov-Smirnov test for each
dependent variable (DSR, BPAQ, BIS-11, STAIS
and BDI total and subscale scores) at each timepoint. Transformations were not necessary for the
STAIS, BDI, BPAQ and BIS-11 data. However,
the majority of dependent variables constituting
the DSR were positively skewed. Hence, the DSR
total and subscale scores were transformed
through a square root transformation. Analysis of
the DSR data was based on the transformed
scores. However, the results interpreted and the
values presented in tables and figures are based on
untransformed data.
Results
Three hundred and seventy-one women expressed an interest in the study and completed the
preliminary screening questionnaire. Of these,
91 women began screening and 36 were randomized, of whom 34 completed the protocol. Figure 1
shows reasons for nonrandomization, premature
termination and exclusion. Two women were
considered placebo responders and excluded
from the analyses, as they no longer met the 30%
increase criterion during each of the two placebo
run-in cycles. This resulted in a similar percentage
of exclusions (6%) as has previously been reported.[87,121] All women who completed the trial
were of Northern European origin, with the
exception of one British-born Asian and one
Eastern European. Baseline demographic characteristics were examined using independent
samples t-tests and Pearsons chi-square tests,
according to the order in which participants
received active and placebo treatment. No significant differences or associations with treatment order were found between the treatment
groups for any characteristic, including age, body
mass index, number of years with PMS, nulli 2010 Adis Data Information BV. All rights reserved.

213

parity, employment, smoking and relationship

status (table I). Baseline symptom severity (table II)
was also examined according to the order in
which participants received active and placebo
treatment, through performing a 4 (phase) 2
(treatment order) doubly multivariate ANOVA
on the mean DSR subscale scores reported during the three screening cycles. A nonsignificant main effect of treatment order (multivariate
F [4, 27] = 1.10; p = 0.38) and a nonsignificant
phase by treatment order interaction (multivariate
F [12, 19] = 1.33; p = 0.28) were produced, indicating that randomization to treatment order did
not result in women with different profiles at
screening receiving different treatment orders.
Total Daily Symptom Report Scores

The mean standard error of the mean (SE)

DSR total scale scores reported during the four
phases of the two cycles of Hypericum perforatum
and placebo treatment are shown in figure 2. A 2
(treatment) 2 (cycle) 4 (phase) 2 (treatment
order) RM ANOVA was conducted on these
scores. This revealed a nonsignificant main effect
of treatment order (F [1, 30] = 0.96; p = 0.34).
There was a significant main effect of treatment
(F [1, 30] = 4.82; p = 0.04; partial Z2 = 0.14), such
that women reported significantly fewer symptoms during Hypericum perforatum (mean = 5.80)
than placebo (mean = 6.58) treatment. The treatment by cycle (F [1, 30] = 0.73; p = 0.40) and
treatment by phase (F [3, 90] = 1.16; p = 0.33) interactions were nonsignificant.
Daily Symptom Report Subgroup Scores

The mean SE DSR subscale scores reported

during the four phases of the two cycles of
Hypericum perforatum and placebo treatment are
shown in figures 3ad. A 2 (treatment) 2 (cycle) 4 (phase) 2 (treatment order) doubly
multivariate ANOVA was performed on these
scores. This revealed a nonsignificant main effect
of treatment order (multivariate F [4, 27] = 0.33;
p = 0.86). There was a nonsignificant main effect
of treatment for the linear combination of the
DSR subscales (multivariate F [4, 27] = 1.99;
p = 0.12) and nonsignificant treatment by cycle
CNS Drugs 2010; 24 (3)

Canning et al.

214

Failed initial screening

or unwilling to
continue (n = 280)

Responded to advertisements
and completed the online
questionnaire (n = 371)

Three screening cycles

(n = 91)

Two placebo run-in cycles

(n = 38)
Discontinuation (n = 2)
One due to indigestion
One moved away

Withdrew (n = 43)
Criteria no longer met (n = 10):
Follicular STAIS 51 (n = 3)
Follicular BDI 12 (n = 2)
Follicular STAIS 51 and
follicular BDI 12 (n = 3)
30% increase criterion not
met (n = 2)

Women randomized (n = 36)

Two cycles of
Hypericum
perforatum (n = 19)

Two cycles of
placebo
(n = 17)

One washout
cycle (n = 18)

One washout
cycle (n = 17)

Two cycles of
placebo
(n = 18)

Two cycles of
Hypericum
perforatum (n = 17)

Discontinuation
due to planning a
pregnancy (n = 1)

Removed from
trial due to
pregnancy (n = 1)
Completed trial
(n = 18)
Removed:
defined as a
placebo responder
(n = 1)

Included in
primary analysis
(n = 17)

Completed trial
(n = 16)

Included in
primary analysis
(n = 15)

Removed:
defined as a
placebo responder
(n = 1)

Fig. 1. Participant flow through the trial. BDI = Beck Depression Inventory; STAIS = State-Trait Anxiety Inventory, State scale.

(multivariate F [4, 27] = 1.27; p = 0.31) and treatment by phase (multivariate F [12, 19] = 0.66;
p = 0.77) interactions. Given the limited previous
research that has assessed the efficacy of Hypericum perforatum for PMS, it is reasonable to hypothesize that this herbal remedy may affect
specific components of PMS, masked by examination of only global scores. Hence, it was considered appropriate to explore the univariate tests
of the main effect of treatment and of the treatment by cycle and treatment by phase interactions for each subscale (table III).
2010 Adis Data Information BV. All rights reserved.

Significant univariate main effects of treatment

were produced for the behavioural (p = 0.032)
and physical (p = 0.013) DSR subscales, such that
women reported significantly fewer of these
symptoms while receiving Hypericum perforatum
than placebo treatment (figures 3b and 3d). The
treatment by cycle and treatment by phase interactions were nonsignificant for each of these
subscales (p > 0.05). Nonsignificant univariate
main effects of treatment were produced for the
mood and pain DSR subscales (p > 0.05). The
treatment by cycle and treatment by phase interCNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

215

Table I. Background characteristics of clinical trial completers

Characteristic

Total (n = 32)

Active first (n = 17)

Placebo first (n = 15)

Age in years [mean (SD)]

35.3 (5.9)

33.6 (6.5)

37.2 (4.6)

No. of PMS years [mean (SD)]

12.7 (7.5)

13.4 (7.1)

11.8 (8.1)

Body mass index [mean (SD)]

25.1 (4.3)

25.7 (5.0)

24.5 (3.5)

Nulliparous (no.)

11

Employed (no.)

26

12

14

single

partner

married/cohabiting

17

divorced/separated

Smoker (no.)
Relationship status (no.)

PMS = premenstrual syndrome.

actions were also nonsignificant for these subscales (p > 0.05).

Secondary Treatment Analyses

The mean (SD) STAIS, BDI, BPAQ and BIS11 total and subscale scores reported during the
four phases of the two cycles of Hypericum perforatum and placebo treatment are shown in
table IV. STAIS and BDI scores were examined
through 2 (treatment) 2 (cycle) 4 (phase) 2
(treatment order) RM ANOVAs. BPAQ and
BIS-11 scores were examined through 2 (treatment) 2 (cycle) 4 (phase) 2 (treatment order)
doubly multivariate ANOVAs. A nonsignificant
main effect of treatment, and nonsignificant
treatment by cycle and treatment by phase interactions, were produced from each of these analyses (all p > 0.05) [table V].

effect of treatment on these biochemical measures

was examined during the follicular and luteal
phases through conducting 2 (treatment) 2
(phase) RM ANOVAs for each hormone and
cytokine under analysis. A nonsignificant main
effect of treatment and a nonsignificant treatment by phase interaction was produced for
each hormone and cytokine that was analysed
(p > 0.05).
Adverse Events

Thirty-five adverse events were reported during the treatment cycles. Of these, 15 were reported during Hypericum perforatum therapy and
20 during placebo. The difference in the frequency of each type of adverse event reported
during the Hypericum perforatum and placebo
treatment cycles was nonsignificant (table VII).
Digestive and respiratory symptoms were the

Biochemical Measures

The hormone (estradiol, progesterone, testosterone, LH, FSH and prolactin) and cytokine
(IL-1b, IL-6, IL-8, IFNg and TNFa) levels measured during the follicular and luteal phases
of Hypericum perforatum and placebo treatment
are shown in table VI. Paired samples t-tests
revealed that there were no significant differences
between the follicular (t [26] = 0.21; p = 0.84)
nor luteal (t [17] = 1.57; p = 0.14) cycle days on
which blood was sampled during Hypericum
perforatum and placebo treatment. Therefore, the
2010 Adis Data Information BV. All rights reserved.

Table II. Baseline symptom severity [mean (SD)], across the menstrual cycle (Daily Symptom Report [DSR][70] total and subscale
scores) of clinical trial completers (n = 32)
Measure
Total DSR score

Phase
menstrual

follicular

rest

luteal

11.4 (7.1)

3.4 (2.5)

4.3 (2.6)

12.6 (7.2)

Subscale scores
mood

4.5 (3.6)

1.6 (1.4)

2.0 (1.4)

5.4 (3.7)

behavioural

3.5 (2.6)

1.4 (1.0)

1.4 (0.9)

3.4 (2.3)

pain

2.1 (1.1)

0.2 (0.2)

0.4 (0.3)

1.9 (1.3)

physical

1.3 (0.8)

0.2 (0.2)

0.5 (0.3)

1.8 (1.0)

CNS Drugs 2010; 24 (3)

Canning et al.

216

Mean total DSR score

Hypericum perforatum
Placebo
12
11
10
9
8
7
6
5
4
3
2
M

F
R
Cycle 1

F
R
Cycle 2

Fig. 2. Mean total Daily Symptom Report (DSR) score is the sum of
severity ratings for each of the 17 DSR symptoms within each phase
divided by the number of days in that phase. F = follicular; L = luteal;
M = menses; R = rest.

most common adverse events, but these were almost equally distributed between the Hypericum
perforatum and placebo treatment cycles. One
serious adverse event occurred during Hypericum
perforatum treatment (chest pains) but this was
believed to be unrelated to Hypericum perforatum,
since a cause other than the administration of
Hypericum perforatum was evident.

Discussion
Principal Findings

The primary objective of this ten-cycle, doubleblind, randomized, controlled trial was to determine whether Hypericum perforatum was more
beneficial than placebo treatment in relieving
PMS symptoms in women experiencing mild
PMS. Hypericum perforatum was shown to benefit physical (food craving, swelling) and behavioural (poor coordination, insomnia, confusion,
headaches, crying, fatigue) PMS symptoms in
comparison with placebo treatment during
both menstrual cycles in which it was taken.
These beneficial effects occurred with minimal
adverse effects, which did not statistically differ
from those experienced during placebo treatment. Mood-related (anxiety, irritability, depression, nervous tension, mood swing, feeling
2010 Adis Data Information BV. All rights reserved.

out of control) and pain-related (aches, cramps,

breast tenderness) PMS symptoms were not significantly relieved by Hypericum perforatum in
comparison with placebo during two cycles of
treatment. However, pain-related symptoms appeared to improve with Hypericum perforatum in
comparison with placebo towards the end of the
treatment period (figure 3c). It is therefore possible that Hypericum perforatum may benefit pain
symptoms after longer treatment duration than
in the current study. Although the separation
between the mood-related symptoms that were
reported during Hypericum perforatum and placebo treatment was less than that for the other
symptom subgroups, a similar pattern emerged,
with women reporting fewer of these symptoms
during Hypericum perforatum than placebo
treatment towards the end of the treatment period (figure 3a). Future studies should determine
whether longer treatment duration could increase
the potential effect suggested. The secondary
analyses revealed that Hypericum perforatum did
not benefit the PMS symptoms of anxiety, depression, aggression or impulsivity. However, as
these are all mood-related PMS symptoms,
longer treatment duration could be necessary for
such benefits to become apparent.
Aetiology

Biopsychosocial models of PMS posit that

symptoms arise from a complex interaction between various biological, psychological and
social factors.[29-33] This proposed multifactorial
aetiology is supported by the finding that
Hypericum perforatum significantly reduced physical and behavioural but not pain- or mood-related
PMS symptoms. Research has demonstrated
Hypericum perforatum to effectively reduce mild
to moderate depression.[81-84] However, in this
study Hypericum perforatum did not significantly
improve premenstrual depression or other moodrelated PMS symptoms. This lack of effect of
Hypericum perforatum on mood symptoms raises
the possibility that PMS-related mood symptoms
have a different aetiology from those seen in clinical depression. The physiological basis of depressive symptoms is well established,[49,122-124] while
CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

217

Mean subscale score/no. of items

comprising subscale (n = 6)

Mean subscale score/no. of items

comprising subscale (n = 6)

a
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
M

F
R
Cycle 1

F
R
Cycle 2

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
M

Cycle 1

Cycle 2

0.9

Mean subscale score/no. of items

comprising subscale (n = 2)

Mean subscale score/no. of items

comprising subscale (n = 3)

Hypericum perforatum
Placebo

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
M

F
R
Cycle 1

F
R
Cycle 2

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
M

F
R
Cycle 1

F
R
Cycle 2

Fig. 3. Effect of treatment during each treatment cycle on: (a) mood symptoms; (b) behavioural symptoms; (c) pain symptoms; and
(d) physical symptoms as assessed by subscales of the Daily Symptom Report. Mean subscale score = sum of the severity ratings on each
item within the subscale for each day in the phase divided by the number of days in the phase and the number of items comprising that
subscale. F = follicular; L = luteal; M = menses; R = rest.

mood-related PMS symptoms may be psychosocial in origin. If this is the case, then this would
explain why Hypericum perforatum did not significantly reduce PMS mood symptoms but is
effective in other types of depression.

Various biological factors have been proposed

to contribute to PMS symptom production.[34-40]
Increasing evidence suggests that serotonin plays
an important role.[23,41,42] SSRIs have been shown
to effectively reduce psychological and physical

Table III. Multivariate and univariate statistics for the main effect of treatment, and for the treatment by cycle and treatment by phase
interactions for the treatment analysis of the Daily Symptom Report subscales
Measure
Multivariate

Treatment

Treatment by cycle

Treatment by phase

statistic

partial Z2

statistic

partial Z2

statistic

partial Z2

F (4, 27) = 1.99

0.23

F (4, 27) = 1.27

0.16

F (12, 19) = 0.66

0.29
0.04

Univariate
mood

F (1, 30) = 2.33

0.07

F (1, 30) = 1.17

0.04

F (3, 90) = 1.18

behavioural

F (1, 30) = 5.07*

0.15

F (1, 30) = 0.75

0.02

F (3, 90) = 0.66

0.02

pain

F (1, 30) = 0.20

0.01

F (1, 30) = 1.12

0.04

F (3, 90) = 1.16

0.04

physical

F (1, 30) = 7.00*

0.19

F (1, 30) = 0.15

0.01

F (3, 90) = 0.90

0.03

* p < 0.05.

2010 Adis Data Information BV. All rights reserved.

CNS Drugs 2010; 24 (3)

Canning et al.

218

Table IV. Secondary outcome symptom scores across four phases of Hypericum perforatum and placebo treatment [mean (SD)]
Measure

Hypericum perforatum

Placebo

40.6 (12.0)

36.7 (10.6)

38.3 (10.4)

45.2 (11.8)

41.4 (12.1)

36.6 (9.7)

40.0 (9.7)

45.6 (12.4)

6.8 (7.1)

5.3 (5.5)

6.0 (5.5)

8.9 (5.5)

8.4 (7.7)

4.7 (7.7)

7.6 (6.4)

10.5 (8.6)

total

57.0 (21.2)

51.9 (17.2)

53.1 (16.1)

61.8 (19.3)

59.0 (19.8)

50.9 (19.8)

54.8 (15.2)

63.4 (21.5)

verbal

10.7 (4.9)

9.0 (3.4)

9.4 (3.2)

12.2 (4.7)

10.9 (4.9)

9.1 (4.0)

9.9 (3.8)

12.2 (5.0)

STAIS
BDI

BPAQ

physical

15.0 (5.2)

14.4 (5.1)

14.3 (4.6)

15.2 (5.5)

15.1 (5.2)

13.4 (4.4)

14.7 (5.0)

15.9 (6.0)

anger

16.6 (6.7)

15.0 (5.5)

15.5 (4.9)

19.0 (6.2)

17.2 (6.2)

14.7 (5.3)

15.9 (4.3)

19.3 (6.4)

hostility

14.8 (6.3)

13.6 (5.4)

14.0 (5.9)

15.3 (6.3)

15.8 (6.8)

13.6 (5.5)

14.4 (5.9)

16.0 (7.6)

total

60.7 (10.0)

58.2 (9.1)

60.2 (8.6)

63.5 (7.7)

62.1 (10.4)

58.1 (8.6)

60.3 (9.7)

64.8 (9.7)

attentional

13.9 (3.7)

13.1 (2.9)

13.5 (2.7)

14.7 (3.5)

14.5 (3.9)

12.7 (2.8)

13.4 (3.5)

14.9 (3.5)

motor

19.6 (2.3)

19.2 (2.6)

19.8 (2.7)

19.7 (2.2)

19.9 (2.9)

19.6 (2.4)

19.7 (2.9)

20.5 (3.4)

non-planning

27.2 (6.1)

25.9 (5.6)

27.0 (5.6)

29.1 (4.7)

27.7 (6.2)

25.8 (5.6)

27.2 (5.5)

29.5 (5.4)

BIS-11

BDI = Beck Depression Inventory[68]; BIS-11 = Barratt Impulsiveness Scale version 11[72]; BPAQ = Aggression Questionnaire[71]; F = follicular;
L = luteal; M = menses; R = rest; STAIS = State-Trait Anxiety Inventory, State scale.[106]

PMS symptoms within a few days.[5,18,23,101,125]

Hypericum perforatum increases brain serotonin
levels[76] and yields an upregulation of serotonin
5-HT1A and 5-HT2A receptors[78] in the frontal
cortex.[77] Hence, the rapid beneficial effects of
Hypericum perforatum on the physical and behavioural PMS symptoms observed here may
have arisen from an increase in serotonin production, biomarkers of which should be assessed
in future evaluations of Hypericum perforatum.
Increased production of proinflammatory cytokines may also be involved in PMS symptom
production. Cytokines, which have been associated with symptoms characteristic of PMS,[64-70]
have been shown to increase during the luteal
phase.[61-63] Hypericum perforatum suppresses
proinflammatory cytokine production.[79,80] In
theory, it is plausible to suggest that Hypericum
perforatum may benefit PMS symptoms by reducing proinflammatory cytokine levels during
the luteal phase. The beneficial effects of Hypericum perforatum found in this study did not
appear to operate through this mechanism of
action, as Hypericum perforatum did not affect
luteal cytokine levels in comparison with placebo
treatment. However, any demonstration of this
mechanism must rely on peripheral measures,
which do not necessarily reflect central changes
2010 Adis Data Information BV. All rights reserved.

and cytokine action. Moreover, although this

research suggests that individual cytokines do not
play a major role in the beneficial effects of
Hypericum perforatum on physical and behavioural PMS symptoms, further analysis of cytokine networks might reveal relevant interactions.
The beneficial properties of Hypericum perforatum may arise from a combination of mechanisms, each singularly too weak to result in a
therapeutic effect.[90,126,127] Hypericum perforatum could benefit some PMS symptoms through
producing an effect on the interaction between
the cytokine and serotonergic systems, in a similar manner to that suggested for the aetiology of
depression.[52,72] Therefore, the sole assessment
of the influence of Hypericum perforatum on
proinflammatory cytokine levels may not be enlightening. Effects may only become apparent
when these levels are assessed in conjunction with
effects on other systems, such as the serotonergic
system. To elucidate the mechanism of action
through which Hypericum perforatum produces
its beneficial effects, further studies assessing the
efficacy of Hypericum perforatum for PMS are
needed, while assessing its impact upon serotonergic transmission in combination with proinflammatory cytokine production. Furthermore,
future studies could utilize qualitative measures
CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

219

to assess womens experiences during Hypericum

perforatum and placebo treatment, to further
understanding of how psychological and social
factors (e.g. life circumstances, relationships and
coping mechanisms) could contribute to PMS
symptoms and their response to treatment. These
measures could also provide insight into the lack
of effect of Hypericum perforatum on moodrelated PMS symptoms if these remained unchanged after a longer treatment duration.[8,14,32]
Previous Research

Few trials have assessed the effectiveness of

Hypericum perforatum for PMS. When this protocol was written, only one small pilot study had
been published.[118] Although these researchers
found Hypericum perforatum to significantly reduce PMS symptoms, their study did not employ
a placebo group or crossover design. Therefore,
their treatment effects cannot be separated from
those arising from the placebo response. Since the
commencement of this study, three randomized,
double-blind, placebo-controlled trials employing a parallel design have been published.[86,88,89]
Hicks et al.[86] found that women treated with
Hypericum perforatum reported fewer symptoms
than those receiving placebo on all symptom
subgroups studied. However, these differences
did not reach statistical significance. As a dosage
of 600 mg/day was used, it is possible that a
higher dosage of 900 mg/day is needed for the
beneficial effects of Hypericum perforatum to be-

come apparent. The findings from the current

study appear compatible to those of Pakgohar
et al.,[88,89] who also found Hypericum perforatum
to reduce physical PMS symptoms.
Limitations

The diagnosis of PMS requires that symptoms

are confined to the luteal phase.[1,97] Many
women who present with PMS are found not to have
the syndrome, but rather a premenstrual exacerbation of a psychiatric disorder, most commonly
anxiety and/or depression.[1,5,99,101] Hence,
women reporting clinical levels of anxiety and/or
depression during the follicular phase were excluded from this trial. However, it is possible that
some participants in this study did not have PMS,
but a psychiatric condition that was not directly
assessed, such as bulimia nervosa, substance abuse
or seasonal affective disorder.[1,99,128,129] Although
this is unlikely, since a physician-led clinical
interview indicated that all participants were
in good psychological health before they were
entered into the trial, future studies could formally verify this information through the administration of a structured clinical interview
such as the Structured Clinical Interview for
DSM-IV.[130]
Trial participants were provided with diary
booklets containing seven DSRs on a weekly
basis. In order to minimize the possibility of retrospective reporting and women inferring patterns in their symptom reporting, each DSR was

Table V. Multivariate and univariate statistics for the main effect of treatment and for the treatment by cycle and treatment by phase
interactions for the secondary treatment analyses
Measure

Treatment
statistic

Treatment by cycle
partial Z2

Treatment by phase

statistic

partial Z2

statistic

partial Z2

BPAQ
total (UV)

F (1, 30) = 0.45

0.01

F (1, 30) = 0.07

<0.01

F (3, 90) = 0.42

0.01

subscales (MV)

F (4, 27) = 0.31

0.04

F (4, 27) = 1.03

0.13

F (12, 19) = 1.09

0.41

BIS-11
total (UV)

F (1, 30) = 0.89

0.03

F (1, 30) = 0.02

<0.01

F (3, 90) = 0.59

0.02

subscales (MV)

F (3, 28) = 0.44

0.05

F (3, 28) = 0.76

0.08

F (9, 22) = 0.98

0.29

STAIS (UV)

F (1, 30) = 0.32

0.01

F (1, 30) = 1.14

0.04

F (3, 90) = 0.26

0.01

BDI (UV)

F (1, 30) = 2.13

0.07

F (1, 30) = 0.12

<0.01

F (3, 90) = 1.22

0.04

BDI = Beck Depression Inventory[68]; BIS-11 = Barratt Impulsiveness Scale version 11[72]; BPAQ = Aggression Questionnaire[71]; MV = multivariate; STAIS = State-Trait Anxiety Inventory, State scale[106]; UV = univariate.

2010 Adis Data Information BV. All rights reserved.

CNS Drugs 2010; 24 (3)

Canning et al.

220

Table VI. Serum hormone and cytokine levels [mean (SD)] during the follicular and luteal phases of Hypericum perforatum and placebo
treatment (n = 12)
Hypericum perforatum
follicular

Placebo
luteal

follicular

luteal

Hormones
Estradiol (pmol/L)

231.8 (179.5)

443.6 (443.7)

311.0 (559.4)

213.6 (113.5)

Progesterone (nmol/L)

5.3 (5.7)

44.3 (50.9)

3.7 (5.2)

18.5 (7.6)

Testosterone (nmol/L)

2.2 (3.4)

3.4 (5.6)

1.1 (2.6)

0.7 (1.1)

LH (mIU/mL)

4.3 (2.5)

4.1 (5.1)

5.0 (3.4)

3.1 (2.3)

FSH (mIU/mL)

5.4 (2.5)

3.3 (3.1)

5.8 (2.2)

3.0 (1.5)

Prolactin (mIU/L)

296.9 (176.3)

321.0 (206.7)

329.7 (190.1)

373.2 (208.9)

IL-1b (pg/mL)

54.9 (80.8)

43.9 (59.5)

52.0 (67.9)

53.1 (70.7)

IL-6 (pg/mL)

393.4 (860.7)

368.4 (784.8)

332.6 (732.4)

373.5 (807.9)

IL-8 (pg/mL)

708.2 (1818.6)

638.8 (1637.8)

610.9 (1606.5)

609.0 (1642.3)

IFNg (pg/mL)

53.0 (46.2)

43.7 (50.9)

51.8 (39.5)

39.2 (31.4)

TNFa (pg/mL)

116.4 (199.6)

106.6 (191.9)

107.6 (181.8)

96.3 (167.7)

Cytokines

FSH = follicle-stimulating hormone; IFN = interferon; IL = interleukin; LH = luteinizing hormone; TNF = tumour necrosis factor.

presented on a separate page. Furthermore,

women were explicitly informed that they were to
complete one DSR each evening, date it, and return each booklet immediately after its completion. However, as each booklet contained seven
DSRs, it is possible that some women may not
have completed their daily ratings in a fully prospective manner. Moreover, some ratings may
have been biased by women looking at previous
DSR completions from that week. Although
some researchers ask women to return their ratings daily,[131] it was thought that applying this
method of data collection to a study of this length
would have led to greater study burden, a higher
attrition rate, and a larger amount of missing
data. Future studies could ask women to complete their ratings on the Internet at the end of
each day, with no access to previous reports.
Implications for Clinicians

These results support the use of Hypericum perforatum (900 mg/day) for women with mild PMS
who are experiencing symptoms predominantly
physical and behavioural in nature. In line with
previous studies that have assessed the effectiveness of OTC preparations for PMS,[86,114,121,132-136]
this research utilized PMS diagnostic criteria that
identified PMS sufferers experiencing symptoms at
2010 Adis Data Information BV. All rights reserved.

a mild severity. For example, the researchers who

developed the DSR used the 30% increase criterion
to diagnose PMS in their treatment trial of the
carbohydrate-rich beverage Escape.[133] The women
identified as PMS sufferers in this research reported
premenstrual symptoms at an almost identical

Table VII. Adverse events reported as number per group during

Hypericum perforatum and placebo treatment
Adverse event

Placebo
(n = 20)

Hypericum
perforatum
(n = 15)

Digestive (stomach cramps,

abdominal pain, nausea, diarrhoea,
dizziness)

Vasomotor (hot flushes, increased

sweating)

Respiratory (cold, sinus ache, sore

throat, swollen glands, viral infection,
laryngitis)

Other
headache/migraine

skin rash

spots

leg/back ache

vaginal discharge

menstrual flooding

forgetfulness

chest pains

CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

severity (mean premenstrual total DSR score

14.70, SD 8.36) to that previously reported by
British women with mild PMS (mean 13.40, SD
9.70),[114] and at a much lower severity than that
previously reported by women experiencing severe PMS (mean 23.00, SD 12.5),[137] and PMDD
(mean 30.17, SD 9.67) in US studies.[138] This
approach was considered appropriate in this research, as it is usually women with mild PMS
symptoms who buy,[133] and who are advised by
their clinicians to take,[5,19] OTC preparations.
PMS sufferers experiencing symptoms at a
greater severity are usually prescribed conventional treatment.[5,17,18] Many women with mild to
moderate premenstrual symptoms who believe
they experience PMS do not meet strict PMS diagnostic criteria (e.g. 75% increase criterion;
modified 30% increase criterion).[13,14] However,
the 30% increase criterion has been shown to
identify the majority of women who perceive
themselves to experience PMS.[13] These women
with mild PMS are most likely to buy OTC preparations to relieve symptoms they attribute to
their premenstrual phase. Stricter diagnostic criteria could have excluded these women, for
whom an evaluation of the efficacy of Hypericum
perforatum to relieve premenstrual symptoms is
most pertinent. The 30% increase criterion used
as the PMS diagnostic method in this research
does render the findings applicable only to PMS
sufferers experiencing PMS symptoms at a mild
severity. Future research is needed if researchers
wish to generalize these findings to PMS sufferers experiencing PMS symptoms at a greater
severity.
Conclusions
Daily Hypericum perforatum treatment at a
dosage of 900 mg/day significantly improved
physical and behavioural premenstrual symptoms in women experiencing mild PMS. These
beneficial effects became apparent during the first
menstrual cycle in which Hypericum perforatum
was taken, and occurred with minimal adverse
effects. The plasma hormone and cytokine analyses suggested that biochemical changes within
these systems were probably not involved in these
2010 Adis Data Information BV. All rights reserved.

221

beneficial effects, although their involvement via

interaction with the serotonergic system is a
possibly interesting avenue for future investigation. Although Hypericum perforatum did not
prove statistically superior to placebo for moodand pain-related PMS symptoms, pain-related
symptoms appeared to abate by the luteal phase
of the second treatment cycle. Future research is
needed to assess the effectiveness of Hypericum
perforatum over longer treatment durations in
order to be able to recommend its use for sufferers of PMS who find these symptoms problematic. Moreover, further studies incorporating
psychosocial measures are required to determine
whether mood-related PMS symptoms would
benefit from longer treatment duration. The
convincing results for Hypericum perforatum that
were found in this trial deserve independent
confirmation by other studies.
Acknowledgements
Thanks are due to Lichtwer Pharma AG (Berlin, Germany)
for the donation of the supplements and the Rosalind Bolton
Bequest for funding the PhD studentship of the corresponding
author. The Rosalind Bolton Bequest played no role in the
production or submission of this manuscript. Thanks are also
due to Biss Hartley for assisting Dr Julie Ayres with clinical
interviews and to Uma Ekbote and Sarah Field for technical
assistance.
No other sources of funding were used to assist in the
preparation of this study. The authors have no conflicts of
interest that are directly relevant to the content of this study.
Authors contributions: SC, LD, MW and NS designed the
study and interpreted the data. SC collected the data. SC and
LD analysed the data. SC wrote the paper. LD, MW, NS and
NO made suggestions for revisions. NO supervised the hormone and cytokine assays. JA undertook clinical interviews
with each participant. JA and NS were the physicians responsible for the study.

References
1. Freeman EW. Premenstrual syndrome and premenstrual
dysphoric disorder: definitions and diagnosis. Psychoneuroendocrinology 2003 Aug; 28 Suppl. 3: 25-37
2. Halbreich U, Backstrom T, Eriksson E, et al. Clinical
diagnostic criteria for premenstrual syndrome and guidelines for their quantification for research studies. Gynecol
Endocrinol 2007 Mar; 23 (3): 123-30
3. Reed SC, Levin FR, Evans SM. Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and

CNS Drugs 2010; 24 (3)

Canning et al.

222

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

without PMDD (premenstrual dysphoric disorder). Horm

Behav 2008 Jun; 54 (1): 185-93
Borenstein JE, Dean BB, Yonkers KA, et al. Using the
daily record of severity of problems as a screening instrument for premenstrual syndrome. Obstet Gynecol
2007 May; 109 (5): 1068-75
Johnson SR. Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: a clinical primer for practitioners. Obstet Gynecol 2004 Oct; 104 (4): 845-59
Diagnostic and Statistical Manual of Mental Disorders.
4th ed. Washington, DC: American Psychiatric Association; Department of Health and Human Services, 1994
Steiner M, Wilkins A. Diagnosis and assessment of premenstrual dysphoria. Psychiatr Ann 1996 Sep; 26 (9):
571-5
Ussher JM. Processes of appraisal and coping in the development and maintenance of premenstrual dysphoric
disorder. J Community Appl Soc Psychol 2002 Sep-Oct;
12 (5): 309-22
Steiner M, Born L. Advances in the diagnosis and treatment of premenstrual dysphoric disorder. CNS Drugs
2000 Apr; 13 (4): 287-304
Steiner M, Pearlstein T. Premenstrual dysphoria and the
serotonin system: pathophysiology and treatment. J Clin
Psychiatry 2000; 61 Suppl. 12: 17-21
Ussher JM. The ongoing silencing of women in families: an
analysis and rethinking of premenstrual syndrome and
therapy. J Fam Ther 2003 Nov; 25 (4): 388-405
Ainscough CE. Premenstrual emotional changes: a prospective study of symptomatology in normal women.
J Psychosom Res 1990; 34 (1): 35-45
Gallant SJ, Popiel DA, Hoffman DM, et al. Using daily
ratings to confirm premenstrual syndrome/late luteal
phase dysphoric disorder: part II. What makes a real
difference? Psychosom Med 1992 Mar-Apr; 54 (2): 167-81
Ussher JM. The role of premenstrual dysphoric disorder in
the subjectification of women. J Med Humanit 2003 Jun;
24 (1-2): 131-46
Bancroft J, Williamson L, Warner P, et al. Perimenstrual
complaints in women complaining of PMS, menorrhagia,
and dysmenorrhea: toward a dismantling of the premenstrual syndrome. Psychosom Med 1993 Mar-Apr; 55
(2): 133-45
Morse CA, Dennerstein L, Varnavides K, et al. Menstrual
cycle symptoms: comparison of a non-clinical sample
with a patient group. J Affect Disord 1988 Jan-Feb; 14 (1):
41-50
Dimmock PW, Wyatt KM, Jones PW, et al. Efficacy of
selective serotonin-reuptake inhibitors in premenstrual
syndrome: a systematic review. Lancet 2000 Sep; 356
(9236): 1131-6
Wyatt KM, Dimmock PW, OBrien PM. Selective serotonin reuptake inhibitors for premenstrual syndrome.
Cochrane Database Syst Rev 2002; (4): CD001396
Connolly M. Premenstrual syndrome: an update on definitions, diagnosis and management. Adv Psychiatr Treat
2001; 7 (6): 469-77
Bendich A. The potential for dietary supplements to reduce
premenstrual syndrome (PMS) symptoms. J Am Coll
Nutr 2000 Feb; 19 (1): 3-12

2010 Adis Data Information BV. All rights reserved.

21. Canning S, Waterman M, Dye L. Dietary supplements

and herbal remedies for premenstrual syndrome (PMS):
a systematic research review of the evidence for their efficacy. J Reprod Infant Psychol 2006 Nov; 24 (4): 363-78
22. Domoney CL, Vashisht A, Studd JW. Premenstrual syndrome and the use of alternative therapies. Ann N Y Acad
Sci 2003 Nov; 997: 330-40
23. Eriksson E, Endicott J, Andersch B. New perspectives on
the treatment of premenstrual syndrome and premenstrual
dysphoric disorder. Arch Womens Ment Health 2002;
4 (4): 111-9
24. Blake F, Salkovskis P, Gath D, et al. Cognitive therapy for
premenstrual syndrome: a controlled trial. J Psychosom
Res 1998 Oct; 45 (4): 307-18
25. Hunter M, Ussher J, Cariss M, et al. A randomised comparison of psychological (cognitive behaviour therapy),
medical (fluoxetine) and combined treatment for women
with premenstrual dysphoric disorder. J Psychosom Obstet Gynaecol 2002 Sep; 23: 193-9
26. Kirkby RJ. Changes in premenstrual symptoms and irrational thinking following cognitive-behavioral coping
skills training. J Consult Clin Psychol 1994 Oct; 62 (5):
1026-32
27. Morse CA, Dennerstein L, Farrell E, et al. A comparison of
hormone therapy, coping skills training, and relaxation
for the relief of premenstrual syndrome. J Behav Med
1991 Oct; 14 (5): 469-89
28. Goodale IL, Domar AD, Benson H. Alleviation of premenstrual syndrome symptoms with the relaxation response. Obstet Gynecol 1990 Apr; 74 (4): 649-55
29. Anson O. Exploring the bio-psycho-social approach to
premenstrual experiences. Soc Sci Med 1999 Jul; 49 (1):
67-80
30. Keye Jr WR, Trunnell EP. A biopsychosocial model of
premenstrual syndrome. Int J Fertil 1986 Sep-Oct; 31 (4):
259-62
31. Rubinow DR, Schmidt PJ. Models for the development
and expression of symptoms in premenstrual syndrome.
Psychiatr Clin North Am 1989 Mar; 12 (1): 53-68
32. Ussher JM, Hunter M, Cariss M. A women-centred
psychological intervention for premenstrual symptoms,
drawing on cognitive-behavioural and narrative therapy.
Clin Psychol Psychother 2002; 9 (5): 319-31
33. Walker AF. Theory and methodology in premenstrual
syndrome research. Soc Sci Med 1995 Sep; 41 (6): 793-800
34. Backstrom T, Carstensen H. Estrogen and progesterone in
plasma in relation to premenstrual tension. J Steroid
Biochem 1974 May; 5 (3): 257-60
35. Horrobin DF. The role of essential fatty acids and prostaglandins in the premenstrual syndrome. J Reprod Med
1983 Jul; 28 (7): 465-8
36. Shamberger RJ. Calcium, magnesium, and other elements
in the red blood cells and hair of normals and patients
with premenstrual syndrome. Biol Trace Elem Res 2003
Aug; 94 (2): 123-9
37. Thys-Jacobs S, Alvir MJ. Calcium-regulating hormones
across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol
Metab 1995 Jul; 80 (7): 2227-32

CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

38. Abraham GE, Lubran MM. Serum and red cell magnesium
levels in patients with premenstrual tension. Am J Clin
Nutr 1981 Nov; 34 (11): 2364-6
39. Brush MG, Watson SJ, Horrobin DF, et al. Abnormal
essential fatty acid levels in plasma of women with premenstrual syndrome. Am J Obstet Gynecol 1984 Oct; 150
(4): 363-6
40. Carroll BJ, Steiner M. The psychobiology of premenstrual
dysphoria: the role of prolactin. Psychoneuroendocrinology 1978 Apr; 3 (2): 171-80
41. Halbreich U. Premenstrual dysphoric disorders: a diversified cluster of vulnerability traits to depression. Acta
Psychiatr Scand 1997 Mar; 95 (3): 169-76
42. Rapkin AJ. The role of serotonin in premenstrual syndrome. Clin Obstet Gynecol 1992 Sep; 35 (3): 629-36
43. Ashby CR, Carr LA, Cook CL, et al. Alteration of platelet
serotonergic mechanisms and monoamine oxidase activity on premenstrual syndrome. Biol Psychiatry 1988 Jun;
24 (2): 225-33
44. Rapkin AJ, Edelmuth E, Chang LC, et al. Whole-blood
serotonin in premenstrual syndrome. Obstet Gynecol
1987 Oct; 70 (4): 533-7
45. Rasgon N, McGuire M, Tanavoli S, et al. Neuroendocrine
response to an intravenous L-tryptophan challenge in
women with premenstrual syndrome. Fertil Steril 2000
Jan; 73 (1): 144-9
46. Taylor DL, Mathew RJ, Ho BT, et al. Serotonin levels and
platelet uptake during premenstrual tension. Neuropsychobiology 1984; 12 (1): 16-8
47. Cleare AJ, Bond AJ. The effects of tryptophan depletion
and enhancement on subjective and behavioural aggression in normal subjects. Psychopharmacology 1995 Mar;
118 (1): 72-81
48. Ho HP, Olsson M, Westberg L, et al. The serotonin
reuptake inhibitor fluoxetine reduces sex steroid-related
aggression in female rats: an animal model of premenstrual
irritability? Neuropsychopharmacology 2001 May; 24 (5):
502-10
49. Hirschfeld RM. History and evolution of the monoamine
hypothesis of depression. J Clin Psychiatry 2000; 61
Suppl. 6: 4-6
50. Kahn RS, van Praag HM, Wetzler S, et al. Serotonin and
anxiety revisited. Biol Psychiatry 1988 Jan; 23 (2): 189-208
51. Russo S, Kema IP, Haagsma EB, et al. Irritability rather
than depression during interferon treatment is linked to
increased tryptophan catabolism. Psychosom Med 2005
Sep-Oct; 67 (5): 773-7
52. Bonaccorso S, Marino V, Puzella A, et al. Increased depressive ratings in patients with hepatitis C receiving
interferon-alpha-based immunotherapy are related to
interferon-alpha-induced changes in the serotonergic
system. J Clin Psychopharmacol 2002 Feb; 22 (1): 86-90
53. Gemma C, Imeri L, De Simoni MG, et al. Interleukin-1
induces changes in sleep, brain temperature, and serotonergic metabolism. Am J Physiol 1997 Feb; 272 (2 Pt 2):
R601-6
54. Gemma C, Imeri L, Opp MR. Serotonergic activation stimulates the pituitary-adrenal axis and alters interleukin-1
(IL-1) mRNA expression in rat brain. Psychoneuroendocrinology 2003 Oct; 28 (7): 875-84

2010 Adis Data Information BV. All rights reserved.

223

55. Linthorst AC, Flachskamm C, Holsboer F, et al. Local

administration of recombinant human interleukin-1 beta
in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis
activity, and body temperature. Endocrinology 1994 Aug;
135 (2): 520-32
56. OBrien SM, Scott LV, Dinan TG. Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 2004 Aug; 19
(6): 397-403
57. Pousset F, Fournier J, Legoux P, et al. Effect of serotonin
on cytokine mRNA expression in rat hippocampal
astrocytes. Brain Res Mol Brain Res 1996 May; 38 (1): 54-62
58. Silverman DH, Imam K, Karnovsky ML. Muramyl peptide/
serotonin receptors in brain-derived preparations. Pept
Res 1989 Sep-Oct; 2 (5): 338-44
59. Gorai I, Taguchi Y, Chaki O, et al. Serum soluble interleukin-6 receptor and biochemical markers of bone metabolism show significant variations during the menstrual
cycle. J Clin Endocrinol Metab 1998 Feb; 83 (2): 326-32
60. Vrieze A, Postma DS, Kerstjens HA. Perimenstrual asthma: a syndrome without known cause or cure. J Allergy
Clin Immunol 2003 Aug; 112 (2): 271-82
61. Cannon JG, Dinarello CA. Increased plasma interleukin-1
activity in women after ovulation. Science 1985 Mar; 227
(4691): 1247-9
62. Polan ML, Kuo A, Loukides J, et al. Cultured human luteal
peripheral monocytes secrete increased levels of interleukin-1. J Clin Endocrinol Metab 1990 Feb; 70 (2): 480-4
63. Konecna L, Yan MS, Miller LE, et al. Modulation of IL-6
production during the menstrual cycle in vivo and in vitro.
Brain Behav Immun 2000 Mar; 14 (1): 49-61
64. Maes M, Meltzer H, Bosmans E, et al. Increased plasma
concentrations of interleukin-6, soluble interleukin-6 receptor, soluble interleukin-2 receptor and transferrin receptor in major depression. J Affect Disord 1995 Aug; 34
(4): 301-9
65. Schlatter J, Ortuno F, Cervera-Enguix S. Differences in
interleukins patterns between dysthymia and major depression. Eur Psychiatry 2001 Aug; 16 (5): 317-9
66. Connor TJ, Song C, Leonard BE, et al. An assessment of
the effects of central interleukin-1beta, -2, -6, and tumor
necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in
the rat. Neuroscience 1998 Jun; 84 (3): 923-33
67. Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000
May; 157 (5): 683-94
68. Martelletti P, Granata M, Giacovazzo M. Serum interleukin-1 beta is increased in cluster headache. Cephalalgia
1993 Oct; 13 (5): 343-5
69. Kapas L, Krueger JM. Tumor necrosis factor-beta induces
sleep, fever, and anorexia. Am J Physiol Regul Integr
Comp Physiol 1992 Sep; 263 (3 Pt 2): 703-7
70. Vgontzas AN, Bixler EO, Lin HM, et al. IL-6 and its circadian secretion in humans. Neuroimmunomodulation
2005 May; 12 (3): 131-40
71. Reichenberg A, Yirmiya R, Schuld A, et al. Cytokineassociated emotional and cognitive disturbances in humans.
Arch Gen Psychiatry 2001 May; 58 (5): 445-52

CNS Drugs 2010; 24 (3)

224

72. Menkes DB, MacDonald JA. Interferons, serotonin and

neurotoxicity. Psychol Med 2000 Mar; 30 (2): 259-68
73. Maes M. The immunoregulatory effects of antidepressants.
Hum Psychopharmacol 2001 Jan; 16 (1): 95-103
74. Sluzewska A, Rybakowski JK, Laciak M, et al. Interleukin-6 serum levels in depressed patients before and
after treatment with fluoxetine. Ann N Y Acad Sci 1995
Jul; 762: 474-6
75. Van Gool AR, Fekkes D, Kruit WH, et al. Serum amino
acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients. Psychiatry Res 2003 Jul; 119 (1-2): 125-32
76. Calapai G, Crupi A, Firenzuoli F, et al. Serotonin,
norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum. Pharmacopsychiatry 2001 Mar; 34 (2): 45-9
77. Muller WE, Singer A, Wonnemann M, et al. Hyperforin
represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998
Jun; 31 Suppl. 1: 16-21
78. Teufel-Mayer R, Gleitz J. Effects of long-term administration of hypericum extracts on the affinity and density
of the central serotonergic 5-HT1 A and 5-HT2 A receptors. Pharmacopsychiatry 1997 Sep; 30 Suppl. 2: 113-6
79. Fiebich BL, Hollig A, Lieb K. Inhibition of substance
P-induced cytokine synthesis by St. Johns wort extracts.
Pharmacopsychiatry 2001 Jul; 34 Suppl. 1: S26-8
80. Thiele B, Brink I, Ploch M. Modulation of cytokine expression by hypericum extract. J Geriatr Psychiatry
Neurol 1994 Oct; 7 Suppl. 1: S60-2
81. Clement K, Covertson CR, Johnson MJ, et al. St Johns
wort and the treatment of mild to moderate depression: a
systematic review. Holist Nurs Pract 2006 Jul-Aug; 20 (4):
197-203
82. Gaster B, Holroyd J. St Johns wort for depression: a systematic review. Arch Intern Med 2000 Jan; 160 (2): 152-8
83. Kim HL, Streltzer J, Goebert D. St Johns wort for
depression: a meta-analysis of well-defined clinical trials.
J Nerv Ment Dis 1999 Sep; 187 (9): 532-8
84. Williams Jr JW, Mulrow CD, Chiquette E, et al. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med
2000 May; 132 (9): 743-56
85. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus
sativus L. (saffron) in the treatment of premenstrual
syndrome: a double-blind, randomised and placebocontrolled trial. BJOG 2008 Mar; 115 (4): 515-9
86. Hicks SM, Walker AF, Gallagher J, et al. The significance
of nonsignificance in randomized controlled studies: a
discussion inspired by a double-blinded study on St.
Johns wort (Hypericum perforatum L.) for premenstrual
symptoms. J Altern Complement Med 2004 Dec; 10 (6):
925-32
87. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the
treatment of premenstrual dysphoria. N Engl J Med 1995
Jun; 332 (23): 1529-34
88. Pakgohar M, Mehran A, Salehi MS, et al. Comparison of
hypericum perforatum and placebo in treatment of physical symptoms of premenstrual syndrome [in Persian].
HAYAT J Tehran Fac Nurs Midwifery 2004; 10 (22): 99

2010 Adis Data Information BV. All rights reserved.

Canning et al.

89. Pakgohar M, Ahmadi M, Surmaghi MH, et al. Effect of

Hypericum perforatum L. for treatment of premenstrual
syndrome [in Persian]. J Med Plants 2005 Sep; 4 (15):
33-42
90. Bennett Jr DA, Phun L, Polk JF, et al. Neuropharmacology of St. Johns wort (Hypericum). Ann Pharmacother
1998 Nov; 32 (11): 1201-8
91. Miller AL. St. Johns wort (Hypericum perforatum): clinical
effects on depression and other conditions. Altern Med
Rev 1998 Feb; 3 (1): 18-26
92. Montgomery S, Hubener W, Gregoleit H. Efficacy and
tolerability of St Johns wort extract compared with
placebo in patients with a mild to moderate depressive
disorder. Phytomedicine 2000; 7 Suppl. 2: 107
93. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness
of St Johns wort in major depression: a randomized
controlled trial. JAMA 2001 Apr; 285 (15): 1978-86
94. Freeman EW, DeRubeis RJ, Rickels K. Reliability and
validity of a daily diary for premenstrual syndrome.
Psychiatry Res 1996 Nov; 65 (2): 97-106
95. Hamilton JA, Parry BL, Alagna S, et al. Premenstrual
mood changes: a guide to evaluation and treatment.
Psychiatr Ann 1984 Jun; 14 (6): 426-35
96. NIMH Workshop on Pre-menstrual Syndrome. Co-sponsored by the Centre for Studies of Affective Disorders and
the Psychobiological Processes and Behavioral Medicine
Section. Rockville (MD): 1983 Apr: 14-15
97. Frye GM, Silverman SD. Is it premenstrual syndrome?
Keys to focused diagnosis, therapies for multiple symptoms. Postgrad Med 2000 May; 107 (5): 151-9
98. Lampe L. Antidepressants: not just for depression. Aust
Prescr 2005 Aug; 28 (4): 91-3
99. Pearlstein TB. Hormones and depression: what are the
facts about premenstrual syndrome, menopause, and
hormone replacement therapy? Am J Obstet Gynecol
1995 Aug; 173 (2): 646-53
100. Wyatt KM, Dimmock PW, Frischer M, et al. Prescribing
patterns in premenstrual syndrome. BMC Womens
Health 2002 Jun; 2 (4): 1-8
101. Landen M, Eriksson E. How does premenstrual dysphoric
disorder relate to depression and anxiety disorders? Depress Anxiety 2003; 17 (3): 122-9
102. Quah-Smith JI, Tang WM, Russell J. Laser acupuncture
for mild to moderate depression in a primary care setting:
a randomised controlled trial. Acupunct Med 2005 Sep;
23 (3): 103-11
103. Nielson A, Williams T. Depression in ambulatory medical
patients, prevalence by self-report questionnaire and
recognition by non-psychiatric physicians. Arch Gen
Psychiatry 1980; 37: 999-1004
104. Beck AT, Ward CH, Mendelson M, et al. An inventory for
measuring depression. Arch Gen Psychiatry 1961 Jun; 4: 561-71
105. Sheenan-Dare RA, Henderson MJ, Cotterill JA. Anxiety
and depression in patients with chronic urticaria and
generalised pruritus. Br J Dermatol 1990; 123 (6): 769-74
106. Spielberger CD. Manual for the State-Trait Anxiety Inventory: STAI (Form Y). Palo Alto (CA): Consulting
Psychologists Press, 1983
107. Pocock SJ. Clinical trials: a practical approach. Chichester:
John Wiley, 1983

CNS Drugs 2010; 24 (3)

Hypericum perforatum for the Treatment of PMS

108. Chisholm G, Jung SO, Cumming CE, et al. Premenstrual

anxiety and depression: comparison of objective psychological tests with retrospective questionnaire. Acta Psychiatr Scand 1990 Jan; 81 (1): 52-7
109. Halbreich U. The etiology, biology, and evolving pathology of premenstrual syndromes. Psychoneuroendocrinology 2003 Aug; 28 Suppl. 3: 55-99
110. Warner P, Bancroft J. Factors related to self-reporting of
the pre-menstrual syndrome. Br J Psychiatry 1990 Aug;
157: 249-60
111. Hartlage SA, Arduino KE. Toward the content validity of
premenstrual dysphoric disorder: do anger and irritability
more than depressed mood represent treatment-seekers
experience? Psychol Rep 2002 Feb; 90 (1): 189-202
112. Buss AH, Perry M. The Aggression Questionnaire. J Pers
Soc Psychol 1992 Sep; 63 (3): 452-9
113. Patton JH, Stanford MS, Barratt ES. Factor structure of
the Barratt impulsiveness scale. J Clin Psychol 1995 Nov;
51 (6): 768-74
114. Bryant M, Cassidy A, Hill C, et al. Effect of consumption
of soy isoflavones on behavioural, somatic and affective
symptoms in women with premenstrual syndrome. Br J
Nutr 2005 May; 93 (5): 731-9
115. Freeman EW, Rickels K, Sondheimer SJ, et al. Differential
response to antidepressants in women with premenstrual
syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch Gen Psychiatry 1999 Oct; 56 (10):
932-9
116. FitzGerald SP, Lamont JV, McConnell RI, et al. Development of a high-throughput automated analyzer using
biochip array technology. Clin Chem 2005 Jul; 51 (7):
1165-76
117. Hildesheim A, Ryan RL, Rinehart E, et al. Simultaneous
measurement of several cytokines using small volumes of
biospecimens. Cancer Epidemiol Biomarkers Prev 2002
Nov; 11 (11): 1477-84
118. Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. BJOG
2000 Jul; 107 (7): 870-6
119. Rosenthal R, Rosnow RL. Essentials of behavioral research: methods and data analysis. 2nd ed. Singapore:
McGraw-Hill, 1999
120. Machin D, Campbell MJ. Statistical tables for the design of
clinical trials. Oxford: Blackwell Scientific Publications,
1987
121. Pearlstein TB, Stone AB, Lund SA, et al. Comparison of
fluoxetine, bupropion, and placebo in the treatment of
premenstrual dysphoric disorder. J Clin Psychopharmacol 1997 Aug; 17 (4): 261-6
122. Carlson NR. Foundations of Physiological Psychology.
Boston (MA): Allyn and Bacon, 1988
123. Dantzer R, Wollman E, Vitkovic L, et al. Cytokines and
depression: fortuitous or causative association? Mol Psychiatry 1999 Jul; 4 (4): 328-32

2010 Adis Data Information BV. All rights reserved.

225

124. Smith RS. The macrophage theory of depression. Med

Hypotheses 1991 Aug; 35 (4): 298-306
125. Yonkers KA, OBrien PMS, Eriksson E. Premenstrual
syndrome. Lancet 2008 Apr; 371 (9619): 1200-10
126. Nangia M, Syed W, Doraiswamy PM. Efficacy and safety
of St. Johns wort for the treatment of major depression.
Public Health Nutr 2000; 3 (4A): 487-94
127. Raffa RB. Screen of receptor and uptake-site activity of hypericin component of St. Johns wort reveals sigma receptor
binding. Life Sci 1998 Mar; 62 (16): PL265-70
128. Lester NA, Keel PA, Lipson SF. Symptom fluctuation in
bulimia nervosa: relation to menstrual-cycle phase and
cortisol levels. Psychol Med 2003; 33 (1): 51-60
129. Price WA, Torem MS, DiMarzio LR. Premenstrual exacerbation of bulimia. Psychosomatics 1987; 28: 378-9
130. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical
Interview for DSM-IV Axis I Disorders Patient Edition
(SCID-I/P, version 2.0). New York: Biometrics Research
Department, New York State Psychiatric Institute, 1995
131. Evans SM, Foltin RW, Fischman MW. Food cravings
and the acute effects of alprazolam on food intake in
women with premenstrual dysphoric disorder. Appetite
1999 Jun; 32 (3): 331-49
132. Facchinetti F, Borella P, Sances G, et al. Oral magnesium
successfully relieves premenstrual mood changes. Obstet
Gynecol 1991 Aug; 78 (2): 177-81
133. Freeman EW, Stout AL, Endicott J, et al. Treatment of
premenstrual syndrome with a carbohydrate-rich beverage. Int J Gynecol Obstet 2002; 77 (3): 253-4
134. De Souza MC, Walker AF, Robinson PA, et al. A synergistic effect of a daily supplementation for 1 month of
200 mg magnesium plus 50 mg vitamin B6 for the relief of
anxiety-related premenstrual symptoms: a randomized,
double-blind, crossover study. J Womens Health Gend
Based Med 2000 Mar; 9 (2): 131-9
135. Sayegh R, Schiff I, Wurtman J, et al. The effect of a
carbohydrate-rich beverage on mood, appetite, and cognitive function in women with premenstrual syndrome.
Obstet Gynecol 1995 Oct; 86 (4 Pt 1): 520-8
136. Walker AF, De Souza MC, Vickers MF, et al. Magnesium
supplementation alleviates premenstrual symptoms of
fluid retention. J Womens Health 1998 Nov; 7 (9): 1157-65
137. Freeman EW, Rickels K, Sondheimer SJ, et al. A doubleblind trial of oral progesterone, alprazolam, and placebo
in treatment of severe premenstrual syndrome. JAMA
1995 Jul; 274 (1): 51-7
138. Freeman EW, Sondheimer SJ, Sammel MD, et al. A preliminary study of luteal phase versus symptom-onset
dosing with escitalopram for premenstrual dysphoric
disorder. J Clin Psychiatry 2005 Jun; 66 (6): 769-73

Correspondence: Dr Sarah Canning, Institute of Psychological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
E-mail: s.e.canning@leeds.ac.uk

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