|
|
J Womens Health (Larchmt). Author manuscript; available in PMC 2007 January 8. Published in final edited form as: doi: 10.1089/jwh.2005.14.634. | PMCID: PMC1764641 NIHMSID: NIHMS14957 |
Botanical and Dietary Supplements for Menopausal Symptoms: What
Works, What Doesn’t Stacie E. Geller, Ph.D., Associate Professor and Laura Studee, MPH All women reach menopause and approximately two-thirds of women develop
menopausal symptoms, primarily hot flashes. Hormone therapy long was considered
the first line of treatment for vasomotor symptoms. However, given the results
of the Women’s Health Initiative, many women are reluctant use
exogenous hormones for symptomatic treatment and are turning to botanicals and
dietary supplement (BDS) products for relief. Despite the fact that there is
limited scientific evidence describing efficacy and long term safety of such
products, many women find these “natural treatments”
appealing. Peri- and postmenopausal women are amongst the highest users of these
products, but 70% of women do not tell their health care providers
about their use. Compounding this issue is the fact that few clinicians ask
their patients about use of BDS, largely because they have not been exposed to
alternative medical practices in their training and are unfamiliar with these
products. This paper reviews the botanicals and dietary supplements commonly
used in menopause, (such as black cohosh, red clover, soy products, among
others) as well as the available data on efficacy and safety. We searched the
MEDLINE database from 1966 to December 2004 using terms related to botanical and
dietary supplements and menopausal symptoms for peri- or postmenopausal women.
Abstracts from relevant meetings as well as reference books and websites on
herbal supplements were also searched. Randomized-controlled trials (RCTs) were
used if available; open trials and comparison group studies were used when RCTs
were not available. The evidence to date suggests that black cohosh is safe and
effective for reducing menopausal symptoms, primarily hot flashes and possibly
mood disorders. Phytoestrogen extracts, including soy foods and red clover
appear to have at best only minimal effect on menopausal symptoms but have
positive health effects on plasma lipid concentrations and may reduce heart
disease. St. John’s wort has been shown to improve mild to moderate
depression in the general population and appears to show efficacy for mood
disorders related to the menopausal transition. Other commonly used botanicals
have limited evidence to demonstrate safety and efficacy for relief of symptoms
related to menopause. Keywords: Menopause, botanical supplements, dietary supplements Approximately two-thirds of perimenopausal women develop symptoms related to
the menopausal transition. Of these, only 10–25% of women
seek treatment from a traditional health care provider and many frequently resist or
are dissatisfied with conventional medical recommendations for their symptoms. 1 Although hormone therapy is still considered
the first line of treatment for vasomotor symptoms, given the published results of
the Women’s Health Initiative, many women are reluctant use exogenous
hormones and are turning to botanical and dietary supplement (BDS) products for
relief. 2, 3Botanicals are classified by the Dietary Supplement Health Education Act
(DSHEA) as dietary supplements, not drugs, that are intended to either (1)
supplement the diet, (2) contain one or more dietary ingredients (vitamins,
minerals, herbs or other botanicals, or amino acids), (3) be taken by mouth as a
pill, capsule, tablet, or liquid, and (4) be labeled as being a dietary supplement.
Botanicals and dietary supplements are not intended for diagnosis, prevention, or
treatment and are not regulated by the Food and Drug Administration (FDA). This fact
results in considerable variability of content, standardization, dosage, purity, and
possible contamination of available products in the United States (US). This is in
contrast to Germany where dietary supplements are scrutinized for safety and
efficacy by their Commission E, an agency similar to the FDA. 4The use of botanical and dietary supplements among menopausal women has
increased in recent years in the US, with the largest increase in the use of so
called “natural hormonal agents”. 5–8
Most women report using such treatments largely because they find these alternatives
to traditional medicine more congruent with their values, beliefs, and
lifestyles. 9, 10 A recent survey of 500 peri- and postmenopausal women
conducted at the University of Illinois Medical Center found that 70% of
women between the ages of 40–60 reported using BDS to treat symptoms or
diseases; however, fewer than 10% of users could actually verbalize the
health benefits of these supplements. 11A particularly troubling fact is that while many women regularly use BDS,
approximately 70% do not tell their clinicians about use of these
products. 11 Many women appear to be under
the misconception that herbal products are “natural” and
therefore safe. 12 Compounding this problem is
that many conventional practitioners do not ask their patients about use of
alternative medicines. 13–16 One study which specifically examined
knowledge, attitudes, and behaviors of 62 physicians and nurses who care for peri-
and postmenopausal women regarding use of BDS found that knowledge about botanical
therapies was quite low. Over two-thirds of clinicians reported they had limited or
no knowledge about BDS, no formal training, and had not studied these supplements on
their own. 16 The promising finding was that
they were open to learning more about these modalities, were interested in
additional training predominantly because of growing patient awareness and use and
were open to using or referring for these therapies if they had adequate knowledge
about efficacy and safety. These results suggest that the more information providers
have about BDS the more likely they are to discuss these options with their
patients. 17This paper reviews the scientific literature related to BDS for relief of
menopausal symptoms including the available data on efficacy and safety focusing
primarily on the most heavily utilized botanicals for menopause, black cohosh, soy
products and red clover. The MEDLINE database from 1966 to December 2004 was searched using terms
related to botanical and dietary supplements and menopausal symptoms. The following
terms were used in the search strategy: dietary supplements, black cohosh, red
clover, soy, isoflavones, medicinal plants, hot flashes, menopause, osteoporosis,
bone mineral density, cognition, blood lipids. All articles related to the topic
were reviewed and the bibliographies of clinical trials (randomized and open
trials), other research studies, and review articles were searched for other
relevant studies. Finally, abstracts from the North American Menopause Society were
searched by hand. Studies were eligible for inclusion if study subjects were peri- or
postmenopausal women and were related to menopausal symptoms or postmenopausal
symptoms related to aging such as bone density, lipids, cognition, or psychological
issues including sleep, anxiety, and memory problems. Randomized, placebo-controlled
trials were used when available, although open trials and comparison group studies
were also used to gain as much information as possible. More detail on study design
for each trial is outlined in the tables and text. Black Cohosh (Cimicifuga racemosa) Black cohosh is a perennial plant native to North America and a member of the
buttercup family. Black cohosh has been traditionally used primarily by American
Indians for a variety of “female complaints” including
menstrual problems and childbirth. At the turn-of-the-last century, black cohosh was
part of Lydia E. Pinkham’s vegetable compound used by women to ease
“all those painful complaints and weaknesses so common to our best
female population”. 18–20 Next to soy,
black cohosh is the most widely studied botanical for menopausal symptoms. Black cohosh contains triterpine glycosides, flavonoids, aromatic acids, and
numerous other constituents 21 but the exact
mechanism of action of this botanical has not been clearly understood. Some of the
older studies have suggested an estrogenic activity, however, new studies show no
effect on serum levels of luteinizing hormone (LH), follicle stimulating hormone
(FSH), prolactin, sex hormone binding globulin (SHBG), and estradiol. 22 Three animal studies conducted using black cohosh
extracts found no estrogenic increases in uterine weight, stimulation of vaginal
cornification, or proliferation of the mammary gland or increases in prolactin, FSH,
or LH. 23–25 Recent data from the University of Illinois at
Chicago/National Institute of Health Center for Botanicals Dietary Supplements
Research in Women’s Health demonstrates that black cohosh does not have
an estrogenic mechanism of action but rather acts on serotonin receptors and may
relieve hot flashes and improve mood through a serotonergic effect. 26, 27Much of what is known about black cohosh is due to its use in Germany since
the 1940’s. There have been at least 12 clinical trials conducted
related to menopause, and all but one showed positive results for relief of
vasomotor symptoms. However, the methodology in some of these studies was weak and
many were sponsored by the manufacturer. The majority of the studies have used a
German brand of black cohosh known as Remifemin and consequently we have the most
information in terms of safety and efficacy about this particular product. 28–31
Table 1 summarizes several of the clinical
trials that have been performed on black cohosh. Overall, these studies show very
promising results for relief of menopausal symptoms, primarily hot flashes and mood
swings. The German health authorities (Commission E) have approved the use of 40
mg/day of black cohosh (the brand Remifemin) for 6 months for relief of menopausal
symptoms, as well as for Premenstrual Syndrome (PMS) and dysmenorrhea. | Table 1Studies of Black Cohosh (Cimifuga racemosa) |
Black cohosh has also been reported to have a positive safety profile when
used for up to 6 months; however, in Germany, many women use this herbal remedy for
longer periods of time with physician oversight. The most commonly reported side
effects are mild gastric complaints, which tend to dissipate over time. High doses
may cause headaches, vomiting, and dizziness. Black cohosh is contraindicated in
pregnancy and lactating women. 36There have been no documented cases of drug interactions. 40 However, recently there have been three case reports
of liver failure in women using black cohosh. 41–43 It is not clear
what the contribution of black cohosh was, if any, in these cases; many questions
remain about the composition and purity of the products used, the multiple
co-morbidities and other possible causes, the concomitant medications of the women
using black cohosh, and an implausible mechanism of hepatotoxicity. Based on the
evidence available from published liver-case reports it cannot be concluded that
black cohosh was a cause. 22, 44, 45An abstract presented in July 2003 at the American Association for Cancer
Research meeting raised concerns of increased metastases, but not incidence, of
breast cancer in infected mice using black cohosh, however, no paper has been
published or plausible mechanism of action presented. 46 This research was conducted on the “transgenic mouse
model” which clearly is unsuitable to reflect the human physiological
situation given tumor development in the mouse and human are different. 47 To the contrary, both in vitro
investigations with breast cancer cells and in vivo data show no stimulation of
estrogen-dependent mammary gland tumors with black cohosh. 22, 24, 29–31In fact, since black cohosh is not estrogenic, it has been suggested for
relief of vasomotor symptoms for women with breast cancer who are prescribed
tamoxifen. Three recent trials have provided somewhat mixed findings of efficacy.
One 6-month study found a significant reduction in number and severity of hot
flashes as compared to placebo (24% vs. 74%). 37 A pilot study of twenty-one postmenopausal women (13
patients had a history of breast cancer and 6 were using tamoxifen or raloxifene)
reported a significant reduction in hot flashes as well as improvement in sleeping,
fatigue levels and abnormal sweating. 39
However, a short term two-month clinical trial found that although black cohosh
cohort had a significant decrease in sweating, there was no difference for other
climacteric symptoms between the treatment and placebo groups. 38 This trial may have been too short to see the well
known placebo effect diminish. Black cohosh has not been studied for the long term health conditions
associated with aging such as heart disease and osteoporosis, although one recent
study compared the effects of black cohosh, conjugated estrogens, and placebo on
menopausal symptoms as well as bone markers. The investigators found that black
cohosh had an equivalent effect of conjugated estrogens on significantly improving
both menopausal symptoms and bone markers compared to placebo. 32In summary, black cohosh shows great promise for relief of menopausal
symptoms, primarily for treatment of vasomotor symptoms and depression with an
overall positive safety profile for up to six months. Soy foods and supplements have been the subject of much interest for the
reduction of menopausal symptoms because of their high concentrations of
phytoestrogens (formononetin, biochanin A, daidzein, and genistein). The three main
classes of phytoestrogens are isoflavones, lignans, and coumestans. The
phytoestrogens found in soy/isoflavones are thought to possess estrogenic
properties, although the mechanism of action is not fully understood. In a study by
Teede et al, 50 women were randomized to consume either soy protein isolates (40 g
soy protein and 118 mg isoflavone) or placebo, and then measures of hepatic proteins
and gonaditropin concentrations were assessed. At the end of three months, there
were no differences between the treatment and control group suggesting that
soy/isoflavones do not affect in vivo biological indicators of estrogenicity and
most likely act more like Selective Estrogen Receptor Modulators (SERMs) and as such
may be safe for breast and endometrial tissue. 48Asian diets are high in soy based foods (40–80 mg per day of
isoflavones in Asian diets as compared to <3 mg per day in American diets),
and many women in these countries express few menopausal complaints. 49 It is unknown if the lower prevalence of hot flashes
and other menopausal symptoms are due to dietary make-up, cultural factors, or a
combination of both. 50Although soy is the most heavily studied plant/food for alleviation of
menopausal symptoms, to date, data from clinical trials have not provided a clear
answer to the role of soy in reducing menopausal symptoms. It is also difficult to
compare these trials since product, dose, formulation (dietary or capsule), and
length of use vary across studies. A recent review of the evidence for the treatment
of menopausal symptoms suggests that phytoestrogens available as soy foods and soy
extracts do not improve hot flashes or other menopausal symptoms. 51 A review of the data from the more rigorous trials
shows, at best, only minimal effects on hot flashes. The most promising news for soy may be its positive effect on lipid
profiles. A meta-analysis of 38 controlled human studies of soy consumption provides
compelling evidence for its positive effect on improved lipid profiles including
reduction in low density lipid (LDL) and triglycerides and an increase in high
density lipid (HDL) levels. 61, 62 The FDA has approved a health claim for
isoflavone rich soy protein to reduce cholesterol with 25 g of soy protein
consumption daily. 63 However, it is important
to note that it appears to require that soy isoflavones are consumed intact in soy
protein. 64The bone data, although not nearly as strong as lipid data, holds some
promise. Animal studies show consistent bone conserving effects or improvement in
bone mineral density (BMD). The human studies are mixed showing some modest yet
significant gains in BMD and bone mineral content. 65–70 However, a
recent study in which 25g of soy protein was substituted for meat in the diet showed
no improvement of calcium retention, cardiovascular, or bone health indicators in
postmenopausal women. 71 Studies of soy in
targeted populations, such as postmenopausal Chinese women with lower bone mass,
have shown a greater effect on increasing bone mineral content for women consuming a
high dose of soy extract compared to placebo. 70Studies of improved cognitive function have shown inconsistent results. The
SOPHIA study, found significant improvement on category fluency (verbal memory)
compared to placebo with a pattern of improvement (although not significant) on
other tests of verbal memory, tracking and attention. 72 These results are similar to the effects seen of estrogen on
cognition. However, a recently published long term study of the effect of soy
protein containing isoflavones on cognitive function, BMD, and plasma lipids showed
no difference from placebo after 1-year. 73The research on soy and breast and endometrial cancer is interesting. Animal
studies show compelling evidence of 25–50% fewer tumors than
controls. 74 Human studies are mixed but
suggest a protective effect of soy on breast tissue, and case-control studies in
Asian countries show decreased rates of breast cancer. 75–77
It is interesting to note, however, that when Japanese women move to the US, the
cancer risk increases. The presumed protective effect of isoflavones may be a
combination of several factors including the consumption of soy early in life, a low
fat and high fiber diet, as well as a less sedentary lifestyle. One paper which presents research on soy and red clover using breast cancer
cells demonstrates different action patterns with soy/red clover exhibiting
estrogen-agonistic activities in the absence of estradiol and antagonistic effects
in estradiol which induced cell proliferation. This may suggest a different
treatment strategy for perimenopausal women (with higher levels of estradiol) and
postmenopausal women (with lower levels of estradiol). 78Similarly, the studies examining the effect of soy on the endometrium have
shown no negative effects without any increased risk of endometrial cancer. 79 In fact, one case-control study showed
higher consumption of isoflavones in the diet was linked to reduced risk for
endometrial cancer. 80Although data on the effects of soy/isoflavones for menopausal symptoms is
minimal at best, considering the cardiovascular benefits as well as the potential
beneficial effects on bone and possibly cognition, it would seems that soy in the
diet of peri and postmenopausal women, not withstanding a soy allergy, is
beneficial. 63Red clover (Trifolium pretense) Red clover was traditionally valued as an antispasmodic 81–83
and an anticancer treatment, not an estrogenic agent. Red clover and soy share
similar but distinct chemical profiles--both contain genistein, daidzein,
formononetin, and biochanin A, but red clover has significantly higher levels of the
O-methylated isoflavones, formononetin and biochanin A. 84–85 It is these isoflavonoid and coumestan components believed
responsible for estrogen-like effects. One of the most commonly used red clover
products is Promensil, a red clover derivative with concentrated levels of
isoflavones (each 500mg tablet contains 40mg isoflavones). Red clover’s use for menopausal symptoms is fairly recent, and
similar to soy products, most studies show at best a minimal effect for relief of
hot flashes with three of four clinical trials showing no significant difference
from placebo. Given its similarity to soy this is not surprising. The Isoflavone
Clover Extract (ICE) Study 86 compared two
doses of red clover (Promensil 82 mg or Rimostol 57 mg) against placebo and found
decreased frequency in hot flashes across all three groups, although the Promensil
group received significant relief faster than the other two groups. One possible
limitation of this study, as with many of the other botanical studies, is that it
lasted for only three months, just about the time one would expect to see the
placebo effect begin to wane. The previously mentioned Krebs review of evidence for
the treatment of menopausal symptoms also suggests that phytoestrogens available as
red clover extracts do not improve hot flashes or other menopausal symptoms. 51
Table 3 summarizes several studies on red
clover. | Table 3Studies of Red Clover (Trifolium pratense) |
Similar to soy, red clover has been suggested as a preventative treatment
for osteoporosis, lipid profiles, and possibly cognition, although once again the
evidence is limited. Two clinical trials showed modest effects for improvement in
BMD compared to placebo. In one study while all women lost BMD, those taking red
clover lost significantly less than the placebo group and the authors also noted
there were no differences in mammographic breast density between the two groups. In
another RCT, women in the red clover group had increased bone mineral density in
proximal radius and ulna only. 89–90Three of the four trials that have been published examining the effects of
red clover on blood lipid levels showed no improvement in lipid profiles, 91–93 and the fourth study showed a significant increase in HDL only
compared to placebo. 90There is disappointing evidence for the use of red clover to relieve
menopausal symptoms, however similar to soy/isoflavones, it remains to be seen if it
will have uses for age related health concerns such as osteoporosis, heart disease,
and cognition. Red clover has a positive safety profile, appears not to negatively
affect the endometrium with few adverse events reported in published
literature. 94 The side effects reported
are mild and include headache, myalgia, and nausea. 86Other commonly used botanicals Many other botanicals are commonly used for menopause including chastetree
( Vitex Agnus Castus), hops ( Humulus lupulus),
dong quai ( Angelica sinensis), evening primrose ( Oenothera
biennis), Ginkgo ( Ginkgo biloba), ginseng
( Panax ginseng), kava ( Piper methysticum),
valerian ( Valeriana officinalis), licorice root
( Glycyrrhiza glabra), motherwort ( Leonurus
cardiaca), St. John’s Wort ( Hypericum
perforatum), lemon balm ( Melissa officinalis) and wild yam
( Dioscorea villosa). There is very little data available on the
efficacy and safety of many of these compounds. Table 4 summarizes the available data on some of the randomized trials
that have been conducted on these botanicals for menopausal women in particular.
However, much of the research that does exist has been conducted on non-menopausal
populations and the findings related to sleep, anxiety, and mood have been
extrapolated to the menopausal experience, which may not be valid. Many of the aforementioned botanicals are not used alone but rather in
combination with other supplements in the form of a multibotanical, of which there
is even less science to support efficacy and safety. For example, licorice is often
used as part of a multibotanical formulation and is thought to be useful for PMS,
but is largely unstudied in menopause. It is worth mentioning because large doses
have been associated with congestive heart failure using as little as 500mg/day for
7 days. Most menopausal remedies contain 75 mg of licorice and if taken
2–3 times per day, this amounts to 150–225 mg of licorice a
day. 103Overall, dong quai is one of the most commonly prescribed Chinese herbs for
problems unique to women and has been traditionally known as “a female
tonic.” Traditional systems of medicine and folk medicine have used dong
quai for a variety of complaints including abnormal menstruation and menopausal
symptoms. 104 Merck introduced the herb
to the Western world in 1899 under the trade name Eumenol®, as a product
that was said to positively affect menstrual disorders. There is debate as to
whether there is any estrogenic activity in dong quai as human studies do not
support any estrogenic mechanism of action. Little research has been conducted on
dong quai for menopausal symptoms. The one RCT of 71 women with hot flashes showed
no difference from placebo in menopausal symptoms (hot flashes, vaginal dryness) and
there was no sign of estrogen-like stimulation of uterine lining in either
group. 95 Taken alone, dong quai does not
appear to be beneficial for menopausal hot flashes; however, it is mostly used in
multibotanical formulations and is still considered to be a valuable female tonic by
herbalists around the world. Botanicals commonly used for PMS and early menopausal symptoms Some of the more commonly used botanicals for PMS and early menopausal
symptoms are chastetree/Vitex, wild yam and evening primrose. Chastetree/Vitex is
often recommended for women in early menopause experiencing irregular menstrual
cycles and has been approved by German health authorities for PMS, breast
tenderness, and irregularities in the menstrual cycle. 105 The progesterone like effect of Vitex has been
verified by endometrial biopsy, analysis of blood hormone levels, and examination of
vaginal secretions. 106 Chastree/Vitex is
often found in combination with black cohosh and other herbs. The majority of
research has been limited to PMS and breast tenderness (mastalgia) and very little
is known about the efficacy related to menopausal symptoms. In a study performed in
peri and postmenopausal women, participants applied 2.5 ml of lotion (a
1.5% solution of essential oil) on the skin, one time per day
5–7 days per week for 7 months and reported improvement in emotional
problems and hot flashes, although the study had no placebo or comparison
group. 102Wild yam was formerly referred to as “colic root”
and has been promoted as effective for gastrointestinal irritation and spasm.
Historically, it was also used for menstrual cramps and postpartum pain. Despite
promotional claims, wild yam does not convert to a progesterone when taken
internally or applied topically. One RCT of topical wild yam extract cream versus
placebo showed no difference in alleviation of menopausal symptoms or serum/salivary
hormone levels. 96 Though popular for
menopause, there is no contemporary or historical evidence of benefit. Evening primrose contains gamolenic acid which is believed to reduce
vasomotor symptoms of menopause. 107 There
has only been one RCT of evening primrose for menopausal symptoms which randomized
56 women to either 500mg of evening primrose oil or placebo for six months. The
investigators found no differences in the reduction of hot flashes between the two
groups. 97Botanicals commonly used for sleep, anxiety, memory and mood disorders A number of botanicals products have been recommended for many of the
problems associated with menopause and aging such as sleep disturbances,
nervousness, depression, mood swings, and memory loss (e.g., ginkgo, hops,
motherwort, ginseng, valerian, kava, and St. John’s wort), although,
most of these products have not been tested specifically on menopausal women. Ginkgo biloba has been promoted as having an effect on the vascular system
by improving blood flow and has been used for Raynauds Syndrome (cold hands and
feet). 108–110 It has been approved by the German Commission E for
cerebral insufficiency, vertigo and tinnitus, and peripheral vascular disease. 111 Ginkgo works primarily by increasing blood
flow to the brain, increasing uptake of glucose by brain cells and improving
transmission of nerve signals. 109 Studies
related to improved memory are promising. 112–114 There have
been 40 clinical trials conducted examining the effect of ginkgo on cognition,
particular difficulty concentrating and memory. Eight were of good quality and seven
showed a positive effect. Some studies have even shown a positive effect for adults
with dementia. 115The German Commission E has approved hops for mood disturbances such as
anxiety and restlessness and sleep disturbance. 116 Hops extracts bind to the estrogen receptor in molecular assays and
animal models have shown hops to have an estrogenic effect on the uterus, however
the data is inconsistent. 28, 117 Its estrogenic effects have been shown to be due to
prenylflavonoids, a class of nonsteroidal phytoestrogens. Because of its estrogenic
actions it may be effective for menopausal symptoms such as hot flashes; however, it
does not appear to exert SERM-like selectivity so it may have uterotrophic effects
in postmenopausal women. 118 More research on
the effect of hops on menopause is needed to determine if it safe and effective. Ginseng is known as a traditional “tonic” herb that
is reported to cope with stress, and boost immunity. The German Commission E lists
its uses as “a tonic for invigoration and fortification in times of
fatigue and debility and for declining capacity for work and
concentration”. 119 An RCT
found that 30 days of therapy with Korean red ginseng reduced fatigue, insomnia, and
depression in 12 postmenopausal women experiencing symptoms and also found that the
cortisol/DHEA-S ratio decreased significantly over this time period. 98 Several other studies have showed no estrogenic
effects, no improvement in vasomotor symptoms, but improvement in somatic complaints
(fatigue, insomnia, depression) and a very favorable effect on depression and
well-being health subscales compared with placebo. 99, 107 Because of increased breast
cell proliferation in vitro, its use may not be advisable in the
presence of breast cancer, although more research on ginseng’s effects
on breast cells in vivo is needed to know its true safety. 120Kava is a South Pacific herb used medicinally and socially and data suggest
efficacy for treatment of anxiety. 121 Two
trials evaluating kava’s effect on menopausal symptoms showed
significant improvement in irritability and insomnia compared with placebo. 100 However, there are a number of safety
issues related to kava. The sale of kava has been banned in Canada, Australia, and
several European countries because of potential hepatotoxicity, although the exact
mechanism of harm is not well understood. The stem peelings may contain a toxic
alkaloid. In response to reports of hepatotoxicity that may be associated with kava,
the FDA, American Botanical Council, and various industry trade organizations have
advised consumers of rare but potential risks of severe liver injury associated with
the use of kava containing preparations. 122
Extreme caution should be exercised if kava is used, limiting duration of use to
6–8 weeks and it is best to avoid this botanical completely. It is
certainly not advised for those taking hepatotoxic medications, consuming excess
alcohol, or with liver problems. Motherwort is another botanical historically revered as a calmative agent
for the heart, especially palpitations. 123
The German Commission E has approved its use for nervous cardiac disorders and as an
adjuvant for thyroid hyperfunction. 124 It is
also found in many menopausal formula for women experiencing this symptom and was
typically combined with black cohosh as a “superior antispasmodic and
nervine,” however, contemporary research is lacking on efficacy and
safety. Valerian has been used for centuries by Greeks, Romans, Chinese, Europeans,
and American Indians. In the 20 th century, it has been approved by the
German Commission E for “states of unrest and nervous sleep
disturbances.” 125 Three RCTs
have been conducted that have shown improved subjective sleep quality, although none
of the studies were conducted with menopausal women. 126–128 There have
been no reported drug interactions; side effects, such as nausea, headache,
dizziness, and upset stomach, have been reported in less than ten percent of
subjects in RCTs. 129St. John’s wort is one of the most heavily studied botanicals
for treatment of depression. The vast majority of studies have been conducted on
non-menopausal populations. In thirty-seven out of thirty-nine clinical trials the
herb has been shown to be superior to placebo or equivalent to antidepressant
medications (61–75% improvement in mild-moderate depression)
with minimal side effects as compared to some of the antidepressants. 130 A recent meta-analysis of St.
John’s wort for depression found that trials restricted to subjects with
major depression found only minor improvements compared to placebo; however, other
trials of patients with mild to moderate depression have shown beneficial effects
similar to standard antidepressants. 131 One
non-placebo controlled clinical trial conducted in women experiencing climacteric
symptoms found that 900 mg of St. Johns wort taken for 12 weeks, significantly
improved psychological and psychosomatic symptoms and sexual well-being. 101St. John’s wort is often combined with black cohosh for
treatment of menopausal symptoms (hot flashes, irritability, minor depression, mood
swings, and insomnia). A multi-center non-placebo-controlled clinical trial of 911
pre, peri and postmenopausal women with psychovegatative disorders demonstrated a
synergistic effect of this combination of botanicals. 132 The adverse herb-drug interactions are well
documented. St. John’s wort can interact with anticoagulants,
cyclosporine, digoxin, and protease inhibitors used for HIV, specifically decreasing
blood concentrations of these drugs. In addition, women using oral contraceptives
have reported breakthrough bleeding and in some cases, unplanned pregnancies. 133Discussion and Future Directions Although there have been a number of observational and epidemiologic studies
conducted for relief of menopausal symptoms, there is a continued need for further
research on the effectiveness and long term safety of botanicals and dietary
supplements. A growing body of scientific literature suggests that incorporation of
some form of alternative therapy could result in improved clinical outcomes. 134, 135Of the botanicals reviewed in this paper, based on the evidence, black
cohosh appears to be the most effective herb for relief of menopausal symptoms,
primarily hot flashes and possibly mood disorders. Phytoestrogen extracts, including
soy foods and red clover appear to have at best only minimal effect on menopausal
symptoms but have positive health effects on plasma lipid concentrations and may
reduce heart disease. St. John’s wort has been shown to improve mild to
moderate depressive symptoms, but not major depression, in the general
population. 130–131 It appears to show efficacy for mood
disorders related to the menopausal transition, although more research should be
done in the menopausal population, especially for the combination of St.
John’s wort and black cohosh. The other commonly used botanicals
discussed in this paper have limited evidence to demonstrate safety and efficacy for
relief of symptoms related to menopause. Whatever decision menopausal women chose to make related to use of
botanicals for relief of menopausal symptoms as well as to promote long term health,
it is critical to discuss these issues with their health care providers so they can
assist them in managing these alternative therapies through an evidence-based
approach. Research within the UIC Botanical Center is supported by NIH grant P50 AT000155 jointly funded by the Office of Dietary Supplements (ODS), the National Center for Complementary and Alternative Medicine (NCCAM), the National Institute for General Medical Sciences (NIGMS), and the Office for Research on Women's Health (ORWH). Stacie E. Geller, Department of Obstetrics and Gynecology, Director, National Center of Excellence in Women’s Health; Laura Studee, Department of Obstetrics and Gynecology; 1. Brosage P. Hormone therapy: the woman’s decision. Contemporary Nurse Practioner. 1995;1:3–4. 2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the Women’s Health
Initiative randomized controlled trial. JAMA. 2002;288:321–333. [PubMed] 3. Kolata G. The New York Times. September 1, 2002. Race to fill the void in menopause drug market. 4. Larsen LL, Berry JA. The regulation of dietary supplements. J Am Acad Nurse Prac. 2003;15:410–414. 5. Weeks J. On the outside moving in: will the alternative medicine
integration movement shape U.S. healthcare? Healthc Forum J. 1998;41:14–19. [PubMed] 6. Eisenberg DM, Davis RB, Ettner SL, 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. [PubMed] 7. Drivdahl CE, Miser WF. The use of alternative health care by a family practice
population. J Am Board Fam Pract. 1998;11:193–199. [PubMed] 8. Lloyd P, Lupton D, Wiesner D, Hasleton S. Choosing alternative therapy: an exploratory study of
sociodemographic characteristics and motives of patients resident in Sydney. Aust J Public Health. 1993;17:135–144. [PubMed] 9. Goldstein MS, Glik D. Use of and satisfaction with homeopathy in a patient population. Altern Ther Health Med. 1998;4:60–65. [PubMed] 10. Kass-Annese B. Alternative therapies for menopause. Clin Obstet Gynecol. 2000;43:162–183. [PubMed] 11. Mahady GB, Parrot J, Lee C, Yun GS, Dan A. Botanical dietary supplement use in peri-and postmenopausal women. Menopause. 2003;10:65–72. [PubMed] 12. Miller LG. Herbal medicinals: selected clinical considerations focusing on
known or potential drug-herb interactions. Arch Intern Med. 1998;158:2200–2211. [PubMed] 13. Schimpff SC. Complementary medicine. Curr Opin Oncol. 1997;9:327–331. [PubMed] 14. Lee MM, Lin SS, Wrensch MR, Adler SR, Eisenberg D. Alternative therapies used by women with breast cancer in four
ethnic populations. J Natl Cancer Inst. 2000;92:42–47. [PubMed] 15. Seidl MM, Stewart DE. Alternative treatments for menopausal symptoms. Qualitative study
of women’s experiences. Can Fam Physician. 1998;44:1271–1276. [PubMed] 16. The Landmark Report on Public Perceptions of Alternative Care. Sacramento, CA: Landmark Healthcare; 1997. 17. Geller SE, Studee L, Chandra G. Knowledge, Attitudes and Behaviors of Health Care Providers for
Botanical and Dietary Supplement Use for Menopausal Health. Menopause. In press. 18. Herrick JW. Iroquois Medical Botany. Syracuse, NY: Syracuse University Press; 1995. 19. Tyler V. Was Lydia E. Pinkham’s vegetable compound and
effective remedy? Pharmacy in History. 1998;37:24–28. [PubMed] 20. Anonymous Harvard Women’s Health Watch. 2000;7:6. 21. Upton R, editor. Black Cohosh Rhizome. American Herbal Pharmacopeia. Santa Cruz, CA: 2002. 22. Dog TL, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in
menopause symptom relief. Menopause. 2003;10:299–313. [PubMed] 23. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and
rats. Maturitas. 1996;25:149–153. [PubMed] 24. Freudenstein J, Dasenbrock C, Nisslein T. Lack of promotion of estrogen-dependent mammary gland tumors in
vivo by an isopropanolic Cimicifuga racemosa extract. Cancer Res. 2002;62:3448–3452. [PubMed] 25. Seidlova-Wuttke D, Jarry H, Becker T, Christoffel V, Wuttke W. Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats:
bone, fat and uterus. Maturitas. 2003;44 (Suppl 1):S39–50. [PubMed] 26. Burdette JE, Liu J, Chen SN, et al. Black cohosh acts as a mixed competitive ligand and partial
agonist of the serotonin receptor. J Agric Food Chem. 2003;51:5661–5670. [PubMed] 27. Mahady GB. Is black cohosh estrogenic? Nutr Rev. 2003;61:183–186. [PubMed] 28. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med. 1998;217:369–378. [PubMed] 29. Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the
potential treatment of menopausal symptoms. J Agric Food Chem. 2001;49:2472–2479. [PubMed] 30. Zierau O, Bodinet C, Kolba S, Wulf M, Vollmer G. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol. 2002;80:125–130. [PubMed] 31. Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen
receptor-positive human breast cancer cells. Breast Cancer Res Treat. 2002;76:1–10. [PubMed] 32. Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a
double-blind placebo-controlled study: effects on menopause symptoms and
bone markers. Maturitas. 2003;44 (Suppl 1):S67–77. [PubMed] 33. Liske E, Hanggi W, Henneicke-von Zepelin HH, Boblitz N, Wustenberg P, Rahlfs VW. Physiological investigation of a unique extract of black cohosh
(Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no
systemic estrogenic effect. J Womens Health Gend Based Med. 2002;11:163–174. [PubMed] 34. Duker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosa on gonadotropin
release in menopausal women and ovariectomized rats. Planta Med. 1991;57:420–424. [PubMed] 35. Lehmann-Willenbrock E, Riedel HH. [Clinical and endocrinologic studies of the treatment
of ovarian insufficiency manifestations following hysterectomy with intact
adnexa]. Zentralbl Gynakol. 1988;110:611–618. [PubMed] 36. Cohosh Black. In: The ABC Clinical Guide to Herbs. Blumenthal M, editor. Austin, TX: American Botanical Council; 2002. pp. 13–22. 37. Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women
surviving breast cancer. Maturitas. 2003;44 (Suppl 1):S59–65. [PubMed] 38. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes
among women with a history of breast cancer. J Clin Oncol. 2001;19:2739–2745. [PubMed] 39. Pockaj BA, Loprinzi CL, Sloan JA, et al. Pilot evaluation of black cohosh for the treatment of hot flashes
in women. Cancer Invest. 2004;22:515–521. [PubMed] 40. Pepping J. Black cohosh: Cimicifuga racemosa. Am J Health Syst Pharm. 1999;56:1400–1402. [PubMed] 41. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal
preparations containing black cohosh. Med J Aust. 2003;179:390–391. [PubMed] 42. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute
hepatitis. Med J Aust. 2002;177:440–443. [PubMed] 43. Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: a
case study. Menopause. 2004;11:575–577. [PubMed] 44. Thomsen M, Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case
report not sufficiently substantiated. J Altern Complement Med. 2003;9:337–340. [PubMed] 45. Thomsen M, Vitetta L, Sali A, Schmidt M. Acute liver failure associated with the use of herbal
preparations containing black cohosh. Med J Aus. 2004;180:598–599. author reply 599–600. 46. Davis VL, Jayo MJ, Hardy ML, et al. Effects of black cohosh on mammary tumor development and
progression in MMTV-neu transgenic mice. Paper presented at: American Association of Cancer Research; 2003. 47. Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ. Amplification of the neu/erbB-2 oncogene in a mouse model of
mammary tumorigenesis. Proc Natl Acad Sci U S A. 2000;97:3444–3449. [PubMed] 48. Teede HJ, Dalais FS, McGrath BP. Dietary soy containing phytoestrogens does not have detectable
estrogenic effects on hepatic protein synthesis in postmenopausal women. Am J Clin Nutr. 2004;79:396–401. [PubMed] 49. Tham DM, Gardner CD, Haskell WL. Clinical review 97: Potential health benefits of dietary
phytoestrogens: a review of the clinical, epidemiological, and mechanistic
evidence. J Clin Endocrinol Metab. 1998;83:2223–2235. [PubMed] 50. Brockie J. An alternative approach to menopausal symptoms. Community Nurse. 1999;5:39–40. [PubMed] 51. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic
review. Obstet Gynecol. 2004;104:824–836. [PubMed] 52. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6–11. [PubMed] 53. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein supplementation on serum lipoproteins,
blood pressure, and menopausal symptoms in perimenopausal women. Menopause. 1999;6:7–13. [PubMed] 54. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in
postmenopausal women: a multicenter, double-blind, randomized,
placebo-controlled study. Menopause. 2000;7:236–242. [PubMed] 55. Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a
multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2002;9:329–334. [PubMed] 56. Crisafulli A, Marini H, Bitto A, et al. Effects of genistein on hot flushes in early postmenopausal
women: a randomized, double-blind EPT- and placebo-controlled study. Menopause. 2004;11:400–404. [PubMed] 57. Van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal
women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol. 2002;20:1449–1455. [PubMed] 58. Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric
symptoms: a multicenter, double-blind, randomized study. Maturitas. 2004;47:11–20. [PubMed] 59. Murkies AL, Lombard C, Strauss BJ, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases post-menopausal hot
flushes: effect of soy and wheat. Maturitas. 1995;21:189–195. [PubMed] 60. Burke GL, Legault C, Anthony M, et al. Soy protein and isoflavone effects on vasomotor symptoms in peri-
and postmenopausal women: the Soy Estrogen Alternative Study. Menopause. 2003;10:147–153. [PubMed] 61. Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal
symptoms. Climacteric. 1999;2:79–84. [PubMed] 62. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum
lipids. N Engl J Med. 1995;333:276–282. [PubMed] 63. Food labeling: Health Claims; Soy Protein and Coronary Heart
Disease. Federal Register: October 26, 1999. 1999;64:57699–57733. 64. Kerckhoffs DAJM, Brouns F, Hornstra G, Mensink RP. Effects on the human serum lipoprotein profile of
β-Glucan, soy protein and isoflavones, plant sterols and
stanols, garlic and tocotrienols. J Nutr. 2002;132:2494–2505. [PubMed] 65. Somekawa Y, Chiguchi M, Ishibashi T, Aso T. Soy intake related to menopausal symptoms, serum lipids, and bone
mineral density in postmenopausal Japanese women. Obstet Gynecol. 2001;97:109–115. [PubMed] 66. Mei J, Yeung SS, Kung AW. High dietary phytoestrogen intake is associated with higher bone
mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab. 2001;86:5217–5221. [PubMed] 67. Ho SC, Chan SG, Yi Q, Wong E, Leung PC. Soy intake and the maintenance of peak bone mass in Hong Kong
Chinese women. J Bone Miner Res. 2001;16:1363–1369. [PubMed] 68. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW., Jr Soy protein and isoflavones: their effects on blood lipids and
bone density in postmenopausal women. Am J Clin Nutr. 1998;68:1375S–379S. [PubMed] 69. Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the
lumbar spine of perimenopausal women. Am J Clin Nutr. 2000;72:844–852. [PubMed] 70. Chen YM, Ho SC, Lam SS, Ho SS, Woo JL. Soy isoflavones have a favorable effect on bone loss in Chinese
postmenopausal women with lower bone mass: a double-blind, randomized,
controlled trial. J Clin Endocrinol Metab. 2003;88:4740–4747. [PubMed] 71. Roughead ZK, Hunt JR, Johnson LK, Badger TM, Lykken GI. Controlled substitution of soy protein for meat protein: effects
on calcium retention, bone, and cardiovascular health indices in
postmenopausal women. J Clin Endocrinol Metab. 2005;90:181–189. [PubMed] 72. Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: the Soy and
Postmenopausal Health In Aging (SOPHIA) Study. Menopause. 2003;10:196–202. [PubMed] 73. Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive
function, bone mineral density, and plasma lipids in postmenopausal women: a
randomized controlled trial. JAMA. 2004;292:65–74. [PubMed] 74. Foth D, Cline JM. Effects of mammalian and plant estrogens on mammary glands and
uteri of macaques. Am J Clin Nutr. 1998 Dec;68:1413S–417S. [PubMed] 75. Dai Q, Shu XO, Jin F, et al. Population-based case-control study of soyfood intake and breast
cancer risk in Shanghai. Br J Cancer. 2001;85:372–378. [PubMed] 76. Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Dietary effects on breast-cancer risk in Singapore. Lancet. 1991;337:1197–1200. [PubMed] 77. Wu AH, Ziegler RG, Horn-Ross PL, et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev. 1996;5:901–906. [PubMed] 78. Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell
proliferation. Menopause. 2004;11:281–289. [PubMed] 79. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial
thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. May. 2003;79(5):1112–1117. [PubMed] 80. Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 2003;95:1158–1164. [PubMed] 81. Coon N. Using Plants for healing, and American herbal. New York: Hearthside Press; 1963. 82. Silverman M. A city herbal: a guide to the lore, legend, and usefulness of 34 plants
that grow in the city. 1st ed. New York: Knopf: distributed by Random House; 1977. 83. Bolyard JL. Medicinal plants and home remedies of Appalachia. Springfield, IL: Thomas; 1981. 84. Hartwell JL. Plants used against cancer: A survey. Lawrence, MA: Quarterman Publications; 1982. 85. Piersen CE, Booth NL, Sun Y, et al. Chemical and biological characterization and clinical evaluation
of botanical dietary supplements: a phase I red clover extract as a model. Curr Med Chem. 2004;11:1361–1374. [PubMed] 86. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the
Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA. 2003;290:207–214. [PubMed] 87. van de Weijer P, Barentsen R. Isoflavones from red clover (Promensil ®)
significantly reduce hot flashes compared with placebo. Paper presented at: The North American Menopause Society 14th Annual
Meeting; 2003. 88. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized placebo-controlled trial of an isoflavone supplement
and menopausal symptoms in women. Climacteric. 1999;2:85–92. [PubMed] 89. Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA. The effects of phytoestrogen isoflavones on bone density in
women: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2004;79:326–333. [PubMed] 90. Clifton-Bligh PB, Baber RJ, Fulcher GR, Nery ML, Moreton T. The effect of isoflavones extracted from red clover (Rimostil) on
lipid and bone metabolism. Menopause. 2001;8:259–265. [PubMed] 91. Blakesmith SJ, Lyons-Wall PM, George C, Joannou GE, Petocz P, Samman S. Effects of supplementation with purified red clover (Trifolium
pratense) isoflavones on plasma lipids and insulin resistance in healthy
premenopausal women. Br J Nutr. 2003;89:467–474. [PubMed] 92. Howes JB, Sullivan D, Lai N, et al. The effects of dietary supplementation with isoflavones from red
clover on the lipoprotein profiles of post menopausal women with mild to
moderate hypercholesterolaemia. Atherosclerosis. 2000;152:143–147. [PubMed] 93. Nestel PJ, Pomeroy S, Kay S, et al. Isoflavones from red clover improve systemic arterial compliance
but not plasma lipids in menopausal women. J Clin Endocrinol Metab. 1999;84:895–898. [PubMed] 94. Nachtigall LE, Nachtigall LB. The effects of isoflavone derived from red clover on vasomotor
symptoms and endometrial thickness. Paper presented at: 9th World Congress on Menopause; Yokohama, Japan. 2000. 95. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A
double-blind, placebo-controlled trial. Fertil Steril. 1997;68:981–986. [PubMed] 96. Komesaroff PA, Black CV, Cable V, Sudhir K. Effects of wild yam extract on menopausal symptoms, lipids and
sex hormones in healthy menopausal women. Climacteric. 2001;4:144–150. [PubMed] 97. Chenoy R, Hussain S, Tayob Y, O’Brien PM, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on
menopausal flushing. BMJ. 1994;308:501–503. [PubMed] 98. Tode T, Kikuchi Y, Hirata J, Kita T, Nakata H, Nagata I. Effect of Korean red ginseng on psychological functions in
patients with severe climacteric syndromes. Int J Gynaecol Obstet. 1999;67:169–174. [PubMed] 99. Wiklund IK, Mattsson LA, Lindgren R, Limoni C. Effects of a standardized ginseng extract on quality of life and
physiological parameters in symptomatic postmenopausal women: a
double-blind, placebo-controlled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res. 1999;19:89–99. [PubMed] 100. Warnecke G. [Psychosomatic dysfunctions in the female
climacteric. Clinical effectiveness and tolerance of Kava Extract WS
1490]. Fortschr Med. 1991;109:119–122. [PubMed] 101. Grube B, Walper A, Wheatley D. St. John’s Wort extract: efficacy for menopausal
symptoms of psychological origin. Adv Ther. 1999;16:177–186. [PubMed] 102. Lucks BC. Vitex agnus castus essential oil and menopausal balance: a
research update. Complement Ther Nurs Midwifery. 2003;9:157–160. [PubMed] 103. de Klerk GJ, Nieuwenhuis MG, Beutler JJ. Hypokalaemia and hypertension associated with use of liquorice
flavoured chewing gum. BMJ. 1997;314:731–732. [PubMed] 104. Radix Angelicae Sinensis. WHO monographs on selected medicinal plants. Geneva: Switzerland; 2001. 105. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Chaste tree fruit. 106. Brown D. The use of Vitex agnus castus for hyperprolactinemia. Quarterly Review of Natural Medicine. 1997:19–21. 107. McMillan TL, Mark S. Complementary and alternative medicine and physical activity for
menopausal symptoms. JAMWA. 2004;59:270–277. [PubMed] 108. Bauer U. 6-Month double-blind randomised clinical trial of Ginkgo biloba
extract versus placebo in two parallel groups in patients suffering from
peripheral arterial insufficiency. Arzneimittelforschung. 1984;34:716–720. [PubMed] 109. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:1136–1139. [PubMed] 110. Rudofsky G. [Effect of Ginkgo biloba extract in arterial
occlusive disease. Randomized placebo controlled crossover
study]. Fortschr Med. 1987;105:397–400. [PubMed] 111. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Ginkgo Biloba leaf extract. 112. Hofferberth B. [The effect of Ginkgo biloba extract on
neurophysiological and psychometric measurement results in patients with
psychotic organic brain syndrome. A double-blind study against
placebo]. Arzneimittelforschung. 1989;39:918–922. [PubMed] 113. Gessner B, Voelp A, Klasser M. Study of the long-term action of a Ginkgo biloba extract on
vigilance and mental performance as determined by means of quantitative
pharmaco-EEG and psychometric measurements. Arzneimittelforschung. 1985;35:1459–1465. [PubMed] 114. Subhan Z, Hindmarch I. The psychopharmacological effects of Ginkgo biloba extract in
normal healthy volunteers. Int J Clin Pharmacol Res. 1984;4:89–93. [PubMed] 115. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355:134–138. [PubMed] 116. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Hops. 117. Eagon CL, Elm MS, Teepe AG, Eagon PK. Medicinal botanicals: estrogenicity in rat uterus and liver. Paper presented at American Association of Cancer Research; March 1997. 118. Piersen CE. Phytoestrogens in botanical dietary supplements: implications for
cancer. Integr Cancer Ther. 2003;2:120–138. [PubMed] 119. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Ginseng root. 120. Amato P, Christophe S, Mellon PL. Estrogenic activity of herbs commonly used as remedies for
menopausal symptoms. Menopause. 2002;9:145–150. [PubMed] 121. Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic review
and meta-analysis. J Clin Psychopharmacol. 2000;20:84–89. [PubMed] 122. Blumenthal M, editor. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council; 2003. p. 259. 124. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Motherwort herb. 125. Blumenthal M, editor. The complete German Commission E monographs. 1st ed. Austin, TX: American Botanical Council; 1998. Valerian root. 126. Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacology (Berl). 1985;87:406–409. [PubMed] 127. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L. )
improves sleep quality in man. Pharmacol Biochem Behav. 1982;17:65–71. [PubMed] 128. Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med. 1985:144–148. 129. Valeriana officinalis [monograph]. . Alternative Medicine Review. 2004;9:438–440. [PubMed] 130. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John’s wort for depression--an overview and
meta-analysis of randomised clinical trials. BMJ. 1996;313:253–258. [PubMed] 131. Linde K, Berner M, Egger M, Mulrow C. St John’s wort for depression: meta-analysis of
randomised controlled trials. Br J Psychiatry. 2005;186:99–107. [PubMed] 132. Liske E. Therapeutic efficacy and safety of Cimicifuga racemosa for
gynecologic disorders. Adv Ther. 1998;15:45–53. [PubMed] 133. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John’s
wort. J Psychopharmacol. 2004;18:262–276. [PubMed] 134. Gardner C. Ease through menopause with homeopathic and herbal medicine. J Perianesth Nurs. 1999;14:139–143. [PubMed] 135. Gordon JS. Manifesto for a new medicine: your guide to healing partnerships and the
wise use of alternative therapies. Reading, MA: Addison-Wesley; 1996.
|
The publisher's final edited version of this article is available at 
anxiety,