Herbal treatments for alleviating premenstrual symptoms: A systematic review

Abstract

Premenstrual syndrome (PMS) is a condition of cyclical and recurrent physical and psychological discomfort occurring 1 to 2 weeks before menstrual period. More severe psychological symptoms have been described for the premenstrual dysphoric disorder (PMDD). No single treatment is universally recognised as effective and many patients often turn to therapeutic approaches outside of conventional medicine. This systematic review is aimed at analysing the effects of herb remedies in the above conditions. Systematic literature searches were performed in electronic databases, covering the period January 1980 to September 2010. Randomised controlled clinical trials (RCTs) were included. Papers quality was evaluated with the Jadad' scale. A further evaluation of PMS/PMDD diagnostic criteria was also done. Of 102 articles identified, 17 RCTs were eligible and 10 of them were included. The heterogeneity of population included, study design and outcome presentation refrained from a meta-analysis. Vitex agnus castus was the more investigated remedy (four trials, about 500 women), and it was reported to consistently ameliorate PMS better than placebo. Single trials also support the use of either Gingko biloba or Crocus sativus. On the contrary, neither evening primrose oil nor St. John's Wort show an effect different than placebo. None of the herbs was associated with major health risks, although the reduced number of tested patients does not allow definitive conclusions on safety. Some herb remedies seem useful for the treatment of PMS. However, more RCTs are required to account for the heterogeneity of the syndrome.

Full text

REVIEW
Herbal treatments for alleviating premenstrual symptoms:
a systematic review
GIULIA DANTE & FABIO FACCHINETTI
Mother Infant Department, University of Modena and Reggio Emilia, Via del Pozzo 71, Modena 41100, Italy
(Received 28 February 2010; revised 2 November 2010; accepted 3 November 2010)
Abstract
Premenstrual syndrome (PMS) is a condition of cyclical and recurrent physical and psychological discomfort occurring 1 to 2
weeks before menstrual period. More severe psychological symptoms have been described for the premenstrual dysphoric
disorder (PMDD). No single treatment is universally recognised as effective and many patients often turn to therapeutic
approaches outside of conventional medicine. This systematic review is aimed at analysing the effects of herb remedies in the
above conditions.
Systematic literature searches were performed in electronic databases, covering the period January 1980 to September
2010. Randomised controlled clinical trials (RCTs) were included. Papers quality was evaluated with the Jadad’ scale. A
further evaluation of PMS/PMDD diagnostic criteria was also done.
Of 102 articles identified, 17 RCTs were eligible and 10 of them were included. The heterogeneity of population included,
study design and outcome presentation refrained from a meta-analysis. Vitex agnus castus was the more investigated remedy
(four trials, about 500 women), and it was reported to consistently ameliorate PMS better than placebo. Single trials also
support the use of either Gingko biloba or Crocus sativus. On the contrary, neither Evening primerose oil nor St. John Worth
show an effect different than placebo. None of the herbs was associated with major health risks, although the reduced number
of tested patients does not allow definitive conclusions on safety.
Some herb remedies seem useful for the treatment of PMS. However, more RCTs are required to account for the
heterogeneity of the syndrome.
Keywords: Premenstrual syndrome, herbal remedies, Vitex agnus castus, Crocus sativus, Hypericum perforatum
Introduction
Premenstrual syndrome (PMS) is a condition of
cyclic, recurrent physical and psychological discom-
fort occurring 1–2 weeks before a woman’s menstrual
period. Symptoms have to be significant enough to
cause disruption in either family, personal or occupa-
tional functions [1,2]. In its most severe form, PMS
affects roughly 5% of women in reproductive age
while in a milder form, it has been estimated to affect
approximately 40% of the population [3,4]. A variant
of PMS entailing more severe psychological symp-
toms has been described by psychiatrists as pre-
menstrual dysphoric disorder (PMDD) [5].
More than 200 symptoms of PMS have been
reported in the literature, none of them being
specifically related to the condition [6]. Commoner
affective symptoms are irritability, anxiety/tension,
mood swings and depression. Commoner physical
symptoms include abdominal bloating, breast tender-
ness, headache, swelling of extremities and food
cravings [3]. The pathophysiology of PMS or PMDD
have not been established and hypotheses included
hormone imbalances, sodium retention, nutritional
deficiencies, abnormal neurotransmitter responses to
normal ovarian function and abnormal hypothalamic-
pituitary-adrenal axis function [7,8].
Apart for the complete elimination of the menstrual
cycle, no single treatment is universally recognised as
effective. Studies have yielded conflicting results with
most approaches, and many trials have not been well
controlled [6]. A limitation of studies concerning
PMS/PMDD is the lack of objective markers. There-
fore, outcomes could be based only on self-reported
Correspondence: Fabio Facchinetti, Mother Infant Department, University of Modena and Reggio Emilia, Via del Pozzo 71, Modena 41100, Italy.
E-mail: facchinetti.fabio@unimore.it
Journal of Psychosomatic Obstetrics & Gynecology, March 2011; 32(1): 42–51
ISSN 0167-482X print/ISSN 1743-8942 online Ó2011 Informa UK, Ltd.
DOI: 10.3109/0167482X.2010.538102
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

questionnaires. Anyway, proven effective phar-
macologic treatments include reproductive hor-
mones, psychoactive drugs and vitamins among
others [9–12].
Many patients often turn to therapeutic approaches
outside of conventional medicine. Women are fre-
quent users of complementary/alternative medicine
(CAM) more than men [13–16]. Indeed, multiple
surveys have shown that women, especially those
of white ethnicity, middle-age, with high levels of
education and income, are more likely to be users of
CAM [17–19]. These surveys found that patients with
PMS try a wide range of CAM remedies including
diet, yoga, massage, exercise, faith healing, hypnosis,
herbs, acupuncture, chiropractic, meditation, ho-
meopathy and vitamins/supplements. The current
stage of knowledge is still inadequate to sufficiently
inform clinicians, researchers and the public about
either benefits or potential risks of everyone among
such interventions [20,21].
However, there is an increasing public interest in
the use of herbal medicine treatment that lies outside
the traditional Western medical practice. There is also
evidence indicating that not all herbs are risk-free and
concerns about self-administration and non-recogni-
sable adverse events are increasing [22].
The present systematic review is aimed at analyse
the effects of herbs in the management of PMS or
PMDD in medical practice.
Methods
Systematic literature searches were performed in
September 2010 in the following electronic data-
bases: Medline, Amed, The Cochrane Library and in
the PDR for Herbal Medicines [23]. We performed a
search over the period from January 1980 to
September 2010 and only randomised controlled
clinical trials (RCT) were included.
The search terms were: ‘premenstrual syndrome
treatment’, ‘late luteal phase dysphoric disorder’,
‘Premenstrual Dysphoric Disorder’, ‘mastalgia treat-
ment’, ‘hyperprolactinaemia’ ‘complementary treat-
ments’, ‘alternative treatments’, ‘phytomedicine’,
‘herbal treatments’, ‘herbs’, ‘vitex agnus castus’,
‘fructus agni casti’, ‘chasteberry’, ‘chaste three’,
‘evening primrose oil,’, ‘oenothera biennis’, ‘hyper-
icum perforatum’, ‘hyperici herba’, ‘St. John’s wort’,
‘ginkgo biloba’, ‘black cohosh root’, ‘cimicifuga
racemosa rhizoma’, ‘Crocus sativus’, ‘whether saf-
fron’ and ‘Dioscorea villosa’.
No language restrictions were imposed. Further
relevant papers were located by hand-searching the
reference lists of recent systematic reviews. Only
human studies were included. Data from herbal
treatments in combination with other herbs as well as
animal and in vitro investigations were excluded.
Chinese herb remedies were also excluded.
Where dual publications existed, the more detailed
and recent paper was admitted.
We attempted to obtain hard copies of all the
papers listed through our own university library or
interlibrary loans.
The papers quality has been evaluated with the
Jadad method [24], which is considered reliable for
RCT assessment [25]. The parameters considered by
this method are the following:
1. Was the study described as randomised?
2. Was the study described as double blind?
3. Follow up: adequate (number and reasons for
dropouts and withdrawals described) or inade-
quate (number or reasons for dropouts and
withdrawals not described).
4. Generation of the allocation sequence: adequate
(computer-generated random numbers, table of
random numbers . . .), or inadequate;
5. Double blinding: adequate (taking placebo, or
similar) or inadequate (not intervened or
different).
For each positive answer, 1 point is assigned, the
overall score going from ‘0’ to ‘5’. Studies scoring
53 were considered of poor quality and then
excluded from the analysis.
In addition to Jadad scale, studies were evaluated
also according to the method used for the clinical
diagnosis. PMS has been defined by the American
College of Obstetrics and Gynecologists (ACOG)
[2], while PMDD has been defined by the American
Psychiatric Association (APA) which previously
defined the Late Luteal Phase Dysphoric Disorder
(LLPDD) in the third revised version of DSM [5].
Apart from the above-mentioned criteria, the diag-
nosis of PMS has been accepted when performed by
a prospective evaluation of symptoms through
validated questionnaires (i.e. MDQ, COPE, etc.),
for at last two menstrual cycles [26,27]. Only studies
using such standard criteria were considered reliable
and then included in the final comparison.
All sources of information obtained were read and
evaluated by one of us (GD), and successively
checked independently by the other author (FF).
Results
Decision tree is reported in Figure 1. Of 102 studies
identified, 25 trials were screened. Eight of them
were excluded because not pertaining PMS (n¼5)
[28–32], duplicate publication (n¼2) [33,34] or
published only in abstract form (n¼1) [35]. The
remaining 17 RCTs were considered eligible for this
review. Eight of them pertains the effects of Vitex
agnus-castus [36–43], four used Oenotera biennis
[44–47], two used Hypericum perforatum [48–49],
two used Ginkgo biloba [50,51] and one Crocus
Herbal treatments for alleviating premenstrual symptoms 43
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

sativus [52]. Each one of such RCT was detailed
in Table I.
The analysis through the Jadad method showed
three studies of poor quality (score 53) [40, 41,47]
which were excluded. In addition, further four
studies were excluded since they did not report a
reliable standardised definition of either PMS or
PMDD diagnosis [36,39,45,50]. Thus, 10 studies
were included [37,38,42,43,44,46,48,49,51,52] for
the final comparison which is reported in Table II.
Vitex agnus-castus (chasteberry)
Vitex agnus-castus (VAC), the fruit of chaste tree, is
native to western Asia and south-western Europe,
and now it is common in much of the south-eastern
United States [23]. Over the past years, VAC has
been widely used in Europe for gynaecologic
conditions such as PMS, cyclical breast discomfort,
menstrual cycle irregularities and dysfunctional
uterine bleeding [53]. Vitex agnus castus shows
central dopaminergic activity in vitro and in vivo
[54].
In the study of Shellemberg [37], fruit extract ZE
440 contains 60% ethanol m/m extract (ratio 6:12:1)
and it was standardised as casticin content. The
reduction of symptoms was 52% (active) versus 24%
(p50.001). Four minor self-resolving AE were
reported in the VAC group, and three in the placebo
group.
In the study by Atmaca et al. [38], VAC extracts
was compared with flexible dosing fluoxetine (range
20–40 mg/day). The composition and the titration of
the herb were not described. Although both treat-
ments showed similar efficacy on PMDD, fluoxetine
was more effective for psychological symptoms while
VAC reduced physical symptoms. AE were reported
in 17 patients (VAC: n¼9; fluoxetine: n¼8),
nausea and headache being often described in either
groups.
Both in the studies by He et al. [42] and Ma
et al. [43], chinese women were enrolled. Each
tablet of VAC (BNO 1095) they used contained
4.0 mg of a dried ethanol (70%) extract of VAC
(corresponding to 40 mg of herbal drug) and
it was identical to Agnucaston
1
/Cyclodynon
1
Figure 1. Decision tree.
44 G. Dante & F. Facchinetti
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

Table I. Eligible RCTs where herb remedies have been evaluated for the treatment of PMS or PMDD.
Reference Study design
Herb remedy
treatment
duration, dose
No. of subjects and
inclusion criteria
Assessment of
the response Comments
[38] Double-blind,
randomised,
controlled vs.
fluoxetine
VAC N: 42/39 DSR, HRSD, Responders
(450%
improvement)
were similar in
VAC (58%)
and
Fluoxetine
(68%) group
8 weeks Age: 24–45 CGI-SI, CGI-I
Dose: 20–40
mg/day
Diagnosis: DSM-IV
OC users: no
[37] Double-blind,
randomised,
placebo-
controlled
VAC N: 178/170 Six symptoms
recorded at the
start of every
cycle
According to the
3 global
impression
items active
treatment was
more effective
than placebo
(p50.001)
3 cycles Age: 18, mean age 36
Dose: 20 mg/day Diagnosis: DSM III-R
OC users: yes
[41] Prospective,
randomised
vs.
bromocriptine
VAC
3 months
Dose: 40 mg/day
N: 80/80
Age: not reported
Diagnosis: mastalgia and
Mild hyperprolactinaemia
OC users: not described
Symptom scoring
not defined
Both VAC and
bromocriptine
Improved
symptoms
(p50.00001)
[40] Double-blind,
randomised,
placebo-
controlled
VAC N: 2500/600 MDQ VAC improved
symptoms
equally than
placebo
3 cycles Age: not described
Dose: 300 mg/day Diagnosis: self-diagnosed
sufferers from PMS based
on the MDQ
OC users: not described
[39] Double-blind,
randomised
controlled vs.
vitamin B6
VAC
3 cycles
Dose: 3.5–4.2 mg/day
N¼175/105
Age: 18–45
Diagnosis: PMTS
OC users: no
PMTS, CGI Treatment with
VAC and B6
reduced
PMTS score
from 15.2 to
5.1 (47.4%)
and from 11.9
to 5.1
(748%).
Similar data
obtained by
using the CGI
scale
[36] Double-blind,
randomised,
placebo-
controlled
VAC
3 cycles
Dose: 32.4 mg/day
N¼100/86
Age: 18–45
Diagnosis: patients had to
suffer from cyclical
mastalgia
OC users: yes
VAS
PMSD and
PMTS
The differences
of the VAS
points for
VAC were
significantly
greater than
those with
placebo
(p¼0.018)
[42] Prospective,
randomised,
multicenter,
placebo-
controlled
VAC
3 cycles
Dose: 40 mg/day
N: 217/202
Age: 18–45
Diagnosis: Chinese version
of PMSD and PMTS
OC users: no
See Table II
[43] Prospective,
randomised,
double-blind,
placebo-
controlled
VAC
3 cycles
Dose: 40 mg/day
N: 67/64
Age: 21–44
Diagnosis: Chinese version
of PMTS and PMTS
OC users: no
PMSD and
PMTS
See Table II
(continued)
Herbal treatments for alleviating premenstrual symptoms 45
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

Table I. (Continued).
Reference Study design
Herb remedy
treatment
duration, dose
No. of subjects and
inclusion criteria
Assessment of
the response Comments
[45] Double-blind,
randomised,
placebo-
controlled,
crossover
EPO
3 cycles
Dose: 500 mg/day
N¼40/38
Age: 20–40
Diagnosis: symptoms
during the 2nd half
of cycle, relieved
within 72-h of menses
OC users: no
10 PMS
symptoms
There was no
difference
between active
and placebo
(RR: 70.026;
95% CI: 72.3
to 2.2)
[44] Double-blind,
randomised,
placebo-
controlled,
crossover
EPO
4 months
Dose: Efamol 1 g/day
Efavit: 2 þ
3 capsules/day
N¼54/10
Age: 26–38
Diagnosis: MDQ
OC users: no
MDQ, BDI,
SAI
At interview, 6/
20 felt better
with placebo,
and 14/20 felt
better with
EPO (not
significant)
[46] Randomised,
double-blind
crossover
EPO
10 cycles
Dose: Efamol 6 g/day
N¼38/27
Age: 30–45
Diagnosis: DSM III-R
OC users: no
Modified scale
from
Hammerback
et al.**
Using spectral
densities,
improvement
was observed
over time
irrespective of
whether
patients
received EPO
or placebo
[47] Placebo-
controlled,
randomised,
crossover
EPO
4 cycles
Dose: Efamol 1.5 g/day
N: 30/30
Age: 25–47
Diagnosis: suffering
severe PMS since a
mean of 8.8 years
OC users: not described
19 symptoms
scored on a
3-point scale
global score
index
Both EPO and
placebo
decreased
PMS score
respect with
baseline.
At patient’s
assessment,
the lack of
(60%) vs. EPO
(38%),
p50.05
[48] Double-blind,
randomised,
placebo-
controlled
Hypericum perforatum
3 cycles.
Dose: 600 mg/day
N¼169/125
Age: not described
Diagnosis: MHQ
OC users: no
Abraham’s
classification***
See Table II
[49] Double-blind,
randomised,
placebo-
controlled
Hypericum perforatum
10 cycles.
Dose: 900 mg/day
N: 36/34
Age: 18–45
Diagnosis: DSR, BDI,
STAIT
OC users: no
DSR, STAIS,
BPAQ
BIS-11
SJW equal to
placebo for
DSR, SJW
better than
placebo for
physical
(p¼0.013)
and
behavioural
symptoms
(p¼0.032)
[50] Double-blind,
randomised,
placebo-
controlled
Ginkgo Biloba
3 cycles.
Dose: 160 mg/day
N¼165/143
Diagnosis: women
suffering since 3
cycles from
congestive PMS
troubles
OC users: no
DSR Active and
placebo were
equally
effective,
except for
breast
symptoms
where Gingko
was more
(continued)
46 G. Dante & F. Facchinetti
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

(Bionorica AG, Neumarkt, Germany) available in
Europe.
In the study enrolling perimenopausal women
[42,] AE (19 patients) were equally reported in the
two groups, headache being the most frequent. In
the study enrolling women in fertile age [43], only
the prolongation of periods was reported as AE,
in the treatment group.
Oenotera biennis (evening primerose oil)
Unbalanced prostaglandin production has been
hypothesised in women with PMS. Indeed, cis-
linoleic acid levels are higher in these patients, with
respect to controls. Since the levels of the metabolites
are reduced, this suggests a failure of conversion
into gamma-linolenic acid [55,56]. On these basis,
Table I. (Continued).
Reference Study design
Herb remedy
treatment
duration, dose
No. of subjects and
inclusion criteria
Assessment of
the response Comments
[51] Single-blind,
randomised,
placebo-
controlled
Ginkgo Biloba
2 cycles
Dose: 120 mg/day
N¼90/85
Age: 18–30
Diagnosis: DSM-IV, BDI
DSM-IV, BDI See Table II
[52] Double-blind,
randomised,
placebo-
controlled
Crocus sativus L.
4 cycles
Dose: 30 mg/day
N¼78/53
Age: 20–45
Diagnosis: ACOG
OC users: no
DSR, HRSD See Table II
*Enrolled/completed the trial.
**Hammerback S, Backstrom T, MacGibbon-TaylorB. Diagnosis of premenstrual tension syndrome: description and evaluation of a
procedure for diagnosis and differential diagnosis. J Psychosom Obstet Gynecol 1989;10:25–42.
***Abraham GE. Nutritional factors in the etiology of the premenstrual tension syndromes. J Reprod Med 1983;28:446–464.
OC: oral contraceptives; DSR: daily symptom reports; HRSD: Hamilton rating scale for depression; CGI_SI: clinical global impression
scale; CGI-I: clinical global improvement; VAC: vitex agnus castus; MDQ: menstrual distress questionnaire; PMS: premenstrual syndrome;
PMTS: premenstrual tension syndrome scale; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders; DSM III-R: Diagnostic and
Statistical Manual of Mental Disorders III revisited; VAS: visual analogue scale; EPO: evening primerose oil; BDI: beck depression
inventory; SAI: Salkind anxiety inventory; MHQ: daily symptom report; HDRS: Hamilton depression rating scale; PMSD: Premenstrual
syndrome diary, STAIT: Trait scale of the State-Trait Anxiety Inventory, STAIS: State scale of the State-Trait Anxiety Inventory, BPAQ
Aggression Questionnaire, BIS-11: Barratt Impulsiveness Scale version 11.
Table II. Efficacy of herbs remedies for PMS/PMDD treatment tested in high-quality trials.
Herb remedy tested Jadad score Diagnosis
Reduction vs. baseline
Herb remedy Placebo p
Vitex agnus castus
Schellemberg [37] 3 PMS 48.8% 30.4% 50.001
Atmaca et al. [38] 4 PMDD N.A. N.A.
He et al. [42] 4 PMS 79.2% 55.1% 50.0001
Ma et al. [43] 4 PMS 85.7% 57.2% 50.0001
Oenotera biennis
Callender et al. [44] 3 PMS BDI: 46.6% 35.6% NS
SAI: 21.2% 24.3% NS
Collins et al. [46] 4 PMS N.A. N.A.
Hypericum perforatum
Hicks et al. [48] 3 PMS 28.5% 30.2% NS
Canning et al. [49] 5 PMS N.A. N.A.
Ginkgo biloba
Ozgoli et al. [51] 4 PMS 23.6% 8.74% 50.001
Crocus sativus
Hosseini et al. [52] 5 PMS 57.9% 21.6% 50.001
Reference to single study is reported in brackets. For Jadad score refers to the text.
The percent changes are calculated by using scores referring to overall symptoms. Effect on subscales is not reported except for Ref. 44 where
a total PMS score was not available.
N.A.: In these studies, data are not available for the calculation, neither from the text, nor from figures/tables. The significance of active/
placebo treatment is reported in Table I.
BDI: Beck depression inventory; SAI: Salkind anxiety inventory.
Herbal treatments for alleviating premenstrual symptoms 47
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

evening primrose oil (Efamol) was promoted for the
treatment of PMS. Each Efamol capsule contains
500 mg of oil (73% cis-linoleic acid, 9% gamma-
linolenic acid and the remaining 18% is a variety of
other fatty acids). In each capsule, 13.6 IU of vitamin
E are added. Since a number of coenzymes are
required in the conversion to gamma-linolenic acid,
Efavit tablets (125 mg ascorbic acid; 5 mg zinc
sulphate; 25 mg niacin; 25 mg pyridoxine) were
added to Efamol in some trials.
In the study by Callender et al. [44], only 10
women completed the trial (seven placebo and three
Evening primrose oil). Depression and anxiety scores
improved in both arms, irrespective of medication
quality. Skin reaction (eight women) was reported on
active treatment. The study of Collins et al. [46] had
a similar design, but the dose of Efamol (12 capsules/
day) was the highest never reported. Neither
essential fatty acids nor placebo reduced premenstr-
ual symptoms.
Hypericum perforatum (St. John’s wort)
A number of reviews suggested that St. John’s Wort
(SJW) can be useful for the treatment of mild, but
not severe depression. Hyperforin (the active com-
pound) inhibits the reuptake of serotonin, dopamine
and norepinephrine and interacts with both GABA
and glutamate receptors. The effectiveness of SJW
correlates with hyperforin rather than with hypericin
content [57,58].
Hicks et al. [48] investigated a SJW extract
standardised to 0.3% of hypericin in volunteers
recruited through newspaper advertisements, fol-
lowed by an interview. Although minor AE are
reported, five subjects in the SJW group, and one in
the placebo group withdrew because of this. Aver-
aging both treatment cycles there was only a trend for
SJW to be superior to placebo.
Canning et al. [49] also recruited trough adver-
tisements but employed a different extract titrated to
0.18% hypericin and 3.38% hyperforin. The subject
evaluation included three observational run-in cycles,
followed by two placebo-cycles before randomisa-
tion, allowing few, very selected subjects to be
treated. Minor AE were reported both in placebo
and SJW group. In a sophisticated multivariate
analysis, SJW was not different than placebo on
overall PMS symptoms. Sub-analyses revealed SJW
efficacy for physical (include food craving) and
behavioural (include headache) symptoms. Unex-
pectedly, SJW did not relieved mood symptoms.
Gingko biloba
The leaf extract of Gingko biloba comes from the
oldest living tree species in the world. Ginkgo was
primarily known for improving memory. Extracts
contain many active compounds including flavo-
noids and terpenoids. The former have antioxidant
and scavenging properties. Gingko also inhibits
platelet-activating factor and has anti-inflammatory
effects, also relaxing vascular smooth muscle
[59,60].
Ozgoli et al. [51] enrolled student volunteers from
Teheran and used a leaf extract titrated to flavonoid
glycoside (24%) and terpene lactone (6%). Very few
minor AE were reported. Either physical or psycho-
logical symptoms of PMS were reduced significantly
more by Gingko respect with placebo. Interestingly,
the extent of placebo reduction was very low
(510%).
Crocus sativus (whether saffron)
Crocus sativus is considered an excellent stomach
ailment and an antispasmodic, helping digestion and
increasing appetite. It also relieves renal colic. In
Persian traditional medicine, it is used for depression
[61], an effect which has been confirmed in a recent
clinical trial [62]. A serotoninergic mechanism
involved in the antidepressant activity has been
suggested [63].
In their small RCT, Agha-Hosseini et al.’s [52]
investigated an extract of Crocus sativus prepared as
follow: 120 g of dried and milled petal was extracted
with 1800 ml ethanol (80%) by percolation proce-
dure in three steps. Both in Saffron and placebo
group, minor AE were observed including decreased/
increased appetite, sedation, nausea, headache and
hypomania. Despite a placebo effect, Saffron was
found to be superior in relieving all symptoms of
PMS.
Discussion
Although the relatively high number of reports
evaluating herb remedies for PMS/PMDD relief,
only a few of them are designed as RCTs, and often
the quality of such trials is far to be satisfactory. In
addition to the quality assessment used in systematic
reviews, we also evaluated the consistency of
diagnostic criteria adopted for PMS/PMDD defini-
tion. Indeed, a correct diagnosis is a crucial issue in
every field lacking objective/instrumental markers of
the disorder/syndrome under investigation [6]. PMS
largely fulfil such needs. Therefore, in agreement to
such stringent evaluation of quality, the evidences on
efficacy and safety in the treatment of PMS/PMDD
became restricted to 10 studies only, and pertain to
five different herb remedies.
The limit of this survey is that a quantitative
estimate of clinical effects, i.e., a meta-analysis was
refrained due to several factors. Some study design
includes run-in cycles thus selecting placebo respon-
ders whereas others did not. Population included
48 G. Dante & F. Facchinetti
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

either volunteers or patients chronically suffering
from several years where the response to any
intervention is obviously different. In many circum-
stances, herb preparations are not standardised. Last,
but not the least the different outcomes are reported
with different statistical approach and cannot be
summarised.
Nonetheless, we have tried to compare studies by
calculating the overall symptoms change respect with
baseline, in active and placebo arm, within each trial.
Confirming the above-discussed heterogeneity, pla-
cebo response showed a 6-fold variation, perhaps
also linked to the cultural attribution of PMS across
populations [64].
Bearing the above limitations in mind, this survey
allows some consideration. Respect to other reme-
dies, the experience with Chasteberry extract is the
main one. Indeed, it was tested in almost 500
patients where it consistently relieves PMS better
than placebo. Moreover, in a subset of women
suffering of PMDD Vitex agnus castus performed
equally to fluoxetine, a first-line drug treatment of
such condition [11]. The available data also indicate
that Chasteberry was not associated with major
health risks. At present, no drug interactions have
been reported.
On the opposite, despite its popularity in the
eighties, Evening primerose oil was evaluated in only
two adequate trials performed in early nineties.
Results indicate an equivalence of such essential
fatty acids supplement with placebo. Therefore, its
clinical application in women with PMS seems
useless.
Also St. John’s Worth was evaluated in two trials.
As a whole, the efficacy of this herb was not different
from placebo. Unexpectedly, small significant bene-
fits were found for physical, while not for psycholo-
gical symptoms.
The remnant two herbs, Gingko biloba and Crocus
sativus were evaluated in single studies. Each herb
relieved PMS better than placebo did. Such evi-
dences however were reached upon very few subjects,
requiring confirmation in further trials.
In terms of tolerability, only minor side effects have
been described so far, and none of the herbs was
associated with major health risks, although the
reduced number of tested patients does not allow
definitive conclusions on safety. Moreover, one has to
be aware that drug interaction represents an issue to
be considered for the case of St. John’s Worth [65].
In conclusion, despite a very large use of herb
remedies in everyday life, few studies have been
devoted to specific clinical investigations. The
evidences are scanty and suggest that the relief of
PMS could possibly be obtained only with few herb
extracts. The heterogeneity of PMS/PMDD presen-
tation and the different cultural value attributed to
premenstrual symptoms in the diverse populations,
suggests that more trials have to be performed before
assuming a single herb remedy as an effective
treatment.
Declaration of interest: None of the authors has
any conflict of interest in the subject matter of this
systematic review.
References
1. Reid R. Premenstrual syndrome. N Engl J Med 1991;324:
1208–1210.
2. ACOG Diagnostic Criteria for PMS. ACOG Practice Bulle-
tin – Number 15, April 2000.
3. Mortola J. Premenstrual syndrome-pathophysiologic consid-
erations. N Engl J Med 1998;338:256–257.
4. Singh BB, Berman BM, Simpson RL, Annechild A. Incidence of
premenstrual syndrome and remedy usage: a national probability
sample study. Altern Ther Health Med 1998;4:75–79.
5. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC:
American Psychiatric Association; 1994. pp 715–718.
6. Halbreich U. The diagnosis of premenstrual syndromes and
premenstrual dysphoric disorder-clinical procedures and
research perspectives. Gynecol Endocrinol 2004;19:320.
7. O’Brien PM. Helping women with premenstrual syndrome.
BMJ 1993;307:1471–1475.
8. Chrousos GP, Torpy DJ, Gold PW. Interactions between the
hypothalamic-pituitary-adrenal axis and the female reproduc-
tive system: clinical implications. Ann Intern Med
1998;129:229–240.
9. Lopez LM, Kaptein AA, Helmerhorst FM. Oral contra-
ceptives containing drospirenone for premenstrual syndrome.
Cochrane Database Syst Rev 2009;15:CD006586.
10. Ford O, Lethaby A, Roberts H, Mol BW. Progesterone for
premenstrual syndrome. Cochrane Database Syst Rev
2009;15:CD003415.
11. Brown J, O’ Brien PM, Marjoribanks J, Wyatt K. Selective
serotonin reuptake inhibitors for premenstrual syndrome.
Cochrane Database Syst Rev 2009;15:CD001396.
12. Wyatt KM, Dimmock PW, Jones PW, Shaughn O, Brien PM.
Efficacy of vitamin B-6 in the treatment of premenstrual
syndrome: systematic review. BMJ 1999;318:1375–1381.
13. MacLennan AH, Wilson DH, Taylor AW. Prevalence and
cost of alternative medicine in Australia. Lancet 1996;347:
569–573.
14. Corney RH, Stanton R. A survey of 658 women who
report symptoms of premenstrual syndrome. J Psychosom
Res 1991;35:471–482.
15. Lloyd KB, Hornsby LB. Complementary and alternative
medications for women’s health issues. Nutr Clin Pract
2009;24:589–608.
16. Himmel W, Schulte M, Kochen MM. Complementary
medicine: are patients’ expectations being met by their general
practitioners? Br J Gen Pract 1993;43:232–235.
17. Eisenberg DM, Davis RB, Ettner SL, Appel S, Van Rompay
M, et al. Trends in alternative medicine use in the United
States, 1990–1997: results of a follow-up national survey.
JAMA 1998;280:1569–1575.
18. Tesch BJ. Herbs commonly used by women. An evidence-
based review. Am J Obstet Gynecol 2003;188:S44–S45.
19. Stevinson C, Ernst E. Complementary/alternative therapies
for premenstrual syndrome: a systematic review of randomized
controlled trials. Am J Obstet Gynecol 2001;185:227–235.
20. Whelan AM, Jurgens TM, Naylor H. Herbs, vitamins and
minerals in the treatment of premenstrual syndrome: a
systematic review. Can J Clin Pharmacol 2009;16:407–429.
Herbal treatments for alleviating premenstrual symptoms 49
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

21. Cho SH, Kim J. Efficacy of acupuncture in management of
premenstrual syndrome: a systematic review. Complement
Ther Med 2010;18:104–111.
22. Lampert N, Xu Y. Chinese herbal nephropathy. Lancet
2002;359:796–797.
23. Gruenwald J, Brendler T, Jaenicke C, editors. PDR for herbal
medicines. 2nd edition. Montvale, New Jersey: Medical
Economics Company; 2000.
24. Jadad AR, Carroll D, Moore A, McQuay H. Developing a
database of published reports of randomised clinical trials in
pain. Research Pain 1996:66:239–246.
25. Jadad AR, McQuay HJ. A high-yield strategy to identify
randomized controlled trials for systematic reviews. Online J
Curr Clin Trials 1993:27;Doc. No. 33.
26. Mortola JF, Girton L, Beck L, Yen SS. Diagnosis of
premenstrual syndrome by a simple, prospective, and reliable
instrument: the calendar of premenstrual experiences. Obstet
Gynecol 1990;76:302–307.
27. Carver CS, Scheier MF, Weintraub JJ. Assessing coping
strategies: a theoretically based approach. J Pers Soc Psychol
1989;56:267–283.
28. Gerhard I, Patek A, Monga B, Blank A, Gorkow C.
Mastodynon (R) bei weiblicher Sterilitaet. Forsch Komple-
mentarmed 1998;5:272–278.
29. Westphal LM, Polan ML, Trant AS, Mooney SB. A
nutritional supplement for improving fertility in women: a
pilot study. J Reprod Med 2004;49:289–293.
30. Cerin A, Collins A, Landgren BM, Eneroth P. Hormonal and
biochemical profiles of premenstrual syndrome. Treatment
with essential fatty acids. Acta Obstet Gynecol Scand
1993;72:337–343.
31. Halaska M, Raus K, Beles P, Martan A, Paithner KG.
Treatment of cyclical mastodynia using an extract of Vitex
agnus castus: results of a double-blind comparison with a
placebo. Ceska Gynekol 1998;63:388–392.
32. Van Die MD, Bone KM, Burger HG, Reece JE, Teede HJ.
Effects of a combination of Hypericum perforatum and Vitex
agnus castus on PMs-like symptoms in late perimenopausal
women: findings from a subpopulation analysis. J Altern
Complement Med 2009;15:1045–1048.
33. Milewicz A, Gejdel E, Sworen H, Sienkiewicz K, et al. Vitex
agnus castus extract in the treatment of luteal phase defects due
to latent hyperprolactinemia. Results of a randomized
placebo-controlled double-blind study Arzneimittelforschung
1993;43:752–756.
34. Ma L, Lin S, Chen R, Zhang Y, Chen F, Wang X. Evaluating
therapeutic effect in symptoms of moderate-to-severe pre-
menstrual syndrome with Vitex agnus castus (BNO 1095) in
Chinese women. Aust NZJ Obstet Gynecol 2010;50:189–193.
35. Hunter JO, Wilson AJ. A double-blind controlled trial of
gamma-linolenic acid (GLA) in the management of pre-
menstrual gastrointestinal symptoms. Proceedings of 2nd
International Symposium on Premenstrual, Postpartum and
Menopausal Mood Disorders, Kiawah Island, South Carolina;
1987. Abstract 44.
36. Halaska M, Beles P, Gorkow C, Sieder C. Treatment of
cyclical mastalgia with a solution containing a Vitex agnus
castus extract: results of a placebo-controlled double-blind
study. The Breast 1993;8:175–218.
37. Shellemberg R. Treatment for the premenstrual syndrome
with agnus castus fruit extract: prospective, randomised,
placebo controlled study. BMJ 2001;322:134–137.
38. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnus
castus extract in the treatment of premenstrual dysphoric
disorder. Hum Psychopharmacol Clin Exp 2003;18:191–195.
39. Lauritzen CH, Reuter HD, Repges R, et al. Treatment of
premenstrual tension syndrome with Vitex agnus castus:
controlled, double-blind study versus pyridoxine. Phytomedi-
cine 1997;4:183–189.
40. Turner S, Mills S. A double-blind clinical trial on a herbal
remedy for premenstrual syndrome: a case study. Comple-
ment Ther Med 1993;1:73–77.
41. Kilicdag EB, Tarim E, Bagis T, Erkanli S, et al. Fructus agni
casti and bromocriptine for treatment of hyperprolactinemia
and mastalgia. Int J Gynecol Obstet 2004;85:292–293.
42. He Z, Chen R, Zhou Y, Geng L, Zhang Z, et al. Treatment for
premenstrual syndrome with Vitex agnus castus: a prospective,
randomized, multi-center placebo controlled study in China.
Maturitas 2009;63:99–103.
43. Ma L, Lin S, Chen R, Zhang Y, Chen F, Wang X. Evaluating
therapeutic effect in symptoms of moderate-to-severe pre-
menstrual syndrome with Vitex agnus castus (BNO 1095) in
Chinese women. Aust N Z J Obstet Gynaecol 2010;50:189–
193.
44. Callender K, Mc Gregor M, Kirk P, Thomas CS. A double
blind trial of evening primerose oil in the premenstrual
syndrome: nervous symptoms subgroup. Hum Psychophar-
macol 1988;3:57–61.
45. Khoo SK, Munro C, Battistutta D. Evening primrose oil and
treatment of premenstrual syndrome. Med J Aust
1990;153:189–192.
46. Collins A, Cerin A, Coleman G, Landgren B-M. Essential
fatty acids in the treatment of premenstrual syndrome. Obstet
Gynecol 1993;81:93–98.
47. Puolakka J, Makirainen L, Viinikka L, Ylikorkala O. Bio-
chemical and clinical effects of treating the premenstrual
syndrome with prostaglandin synthesis precursors. J Reprod
Med 1985;30:149–153.
48. Hicks SM, Walker AF, Gallagher J, Middleton RW, Wright J.
The significance of ‘‘nonsignificance’’ in randomized con-
trolled studies: a discussion inspired by a double-blinded
study on St. John’s wort (Hypericum perforatum L.) for
premenstrual symptoms. J Altern Complement Med
2004;10:925–932.
49. Canning S, Waterman M, Orsi N, Ayres J, Simpson N, Dye L.
The efficacy of Hypericum perforatum (St John’s Wort) for the
treatment of premenstrual syndrome. A randomized, double-
blind, placebo-controlled trial. CNS Drugs 2010;24:207–225.
50. Tamborini A, Taurelle R. Value of standardized Ginkgo
biloba extract (Egb 761) in the management of congestive
symptoms of premenstrual syndrome. Rev Fr Gynecol Obstet
1993;88:447–457.
51. Ozgoli G, Selselei EA, Mojab F, Majd HA. A randomized,
placebo-controlled trial of Ginkgo biloba L. in treatment of
premenstrual syndrome. J Altern Complement Med
2009;15:845–851.
52. Agha-Hosseini M, Kashani L, Aleyaseen A, Ghoreishi A, et al.
Crocus sativus L. (saffron) in the treatment of premenstrual
syndrome: a double-blind, randomised and placebo-con-
trolled trial. BJOG 2008;115:515–519.
53. Jarry H, Leonhardt S, Gorkow C, Wuttke W. In vitro prolactin
but not LH and FSH release is inhibited by compounds in
extracts of Agnus castus: direct evidence for a dopaminergic
principle by the dopamine receptor assay. Exp Clin Endocri-
nol 1994;102:448–454.
54. Rotblatt M, Ziment I, editors. Evidence-based herbal medi-
cine. Philadelphia: Hanley & Belfus Publ; 2002.
55. Brush MG, Watson SJ, Horrobin DF, Manku MS. Abnormal
essential fatty acid levels in plasma of women with premenstr-
ual syndrome. Am J Obstet Gynecol 1984;150:363–366.
56. Graham J. Premenstrual syndrome: evening primrose oil.
Thorsens 1984:36–40.
57. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of
St. John’s Wort in major depression: a randomized placebo
controlled trial. JAMA 2001;285:1978–1986.
58. Laakmann G, Schule C, Baghai T, et al. St. John’s Wort in
mild to moderate depression: the relevance of hyperforin for
the clinical efficacy. Pharmacopsychiat 1998;31:54–59.
50 G. Dante & F. Facchinetti
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.

59. Pang Z, Pan F, He S. Ginkgo biloba L.: history, current status,
and future prospects. J Altern Complement Med 1996;2:359–
363.
60. McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of
Ginkgo Biloba in clinical and preclinical applications. Altern
Ther Health Med 2001;7:70–90.
61. Noorbala AA, Akhondzadeh S, Tamacebi-pour N, Jamshidi
AH. Hydroalcoholic extract of Crocus sativus L. versus
fluoxetine in the treatment of mild to moderate depression:
a double-blind, randomized pilot trial. J Ethnopharmacol
2005;97:281–284.
62. Akhondzadeh S, Tamacebi-pour N, Noorbala AA, Amini H,
Fallah Pour H, Jamshidi AH, et al. Crocus sativus L. in the
treatment of mild to moderate depression: a double-blind,
randomized and placebo controlled trial. Phytother Res
2005;19:25–29.
63. Wang Y, Han T, Zhu Y, Zheng CJ, Ming QL, Rahman K, Qin
LP. Antidepressant properties of bioactive fractions from the
extract of Crocus sativus L. J Nat Med 2010;64:24–30.
64. Monagle L, Dan A, Krogh V, Jossa F, Farinaro E, Trevisan
M. Perimenstrual symptom prevalence rates: an Italian-
American comparison. Am J Epidemiol 1993;138:1070–
1081.
65. Borrelli F, Izzo AA. Herb-drug interactions with St John’s
wort (Hypericum perforatum): an update on clinical observa-
tions. AAPS J 2009;11:710–727.
Current knowledge on this subject
.No single treatment is universally recognised as effective for PMS or PMDD. Several treatments have
proven effective including reproductive hormones, central nervous system acting drugs, diuretics,
vitamins and minerals.
.Patients with PMS try a wide range of Complementary Alternative medicines
.Efficacy and safety of herb remedies are poorly known.
What this study adds
.Few studies are designed as a RCTs, and often the quality is far to be satisfactory. Adding an
evaluation of PMS/PMDD diagnosis, only 10 trials remain available for clinical conclusions.
.Vitex agnus castus,Gingko biloba and Crocus sativus extracts relief PMS better than placebo. In women
suffering of PMDD, Vitex agnus castus performed equally to fluoxetine. Evening primerose oil is
effective as placebo, whereas St. John Worth relief physical/behavioural symptoms but not
psychological discomfort.
.None of the herb remedies is associated with major health risks, although the reduced number of
tested patients does not allow definitive conclusions on safety.
Herbal treatments for alleviating premenstrual symptoms 51
J Psychosom Obstet Gynaecol Downloaded from informahealthcare.com by Univ Studi di Modena on 01/24/14
For personal use only.